• Short-bowel syndrome, 400 mg twice daily (with  breakfast and at bedtime) adjusted according to  response   1 Cimetidine (Non-proprietary) (S  Tablets, cimetidine 200 mg, net price 60-tab pack =  £9.08; 400 mg, 60-tab pack = £7.61; 800 mg, 30-tab  pack = £22.86   Oral solution, cimetidine 200 mg/5 mL, net price  300 mL = £14.56   1. Cimetidine can be sold to the public for adults and children  over 16 years (provided packs do not contain more than 2  weeks’ supply) for the short-term symptomatic relief of  heartburn, dyspepsia, and hyperacidity (max. single dose  200 mg, max. daily dose 800 mg), and for the prophylactic  management of nocturnal heartburn (single night-time dose  100 mg)   Tagamet® (Chemidex) (Ml  Tablets, all green, f/c, cimetidine 200 mg, net price  120-tab pack = £19.58; 400 mg, 60-tab pack = £22.62;  800 mg, 30-tab pack = £22.62  Syrup, orange, cimetidine 200 mg/5 mL. Net price  600 mL = £28.49   Indications see under Dose  Cautions see notes above; interactions: Appendix 1  (histamine H 2 -antagonists) and notes above  Renal impairment use normal dose every 36-48  hours or use half normal dose if eGFR less than  50mL/minute/1.73m 2 ; seizures reported very rarely  Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk  Breast-feeding present in milk — not known to be  harmful but manufacturer advises avoid  Side-effects see notes above; also constipation; less  commonly dry mouth, nausea, vomiting, flatulence,  taste disorders, anorexia, fatigue; very rarely chest  tightness, interstitial pneumonia, seizures, paraes-  thesia   40 mg at night for 4-8 weeks; maintenance (duodenal  ulceration), 20 mg at night   • Reflux oesophagitis, 20-40 mg twice daily for 6-  12 weeks; maintenance, 20 mg twice daily   famotidine (Non-proprietary) (Ml  Tablets, famotidine 20 mg, net price 28-tab pack =  £4.47; 40 mg, 28-tab pack = £5.64  1 . Famotidine can be sold to the public for adults and children  over 16 years (provided packs do not contain more than 2  weeks’ supply) for the short-term symptomatic relief of  heartburn, dyspepsia, and hyperacidity, and for the preven-  tion of these symptoms when associated with consumption  of food or drink including when they cause sleep disturbance  (max. single dose 10 mg, max. daily dose 20 mg)   Tablets, f/c, famotidine 20 mg (beige), net price 28-  tab pack = £13.37; 40 mg (brown), 28-tab pack =  £25.40   Indications see under Dose  Cautions see notes above; also avoid rapid intra-  venous injection (risk of arrhythmias and postural  hypotension); interactions: Appendix 1 (histamine  H 2 -antagonists) and notes above  Hepatic impairment manufacturer advises caution  Renal impairment use half normal dose if eGFR 20-  50 mL/minute/ 1.73 m 2 ; use one-quarter normal dose  if eGFR less than 20 mL/minute/ 1.73 m 2  Pregnancy manufacturer advises avoid unless essen-  tial   Breast-feeding amount too small to be harmful  Side-effects see notes above; also sweating; rarely  nausea, fever, vasculitis, hyperuricaemia   • By mouth, benign gastric, duodenal or NSAID-asso-  ciated ulceration, treatment, 300 mg in the evening or  150 mg twice daily for 4-8 weeks; maintenance,   Gastro-oesophageal reflux disease, 150-300 mg twice  daily for up to 12 weeks   • By intravenous infusion, for short-term use in peptic  ulcer as alternative to oral route (for hospital inpati-  ents), by intermittent intravenous infusion over 15  minutes, 100 mg 3 times daily, or by continuous  intravenous infusion, 10 mg/hour; max. 480 mg daily   Nizatidine (Non-proprietary) (Ml  Capsules, nizatidine 150 mg, net price 30-cap pack =  £12.04; 300 mg, 30-cap pack = £14.28  1 . Nizatidine can be sold to the public for the prevention and  treatment of symptoms of food-related heartburn and meal-  induced indigestion in adults and children over 16 years;  max. single dose 75 mg, max. daily dose 150 mg for max. 14  days   Capsules, nizatidine 150 mg (pale yellow/dark yel-  low), net price 28-cap pack (hosp. only) = £6.87, 30-  cap pack = £7.97; 300 mg (pale yellow/brown), 30-  cap pack = £15.80   Cautions see notes above; also acute porphyria;  interactions: Appendix 1 (histamine H 2 -antagonists)  and notes above   Renal impairment use half normal dose if eGFR less  than 50 mL/minute/ 1.73 m 2   Breast-feeding significant amount present in milk,  but not known to be harmful   Side-effects see notes above; less commonly blurred  vision; also reported pancreatitis, involuntary move-  ment disorders, interstitial nephritis, alopecia   • By mouth, benign gastric and duodenal ulceration,  chronic episodic dyspepsia, ADULT and CHILD over 12  years, 150 mg twice daily or 300 mg at night for 4-8  weeks in benign gastric and duodenal ulceration, up  to 6 weeks in chronic episodic dyspepsia, and up to 8  weeks in NSAID-associated ulceration (in duodenal  ulcer 300 mg can be given twice daily for 4 weeks to  achieve a higher healing rate); CHILD 3-12 years,  (benign gastric and duodenal ulceration) 2-4 mg/kg  (max. 150 mg) twice daily for 4-8 weeks  Prophylaxis of NSAID-associated gastric or duodenal  ulcer [unlicensed dose], ADULT and CHILD over 12  years, 300 mg twice daily   Gastro-oesophageal reflux disease, ADULT and CHILD  over 12 years, 150 mg twice daily or 300 mg at night  for up to 8 weeks or if necessary 12 weeks (moderate  to severe, 600 mg daily in 2-4 divided doses for up to  12 weeks); long-term treatment of healed gastro-  oesophageal reflux disease, 150 mg twice daily; CHILD  3-12 years, 2.5-5 mg/kg (max. 300 mg) twice daily  Gastric acid reduction (prophylaxis of acid aspiration)  in obstetrics, ADULT and CHILD over 12 years, by mouth,  150 mg at onset of labour, then every 6 hours; surgical  procedures, by intramuscular or slow intravenous  injection, 50 mg 45-60 minutes before induction of  anaesthesia (intravenous injection diluted to 20 mL  and given over at least 2 minutes), or by mouth,   150 mg 2 hours before induction of anaesthesia and  also when possible on the preceding evening   • By slow intravenous injection, ADULT and CHILD over  12 years, 50 mg diluted to 20 mL and given over at  least 2 minutes; may be repeated every 6-8 hours   • Prophylaxis of stress ulceration [unlicensed dose],  ADULT and CHILD over 12 years, by slow intravenous  injection over at least 2 minutes, 50 mg diluted to  20 mL every 8 hours (may be changed to 150 mg  twice daily by mouth when oral feeding commences)   Tablets, ranitidine (as hydrochloride) 150 mg, net  price 60-tab pack = £1.97; 300 mg, 30-tab pack =  £2.17   Effervescent tablets, ranitidine (as hydrochloride)  150mg, net price 60-tab pack = £18.04; 300 mg, 30-  tab pack = £17.03. Label: 13    Oral solution, ranitidine (as hydrochloride) 75 mg/  5mL, net price 100 mL = £7.44, 300 mL = £19.61   Note Ranitidine can be sold to the public for adults and  children over 16 years (provided packs do not contain more  than 2 weeks’ supply) for the short-term symptomatic relief of  heartburn, dyspepsia, and hyperacidity, and for the prevention  of these symptoms when associated with consumption of food  or drink (max. single dose 75 mg, max. daily dose 300 mg)   Tablets, f/c, ranitidine (as hydrochloride) 150 mg, net  price 60-tab pack = £1.30; 300 mg, 30-tab pack =  £1.30    Pirenzepine is a selective antimuscarinic drug which  was used for the treatment of gastric and duodenal  ulcers. It has been discontinued.    Tripotassium dicitratobismuthate is a bismuth chelate  effective in healing gastric and duodenal ulcers. For the  role of tripotassium dicitratobismuthate in a Helico-  bacter pylori eradication regimen for those who have  not responded to first-line regimens, see section 1.3.    The bismuth content of tripotassium dicitratobismuth-  ate is low but absorption has been reported; encephalo-  pathy (described with older high-dose bismuth prepara-  tions) has not been reported.    Sucralfate may act by protecting the mucosa from acid-  pepsin attack in gastric and duodenal ulcers. It is a  complex of aluminium hydroxide and sulphated sucrose  but has minimal antacid properties. It should be used  with caution in patients under intensive care (impor-  tant: reports of bezoar formation, see Bezoar Formation  below)   see also Helicobacter pylori infection, section 1.3  Cautions see notes above; interactions: Appendix 1  (tripotassium dicitratobismuthate)   Breast-feeding no information available  Side-effects may darken tongue and blacken faeces;  less commonly nausea, vomiting, diarrhoea, consti-  pation, rash, and pruritus reported   Tablets, f/c, tripotassium dicitratobismuthate 120 mg,  net price 1 12-tab pack = £5.09. Counselling, see below   Dose 2 tablets twice daily or 1 tablet 4 times daily; taken for 28  days followed by further 28 days if necessary; maintenance not  indicated but course may be repeated after interval of 1 month;  CHILD not recommended   Counselling To be swallowed with half a glass of water; twice-  daily dosage to be taken 30 minutes before breakfast and main  evening meal; four-times-daily dosage to be taken as follows: one  dose 30 minutes before breakfast, midday meal and main evening  meal, and one dose 2 hours after main evening meal; milk should  not be drunk by itself during treatment but small quantities may  be taken in tea or coffee or on cereal; antacids, fruit, or fruit juice  should not be taken half an hour before or after a dose; may  darken tongue and blacken faeces   feeds should be separated by 1 hour; interactions:  Appendix 1 (sucralfate)   Bezoar formation Following reports of bezoar formation  associated with sucralfate, caution is advised in seriously ill  patients, especially those receiving concomitant enteral  feeds or those with predisposing conditions such as delayed  gastric emptying   Renal impairment use with caution; aluminium is  absorbed and may accumulate    Pregnancy no evidence of harm; absorption from  gastro-intestinal tract negligible  Breast-feeding amount probably too small to be  harmful    Side-effects constipation; less frequently diarrhoea,  nausea, indigestion, flatulence, gastric discomfort,  back pain, dizziness, headache, drowsiness, bezoar  formation (see above), dry mouth and rash   • Benign gastric and duodenal ulceration and chronic  gastritis, ADULT and CHILD over 15 years, 2 g twice daily  (on rising and at bedtime) or 1 g 4 times daily 1 hour  before meals and at bedtime, taken for 4-6 weeks or in  resistant cases up to 12 weeks; max. 8g daily   • Prophylaxis of stress ulceration, ADULT and CHILD over  15 years, 1 g 6 times daily; max. 8 g daily   Cautions conditions where hypotension might preci-  pitate severe complications (e.g. cerebrovascular dis-  ease, cardiovascular disease)   Contra-indications planning pregnancy (important:  see Women of Childbearing Age, and also Pregnancy,  below)   Women of childbearing age Manufacturer advises that  misoprostol should not be used in women of childbearing  age unless the patient requires non-steroidal anti-inflamm-  atory (NSAID) therapy and is at high risk of complications  from NSAID-induced ulceration. In such patients it is advised  that misoprostol should only be used if the patient takes  effective contraceptive measures and has been advised of the  risks of taking misoprostol if pregnant.   Side-effects diarrhoea (may occasionally be severe  and require withdrawal, reduced by giving single  doses not exceeding 200 micrograms and by avoiding  magnesium-containing antacids); also reported:  abdominal pain, dyspepsia, flatulence, nausea and  vomiting, abnormal vaginal bleeding (including inter-  menstrual bleeding, menorrhagia, and postmenopau-  sal bleeding), rashes, dizziness  Dose   • Benign gastric and duodenal ulceration and NSAID-  associated ulceration, ADULT over 18 years, 800 micr-  ograms daily (in 2-4 divided doses) with breakfast (or  main meals) and at bedtime; treatment should be  continued for at least 4 weeks and may be continued  for up to 8 weeks if required   • Prophylaxis of NSAID-induced gastric and duodenal  ulcer, ADULT over 18 years, 200 micrograms 4 times  daily (if not tolerated, reduced to 200 micrograms 2-3  times daily, but less effective)   Cytotec® (Pharmacia) (Ml  Tablets, scored, misoprostol 200 micrograms, net  price 60-tab pack = £10.03. Label: 21   Tablets, scored, sucralfate 1 g, net price 50-tab pack =  £5.77. Label: 5   Note Crushed tablets may be dispersed in water  Suspension, sucralfate, 1 g/5mL, net price 250 mL  (aniseed- and caramel-flavoured) = £5.77. Label: 5    Misoprostol, a synthetic prostaglandin analogue has  antisecretory and protective properties, promoting heal-  ing of gastric and duodenal ulcers. It can prevent  NSAID-associated ulcers, its use being most appropriate  for the frail or very elderly from whom NSAIDs cannot  be withdrawn.    For comment on the use of misoprostol to induce abor-  tion or labour [unlicensed indications], see section 7.1.1.    Proton pump inhibitors inhibit gastric acid secretion by  blocking the hydrogen-potassium adenosine triphospha-  tase enzyme system (the ‘proton pump’) of the gastric  parietal cell. Proton pump inhibitors are effective short-  term treatments for gastric and duodenal ulcers', they  are also used in combination with antibacterials for the  eradication of Helicobacter pylori (see p. 50 for specific  regimens). Following endoscopic treatment of severe  peptic ulcer bleeding, an intravenous, high-dose proton  pump inhibitor reduces the risk of rebleeding and the  need for surgery. Proton pump inhibitors can be used for  the treatment of dyspepsia and gastro-oesophageal  reflux disease (section 1.1).    Proton pump inhibitors are also used for the prevention  and treatment of NSAID-associated ulcers (see p. 50). In  patients who need to continue NSAID treatment after an    ulcer has healed, the dose of proton pump inhibitor  should normally not be reduced because asymptomatic  ulcer deterioration may occur.   A proton pump inhibitor can be used to reduce the  degradation of pancreatic enzyme supplements (section  1.9.4) in patients with cystic fibrosis. They can also be  used to control excessive secretion of gastric acid in  Zollinger— Ellison syndrome', high doses are often  required.   Cautions Proton pump inhibitors may mask the symp-  toms of gastric cancer; particular care is required in  those presenting with ‘alarm features’ (see p. 43), in  such cases gastric malignancy should be ruled out  before treatment.   Side-effects Side-effects of the proton pump inhi-  bitors include gastro-intestinal disturbances (including  nausea, vomiting, abdominal pain, flatulence, diarrhoea,  constipation), and headache. Less frequent side-effects  include dry mouth, peripheral oedema, dizziness, sleep  disturbances, fatigue, paraesthesia, arthralgia, myalgia,  rash, and pruritus. Other side-effects reported rarely or  very rarely include taste disturbance, stomatitis, hepat-  itis, jaundice, hypersensitivity reactions (including  anaphylaxis, bronchospasm), fever, depression, halluci-  nations, confusion, gynaecomastia, interstitial nephritis,  hyponatraemia, blood disorders (including leucopenia,  leucocytosis, pancytopenia, thrombocytopenia), visual  disturbances, sweating, photosensitivity, alopecia, Ste-  vens- Johnson syndrome, and toxic epidermal necroly-  sis. By decreasing gastric acidity, proton pump inhibitors  may increase the risk of gastro-intestinal infections  (including Clostridium difficile infection).   Hepatic impairment in severe hepatic impairment  max. 20 mg daily (CHILD 1-12 years max. 10 mg daily);  for severe peptic ulcer bleeding in severe hepatic  impairment, initial intravenous infusion of 80 mg, then  by continuous intravenous infusion, 4 mg/hour for 72  hours   • By mouth duodenal ulcer associated with Helico-  bacter pylori, see eradication regimens on p. 50  NSAID-associated gastric ulcer, ADULT over 18 years,  20 mg once daily for 4-8 weeks; prophylaxis in  patients with an increased risk of gastroduodenal  complications who require continued NSAID treat-  ment, 20 mg daily   Gastro-oesophageal reflux disease (in the presence of  erosive reflux oesophagitis), ADULT and CHILD over 12  years, 40 mg once daily for 4 weeks, continued for  further 4 weeks if not fully healed or symptoms  persist; maintenance 20 mg daily; CHILD 1-12 years,  body-weight 10-20 kg, 10 mg once daily for 8 weeks;  body-weight over 20 kg, 10-20 mg once daily for 8  weeks    Symptomatic treatment of gastro-oesophageal reflux  disease (in the absence of oesophagitis), ADULT and  CHILD over 12 years, 20 mg once daily for up to 4  weeks, then 20 mg daily when required; CHILD 1-12  years, body-weight over 10 kg, 10 mg once daily for  up to 8 weeks   Zollinger-Ellison syndrome, ADULT over 18 years,  initially 40 mg twice daily, adjusted according to  response; usual range 80-160 mg daily (above 80 mg  in 2 divided doses)   • By intravenous injection over at least 3 minutes or by  intravenous infusion, ADULT over 18 years, gastro-  oesophageal reflux disease, 40 mg once daily; symp-  tomatic reflux disease without oesophagitis, treat-  ment of NSAID-associated gastric ulcer, prevention of  NSAID-associated gastric or duodenal ulcer, 20 mg  daily; continue until oral administration possible   • Severe peptic ulcer bleeding (following endoscopic  treatment), ADULT over 18 years, initial intravenous  infusion of 80 mg over 30 minutes, then by continu-  ous intravenous infusion 8 mg/hour for 72 hours,  then by mouth 40 mg once daily for 4 weeks    Nexium® (AstraZeneca) (Ml  Tablets, f/c, esomeprazole (as magnesium trihydrate)  20 mg (light pink), net price 28-tab pack = £18.50;   Granules, yellow, e/c, esomeprazole (as magnesium  trihydrate) 10 mg/sachet, net price 28-sachet pack =  £25.19. Label: 25, counselling, administration  Counselling Disperse the contents of each sachet in approx.  15 mL water. Stir and leave to thicken for a few minutes; stir  again before administration and use within 30 minutes; rinse  container with 15 mL water to obtain full dose; can be  administered through nasogastric or gastric tube  Injection, powder for reconstitution, esomeprazole  (as sodium salt), net price 40-mg vial = £3.13   Side-effects see notes above; also glossitis, pan-  creatitis, anorexia, restlessness, tremor, impotence,  petechiae, and purpura; very rarely colitis, raised  serum cholesterol or triglycerides   • Benign gastric ulcer, 30 mg daily in the morning for 8  weeks   • Duodenal ulcer, 30 mg daily in the morning for 4  weeks; maintenance 15 mg daily   • NSAID-associated duodenal or gastric ulcer, 30 mg  once daily for 4 weeks, continued for further 4 weeks if  not fully healed; prophylaxis, 15-30 mg once daily   • Eradication of Helicobacter pylori associated with  duodenal ulcer or ulcer-like dyspepsia, see eradica-  tion regimens on p. 50    • Zollinger-Ellison syndrome (and other hypersecretory  conditions), initially 60 mg once daily adjusted  according to response; daily doses of 120 mg or more  given in two divided doses   • Gastro-oesophageal reflux disease, 30 mg daily in the  morning for 4 weeks, continued for further 4 weeks if  not fully healed; maintenance 15-30 mg daily   • Acid-related dyspepsia, 15-30 mg daily in the morn-  ing for 2-4 weeks   Lansoprazole (Non-proprietary) Ml  Capsules, enclosing e/c granules, lansoprazole  15 mg, net price 28-cap pack = £1.44; 30 mg, 28-cap  pack = £2.23. Label: 5, 22, 25   FasTab® (= orodispersible tablet), lansoprazole  15 mg, net price 28-tab pack = £2.99; 30 mg, 28-tab  pack = £5.50. Label: 5, 22, counselling, administration   Counselling Tablets should be placed on the tongue, allowed to  disperse and swallowed, or may be swallowed whole with a glass  of water. Alternatively, tablets can be dispersed in a small amount  of water and administered by an oral syringe or nasogastric tube   Hepatic impairment not more than 20 mg daily  should be needed   • By mouth, benign gastric and duodenal ulcers, 20 mg  once daily for 4 weeks in duodenal ulceration or 8  weeks in gastric ulceration; in severe or recurrent  cases increase to 40 mg daily; maintenance for  recurrent duodenal ulcer, 20 mg once daily; preven-  tion of relapse in duodenal ulcer, 10 mg daily  increasing to 20 mg once daily if symptoms return  NSAID-associated duodenal or gastric ulcer and gas-  troduodenal erosions, 20 mg once daily for 4 weeks,  continued for further 4 weeks if not fully healed;  prophylaxis in patients with a history of NSAID-  associated duodenal or gastric ulcers, gastroduodenal  lesions, or dyspeptic symptoms who require contin-  ued NSAID treatment, 20 mg once daily  Duodenal or benign gastric ulcer associated with  Helicobacter pylori, see eradication regimens on  p. 50   Zollinger-Ellison syndrome, initially 60 mg once daily;  usual range 20-120 mg daily (above 80 mg in 2  divided doses)   Gastric acid reduction during general anaesthesia  (prophylaxis of acid aspiration), 40 mg on the pre-  ceding evening then 40 mg 2-6 hours before surgery  Gastro-oesophageal reflux disease, 20 mg once daily  for 4 weeks, continued for further 4-8 weeks if not  fully healed; 40 mg once daily has been given for 8  weeks in gastro-oesophageal reflux disease refractory  to other treatment; maintenance 20 mg once daily    Acid reflux disease (long-term management), 10 mg  daily increasing to 20 mg once daily if symptoms  return   Acid-related dyspepsia, 10-20 mg once daily for 2-4  weeks according to response  Severe ulcerating reflux oesophagitis, CHILD over 1  year, body-weight 10-20 kg, 10 mg once daily  increased if necessary to 20 mg once daily for 4-12  weeks; body-weight over 20 kg, 20 mg once daily  increased if necessary to 40 mg once daily for 4-12  weeks; to be initiated by hospital paediatrician   • By intravenous injection over 5 minutes or by intra-  venous infusion over 20-30 minutes, prophylaxis of  acid aspiration, 40 mg completed 1 hour before sur-  gery   Benign gastric ulcer, duodenal ulcer and gastro-  oesophageal reflux, 40 mg once daily until oral  administration possible   • Major peptic ulcer bleeding (following endoscopic  treatment) [unlicensed indication], initial intravenous  infusion of 80 mg over 40-60 minutes, then by con-  tinuous intravenous infusion, 8 mg/hour for 72 hours  (then change to oral therapy)   Omeprazole (Non-proprietary) (Ml  Capsules, enclosing e/c granules, omeprazole 10 mg,  net price 28-cap pack = £1.81; 20 mg, 28-cap pack =  £1.92; 40 mg, 7-cap pack = £1.95, 28-cap pack =  £21.65. Counselling, administration  Dental prescribing on NHS Gastro-resistant omeprazole  capsules may be prescribed   Capsules, enclosing e/c tablet, omeprazole 10 mg,  net price 28-cap pack = £1.81; 20 mg, 28-cap pack =  £1.92. Counselling, administration  Brands include Mepradec ®   1 Tablets, e/c, omeprazole 10 mg, net price 28-tab  pack = £5.84; 20 mg, 28-tab pack = £5.71; 40 mg, 7-tab  pack = £5.15. Label: 25   Intravenous infusion, powder for reconstitution,  omeprazole (as sodium salt), net price 40-mg vial =  £5.18   1. Omeprazole 10 mg tablets can be sold to the public for the  short-term relief of reflux-like symptoms (e.g. heartburn) in  adults over 18 years, max. daily dose 20 mg for max. 4  weeks, and a pack size of 28 tablets   Losec® (AstraZeneca) Ml  MUPS® (multiple-unit pellet system = dispersible  tablets), f/c, omeprazole 10 mg (light pink), net price  28-tab pack = £7.75; 20 mg (pink), 28-tab pack =  £11.60; 40 mg (red-brown), 7-tab pack = £5.80.  Counselling, administration   Capsules, enclosing e/c granules, omeprazole 10 mg  (pink), net price 28-cap pack = £7.75; 20 mg (pink/  brown), 28-cap pack = £11.60; 40 mg (brown), 7-cap  pack = £5.80. Counselling, administration  Intravenous infusion, powder for reconstitution,  omeprazole (as sodium salt), net price 40-mg vial =  £5.41   Injection, powder for reconstitution, omeprazole (as  sodium salt), net price 40-mg vial (with solvent) =  £5.41   Indications see under Dose  Cautions see notes above; interactions: Appendix 1  (proton pump inhibitors)   • By mouth, benign gastric ulcer, ADULT over 18 years,  40-80 mg daily in the morning for 4 weeks, continued  for further 4 weeks if not fully healed  Gastro-oesophageal reflux disease, ADULT and CHILD  over 12 years, 20-80 mg daily in the morning for 4  weeks, continued for further 4 weeks if not fully  healed; maintenance 20 mg daily, increased to 40 mg  daily if symptoms return   Duodenal ulcer, ADULT over 18 years, 40-80 mg daily  in the morning for 2 weeks, continued for further 2  weeks if not fully healed   Duodenal ulcer associated with Helicobacter pylori,  see eradication regimens on p. 50  Prophylaxis of NSAID-associated gastric or duodenal  ulcer in patients with an increased risk of gastroduo-  denal complications who require continued NSAID  treatment, ADULT over 18 years, 20 mg daily  Zollinger-Ellison syndrome (and other hypersecre-  tory conditions), ADULT over 18 years, initially 80 mg  once daily adjusted according to response (ELDERLY  max. 40 mg daily); daily doses above 80 mg given in 2  divided doses   • By intravenous injection over at least 2 minutes or by  intravenous infusion, ADULT over 18 years, duodenal  ulcer, gastric ulcer, and gastro-oesophageal reflux,   40 mg daily until oral administration can be resumed  Zollinger-Ellison syndrome (and other hypersecre-  tory conditions), ADULT over 18 years, initially 80 mg  (160 mg if rapid acid control required) then 80 mg  once daily adjusted according to response; daily doses  above 80 mg given in 2 divided doses   Tablets, e/c, pantoprazole 20 mg, net price 28-tab  pack = £1.79; 40 mg, 28-tab pack = £2.82. Label: 25  Note Pantoprazole 20 mg tablets can be sold to the public for  the short-term treatment of reflux symptoms (e.g. heartburn)  in adults over 18 years, max. daily dose 20 mg for max. 4  weeks   Injection, powder for reconstitution, pantoprazole (as  sodium salt), net price 40-mg vial = £5.11   Indications see under Dose  Cautions see notes above; interactions: Appendix 1  (proton pump inhibitors)   Side-effects see notes above; also cough, influenza-  like syndrome, and rhinitis; less commonly chest pain  and nervousness; rarely anorexia and weight gain    • Benign gastric ulcer, 20 mg daily in the morning for 6  weeks, continued for further 6 weeks if not fully healed   • Duodenal ulcer, 20 mg daily in the morning for 4  weeks, continued for further 4 weeks if not fully healed   • Gastro-oesophageal reflux disease, 20 mg once daily  for 4-8 weeks; maintenance 10-20 mg daily; symp-  tomatic treatment in the absence of oesophagitis,   10 mg daily for up to 4 weeks, then 10 mg daily when  required   • Zollinger-Ellison syndrome, initially 60 mg once daily  adjusted according to response (max. 120 mg daily);  doses above 100 mg daily given in 2 divided doses   Pariet® (Janssen-Cilag, Eisai) LmD  Tablets, e/c, rabeprazole sodium 10 mg (pink), net  price 28-tab pack = £11.56; 20 mg (yellow), 28-tab  pack = £19.55. Label: 25   The priority in acute diarrhoea, as in gastro-enteritis, is  the prevention or reversal of fluid and electrolyte deple-  tion. This is particularly important in infants and in frail  and elderly patients. For details of oral rehydration  preparations, see section 9.2. 1.2. Severe depletion of  fluid and electrolytes requires immediate admission to  hospital and urgent replacement.   Antimotility drugs (section 1.4.2) relieve symptoms of  acute diarrhoea. They are used in the management of  uncomplicated acute diarrhoea in adults; fluid and  electrolyte replacement may be necessary in case of  dehydration. However, antimotility drugs are not  recommended for acute diarrhoea in young children.  Antispasmodics (section 1.2) are occasionally of value in  treating abdominal cramp associated with diarrhoea but  they should not be used for primary treatment. Anti-  spasmodics and antiemetics should be avoided in  young children with gastro-enteritis because they are  rarely effective and have troublesome side-effects.   Antibacterial drugs are generally unnecessary in simple  gastro-enteritis because the complaint usually resolves  quickly without them, and infective diarrhoeas in the UK  often have a viral cause. Systemic bacterial infection  does, however, need appropriate systemic treatment; for  drugs used in Campylobacter enteritis, shigellosis, and  salmonellosis, see Table 1, section 5.1. Ciprofloxacin is  occasionally used for prophylaxis against travellers’  diarrhoea, but routine use is not recommended. Lacto-  bacillus preparations have not been shown to be effec-  tive.    Colestyramine (section 1.9.2), binds unabsorbed bile  salts and provides symptomatic relief of diarrhoea fol-  lowing ileal disease or resection.   Adsorbents such as kaolin are not recommended for  acute diarrhoeas. Bulk-forming drugs, such as isp-  aghula, methylcellulose, and sterculia (section 1.6.1)  are useful in controlling diarrhoea associated with  diverticular disease.   Oral suspension, light kaolin or light kaolin (natural)  20%, light magnesium carbonate 5%, sodium bicarb-  onate 5% in a suitable vehicle with a peppermint  flavour.    Antimotility drugs have a role in the management of  uncomplicated acute diarrhoea in adults but not in  young children; see also section 1.4. However, in severe  cases, fluid and electrolyte replacement (section 9.2. 1.2)  are of primary importance.    For comments on the role of antimotility drugs in  chronic bowel disorders see section 1.5. For their role  in stoma care see section 1.8.    Loperamide can be used for faecal incontinence [unli-  censed indication] after the underlying cause of incont-  inence has been addressed.   Contra-indications section 4.7.2; also conditions  where inhibition of peristalsis should be avoided,  where abdominal distension develops, or in acute  diarrhoeal conditions such as acute ulcerative colitis  or antibiotic-associated colitis  Hepatic impairment section 4.7.2  Renal impairment section 4.7.2  Pregnancy section 4.7.2  Breast-feeding section 4.7.2  Side-effects section 4.7.2  Dose   • Acute diarrhoea, ADULT and CHILD over 12 years, 30 mg  3-4 times daily (range 15-60 mg)   A mixture of diphenoxylate hydrochloride and atro-  pine sulphate in the mass proportions 100 parts to 1  part respectively   Indications adjunct to rehydration in acute diarrhoea  (but see notes above); control of faecal consistency  after colostomy or ileostomy (section 1.8)   Cautions section 4.7.2; also young children are parti-  cularly susceptible to overdosage and symptoms may  be delayed and observation is needed for at least 48  hours after ingestion; presence of subclinical doses of  atropine may give rise to atropine side-effects in  susceptible individuals or in overdosage (section 1.2);  interactions: Appendix 1 (antimuscarinics, opioid  analgesics)   Breast-feeding may be present in milk  Side-effects section 4.7.2 and also see under Anti-  muscarinics (section 1.2); also abdominal pain, ano-  rexia, and fever  Dose   Co-phenotrope (Non-proprietary) (Ml  Tablets, co-phenotrope 2.5/0.025 (diphenoxylate  hydrochloride 2.5 mg, atropine sulphate 25 micr-  ograms), net price 100 = £8.95  Brands include Lomotil   Dose initially 4 tablets, followed by 2 tablets every 6 hours until  diarrhoea controlled; CHILD under 4 years see BNF for Children,  4-9 years 1 tablet 3 times daily, 9-12 years 1 tablet 4 times daily,  12-16 years 2 tablets 3 times daily, but see also notes above  Note Co-phenotrope 2.5/0.025 can be sold to the public for adults  and children over 16 years (provided packs do not contain more  than 20 tablets) as an adjunct to rehydration in acute diarrhoea  (max. daily dose 10 tablets)   Indications symptomatic treatment of acute diarr-  hoea; adjunct to rehydration in acute diarrhoea in  adults and children over 4 years (but see notes above);  chronic diarrhoea in adults only   Contra-indications conditions where inhibition of  peristalsis should be avoided, where abdominal dis-  tension develops, or in conditions such as active  ulcerative colitis or antibiotic-associated colitis   Side-effects abdominal cramps, dizziness, drowsi-  ness, and skin reactions including urticaria; paralytic  ileus and abdominal bloating also reported   • Acute diarrhoea, 4 mg initially followed by 2 mg after  each loose stool for up to 5 days; usual dose 6-8 mg  daily; max. 16 mg daily; CHILD under 4 years not    recommended; 4-8 years, 1 mg 3-4 times daily for up  to 3 days only, 8-12 years, 2 mg 4 times daily for up to  5 days   • Chronic diarrhoea in adults, initially, 4-8 mg daily in  divided doses, subsequently adjusted according to  response and given in 2 divided doses for mainte-  nance; max. 16 mg daily; CHILD under 18 years see  BNF for Children   • Faecal incontinence [unlicensed indication], initially  500 micrograms daily, adjusted according to response;  max. 16 mg daily in divided doses   Loperamide (Non-proprietary) [Ml  Capsules, loperamide hydrochloride 2 mg, net price  30-cap pack = £1.07   Note Loperamide can be sold to the public, provided it is licensed  and labelled for the treatment of acute diarrhoea in adults and  children over 12 years of age, or for acute diarrhoea associated with  irritable bowel syndrome (after initial diagnosis by a doctor) in adults  over 18 years of age   Imodium® (Janssen-Cilag) (MO  Capsules, green/grey, loperamide hydrochloride  2 mg. Net price 30-cap pack = £1.09  Syrup, sugar free, red, loperamide hydrochloride  lmg/5mL. Net price 100 mL = £1.17   Caplets (= tablets), loperamide hydrochloride 2 mg,  simeticone 125 mg, net price 6-tab pack = £2.27, 12-  tab pack = £3.58   Dose acute diarrhoea with abdominal colic, initially 2 caplets  (CHILD 12-18 years 1 caplet) then 1 caplet after each loose stool;  max. 4 caplets daily for up to 2 days; CHILD under 12 years not  recommended   Indications see notes above; cough in terminal dis-  ease (section 3.9.1); pain (section 4.7.2)   Side-effects see notes above and under Morphine  Salts (section 4.7.2); sedation and the risk of depend-  ence are greater   Kaolin and Morphine Mixture, BP I  (Kaolin and Morphine Oral Suspension)   Oral suspension, light kaolin or light kaolin (natural)  20%, sodium bicarbonate 5%, and chloroform and  morphine tincture 4% in a suitable vehicle. Contains  anhydrous morphine 550-800 micrograms/ 10 mL.  Dose ADULT and CHILD over 12 years, 10 mL every 6 hours in  water    Once tumours are ruled out individual symptoms of  chronic bowel disorders need specific treatment includ-  ing dietary manipulation as well as drug treatment and  the maintenance of a liberal fluid intake.   Chronic inflammatory bowel diseases include ulcerative  colitis and Crohn’s disease. Effective management  requires drug therapy, attention to nutrition, and in  severe or chronic active disease, surgery.   Aminosalicylates (balsalazide, mesalazine, olsalazine,  and sulfasalazine), corticosteroids (hydrocortisone,  beclometasone, budesonide, and prednisolone), and  drugs that affect the immune response are used in  the treatment of inflammatory bowel disease.    Treatment of acute ulcerative colitis and Crohn’s  disease Acute mild to moderate disease affecting the  rectum (proctitis) or the recto-sigmoid is treated initially  with local application of an aminosalicylate (section  1.5.1); alternatively, a local corticosteroid can be used  but it is less effective. A combination of a local amino-  salicylate and a local corticosteroid can be used for  proctitis that does not respond to a local aminosalicylate  alone. Foam preparations and suppositories are espe-  cially useful when patients have difficulty retaining liq-  uid enemas.   Diffuse inflammatory bowel disease or disease that does  not respond to local therapy requires oral treatment.  Mild disease affecting the proximal colon can be treated  with an oral aminosalicylate alone; a combination of a  local and an oral aminosalicylate can be used in proctitis  or distal colitis. Refractory or moderate inflammatory  bowel disease usually requires adjunctive use of an oral  corticosteroid such as prednisolone (section 1.5.2) for  4-8 weeks. Modified-release budesonide is licensed for  Crohn’s disease affecting the ileum and the ascending  colon; it causes fewer systemic side-effects than oral  prednisolone but may be less effective. Beclometasone  dipropionate by mouth is licensed as an adjunct to  mesalazine for mild to moderate ulcerative colitis, but it  is not known whether it is as effective as other corti-  costeroids.    Severe inflammatory bowel disease or disease that is  not responding to an oral corticosteroid requires hospi-  tal admission and treatment with an intravenous  corticosteroid (such as hydrocortisone or methyl-  prednisolone, section 6.3.2); other therapy may include  intravenous fluid and electrolyte replacement, and pos-  sibly parenteral nutrition. Specialist supervision is  required for patients who fail to respond adequately to  these measures. Patients with severe ulcerative colitis  that has not responded to intravenous corticosteroids,  may benefit from a short course of intravenous ciclos-  porin [unlicensed indication] (section 1.5.3). Patients  with unresponsive or chronically active Crohn’s disease  may benefit from azathioprine (section 1.5.3),  mercaptopurine (section 1.5.3), or once-weekly  methotrexate (section 1.5.3) [all unlicensed indica-  tions]; these drugs have a slower onset of action.   Infliximab (section 1.5.3) is licensed for the manage-  ment of severe active Crohn’s disease and severe ulcer-  ative colitis in patients whose condition has not    responded adequately to treatment with a corticosteroid  and a conventional drug that affects the immune  response, or who are intolerant of them.   Infliximab or adalimumab is recommended for the  treatment of severe active Crohn’s disease that has  not responded to conventional therapy (including  corticosteroids and other drugs affecting the  immune response) or when conventional therapy  cannot be used because of intolerance or contra-  indications; infliximab can also be used in a similar  way in children over 6 years of age. In adults over 18  years of age, infliximab is recommended for the  treatment of fistulating Crohn’s disease that has  not responded to conventional therapy (including  antibacterials, drainage, and other drugs affecting  the immune response) or when conventional therapy  cannot be used because of intolerance or contra-  indications.   Infliximab or adalimumab should be given as a  planned course of treatment for 12 months or until   B treatment failure, whichever is shorter. Treatment  should be continued beyond 12 months only if there  is evidence of active disease — in these cases the  need for treatment should be reviewed at least  annually. If the disease relapses after stopping treat-  ment, adalimumab or infliximab can be restarted  (but see Hypersensitivity Reactions under Inflixi-  mab, p. 66).   Infliximab is not recommended for the treatment of  subacute manifestations of moderate to severe  active ulcerative colitis that would normally be man-  aged in an outpatient setting.   Infliximab is recommended as an option for the  treatment of acute exacerbations of severe ulcer-  ative colitis when treatment with ciclosporin is con-  tra-indicated or inappropriate.    Adalimumab (section 1.5.3) is licensed for the treat-  ment of severe active Crohn’s disease in patients whose  condition has not responded adequately to treatment  with a corticosteroid and a conventional drug that  affects the immune response, or who are intolerant of  them. For inducing remission, adalimumab should be  used in combination with a corticosteroid, but it may be  given alone if a corticosteroid is inappropriate or is not  tolerated. Adalimumab may also be used for Crohn’s  disease in patients who have relapsed while taking  infliximab or who cannot tolerate infliximab because  of hypersensitivity reactions.   Maintenance of remission of acute ulcerative  colitis and Crohn’s disease Smoking cessation  (section 4.10.2) reduces the risk of relapse in Crohn’s  disease and should be encouraged. Aminosalicylates  are efficacious in the maintenance of remission of ulcer-    ative colitis, but there is no evidence of efficacy in the  maintenance of remission of Crohn’s disease. Corticos-  teroids are not suitable for maintenance treatment  because of their side-effects. In resistant or frequently  relapsing cases either azathioprine (section 1.5.3) [unli-  censed indication] or mercaptopurine (section 1.5.3)  [unlicensed indication], given under close supervision  may be helpful. Methotrexate (section 1.5.3) is tried in  Crohn’s disease if azathioprine or mercaptopurine can-  not be used [unlicensed indication]. Maintenance ther-  apy with infliximab should be considered for patients  with Crohn’s disease or ulcerative colitis who respond to  the initial induction course of infliximab; fixed-interval  dosing is superior to intermittent dosing. Adalimumab  is licensed for maintenance therapy in Crohn’s disease.   necessary for simple, asymptomatic perianal fistulas.  Metronidazole (section 5.1.11) or ciprofloxacin (sec-  tion 5.1.12) can improve symptoms of fistulating  Crohn’s disease but complete healing occurs rarely  [unlicensed indication]. Metronidazole by mouth is  used at a dose of 10-20 mg/kg daily in divided doses  (usual dose 400-500 mg 3 times daily); it is usually given  for 1 month but no longer than 3 months because of  concerns about peripheral neuropathy. Ciprofloxacin by  mouth is given at a dose of 500 mg twice daily. Other  antibacterials should be given if specifically indicated  (e.g. sepsis associated with fistulas and perianal disease)  and for managing bacterial overgrowth in the small  bowel. Fistulas may also require surgical exploration  and local drainage.   Either azathioprine or mercaptopurine is used as a  second-line treatment for fistulating Crohn’s disease and  continued for maintenance [unlicensed indication].  Infliximab is used for fistulating Crohn’s disease refrac-  tory to conventional treatments; fixed-interval dosing is  superior to intermittent dosing. Maintenance therapy  with infliximab should be considered for patients who  respond to the initial induction course of infliximab.  Adalimumab can be used if there is intolerance to  infliximab [unlicensed indication]   Adjunctive treatment of inflammatory bowel dis-  ease Due attention should be paid to diet; high-fibre or  low-residue diets should be used as appropriate.  Antimotility drugs such as codeine and loperamide, and  antispasmodic drugs may precipitate paralytic ileus and  megacolon in active ulcerative colitis; treatment of the  inflammation is more logical. Laxatives may be required  in proctitis. Diarrhoea resulting from the loss of bile-salt  absorption (e.g. in terminal ileal disease or bowel resec-  tion) may improve with colestyramine (section 1.9.2),  which binds bile salts.   Clostridium difficile infection is caused by colonisation  of the colon with Clostridium difficile and production of  toxin. It often follows antibiotic therapy and is usually of  acute onset, but may become chronic. It is a particular  hazard of ampicillin, amoxicillin, co-amoxiclav, second-  and third-generation cephalosporins, clindamycin, and  quinolones, but few antibiotics are free of this side-  effect. Oral metronidazole (see section 5.1.11) or oral  vancomycin (see section 5.1.7) are used as specific  treatment; vancomycin may be preferred for very sick  patients. Metronidazole can be given by intravenous  infusion if oral treatment is inappropriate.   Diverticular disease is treated with a high-fibre diet,  bran supplements, and bulk-forming drugs (section  1.6.1). Antispasmodics may provide symptomatic relief  when colic is a problem (section 1.2). Antibacterials are  used only when the diverticula in the intestinal wall  become infected. Antimotility drugs which slow intes-  tinal motility, e.g. codeine, diphenoxylate, and loper-  amide could possibly exacerbate the symptoms of  diverticular disease and are contra-indicated.   Irritable bowel syndrome can present with pain, con-  stipation, or diarrhoea. In some patients there may be  important psychological aggravating factors which  respond to reassurance and possibly specific treatment  e.g. with an antidepressant.   The fibre intake of patients with irritable bowel  syndrome should be reviewed. If an increase in dietary  fibre is required, soluble fibre (e.g. ispaghula husk,  sterculia, or oats) is recommended; insoluble fibre (e.g.  bran) may exacerbate symptoms and its use should be  discouraged. A laxative (section 1.6) can be used to  treat constipation. An osmotic laxative, such as a  macrogol, is preferred; lactulose may cause bloating.  Stimulant laxatives should be avoided or used only  occasionally Loperamide (section 1.4.2) may relieve  diarrhoea and antispasmodic drugs (section 1.2) may  relieve pain. Opioids with a central action, such as  codeine, are better avoided because of the risk of dep-  endence.   A tricyclic antidepressant (section 4.3.1) can be used  for abdominal pain or discomfort [unlicensed indication]  in patients who have not responded to laxatives, loper-  amide, or antispasmodics. Low doses of a tricyclic anti-  depressant are used (e.g. amitriptyline, initially 5-10 mg  each night, increased if necessary in steps of 10 mg at  intervals of at least 2 weeks to max. 30 mg each night). A  selective serotonin reuptake inhibitor (section 4.3.3)  may be considered in those who do not respond to a  tricyclic antidepressant [unlicensed indication].   Individual conditions need specific management and  also general nutritional consideration. Coeliac disease  (gluten enteropathy) usually needs a gluten-free diet and  pancreatic insufficiency needs pancreatin supplements  (section 1.9.4)   For further information on foods for special diets  (ACBS), see Appendix 7.    Sulfasalazine is a combination of 5-aminosalicylic acid  (‘5-ASA’) and sulfapyridine; sulfapyridine acts only as a  carrier to the colonic site of action but still causes side-  effects. In the newer aminosalicylates, mesalazine (5-  aminosalicylic acid), balsalazide (a prodrug of 5-amino-  salicylic acid) and olsalazine (a dimer of 5-aminosali-    cylic acid which cleaves in the lower bowel), the sul-  phonamide-related side-effects of sulfasalazine are  avoided, but 5-aminosalicylic acid alone can still cause  side-effects including blood disorders (see recommen-  dation below) and lupus-like syndrome also seen with  sulfasalazine.   Cautions Renal function should be monitored before  starting an oral aminosalicylate, at 3 months of treat-  ment, and then annually during treatment (more fre-  quently in renal impairment). Blood disorders can occur  with aminosalicylates (see recommendation below).   Patients receiving aminosalicylates should be  advised to report any unexplained bleeding, bruis-  ing, purpura, sore throat, fever or malaise that  occurs during treatment. A blood count should be  performed and the drug stopped immediately if  there is suspicion of a blood dyscrasia.   Side-effects Side-effects of the aminosalicylates  include diarrhoea, nausea, vomiting, abdominal pain,  exacerbation of symptoms of colitis, headache, hyper-  sensitivity reactions (including rash and urticaria); side-  effects that occur rarely include acute pancreatitis,  hepatitis, myocarditis, pericarditis, lung disorders  (including eosinophilia and fibrosing alveolitis), periph-  eral neuropathy, blood disorders (including agranulo-  cytosis, aplastic anaemia, leucopenia, methaemoglobin-  aemia, neutropenia, and thrombocytopenia — see also  recommendation above), renal dysfunction (interstitial  nephritis, nephrotic syndrome), myalgia, arthralgia, skin  reactions (including lupus erythematosus-like  syndrome, Stevens-Johnson syndrome), alopecia.   Indications treatment of mild to moderate ulcerative  colitis and maintenance of remission  Cautions see notes above; also history of asthma;  interactions: Appendix 1 (aminosalicylates)   Blood disorders See recommendation above  Contra-indications see notes above  Hepatic impairment avoid in severe impairment  Renal impairment manufacturer advises avoid in  moderate to severe impairment  Pregnancy manufacturer advises avoid  Breast-feeding monitor infant for diarrhoea  Side-effects see notes above; also cholelithiasis  Dose   • Acute attack, 2.25 g 3 times daily until remission  occurs or for up to max. 12 weeks   • Maintenance, 1.5 g twice daily, adjusted according to  response (max. 6 g daily)   Indications treatment of mild to moderate ulcerative  colitis and maintenance of remission; see also under  preparations   Blood disorders See recommendation above  Contra-indications see notes above  Hepatic impairment avoid in severe impairment  Renal impairment use with caution; avoid if eGFR  less than 20 mL/minute/ 1.73 m 2  Pregnancy negligible quantities cross placenta  Breast-feeding diarrhoea reported but negligible  amounts detected in breast milk; monitor infant for  diarrhoea   • See under preparations, below  Note The delivery characteristics of oral mesalazine pre-  parations may vary; these preparations should not be con-  sidered interchangeable   Dose acute attack affecting the rectosigmoid region, 1 metered  application (mesalazine 1 g) into the rectum daily for 4-6 weeks;  acute attack affecting the descending colon, 2 metered applica-  tions (mesalazine 2 g) once daily for 4-6 weeks; CHILD 12-18  years, see BNF for Children   Suppositories, mesalazine 250 mg, net price 20-sup-  pos pack = £4.82; 500 mg, 10-suppos pack = £4.82.  Counselling, blood disorder symptoms (see recom-  mendation above)   Dose acute attack or maintenance, by rectum 0.75-1.5 g daily in  divided doses, with last dose at bedtime; CHILD 12-18 years, see  BNF for Children   Asacol® MR (Warner Chilcott) (Ml  Tablets, red, e/c, mesalazine 400 mg, net price 90-tab  pack = £29.41, 120-tab pack= £39.21. Label: 5, 25,  counselling, blood disorder symptoms (see recom-  mendation above)   Dose ulcerative colitis, acute attack, 2.4 g daily in divided doses;  maintenance of remission of ulcerative colitis and Crohn’s ileo-  colitis, 1.2-2.4g daily in divided doses; CHILD 12-18 years, see  BNF for Children   Tablets, red-brown, e/c, mesalazine 800 mg, net price  180-tab pack = £117.62. Label: 5, 25, counselling,  blood disorder symptoms (see recommendation  above)   Dose ADULT over 18 years, ulcerative colitis, acute attack, 2.4-  4.8 g daily in divided doses; maintenance of remission of ulcer-  ative colitis and Crohn’s ileo-colitis, up to 2.4 g daily in divided  doses   Note Preparations that lower stool pH (e.g. lactulose) may  prevent release of mesalazine   Dose acute attack, 2.4 g daily in divided doses; maintenance,  1.2-2.4g daily in divided doses; CHILD 12-18 years, see BNF for  Children   Note Preparations that lower stool pH (e.g. lactulose) may prevent  release of mesalazine   Tablets, red-brown, e/c, mesalazine 400 mg, net price  90-tab pack = £19.50, 120-tab pack = £26.00. Label: 5,  25, counselling, blood disorder symptoms (see  recommendation above)   Dose ADULT and CHILD over 12 years, ulcerative colitis, acute  attack, 2.4 g daily in divided doses; maintenance of remission of  ulcerative colitis and Crohn’s ileo-colitis, 1. 2-2.4 g daily in divided  doses    Mezavant® XL (Shire) (Ml  Tablets, m/r, red-brown, e/c, mesalazine 1.2 g, net  price 60-tab pack = £62.44. Label: 21, 25, counselling,  blood disorder symptoms (see recommendations  above)   Dose ADULT over 18 years, acute attack, 2.4 g once daily, increase  if necessary to 4.8 g once daily (review treatment at 8 weeks);  maintenance, 2.4 g once daily   Tablets, m/r, scored, mesalazine 500 mg (grey), net  price 100-tab pack = £24.21. Counselling, adminis-  tration, see dose, blood disorder symptoms (see  recommendation above)   Dose ADULT and CHILD over 15 years, acute attack, up to 4 g daily  in 2-3 divided doses; maintenance, 2 g once daily; tablets may be  dispersed in water, but should not be chewed; CHILD 5-15 years  see BNF for Children   Granules, m/r, pale grey-brown, mesalazine 1 g/  sachet, net price 50-sachet pack = £28.82; 2 g/sachet,  60-sachet pack = £72.05. Counselling, administration,  see dose, blood disorder symptoms (see recommen-  dation above)   Dose acute attack, up to 4 g daily in 2-4 divided doses; main-  tenance, 2 g once daily; granules should be placed on tongue and  washed down with water or orange juice without chewing; CHILD   Dose by rectum ulcerative proctitis, ADULT and CHILD over 15  years, acute attack, 1 g daily for 2-4 weeks; maintenance, 1 g daily;  CHILD 12-15 years see BNF for Children   Tablets, e/c, yellow, mesalazine 250 mg. Net price  100-tab pack = £16.19. Label: 5, 25, counselling, blood  disorder symptoms (see recommendation above)  Dose acute attack, 0.5-1 g 3 times daily; maintenance, 500 mg  three times daily; CHILD 12-18 years see BNF for Children   Granules, m/r, grey, e/c, vanilla-flavoured, mesal-  azine 500 mg/sachet, net price 100-sachet pack =  £28.74; 1 g/sachet, 50-sachet pack = £28.74; 1.5 g/  sachet, 60-sachet pack = £48.85. Label: 25, counsel-  ling, administration, see dose, blood disorder symp-  toms (see recommendation above)   Dose acute attack, 1.5-3 g once daily (preferably in the morning)  or 0.5-1 g 3 times daily; maintenance, 500 mg 3 times daily; CHILD   Counselling granules should be placed on tongue and washed  down with water without chewing   Note Preparations that lower stool pH (e.g. lactulose) may prevent  release of mesalazine   Dose ADULT and CHILD over 15 years, acute attack, by rectum,  0.5-1 g 2-3 times daily adjusted according to response; CHILD 12-  15 years see BNF for Children   Excipients include cetostearyl alcohol, disodium edetate, polysorbate  60, propylene glycol, sodium metabisulphite  Dose mild ulcerative colitis affecting sigmoid colon and rectum,  ADULT and CHILD over 12 years, 2 metered applications (mesal-  azine 2 g) into the rectum at bedtime or in 2 divided doses   Blood disorders See recommendation above  Contra-indications see notes above  Renal impairment use with caution; manufacturer  advises avoid in significant impairment  Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk  Breast-feeding monitor infant for diarrhoea  Side-effects see notes above; watery diarrhoea com-  mon; also reported, tachycardia, palpitation, pyrexia,  blurred vision, and photosensitivity  Dose   • ADULT and CHILD over 12 years, acute attack, 1 g daily  in divided doses after meals increased if necessary  over 1 week to max. 3 g daily (max. single dose 1 g);  maintenance, 500 mg twice daily after meals   Indications treatment of mild to moderate and severe  ulcerative colitis and maintenance of remission; active  Crohn’s disease; rheumatoid arthritis (section 10.1.3)  Cautions see notes above; also history of allergy or  asthma; G6PD deficiency (section 9.1.5); slow acety-  lator status; risk of haematological and hepatic toxi-  city (differential white cell, red cell, and platelet  counts initially and at monthly intervals for first 3  months; liver function tests at monthly intervals for  first 3 months); maintain adequate fluid intake; upper  gastro-intestinal side-effects common over 4 g daily;  acute porphyria (section 9.8.2); interactions: Appen-  dix 1 (aminosalicylates)    Contra-indications see notes above; also sulphona-  mide hypersensitivity; child under 2 years of age  Hepatic impairment use with caution  Renal impairment risk of toxicity, including crystal-  luria, in moderate impairment — ensure high fluid  intake; avoid in severe impairment  Pregnancy theoretical risk of neonatal haemolysis in  third trimester; adequate folate supplements should  be given to mother   Breast-feeding small amounts in milk (1 report of  bloody diarrhoea); theoretical risk of neonatal hae-  molysis especially in G6PD-deficient infants    Side-effects see notes above; also cough, insomnia,  dizziness, fever, blood disorders (including Heinz  body anaemia, megaloblastic anaemia), proteinuria,  tinnitus, stomatitis, taste disturbances, and pruritus;  less commonly dyspnoea, depression, convulsions,  vasculitis, and alopecia; also reported loss of appetite,  hypersensitivity reactions (including exfoliative  dermatitis, epidermal necrolysis, photosensitivity,  anaphylaxis, serum sickness), ataxia, hallucinations,  aseptic meningitis, oligospermia, crystalluria, distur-  bances of smell, and parotitis; yellow-orange disco-  loration of skin, urine, and other body fluids; some soft  contact lenses may be stained  Dose   • By mouth, acute attack 1-2 g 4 times daily (but see  cautions) until remission occurs (if necessary corti-  costeroids may also be given), reducing to a main-  tenance dose of 500 mg 4 times daily; CHILD 2-12  years see BNF for Children   • By rectum, in suppositories, alone or in conjunction  with oral treatment 0.5-1 g morning and night after a  bowel movement; CHILD 5-12 years see BNF for  Children    Salazopyrin® (Pharmacia) (Ml  Tablets, yellow, scored, sulfasalazine 500 mg, net  price 112-tab pack = £6.97. Label: 14, counselling,  blood disorder symptoms (see recommendation  above), contact lenses may be stained  EN-Tabs® (= tablets e/c), yellow, f/c, sulfasalazine  500 mg, net price 112-tab pack = £8.43. Label: 5, 14,  25, counselling, blood disorder symptoms (see  recommendation above), contact lenses may be  stained    For the role of corticosteroids in acute ulcerative colitis  and Crohn’s disease, see Inflammatory Bowel Disease,  p. 59.   Indications adjunct to aminosalicylates in acute mild  to moderate ulcerative colitis; asthma (section 3.2);  allergic and vasomotor rhinitis (section 12.2.1); oral  ulceration [unlicensed indication] (section 12.3.1)  Cautions section 6.3.2; interactions: Appendix 1  (corticosteroids)   Contra-indications section 6.3.2  Hepatic impairment manufacturer advises avoid in  severe impairment — no information available  Pregnancy section 6.3.2  Breast-feeding section 6.3.2  Side-effects section 6.3.2; also nausea, constipation,   • 5 mg in the morning; max. duration of treatment 4  weeks; CHILD safety and efficacy not established   Tablets, m/r, ivory, beclometasone dipropionate  5 mg, net price 30-tab pack = £56.56. Label: 25   Indications see preparations  Cautions section 6.3.2; for autoimmune hepatitis,  monitor liver function tests every 2 weeks for 1  month, then at least every 3 months; interactions:  Appendix 1 (corticosteroids)   Contra-indications section 6.3.2  Hepatic impairment section 6.3.2  Pregnancy section 6.3.2  Breast-feeding section 6.3.2  Side-effects section 6.3.2  Dose   Budenofalk® (Dr Falk) (Ml  Capsules, pink, enclosing e/c granules, budesonide  3 mg, net price 100-cap pack = £75.05. Label: 5, 10,  steroid card, 22, 25   Dose mild to moderate Crohn’s disease affecting ileum or  ascending colon, chronic diarrhoea due to collagenous colitis,  ADULT over 18 years, 3 mg 3 times daily for up to 8 weeks; reduce  dose for the last 2 weeks of treatment (see also section 6.3.2);  CHILD 12-18 years see BNF for Children  Autoimmune hepatitis, ADULT over 18 years, induction of remis-  sion, 3 mg 3 times daily; maintenance, 3 mg twice daily   Dose ulcerative colitis affecting sigmoid colon and rectum, by  rectum, ADULT over 18 years, 1 metered application (budesonide  2 mg) once daily for up to 8 weeks    Entocort® (AstraZeneca) (Ml  CR Capsules, grey/pink, enclosing e/c, m/r granules,  budesonide 3 mg, net price 100-cap pack = £99.00.  Label: 5, 10, steroid card, 25  Note Dispense in original container (contains desiccant)   Dose mild to moderate Crohn’s disease affecting the ileum or  ascending colon, 9 mg once daily in the morning for up to 8  weeks; reduce dose for the last 2-4 weeks of treatment (see also  section 6.3.2); CHILD 12-18 years see BNF for Children   Enema, budesonide 2 mg/ 100 mL when dispersible  tablet reconstituted in isotonic saline vehicle, net  price pack of 7 dispersible tablets and bottles of  vehicle = £33.00   Dose ulcerative colitis involving rectal and recto-sigmoid dis-  ease, by rectum, 1 enema at bedtime for 4 weeks; CHILD 12-18  years see BNF for Children   Cautions section 6.3.2; systemic absorption may  occur; prolonged use should be avoided  Contra-indications intestinal obstruction, bowel per-  foration, recent intestinal anastomoses, extensive fis-  tulas; untreated infection  Side-effects section 6.3.2; also local irritation  Dose   Dose initially 1 metered application (125 mg hydrocortisone  acetate) inserted into the rectum once or twice daily for 2-3  weeks, then once on alternate days; CHILD 2-18 years see BNF for  Children   Cautions section 6.3.2; systemic absorption may  occur with rectal preparations; prolonged use should  be avoided   Contra-indications section 6.3.2; intestinal obstruc-  tion, bowel perforation, recent intestinal anastomoses,  extensive fistulas; untreated infection   • By mouth, initially 20-40 mg daily (up to 60 mg daily  in some cases), preferably taken in the morning after  breakfast; continued until remission occurs, followed  by reducing doses   Predenema® (Chemidex) (Ml  Retention enema, prednisolone 20 mg (as sodium  metasulphobenzoate) in 100-mL single-dose dispo-  sable pack. Net price 1 (standard tube) = 71p, 1 (long  tube) = £1.21   Dose ulcerative colitis, by rectum, ADULT and CHILD over 12  years, initially 20 mg at bedtime for 2-4 weeks, continued if good  response   Dose proctitis and distal ulcerative colitis, 1 metered application  (20 mg prednisolone) inserted into the rectum once or twice daily  for 2 weeks, continued for further 2 weeks if good response; CHILD  not recommended   Predsol® (UCB Pharma) (Ml  Retention enema, prednisolone 20 mg (as sodium  phosphate) in 100-mL single-dose disposable packs  fitted with a nozzle. Net price 7 = £6.00  Dose rectal and rectosigmoidal ulcerative colitis and Crohn’s  disease, by rectum, initially 20 mg at bedtime for 2-4 weeks,  continued if good response; CHILD not recommended    For the role of azathioprine, ciclosporin, mercapto-  purine, and methotrexate in the treatment of inflamm-  atory bowel disease, see p. 59.    Folic acid (section 9.1.2) should be given to reduce the  possibility of methotrexate toxicity [unlicensed indica-  tion], Folic acid is usually given at a dose of 5 mg once  weekly on a different day to the methotrexate; alter-  native regimens may be used in some settings.   Indications see under Inflammatory Bowel Disease,  p. 59; autoimmune conditions and prophylaxis of  transplant rejection (section 8.2.1); rheumatoid arth-  ritis (section 10.1.3); severe refractory eczema (sec-  tion 13.5.3)   Contra-indications section 8.2.1  Hepatic impairment section 8.2.1  Renal impairment section 8.2.1  Pregnancy section 8.2.1  Breast-feeding section 8.2.1  Side-effects section 8.2.1  Dose    Indications severe acute ulcerative colitis refractory  to corticosteroid treatment [unlicensed indication];  transplantation and graft-versus-host disease,  nephrotic syndrome (section 8.2.2); rheumatoid arth-  ritis (section 10.1.3); atopic dermatitis and psoriasis  (section 13.5.3)   • By continuous intravenous infusion, ADULT over 18  years, 2 mg/kg daily over 24 hours; dose adjusted  according to blood-ciclosporin concentration and  response   Hepatic impairment section 8.1.3  Renal impairment section 8.1.3  Pregnancy section 8.1.3  Breast-feeding section 8.1.3  Side-effects section 8.1.3  Dose   • Severe acute Crohn’s disease, maintenance of remis-  sion of Crohn’s disease or ulcerative colitis [unli-  censed indications], ADULT over 18 years, by mouth, 1-  1.5 mg/kg daily; some patients may respond to lower  doses   Indications see under Inflammatory Bowel Disease,  p. 59; malignant disease (section 8.1.3); rheumatoid  arthritis (section 10.1.3); psoriasis (section 13.5.3)  Cautions section 10.1.3   Contra-indications section 10.1.3  Hepatic impairment section 10.1.3  Renal impairment section 10.1.3  Pregnancy section 10.1.3   • By intramuscular injection, severe Crohn’s disease  [unlicensed indication], ADULT over 18 years, induction  of remission, 25 mg once weekly; maintenance, 15 mg  once weekly   • By mouth, maintenance of remission of severe  Crohn’s disease [unlicensed indication], ADULT over 18  years, 10-25 mg once weekly   Note that the above dose is a weekly dose. To avoid  error with low-dose methotrexate, it is recommended  that:   • the patient is carefully advised of the dose and frequency  and the reason for taking methotrexate and any other  prescribed medicine (e.g. folic acid);   • only one strength of methotrexate tablet (usually 2.5 mg) is  prescribed and dispensed;   • the prescription and the dispensing label clearly show the  dose and frequency of methotrexate administration;   • the patient is warned to report immediately the onset of  any feature of blood disorders (e.g. sore throat, bruising,  and mouth ulcers), liver toxicity (e.g. nausea, vomiting,  abdominal discomfort, and dark urine), and respiratory  effects (e.g. shortness of breath).   Infliximab and adalimumab are monoclonal anti-  bodies which inhibit the pro-inflammatory cytokine,  tumour necrosis factor alpha. They should be used  under specialist supervision. Adequate resuscitation  facilities must be available when infliximab is used.   Indications see under Inflammatory Bowel Disease,  p. 60; ankylosing spondylitis, psoriatic arthritis, rheu-  matoid arthritis, juvenile idiopathic arthritis, (section  10.1.3); psoriasis (section 13.5.3)   Cautions section 10.1.3  Contra-indications section 10.1.3  Pregnancy section 10.1.3  Breast-feeding section 10.1.3  Side-effects section 10.1.3  Dose   • By subcutaneous injection, severe active Crohn’s  disease, ADULT over 18 years, initially 80 mg, then  40 mg 2 weeks after initial dose or accelerated regi-  men, initially 160 mg in 4 divided doses over 1-2 days,  then 80 mg 2 weeks after initial dose; maintenance,  40 mg on alternate weeks, increased if necessary to  40 mg weekly; review treatment if no response within  12 weeks of initial dose   Indications see under Inflammatory Bowel Disease,  p. 59; ankylosing spondylitis, rheumatoid arthritis  (section 10.1.3); psoriasis (section 13.5.3)   Hypersensitivity reactions Risk of delayed hypersensi-  tivity if drug-free interval exceeds 16 weeks    Contra-indications see section 10.1.3  Pregnancy section 10.1.3  Breast-feeding section 10.1.3  Side-effects see section 10.1.3; also hepatosplenic T-  cell lymphoma  Dose   • By intravenous infusion, severe active Crohn’s dis-  ease, ADULT over 18 years, initially 5 mg/kg, then  5 mg/kg 2 weeks after initial dose; then if the condi-  tion has responded, maintenance 5 mg/kg 6 weeks  after initial dose, then 5 mg/kg every 8 weeks; CHILD  6-18 years, initially 5 mg/kg, then 5 mg/kg 2 weeks  and 6 weeks after initial dose, then 5 mg/kg every 8  weeks; interval between maintenance doses adjusted  according to response; discontinue if no response  within 10 weeks of initial dose  Fistulating Crohn’s disease, ADULT over 18 years,  initially 5 mg/kg, then 5 mg/kg 2 weeks and 6 weeks  after initial dose, then if condition has responded,  consult product literature for guidance on further  doses; CHILD under 18 years, see BNF for Children  Severe active ulcerative colitis, ADULT over 18 years,  initially 5 mg/kg, then 5 mg/kg 2 weeks and 6 weeks  after initial dose, then 5 mg/kg every 8 weeks; dis-  continue if no response 14 weeks after initial dose    Allergy with classical symptoms of vomiting, colic and  diarrhoea caused by specific foods such as shellfish  should be managed by strict avoidance. The condition  should be distinguished from symptoms of occasional  food intolerance in those with irritable bowel syndrome.  Sodium cromoglicate may be helpful as an adjunct to  dietary avoidance.   Indications food allergy (in conjunction with dietary  restriction); asthma (section 3.3.1); allergic con-  junctivitis (section 11.4.2); allergic rhinitis (section  12 . 2 . 1 )   • 200 mg 4 times daily before meals; may be increased if  necessary after 2-3 weeks to a max. of 40 mg/kg daily  and then reduced according to response; CHILD 2-14  years 100 mg 4 times daily before meals; may be  increased if necessary after 2-3 weeks to a max. of  40 mg/kg daily and then reduced according to  response   Counselling Capsules may be swallowed whole or the  contents dissolved in hot water and diluted with cold water  before taking   Nalcrom® (Sanofi-Aventis) (Ml  Capsules, sodium cromoglicate 100 mg. Net price  100-cap pack = £59.75. Label: 22, counselling, see  dose above   Bulk-forming laxatives  Stimulant laxatives  Faecal softeners  Osmotic laxatives  Bowel cleansing preparations  Peripheral opioid-receptor  antagonists  5HT 4 -receptor agonists   Before prescribing laxatives it is important to be sure  that the patient is constipated and that the constipation  is not secondary to an underlying undiagnosed com-  plaint.   It is also important for those who complain of constipa-  tion to understand that bowel habit can vary consider-  ably in frequency without doing harm. Some people  tend to consider themselves constipated if they do not  have a bowel movement each day. A useful definition of  constipation is the passage of hard stools less frequently  than the patient’s own normal pattern and this can be  explained to the patient.   Misconceptions about bowel habits have led to exces-  sive laxative use. Abuse may lead to hypokalaemia.   Thus, laxatives should generally be avoided except  where straining will exacerbate a condition (such as  angina) or increase the risk of rectal bleeding as in  haemorrhoids. Laxatives are also of value in drug-  induced constipation, for the expulsion of parasites  after anthelmintic treatment, and to clear the alimentary  tract before surgery and radiological procedures. Pro-  longed treatment of constipation is sometimes neces-  sary.   For the role of laxatives in the treatment of irritable  bowel syndrome, see p. 61. For the prevention of opioid-  induced constipation in palliative care, see p. 22.   Children Laxatives should be prescribed by a health-  care professional experienced in the management of  constipation in children. Delays of greater than 3 days  between stools may increase the likelihood of pain on  passing hard stools leading to anal fissure, anal spasm  and eventually to a learned response to avoid defaeca-  tion.   In infants, increased intake of fluids, particularly fruit  juice containing sorbitol (e.g. prune, pear, or apple), may  be sufficient to soften the stool. In infants under 1 year  of age with mild constipation, lactulose (section 1.6.4)  can be used to soften the stool; either an oral prepara-  tion containing macrogols or, rarely, glycerol supposi-  tories can be used to clear faecal impaction. The infant  should be referred to a hospital paediatric specialist if  these measures fail.   The diet of children over 1 year of age should be  reviewed to ensure that it includes an adequate intake  of fibre and fluid. An osmotic laxative containing  macrogols (section 1.6.4) can also be used, particularly  in children with chronic constipation; lactulose is an  alternative in children who cannot tolerate a macrogol.  If there is an inadequate response to the osmotic laxa-  tive, a stimulant laxative (section 1.6.2) can be added.   Treatment of faecal impaction may initially increase  symptoms of soiling and abdominal pain. In children   over 1 year of age with faecal impaction, an oral pre-  paration containing macrogols (section 1.6.4) is used to  clear faecal mass and to establish and maintain soft  well-formed stools. If disimpaction does not occur after  2 weeks, a stimulant laxative (section 1.6.2) can be  added. If the impacted mass is not expelled following  treatment with macrogols and a stimulant laxative, a  sodium citrate enema can be administered. Although  rectal administration of laxatives may be effective, this  route is frequently distressing for the child and may lead  to persistence of withholding. A phosphate enema may  be administered under specialist supervision if disim-  paction does not occur after a sodium citrate enema; a  bowel cleansing preparation (section 1.6.5) is an alter-  native. Manual evacuation under anaesthetic may be  necessary if disimpaction does not occur after oral and  rectal treatment, or if the child is afraid.   Long-term regular use of laxatives is essential to main-  tain well-formed stools and prevent recurrence of faecal  impaction; intermittent use may provoke relapses.   For children with chronic constipation, it may be  necessary to exceed the licensed doses of some  laxatives. Parents and carers of children should be  advised to adjust the dose of laxative in order to  establish a regular pattern of bowel movements in  which stools are soft, well-formed, and passed with-  out discomfort.   Laxatives should be administered at a time that  produces an effect that is likely to fit in with the  child’s toilet routine.   Pregnancy If dietary and lifestyle changes fail to  control constipation in pregnancy, moderate doses of  poorly absorbed laxatives may be used. A bulk-forming  laxative should be tried first. An osmotic laxative, such  as lactulose, can also be used. Bisacodyl or senna may  be suitable, if a stimulant effect is necessary.    The laxatives that follow have been divided into 5  main groups (sections 1.6. 1-1. 6.5). This simple clas-  sification disguises the fact that some laxatives have  a complex action.    Bulk-forming laxatives relieve constipation by increas-  ing faecal mass which stimulates peristalsis; patients  should be advised that the full effect may take some  days to develop.    Bulk-forming laxatives are of particular value in those  with small hard stools, but should not be required unless  fibre cannot be increased in the diet. A balanced diet,  including adequate fluid intake and fibre is of value in  preventing constipation.    Bulk-forming laxatives are useful in the management of  patients with colostomy, ileostomy, haemorrhoids, anal  fissure, chronic diarrhoea associated with diverticular  disease, irritable bowel syndrome, and as adjuncts in  ulcerative colitis (section 1.5). Adequate fluid intake  must be maintained to avoid intestinal obstruction.  Unprocessed wheat bran, taken with food or fruit  juice, is a most effective bulk-forming preparation.    Finely ground bran, though more palatable, has poorer  water-retaining properties, but can be taken as bran  bread or biscuits in appropriately increased quantities.  Oat bran is also used.   Methylcellulose, ispaghula, and sterculia are useful in  patients who cannot tolerate bran. Methylcellulose also  acts as a faecal softener.   Indications see notes above  Cautions adequate fluid intake should be maintained  to avoid intestinal obstruction — it may be necessary  to supervise elderly or debilitated patients or those  with intestinal narrowing or decreased motility  Contra-indications difficulty in swallowing, intestinal  obstruction, colonic atony, faecal impaction  Side-effects flatulence, abdominal distension, gastro-  intestinal obstruction or impaction; hypersensitivity  reported  Dose   B should always be carefully swallowed with water and should  not be taken immediately before going to bed   Granules, sugar- and gluten-free, ispaghula husk  3.5g/sachet (natural or orange flavour), net price 10  sachets = £1.23, 30 sachets = £2.07. Label: 13, coun-  selling, see above   Dose ADULT and CHILD over 12 years, 1-6 sachets daily in water  in 1-3 divided doses, preferably after meals   Granules, buff, effervescent, sugar- and gluten-free,  ispaghula husk 3.5 g/sachet (low Na + ), net price 30  sachets (plain, lemon, or orange flavour) = £1.84.  Label: 13, counselling, see above   Dose 1 sachet or 2 level 5-mL spoonfuls in water twice daily  preferably after meals; CHILD (but see section 1.6) 2-12 years V 2 -I  level 5-mL spoonful in water, twice daily preferably after meals  (CHILD 2-6 years on specialist practitioner’s advice only)   Granules, brown, sugar- and gluten-free, ispaghula  husk 90%. Net price 200 g = £2.67. Label: 13, coun-  selling, see above   Dose constipation, 2 level 5-mL spoonfuls in water once or twice  daily, preferably at mealtimes; CHILD (but see section 1.6) 2-12  years, 1 level 5-mL spoonful in water once or twice daily, pre-  ferably at mealtimes   Diarrhoea (section 1.4.1), 1 level 5-mL spoonful 3 times daily  Note May be difficult to obtain   Granules, beige, effervescent, sugar- and gluten-free,  ispaghula husk 3.5 g/sachet, net price 30 sachets =  £2.10. Label: 13, counselling, see above   Dose 1 sachet in water 1-3 times daily, preferably after meals;  CHILD (but see section 1.6) 2-12 years see BNF for Children   Powder, beige, sugar- and gluten-free, ispaghula husk  3.4g/5.85-g sachet (orange or lemon/lime flavour).  Net price 30 sachets = £2.44. Label: 13, counselling,  see above   Dose 1 sachet in 150 mL water 1-3 times daily, preferably after  meals; CHILD (but see section 1.6) 2-6 years, see BNF for  Children ; 6-12 years 2.5-5 mL in water 1-3 times daily, preferably  after meals   Indications see notes above  Cautions see under Ispaghula Husk  Contra-indications see under Ispaghula Husk; also  infective bowel disease  Side-effects see under Ispaghula Husk  Dose   Counselling Preparations that swell in contact with liquid  should always be carefully swallowed with water and should  not be taken immediately before going to bed   Dose constipation and diarrhoea, 3-6 tablets twice daily; in  constipation the dose should be taken with at least 300 mL liquid;  in diarrhoea, ileostomy, and colostomy control, avoid liquid intake  for 30 minutes before and after dose; CHILD 7-12 years see BNF  for Children   Indications see notes above  Cautions see under Ispaghula Husk  Contra-indications see under Ispaghula Husk  Side-effects see under Ispaghula Husk   Counselling Preparations that swell in contact with liquid  should always be carefully swallowed with water and should  not be taken immediately before going to bed   Granules, coated, gluten-free, sterculia 62%. Net  price 500 g = £5.94; 60 x 7-g sachets = £4.99.   Dose 1-2 heaped 5-mL spoonfuls, or the contents of 1-2 sachets,   Granules, brown, coated, gluten-free, sterculia 62%,  frangula (standardised) 8%. Net price 500 g = £6.34;  60 x 7 g sachets = £5.34. Label: 25, 27, counselling,  see above   Dose constipation and after haemorrhoidectomy, 1-2 heaped 5-  mL spoonfuls or the contents of 1-2 sachets washed down with-  out chewing with plenty of liquid once or twice daily after meals;  CHILD 6-12 years see BNF for Children    Stimulant laxatives include bisacodyl, sodium picosul-  fate, and members of the anthraquinone group, senna  and dantron. The indications for dantron are limited  (see below) by its potential carcinogenicity (based on  rodent carcinogenicity studies) and evidence of geno-  toxicity. Powerful stimulants such as cascara (an anthra-  quinone) and castor oil are obsolete. Docusate sodium  probably acts both as a stimulant and as a softening  agent.    Stimulant laxatives increase intestinal motility and often  cause abdominal cramp; they should be avoided in  intestinal obstruction. Excessive use of stimulant laxa-  tives can cause diarrhoea and related effects such as  hypokalaemia; however, prolonged use may be justifi-  able in some circumstances (see section 1.6 for the use  of stimulant laxatives in children).    Glycerol suppositories act as a rectal stimulant by virtue  of the mildly irritant action of glycerol.   The parasympathomimetics bethanechol, distigmine,  neostigmine, and pyridostigmine (see section 7.4.1 and  section 10.2.1) enhance parasympathetic activity in the  gut and increase intestinal motility. They are rarely used  for their gastro-intestinal effects. Organic obstruction of  the gut must first be excluded and they should not be  used shortly after bowel anastomosis.   Indications see under Dose  Cautions see notes above  Contra-indications see notes above, acute surgical  abdominal conditions, acute inflammatory bowel  disease, severe dehydration  Pregnancy see Pregnancy, p. 67  Side-effects see notes above; nausea and vomiting;   • Constipation, by mouth, 5-10 mg at night, increased if  necessary to max. 20 mg at night; CHILD (but see  section 1.6) 4-18 years 5-20 mg once daily, adjusted  according to response   By rectum in suppositories, 10 mg in the morning;  CHILD (but see section 1.6) 2-18 years 5-10 mg once  daily, adjusted according to response   • Before radiological procedures and surgery, by mouth,  10 mg in the morning and 10 mg in the evening on the  day before procedure, and by rectum in suppositories,  10 mg 1-2 hours before procedure the following day;  CHILD 4-18 years see BNF for Children   Note tablets act in 10-12 hours; suppositories act in 20-60  minutes   Note Co-danthramer suspension 5mL = one co-danthramer  capsule, but strong co-danthramer suspension 5 mL = two  strong co-danthramer capsules    Co-danthramer (Non-proprietary) (Ml  Capsules, co-danthramer 25/200 (dantron 25 mg,  poloxamer ‘188’ 200 mg). Net price 60-cap pack =  £12.86. Label: 14, (urine red)   Dose 1-2 capsules at bedtime; CHILD 1 capsule at bedtime  (restricted indications, see notes above)   Dose ADULT and CHILD over 12 years, 1-2 capsules at bedtime  (restricted indications, see notes above)   Suspension, co-danthramer 25/200 in 5 mL (dantron  25 mg, poloxamer ‘188’ 200 mg/5 mL). Net price  300 mL = £11.27, 1 litre = £37.57. Label: 14, (urine  red)   Dose 5-10 mL at night; CHILD 2.5-5 mL (restricted indications,  see notes above)   dWith docusate sodium (as co-danthrusate)  Co-danthrusate (Non-proprietary) (Ml  Capsules, co-danthrusate 50/60 (dantron 50 mg,  docusate sodium 60 mg). Net price 63-cap pack =  £15.87. Label: 14, (urine red)   Dose 1-3 capsules at night; CHILD 6-12 years 1 capsule at night  (restricted indications, see notes above)   Tablets, e/c, bisacodyl 5 mg. Net price 100 = £3.27.  Label: 5, 25   Suppositories, bisacodyl 10 mg. Net price 12 =£1.11  Paediatric suppositories, bisacodyl 5 mg. Net price 5  = 94p   Note The brand name Dulcolax ® (JM>\ (Boehringer Ingelheim) is  used for bisacodyl tablets, net price 10-tab pack = 74p;  suppositories (10 mg), 10 = £1.57; paediatric suppositories (5 mg),  5 = 94p   The brand names Dulcolax® Pico Liquid and Dulcolax® Pico  Perles are used for sodium picosulfate preparations   Indications only for constipation in terminally ill  patients of all ages   Cautions see notes above; rodent studies indicate  potential carcinogenic risk; avoid prolonged contact  with skin (as in incontinent patients or infants wearing  nappies) — risk of irritation and excoriation  Contra-indications See notes above  Pregnancy manufacturers of co-danthramer and co-  danthrusate advise avoid — no information available  Breast-feeding manufacturers of co-danthramer and  co-danthrusate advise avoid — limited information  available    Suspension, yellow, co-danthrusate 50/60 (dantron  50 mg, docusate sodium 60 mg/5 mL). Net price  200 mL = £8.75. Label: 14, (urine red)   Dose 5-15 mL at night; CHILD 6-12 years 5mL at night  (restricted indications, see notes above)   Cautions see notes above; do not give with liquid  paraffin; rectal preparations not indicated if  haemorrhoids or anal fissure   • By mouth, chronic constipation, up to 500 mg daily in  divided doses; CHILD (but see section 1.6) 6 months-2  years 12.5 mg 3 times daily, adjusted according to  response (use paediatric solution); 2-12 years 12.5-  25 mg 3 times daily, adjusted according to response  (use paediatric oral solution)   Capsules, yellow/white, docusate sodium 100 mg,  net price 30-cap pack = £1.92, 100-cap pack = £6.40   Adult oral solution, sugar-free, docusate sodium  50 mg/5 mL, net price 300 mL = £5.49  Paediatric oral solution, sugar-free, docusate sodium  12.5 mg/5 mL, net price 300 mL = £5.29   Enema, docusate sodium 120 mg in 10-g single-dose  disposable packs. Net price 10-g unit = 57p  Dose ADULT and CHILD (but see section 1.6) over 12 years, 10-g  unit   Suppositories, gelatin 140 mg, glycerol 700 mg, pur-  ified water to lg, net price 12 =£1.27 (1 g), £1.29 (2g),  £1.48 (4 g)   Dose 1 suppository moistened with water before use, when  required. The usual sizes are for INFANT under 1 year, small (1-g  mould), CHILD 1-12 years medium (2-g mould), ADULT and CHILD  over 12 years, large (4-g mould)   Indications constipation  Cautions see notes above  Contra-indications see notes above  Pregnancy see Pregnancy, p. 67  Breast-feeding not known to be harmful  Side-effects see notes above  Dose   Tablets, total sennosides (calculated as sennoside B)  7.5 mg. Net price 60 = £1.47   Dose 2-4 tablets, usually at night; initial dose should be low then  gradually increased; CHILD (but see section 1.6) 2-6 years see  BNF for Children ; 6-18 years 1-4 tablets once daily, adjusted  according to response   Excipients include sucrose 800 mg per level 5-mL spoonful of granules  Dose ADULT and CHILD over 12 years, 1-2 level 5-mL spoonfuls  at night with at least 150 mL water, fruit juice, milk or warm drink  Counselling Preparations that swell in contact with liquid should  always be carefully swallowed with water or appropriate fluid and  should not be taken immediately before going to bed   Syrup, sugar-free, brown, total sennosides (calculated  as sennoside B) 7.5 mg/5 mL, net price 500 mL =  £2.69   Dose 10-20 mL, usually at bedtime; CHILD (but see section 1.6)  1 month-2 years see BNF for Children, 2-4 years 2.5-10 mL once   Indications constipation; bowel evacuation before  abdominal radiological and endoscopic procedures  on the colon, and surgery (section 1.6.5); acts within  6-12 hours   Breast-feeding not known to be present in milk but  manufacturer advises avoid unless potential benefit  outweighs risk   • 5-10 mg at night; CHILD (but see section 1.6) 1 month-  4 years 2.5-10 mg once daily, adjusted according to  response; 4-18 years 2.5-20 mg once daily, adjusted  according to response   Note Sodium picosulfate doses in BNF may differ from those  in product literature   Note The brand name Dulcolax® Pico Liquid (Boehringer  Ingelheim) is used for sodium picosulfate elixir 5 mg/ 5 mL   Perles® (= capsules), sodium picosulfate 2.5 mg, net  price 20-cap pack = £1.93, 50-cap pack = £2.73  Note The brand name Dulcolax ® is also used for bisacodyl tablets  and suppositories   Unstandardised preparations of cascara, frangula, rhu-  barb, and senna should be avoided as their laxative  action is unpredictable. Aloes, colocynth, and jalap  should be avoided as they have a drastic purgative  action.    Liquid paraffin, the traditional lubricant, has disadvan-  tages (see below). Bulk laxatives (section 1.6.1) and non-  ionic surfactant ‘wetting’ agents e.g. docusate sodium  (section 1.6.2) also have softening properties. Such  drugs are useful for oral administration in the manage-  ment of haemorrhoids and anal fissure; glycerol (section  1.6.2) is useful for rectal use.    Enemas containing arachis oil (ground-nut oil, peanut  oil) lubricate and soften impacted faeces and promote a  bowel movement.   Enema, arachis (peanut) oil in 130-mL single-dose  disposable packs. Net price 130 mL = £7.98  Dose to soften impacted faeces, 130 mL; the enema should be  warmed before use; CHILD (but see section 1.6) under 3 years not  recommended; over 3 years reduce adult dose in proportion to  body-weight (medical supervision only), see BNF for Children   Side-effects anal seepage of paraffin and consequent  anal irritation after prolonged use, granulomatous  reactions caused by absorption of small quantities of  liquid paraffin (especially from the emulsion), lipoid  pneumonia, and interference with the absorption of  fat-soluble vitamins  Dose   Oral emulsion, liquid paraffin 5mL, vanillin 5 mg,  chloroform 0.025 mL, benzoic acid solution 0.2 mL,  methylcellulose-20 200 mg, saccharin sodium  500 micrograms, water to 10 mL  Dose ADULT over 18 years, 10-30 mL at night when required  Counselling Should not be taken immediately before going to bed    Osmotic laxatives increase the amount of water in the  large bowel, either by drawing fluid from the body into  the bowel or by retaining the fluid they were adminis-  tered with.    Lactulose is a semi-synthetic disaccharide which is not  absorbed from the gastro-intestinal tract. It produces an  osmotic diarrhoea of low faecal pH, and discourages the  proliferation of ammonia-producing organisms. It is  therefore useful in the treatment of hepatic encephalo-  pathy.   Macrogols are inert polymers of ethylene glycol which  sequester fluid in the bowel; giving fluid with macrogols  may reduce the dehydrating effect sometimes seen with  osmotic laxatives.   Saline purgatives such as magnesium hydroxide are  commonly abused but are satisfactory for occasional  use; adequate fluid intake should be maintained.  Magnesium salts are useful where rapid bowel evacua-  tion is required. Sodium salts should be avoided as they  may give rise to sodium and water retention in suscep-  tible individuals. Phosphate enemas are useful in bowel  clearance before radiology, endoscopy, and surgery.    Side-effects nausea (can be reduced by administra-  tion with water, fruit juice or with meals), vomiting,  flatulence, cramps, and abdominal discomfort   Solution, lactulose 3. 1-3.7 g/5mL with other ketoses.  Net price 300-mL pack = £2.10, 500-mL pack = £2.59  Dose constipation, initially 1 5 mL twice daily, adjusted according  to response; CHILD (but see section 1.6) under 1 year 2.5 mL twice  daily, adjusted according to response; 1-5 years 2.5-10 mL twice  daily, adjusted according to response; 5-18 years 5-20 mL twice  daily, adjusted according to response  Hepatic encephalopathy, 30-50 mL 3 times daily, subsequently  adjusted to produce 2-3 soft stools daily; CHILD 12-18 years see  BNF for Children   Note Lactulose doses in BNF may differ from those in product  literature    Indications see preparations below  Cautions discontinue if symptoms of fluid and  electrolyte disturbance; see also preparations below  Contra-indications intestinal perforation or obstruc-  tion, paralytic ileus, severe inflammatory conditions  of the intestinal tract (such as Crohn’s disease, ulcer-  ative colitis, and toxic megacolon), see also prepara-  tions below   Pregnancy manufacturers advice use only if essen-  tial — no information available  Breast-feeding manufacturers advice use only if  essential — no information available  Side-effects abdominal distension and pain, nausea,  flatulence    Macrogol Oral Powder, Compound (Non-proprietary)  Oral powder, macrogol ‘3350’ (polyethylene glycol  ‘3350’) 13.125 g, sodium bicarbonate 178.5 mg, sod-  ium chloride 350.7 mg, potassium chloride 46.6 mg/  sachet, net price 20-sachet pack = £4.45, 30-sachet  pack = £6.68. Label: 13  Brands include Laxido ® Orange, Molaxole ®   Cautions patients with cardiovascular impairment should not  take more than 2 sachets in any 1 hour  Dose chronic constipation, ADULT and CHILD over 12 years, 1-3  sachets daily in divided doses usually for up to 2 weeks; contents  of each sachet dissolved in half a glass (approx. 125 mL) of water;  maintenance, 1-2 sachets daily   Faecal impaction, ADULT and CHILD over 12 years, 8 sachets daily  dissolved in 1 litre of water and drunk within 6 hours, usually for  max. 3 days   After reconstitution the solution should be kept in a refrigerator  and discarded if unused after 6 hours   Indications constipation (may take up to 48 hours to  act), hepatic encephalopathy (portal systemic  encephalopathy)   Oral powder, macrogol ‘3350’ (polyethylene glycol  ‘3350’) 13.125 g, sodium bicarbonate 178.5 mg, sod-  ium chloride 350.7 mg, potassium chloride 46.6 mg/  sachet, net price 20-sachet pack (lime and lemon  flavour) = £4.45, 30-sachet pack (lime- and lemon- or  chocolate- or plain-flavoured) = £6.68, 50-sachet  pack (lime- and lemon- or plain-flavoured) = £11.13.  Label: 13   Note Amount of potassium chloride varies according to flavour  of Movicol ® as follows: plain-flavour (sugar-free) = 50.2 mg/  sachet; lime and lemon flavour = 46.6 mg/sachet;    chocolate flavour = 31.7 mg/sachet. 1 sachet when reconstituted  with 125 mL water provides K + 5.4 mmol/litre  Cautions patients with cardiovascular impairment should not  take more than 2 sachets in any 1 hour  Dose chronic constipation, ADULT and CHILD over 12 years, 1-3  sachets daily in divided doses usually for up to 2 weeks; contents  of each sachet dissolved in half a glass (approx. 125 mL) of water;  maintenance, 1-2 sachets daily   Faecal impaction, ADULT and CHILD over 12 years, 8 sachets daily  dissolved in 1 litre of water and drunk within 6 hours, usually for  max. 3 days   After reconstitution the solution should be kept in a refrigerator  and discarded if unused after 6 hours   Oral powder, sugar-free, macrogol ‘3350’ (polyethy-  lene glycol ‘3350’) 6.563 g, sodium bicarbonate   89.3 mg, sodium chloride 175.4 mg, potassium chlor-  ide 23.3 mg/sachet, net price 20-sachet pack (lime  and lemon flavour) = £2.67, 30-sachet pack = £4.01.  Label: 13   6 sachets daily in divided doses usually for up to 2 weeks; content   of each sachet dissolved in quarter of a glass (approx. 60-65 mL)   Faecal impaction, ADULT and CHILD over 12 years, 16 sachets daily   dissolved in 1 litre of water and drunk within 6 hours, usually for   After reconstitution the solution should be kept in a refrigerator  and discarded if unused after 6 hours    Movicol® Paediatric Plain (Norgine) (Ml  Oral powder, sugar-free, macrogol ‘3350’ (polyethy-  lene glycol ‘3350’) 6.563 g, sodium bicarbonate   89.3 mg, sodium chloride 175.4 mg, potassium chlor-  ide 25.1 mg/sachet, net price 30-sachet pack = £4.45.  Label: 13   Cautions with high doses, impaired gag reflex, reflux oeso-  phagitis, impaired consciousness   Contra-indications cardiovascular impairment; renal impairment  Dose chronic constipation and prevention of faecal impaction,  CHILD under 2 years see BNF for Children, 2-6 years 1 sachet  daily, adjusted according to response (max. 4 sachets daily); 6-12  years 2 sachets daily, adjusted according to response (max. 4  sachets daily)   Faecal impaction, CHILD under 5 years see BNF for Children, 5-12  years 4 sachets on first day then increased in steps of 2 sachets  daily to 12 sachets daily (taken in divided doses over 12 hours  each day until impaction resolves); content of each sachet dis-  solved in quarter of a glass (approx. 60-65 mL) of water  After reconstitution the solution should be kept in a refrigerator  and discarded if unused after 24 hours   interactions: Appendix 1 (antacids)  Contra-indications acute gastro-intestinal conditions  Hepatic impairment avoid in hepatic coma if risk of  renal failure   Aqueous suspension containing about 8% hydrated  magnesium oxide. Do not store in cold place  Dose constipation, 30-45 mL with water at bedtime when  required; CHILD 3-12 years, 5-10 mL with water at bedtime when  required   Oral emulsion, 25% liquid paraffin in aqueous sus-  pension containing 6% hydrated magnesium oxide  Dose constipation, 5-20 mL when required  Note Liquid paraffin and magnesium hydroxide preparations on  sale to the public include: Milpar® CSiH   Dose rapid bowel evacuation (acts in 2-4 hours) 5-10 g in a glass  of water preferably before breakfast   Note Magnesium sulphate is on sale to the public as Epsom Salts   Indications rectal use in constipation; bowel evacua-  tion before abdominal radiological procedures, endo-  scopy, and surgery   Cautions elderly and debilitated; with enema,  electrolyte disturbances, congestive heart failure,  ascites, uncontrolled hypertension, maintain adequate  hydration   Contra-indications acute gastro-intestinal conditions  (including gastro-intestinal obstruction, inflammatory  bowel disease, and conditions associated with  increased colonic absorption)   Enema, sodium acid phosphate 21.4 g, sodium phos-  phate 9.4g/118mL, net price 133-mL pack (delivers  118mL dose) with standard tube = 57p  Dose ADULT and CHILD (but see section 1.6) over 12 years,   Enema, sodium dihydrogen phosphate dihydrate  12.8 g, disodium phosphate dodecahydrate 10.24 g,  purified water, freshly boiled and cooled, to 128 mL.  Net price 128 mL with standard tube = £2.98, with  long rectal tube = £3.98   Enema, sodium citrate 450 mg, sodium lauryl sul-  phoacetate 45 mg, glycerol 625 mg, together with  potassium sorbate and sorbitol in a viscous solution,   Dose ADULT and CHILD over 3 years, 5-10 mL (but see section  1.6)   Enema, sodium citrate 450 mg, sodium alkylsul-  phoacetate 45 mg, sorbic acid 5 mg, together with  glycerol and sorbitol in a viscous solution in 5-mL  single-dose disposable packs with nozzle. Net price  5 mL = 41p   Enema, sodium citrate 450 mg, sodium lauryl sul-  phate 75 mg, sorbic acid 5 mg, together with glycerol  and sorbitol in a viscous solution in 5-mL single-dose  disposable packs with nozzle. Net price 5mL = 32p  Dose ADULT and CHILD (but see section 1.6) 5 mL (insert only half  nozzle length in child under 3 years)   Bowel cleansing preparations are used before colonic  surgery, colonoscopy, or radiological examination to  ensure the bowel is free of solid contents. They are  not treatments for constipation.   Cautions Renal function should be measured before  starting treatment. Bowel cleansing preparations should  be used with caution in patients with fluid and electro-  lyte disturbances. Hypovolaemia should be corrected  before administration of bowel cleansing preparations.  Adequate hydration should be maintained during treat-  ment. Bowel cleansing preparations should be used with  caution in colitis (avoid if acute severe colitis), in chil-  dren, in the elderly, or in those who are debilitated. They  should also be used with caution in patients with an  impaired gag reflex, reduced levels of consciousness, or  possibility of regurgitation or aspiration. Other oral  drugs should not be taken one hour before or after  administration of bowel cleansing preparations because  absorption may be impaired.   Contra-indications Bowel cleansing preparations are  contra-indicated in patients with gastro-intestinal  obstruction or perforation, gastric retention, acute  severe colitis, or toxic megacolon.   Side-effects Side-effects of bowel cleansing prepara-  tions include nausea, vomiting, abdominal pain (usually  transient — reduced by taking more slowly), and abdo-  minal distention. Less frequent side-effects include  headache, dizziness, dehydration, and electrolyte distur-  bances.   Indications see notes above  Cautions see notes above; also heart failure; acute  inflammatory bowel disease  Contra-indications see notes above  Pregnancy manufacturers advise use only if essen-  tial — no information available  Breast-feeding manufacturers advise use only if  essential — no information available  Side-effects see notes above; also fatigue, sleep dis-  turbances, and anal discomfort   Oral powder, sugar-free, macrogol ‘3350’ (polyethy-  lene glycol ‘3350’) 59 g, anhydrous sodium sulphate  5.685 g, sodium bicarbonate 1.685 g, sodium chloride  1.465 g, potassium chloride 743 mg/sachet, net price  4 sachets = £8.23. Label: 10, patient information  leaflet, 13, counselling   Electrolytes 1 sachet when reconstituted with 1 litre of water provides  Na + 125 mmol, K + 10 mmol, Cl" 35 mmol, HC0 3 " 20 mmol  Dose bowel evacuation before surgery, colonoscopy, or radi-  ological examination, a glass (approx. 250 mL) of reconstituted  solution every 10-15 minutes, or by nasogastric tube 20-30 mL/  minute, starting on the day before procedure until 4 litres have  been consumed; alternatively, administration may be divided into  two (2 litres of reconstituted solution taken on the evening before  procedure and 2 litres of reconstituted solution taken on the  morning of procedure). Treatment can be stopped if bowel  motions become watery and clear. To facilitate gastric emptying,  domperidone or metoclopramide may be given 30 minutes before  starting; CHILD 12-18 years see BNF for Children  Counselling 1 sachet should be reconstituted with 1 litre of water.  Flavouring such as clear fruit cordials may be added if required.  Solid food should not be taken for at least 2 hours before starting  treatment. After reconstitution the solution should be kept in a  refrigerator and discarded if unused after 24 hours   Oral powder, lemon- or orange-flavoured, Sachet A  (containing macrogol ‘3350’ (polyethylene glycol  ‘3350’) 100 g, anhydrous sodium sulphate 7.5 g, sod-  ium chloride 2.691 g, potassium chloride 1.015 g) and  Sachet B (containing ascorbic acid 4.7 g, sodium  ascorbate 5.9 g), net price 4-sachet pack (2 each of  sachet A and B) = £9.87. Label: 10, patient informa-  tion leaflet, 13, counselling, see below   Electrolytes 1 pair of sachets (A+B) when reconstituted with 1 litre of  water provides Na + 181.6 mmol (Na + 56.2 mmol absorbable), K +   Dose bowel evacuation for surgery, colonoscopy or radiological  examination, ADULT over 18 years, 2 litres of reconstituted solu-  tion on the evening before procedure or 1 litre of reconstituted  solution on the evening before procedure and 1 litre of reconsti-  tuted solution early on the morning of procedure; treatment  should be completed at least 1 hour before colonoscopy  Counselling One pair of sachets (A and B) should be reconstituted  in 1 litre of water and taken over 1-2 hours. Solid food should not  be taken during treatment until procedure completed. 1 litre of  other clear fluid should also be taken during treatment. Treatment  can be stopped if bowel motions become watery and clear   Reconstitution of a sachet containing 1 1.57 g magnesium  carbonate and 17.79 g anhydrous citric acid produces a solu-  tion containing magnesium citrate   Oral powder, sugar-free, effervescent, magnesium  carbonate 1 1.57 g, anhydrous citric acid 17.79 g/  sachet, net price 10-sachet pack (lemon and lime  flavour) = £17.20. Label: 10, patient information  leaflet, 13, counselling, see below   Dose bowel evacuation for surgery, colonoscopy or radiological  examination, on day before procedure, 1 sachet at 8 a.m. and 1  sachet between 2 and 4 p.m.; CHILD 5-10 years one-third adult  dose; over 10 years and frail ELDERLY one-half adult dose  Counselling One sachet should be reconstituted with 200 mL of  hot water; the solution should be allowed to cool for approx. 30  minutes before drinking. Low residue or fluid only diet (e.g. water,  fruit squash, clear soup, black tea or coffee) recommended before  procedure (according to prescriber’s advice) and copious intake of  clear fluids recommended until procedure   Cautions see notes above; also cardiac disease (avoid  in congestive cardiac failure)   Renal impairment avoid if eGFR less than 60 mL/  minute/ 1.73 m 2  Pregnancy caution  Breast-feeding caution   Side-effects see notes above; also chest pain, arrhy-  thmias, asthenia, and renal failure   Tablets, monobasic sodium phosphate monohydrate  1.102 g, disodium phosphate 398 mg, net price 32-tab  pack = £8.50. Label: 10, patient information leaflet,  counselling, see below   Electrolytes Na + 13.6 mmol, Mg 2+ 0.34 mmol, phosphate 10.8 mmol/  tablet   Dose bowel evacuation before diagnostic procedure, ADULT over  18 years, 4 tablets every 15 minutes until a total of 20 tablets have  been consumed on the evening before procedure, then on the next  day (starting 3-5 hours before procedure) 4 tablets every 15  minutes until a total of 12 tablets have been consumed; do not  repeat course within 7 days   Counselling On the day before procedure, a light, low-fibre  breakfast may be consumed in the morning, clear liquid diet  recommended after 12 noon. Each dose of 4 tablets to be taken  with 250 mL clear liquid. Copious intake of water or other clear  liquids recommended during treatment   Oral solution, sugar-free, sodium dihydrogen phos-  phate dihydrate 24.4 g, disodium phosphate dodeca-  hydrate 10.8g/45mL. Net price 2 x 45-mL bottles =  £4.79. Label: 10, patient information leaflet, counsel-  ling   Electrolytes Na + 217 mmol, phosphate 186 mmol/45 mL  Dose bowel evacuation before colonic surgery, colonoscopy or  radiological examination, ADULT over 18 years, 45 mL diluted with  half a glass (120 mL) of cold water, followed by one full glass  (240 mL) of cold water   Timing of doses is dependent on the time of the procedure   For morning procedure, first dose should be taken at 7 a.m. and   For afternoon procedure, first dose should be taken at 7 p.m. on   day before and second dose at 7 a.m. on day of the procedure   Counselling Intake of solid food should be stopped for at least 6   Copious intake of water or other clear fluids (e.g. clear soup,    strained fruit juice without pulp, black tea or coffee) recom-  mended until midnight before morning procedure and until 8 a.m.  before afternoon procedure. At least one glass (approx 240 mL) of  water or other clear fluid should also be taken immediately before  each dose   Cautions see notes above; also recent gastro-intestinal  surgery; cardiac disease (avoid in congestive cardiac  failure)   Contra-indications see notes above; also gastro-  intestinal ulceration; ascites; congestive cardiac fail-  ure   Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2 — risk of hypermagnesaemia  Pregnancy caution  Breast-feeding caution   Side-effects see notes above; also anal discomfort,  sleep disturbances, fatigue, and rash   Oral powder, sodium picosulfate 10 mg/sachet, with  magnesium citrate, net price 2-sachet pack (lemon-  flavoured) = £3.25. Label: 10, patient information  leaflet, 13, counselling, see below   endoscopy, or surgery, ADULT over 18 years, 1 sachet before 8 a.m.   Counselling One sachet should be reconstituted with 150 mL  (approx, half a glass) of cold water; patients should be warned  that heat is generated during reconstitution and that the solution  should be allowed to cool before drinking. Low residue diet  recommended on the day before procedure and copious intake of  water or other clear fluids recommended during treatment   Oral powder, sugar-free, sodium picosulfate 10 mg/  sachet, with magnesium citrate, net price 20-sachet  pack = £33.90. Label: 10, patient information leaflet,  13, counselling, see below   Electrolytes K + 5 mmol, Mg 2+ 87 mmol/sachet  Dose bowel evacuation on day before radiological procedure,  endoscopy, or surgery, ADULT and CHILD over 9 years, 1 sachet  before 8 a.m. then 1 sachet 6-8 hours later; CHILD 1-2 years,  quarter sachet before 8 a.m. then quarter sachet 6-8 hours later;  2-4 years, half sachet before 8 a.m. then half sachet 6-8 hours  later; 4-9 years, 1 sachet before 8 a.m. then half sachet 6-8 hours  later   Counselling One sachet should be reconstituted with 150 mL  (approx, half a glass) of cold water; patients should be warned  that heat is generated during reconstitution and that the solution  should be allowed to cool before drinking. Low residue diet  recommended on the day before procedure and copious intake of  water or other clear fluids recommended during treatment   Methylnaltrexone is a peripherally acting opioid-recep-  tor antagonist that is licensed for the treatment of  opioid-induced constipation in patients receiving pallia-  tive care, when response to other laxatives is inade-    quate; it should be used as an adjunct to existing  laxative therapy. Methylnaltrexone does not alter the  central analgesic effect of opioids. For the prevention of  opioid-induced constipation in palliative care, see p. 22.   Indications opioid-induced constipation in terminally  ill patients, when response to other laxatives is  inadequate   Cautions diverticular disease; faecal impaction;  patients with colostomy or peritoneal catheter   Renal impairment if eGFR less than 30mL/minute/  1.73 m 2 , reduce dose as follows: body-weight under  62 kg, 75 micrograms /kg on alternate days; body-  weight 62-1 14 kg, 8 mg on alternate days; body-  weight over 114 kg, 75 micrograms/kg on alternate  days   Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — present in milk in  animal studies   Side-effects abdominal pain, nausea, diarrhoea,  flatulence; dizziness; injection site reactions, hyper-  hidrosis; also reported gastro-intestinal perforation   • By subcutaneous injection, ADULT over 18 years, body-  weight under 38 kg, 150 micrograms/kg on alternate  days; body-weight 38-62 kg, 8 mg on alternate days;  body-weight 62-1 14 kg, 12 mg on alternate days;  body-weight over 114 kg, 150 micrograms/kg on  alternate days; may be given less frequently depend-  ing on response; 2 consecutive doses may be given 24  hours apart if no response to treatment on the pre-  ceding day; rotate sites of injection; max. duration of  treatment 4 months   Injection, methylnaltrexone bromide 20mg/mL, net  price 0.6-mL vial = £21.05, 7-vial pack (with syringes  and needles) = £147.35    Prucalopride is a selective serotonin 5HT 4 -receptor  agonist with prokinetic properties. It is licensed for the  treatment of chronic constipation in women, when other  laxatives have failed to provide an adequate response.  Headache and gastro-intestinal symptoms (including  abdominal pain, nausea, and diarrhoea) are the most  frequent side-effects. The side-effects generally occur at  the start of treatment and are usually transient.   Indications chronic constipation in women when  other laxatives fail to provide an adequate response  Cautions history of arrhythmias or ischaemic heart  disease; concomitant use with drugs that prolong QT  interval; severe, unstable chronic illness    Contra-indications intestinal perforation or obstruc-  tion; severe inflammatory conditions of the intestinal  tract (such as Crohn’s disease, ulcerative colitis, and  toxic megacolon)   Renal impairment max. 1 mg daily if eGFR less than  30 mL/minute/ 1.73 m 2   Side-effects nausea, vomiting, abdominal pain, dys-  pepsia, flatulence, diarrhoea, rectal bleeding; head-  ache, dizziness, fatigue; polyuria; less commonly  anorexia, palpitation, tremor, and fever   • ADULT over 18 years, 2 mg once daily; ELDERLY over 65  years, initially 1 mg once daily, increased if necessary  to 2 mg once daily   Tablets, f/c, prucalopride (as succinate) 1 mg (white),  net price 28-tab pack = £38.69; 2 mg (pink), 28-tab  pack = £59.52   Soothing haemorrhoidal preparations  Compound haemorrhoidal  preparations with corticosteroids  Rectal sclerosants  Management of anal fissures   Anal and perianal pruritus, soreness, and excoriation are  best treated by application of bland ointments and  suppositories (section 1.7.1). These conditions occur  commonly in patients suffering from haemorrhoids,  fistulas, and proctitis. Cleansing with attention to any  minor faecal soiling, adjustment of the diet to avoid hard  stools, the use of bulk-forming materials such as bran  (section 1.6.1) and a high residue diet are helpful. In  proctitis these measures may supplement treatment  with corticosteroids or sulfasalazine (see section 1.5).   When necessary, topical preparations containing local  anaesthetics (section 1.7.1) or corticosteroids (section  1.7.2) are used, provided perianal thrush has been  excluded. Perianal thrush is treated with a topical anti-  fungal preparation (section 13.10.2).   Soothing preparations containing mild astringents such  as bismuth subgallate, zinc oxide, and hamamelis may  give symptomatic relief in haemorrhoids. Many proprie-  tary preparations also contain lubricants, vaso-  constrictors, or mild antiseptics.   Local anaesthetics are used to relieve pain associated  with haemorrhoids and pruritus ani but good evidence    is lacking. Lidocaine ointment (section 15.2) is used  before emptying the bowel to relieve pain associated  with anal fissure. Alternative local anaesthetics include  tetracaine, cinchocaine (dibucaine), and pramocaine  (pramoxine), but they are more irritant. Local anaes-  thetic ointments can be absorbed through the rectal  mucosa therefore excessive application should be  avoided, particularly in infants and children. Prepara-  tions containing local anaesthetics should be used for  short periods only (no longer than a few days) since they  may cause sensitisation of the anal skin.   Corticosteroids are often combined with local anaes-  thetics and soothing agents in preparations for haemorr-  hoids. They are suitable for occasional short-term use   prolonged use can cause atrophy of the anal skin. See  section 13.4 for general comments on topical corticos-  teroids and section 1.7.1 for comment on local anaes-  thetics.   Children Haemorrhoids in children are rare. Treat-  ment is usually symptomatic and the use of a locally  applied cream is appropriate for short periods; however,  local anaesthetics can cause stinging initially and this  may aggravate the child’s fear of defaecation.   Cream, benzyl benzoate 1.2%, bismuth oxide 0.875%,  hydrocortisone acetate 0.5%, Peru balsam 1.85%,  pramocaine hydrochloride 1%, zinc oxide 12.35%. Net  price 30 g (with rectal nozzle) = £3.71  Dose apply night and morning and after a bowel movement; do  not use for longer than 7 days; CHILD not recommended   Suppositories, buff, benzyl benzoate 33 mg, bismuth  oxide 24 mg, bismuth subgallate 59 mg, hydrocorti-  sone acetate 5 mg, Peru balsam 49 mg, pramocaine  hydrochloride 27 mg, zinc oxide 296 mg, net price 12  = £2.69   Dose insert 1 suppository night and morning and after a bowel  movement; do not use for longer than 7 days; CHILD not recom-  mended   Anusol-HC® (McNeil) (Ml  Ointment, benzyl benzoate 1.25%, bismuth oxide  0.875%, bismuth subgallate 2.25%, hydrocortisone  acetate 0.25%, Peru balsam 1.875%, zinc oxide  10.75%. Net price 30 g (with rectal nozzle) = £3.29  Dose apply night and morning and after a bowel movement; do  not use for longer than 7 days; CHILD not recommended  Note A proprietary brand (Anusol Plus HC ® ointment) is on sale  to the public   Suppositories, benzyl benzoate 33 mg, bismuth oxide  24 mg, bismuth subgallate 59 mg, hydrocortisone  acetate 10 mg, Peru balsam 49 mg, zinc oxide 296 mg.  Net price 12 = £2.31   Dose insert 1 suppository night and morning and after a bowel  movement; do not use for longer than 7 days; CHILD not recom-  mended   Note A proprietary brand [Anusol Plus HC® suppositories) is on  sale to the public   Spray application, hydrocortisone 0.2%, lidocaine  hydrochloride 1%. Net price 30-mL pack = £6.11  Dose ADULT and CHILD over 14 years, spray once over the  affected area up to 3 times daily; do not use for longer than 7 days  without medical advice; CHILD under 14 years on medical advice  only    Proctofoam HC® (Meda) (Ml  Foam in aerosol pack, hydrocortisone acetate 1%,  pramocaine hydrochloride 1%. Net price 21.2-g pack  (approx. 40 applications) with applicator = £5.06  Dose haemorrhoids and proctitis, 1 applicatorful (4-6 mg  hydrocortisone acetate, 4-6 mg pramocaine hydrochloride) by  rectum 2-3 times daily and after each bowel movement (max. 4  times daily); do not use for longer than 7 days; CHILD not  recommended   Ointment, cinchocaine (dibucaine) hydrochloride  0.5%, hydrocortisone 0.5%. Net price 30 g = £10.34  (with cannula)   Dose apply morning and night and after a bowel movement,  externally or by rectum; do not use for longer than 7 days   Suppositories, cinchocaine (dibucaine) hydro-  chloride 5 mg, hydrocortisone 5 mg. Net price 12 =  £4.66   Dose insert 1 suppository night and morning and after a bowel  movement; do not use for longer than 7 days    Scheriproct® (Bayer Schering) (Ml  Ointment, cinchocaine (dibucaine) hydrochloride  0.5%, prednisolone hexanoate 0.19%. Net price 30 g =  £2.94   Dose apply twice daily for 5-7 days (3-4 times daily on 1st day if  necessary), then once daily for a few days after symptoms have  cleared   Suppositories, cinchocaine (dibucaine) hydro-  chloride lmg, prednisolone hexanoate 1.3 mg. Net  price 12 = £1.38   Dose insert 1 suppository daily after a bowel movement, for 5-7  days (in severe cases initially 2-3 times daily)    Ultraproct® (Meadow) (Ml  Ointment, cinchocaine (dibucaine) hydrochloride  0.5%, fluocortolone caproate 0.095%, fluocortolone  pivalate 0.092%, net price 30 g (with rectal nozzle) =  £4.57   Dose apply twice daily for 5-7 days (3-4 times daily on 1st day if  necessary), then once daily for a few days after symptoms have  cleared   Suppositories, cinchocaine (dibucaine) hydro-  chloride 1 mg, fluocortolone caproate 630 micr-  ograms, fluocortolone pivalate 610 micrograms, net  price 12 = £2.15   Dose insert 1 suppository daily after a bowel movement, for 5-7  days (in severe cases initially 2-3 times daily) then 1 suppository  every other day for 1 week    Uniroid-HC® (Chemidex) (Mi  Ointment, cinchocaine (dibucaine) hydrochloride  0.5%, hydrocortisone 0.5%. Net price 30 g (with  applicator) = £4.23   Dose ADULT and CHILD over 12 years, apply twice daily and after  a bowel movement, externally or by rectum; do not use for longer  than 7 days; CHILD under 12 years on medical advice only   Suppositories, cinchocaine (dibucaine) hydro-  chloride 5 mg, hydrocortisone 5 mg. Net price 12 =  £1.91   Dose ADULT and CHILD over 12 years, insert 1 suppository twice  daily and after a bowel movement; do not use for longer than 7  days    Xyloproct® (AstraZeneca) (Ml  Ointment (water-miscible), aluminium acetate 3.5%,  hydrocortisone acetate 0.275%, lidocaine 5%, zinc  oxide 18%, net price 20 g (with applicator) = £2.26  Dose apply several times daily; short-term use only    Oily phenol injection is used to inject haemorrhoids  particularly when unprolapsed.    Prescribing for patients with stoma calls for special care.  The following is a brief account of some of the main  points to be borne in mind.   Enteric-coated and modified-release preparations are  unsuitable, particularly in patients with an ileostomy,  as there may not be sufficient release of the active  ingredient.   Dose 2-3 mL into the submucosal layer at the base of the pile;  several injections may be given at different sites, max. total  injected 10 mL at any one time   The management of anal fissures requires stool soft-  ening by increasing dietary fibre in the form of bran or  by using a bulk-forming laxative. Short-term use of local  anaesthetic preparations may help (section 1.7.1). If  these measures are inadequate, the patient should be  referred for specialist treatment in hospital. The use of a  topical nitrate (e.g. glyceryl trinitrate 0.4% ointment)  may be considered. Before considering surgery, topical  diltiazem 2% may be used twice daily [unlicensed indi-  cation] in patients with chronic anal fissures unrespon-  sive to topical nitrates.   The Scottish Medicines Consortium (p. 4) has advised  (January 2008) that glyceryl trinitrate 0.4% ointment  ( Recto gesic ®) is not recommended for use within NHS  Scotland for the relief of pain associated with chronic  anal fissure.   Laxatives Enemas and washouts should not be pre-  scribed for patients with an ileostomy as they may cause  rapid and severe loss of water and electrolytes.   Colostomy patients may suffer from constipation and  whenever possible should be treated by increasing fluid  intake or dietary fibre. Bulk-forming drugs (section  1.6.1) should be tried. If they are insufficient, as small  a dose as possible of senna (section 1.6.2) should be  used.   Antidiarrhoeals Drugs such as loperamide, codeine  phosphate, or co-phenotrope (diphenoxylate with  atropine) are effective. Bulk-forming drugs (section 0  1.6.1) may be tried but it is often difficult to adjust the  dose appropriately.   Antibacterials should not be given for an episode of  acute diarrhoea.   Antacids The tendency to diarrhoea from magnesium  salts or constipation from aluminium salts may be  increased in these patients.   Diuretics Diuretics should be used with caution in  patients with an ileostomy as they may become exces-  sively dehydrated and potassium depletion may easily  occur. It is usually advisable to use a potassium-spar-  ing diuretic (see section 2.2.3).   Digoxin Patients with a stoma are particularly suscep-  tible to hypokalaemia if on digoxin therapy and potas-  sium supplements or a potassium-sparing diuretic may  be advisable (for comment see section 9.2. 1.1).   Indications anal fissure; angina, left ventricular failure  (section 2.6.1); extravasation (section 10.3)   Excipients include lanolin, propylene glycol  Dose ADULT over 18 years, apply 2.5 cm of ointment to anal canal  every 12 hours until pain stops; max. duration of use 8 weeks  Note 2.5 cm of ointment contains glyceryl trinitrate 1.5 mg; dis-  card tube 8 weeks after first opening    Potassium supplements Liquid formulations are  preferred to modified-release formulations (see above).   Analgesics Opioid analgesics (see section 4.7.2) may  cause troublesome constipation in colostomy patients.  When a non-opioid analgesic is required paracetamol is  usually suitable but anti-inflammatory analgesics may  cause gastric irritation and bleeding.   Iron preparations Iron preparations may cause loose  stools and sore skin in these patients. If this is trouble-  some and if iron is definitely indicated an intramuscular  iron preparation (see section 9. 1.1.2) should be used.  Modified-release preparations should be avoided for  the reasons given above.   Care of stoma Patients are usually given advice about  the use of cleansing agents, protective creams, lotions,  deodorants, or sealants whilst in hospital, either by the  surgeon or by stoma care nurses. Voluntary organisa-  tions offer help and support to patients with stoma.   The use of laparoscopic cholecystectomy and of endo-  scopic biliary techniques has limited the place of the bile  acid ursodeoxycholic acid in gallstone disease. Urso-  deoxycholic acid is suitable for patients with unimpaired  gall bladder function, small or medium-sized radiolu-  cent stones, and whose mild symptoms are not amen-  able to other treatment; it should be used cautiously in   B those with liver disease (but see below). Patients should  be given dietary advice (including avoidance of exces-  sive cholesterol and calories) and they require radiolo-  gical monitoring. Long-term prophylaxis may be needed  after complete dissolution of the gallstones has been  confirmed because they may recur in up to 25% of  patients within one year of stopping treatment.   Ursodeoxycholic acid is also used in primary biliary  cirrhosis; liver tests improve in most patients but the  effect on overall survival is uncertain.   Capsules, ursodeoxycholic acid 250 mg, net price 60-  cap pack = £30.17, 100-cap pack = £31.88. Label: 21  Suspension, sugar-free, ursodeoxycholic acid  250 mg/5 mL, net price 250 mL = £26.98. Label: 21  Dose primary biliary cirrhosis, 10-15 mg/kg daily as a single  daily dose or in 2-4 divided doses  Dissolution of gallstones, see Dose, above   Tablets, scored, ursodeoxycholic acid 150 mg, net  price 60-tab pack = £17.05. Label: 21  Capsules, ursodeoxycholic acid 250 mg, net price 60-  cap pack = £30.50. Label: 21   A terpene mixture ( Rowachol ®) raises biliary choles-  terol solubility. It is not considered to be a useful  adjunct.   Rowachol® (Rowa) (m\ CM  Capsules, green, e/c, bomeol 5 mg, camphene 5 mg,  cineole 2 mg, menthol 32 mg, menthone 6 mg, pinene  17 mg in olive oil. Net price 50-cap pack = £7.35.  Label: 22   Dose 1-2 capsules 3 times daily before food (but see notes  above)   Contra-indications radio-opaque stones, non-func-  tioning gall bladder, inflammatory diseases and other  conditions of the small intestine, colon and liver which  interfere with entero-hepatic circulation of bile salts   Hepatic impairment avoid in chronic liver disease  (but used in primary biliary cirrhosis)   Breast-feeding not known to be harmful but manu-  facturer advises avoid   • Dissolution of gallstones, 8-12 mg/kg daily as a single  dose at bedtime or in two divided doses, for up to 2  years; treatment is continued for 3-4 months after  stones dissolve   Ursodeoxycholic Acid (Non-proprietary) (Ml  Tablets, ursodeoxycholic acid 150 mg, net price 60-  tab pack = £20.48. Label: 21  Capsules, ursodeoxycholic acid 250 mg, net price 60-  cap pack = £38.86. Label: 21    Colestyramine is an anion-exchange resin that is not  absorbed from the gastro-intestinal tract. It relieves  diarrhoea and pruritus by forming an insoluble complex  with bile acids in the intestine. Colestyramine can inter-  fere with the absorption of a number of drugs. Colestyr-  amine is also used in hypercholesterolaemia (section  2 . 12 ).   Indications pruritus associated with partial biliary  obstruction and primary biliary cirrhosis; diarrhoea  associated with Crohn’s disease, ileal resection,  vagotomy, diabetic vagal neuropathy, and radiation;  hypercholesterolaemia (section 2.12)   Cautions section 2.12  Contra-indications section 2.12  Pregnancy section 2.12  Breast-feeding section 2.12  Side-effects section 2.12  Dose   • Pruritus, 4-8 g daily in a suitable liquid; CHILD 1-18  years see BNF for Children   • Diarrhoea, initially 4 g daily increased by 4 g at weekly  intervals to 12-24 g daily in a suitable liquid in 1-4    divided doses, then adjusted as required; max. 36 g  daily; CHILD 1-18 years see BNF for Children  Counselling Other drugs should be taken at least 1 hour  before or 4-6 hours after colestyramine to reduce possible  interference with absorption   Note The contents of each sachet should be mixed with at  least 150 mL of water or other suitable liquid such as fruit  juice, skimmed milk, thin soups, and pulpy fruits with a high  moisture content    Aprotinin is no longer used for the treatment of acute  pancreatitis.    Supplements of pancreatin are given by mouth to com-  pensate for reduced or absent exocrine secretion in  cystic fibrosis, and following pancreatectomy, gastrec-  tomy, or chronic pancreatitis. They assist the digestion  of starch, fat, and protein. Pancreatin may also be  necessary if a tumour (e.g. pancreatic cancer) obstructs  outflow from the pancreas.    Pancreatin is inactivated by gastric acid therefore pan-  creatin preparations are best taken with food (or imme-  diately before or after food). Gastric acid secretion may  be reduced by giving cimetidine or ranitidine an hour  beforehand (section 1.3). Concurrent use of antacids  also reduces gastric acidity. Enteric-coated preparations  deliver a higher enzyme concentration in the duodenum  (provided the capsule contents are swallowed whole  without chewing). Higher-strength preparations are  also available (important: see CSM advice below).    Since pancreatin is also inactivated by heat, excessive  heat should be avoided if preparations are mixed with  liquids or food; the resulting mixtures should not be kept  for more than one hour.    Dosage is adjusted according to size, number, and  consistency of stools, so that the patient thrives; extra  allowance will be needed if snacks are taken between  meals.    Pancreatin can irritate the perioral skin and buccal  mucosa if retained in the mouth, and excessive doses  can cause perianal irritation. The most frequent side-  effects are gastro-intestinal, including nausea, vomiting,  and abdominal discomfort; hyperuricaemia and hyper-  uricosuria have been associated with very high doses.  Hypersensitivity reactions occur occasionally and may  affect those handling the powder.   Capsules, brown/clear, enclosing buff-coloured e/c  granules of pancreatin (pork), providing: protease  600 units, lipase 10 000 units, amylase 8000 units. Net  price 100-cap pack = £12.93. Counselling, see dose  Dose ADULT and CHILD initially 1-2 capsules with each meal  either taken whole or contents mixed with fluid or soft food (then  swallowed immediately without chewing)   Gastro-resistant granules, brown, pancreatin (pork),  providing: protease 200 units, lipase 5000 units, amy-  lase 3600 units per 100 mg, net price 20 g = £31.50  Counselling, see dose   Capsules, red/yellow, enclosing e/c minitablets of  pancreatin (pork), providing minimum of: protease  500 units, lipase 10 000 units, amylase 9000 units. Net  price 100 = £14.47. Counselling, see dose  Dose ADULT and CHILD 1-2 capsules with meals and 1 capsule  with snacks, swallowed whole or contents taken with water or  mixed with soft food (then swallowed immediately without  chewing); higher doses may be required according to response   Granules, pancreatin (pork), providing minimum of:  protease 300 units, lipase 5000 units, amylase  4000units/g. Net price 300 g = £20.39. Label: 25,  counselling, see dose   Dose ADULT and CHILD 5-10 g just before meals washed down or  mixed with a little milk or water   Dose ADULT and CHILD over 1 year 2-6 capsules with each meal,  swallowed whole or sprinkled on food; INFANT up to 1 year  contents of 1-2 capsules mixed with feeds   Dose NEONATE contents of 1-2 capsules mixed with feeds  Tablets, e/c, pancreatin (pork), providing minimum  of: protease 110 units, lipase 1900 units, amylase  1700 units. Net price 300-tab pack = £4.51. Label: 5,  25, counselling, see dose  Dose ADULT and CHILD 5-15 tablets before each meal  Tablets forte, e/c, pancreatin (pork), providing mini-  mum of: protease 330 units, lipase 5600 units, amylase  5000 units. Net price 300-tab pack = £13.74. Label: 5,  25, counselling, see dose  Dose ADULT and CHILD 6-10 tablets before each meal  Powder, pancreatin (pork), providing minimum of:  protease 1400 units, lipase 25 000 units, amylase  30 OOOunits/g. Net price 300 g = £24.28. Counselling,  see dose   Dose ADULT and CHILD over 1 month, 0.5-2 g before each meal,  washed down or mixed with liquid; NEONATE 250-500 mg with  each feed    ^ Higher-strength preparations  The high-strength pancreatin preparations Nutrizym  22® and Pancreatin HL® have been associated with  the development of large bowel strictures (fibrosing  colonopathy) in children with cystic fibrosis aged  between 2 and 13 years. No association was found  with Creon® 25 000 and Creon® 40 000. The follow-  ing is recommended:   • Pancrease HL® and Nutrizym 22® should not be  used in children aged 15 years or less with cystic  fibrosis;   • the total dose of pancreatic enzyme supplements  used in patients with cystic fibrosis should not  usually exceed 10 000 units of lipase per kg body-  weight daily;   • if a patient on any pancreatin preparation develops  new abdominal symptoms (or any change in exist-  ing abdominal symptoms) the patient should be  reviewed to exclude the possibility of colonic  damage.   Possible risk factors are gender (boys at greater risk  than girls), more severe cystic fibrosis, and concomi-  tant use of laxatives. The peak age for developing   Counselling It is important to ensure adequate hydration at all  times in patients receiving higher-strength pancreatin pre-  parations.   Creon® 25 000 (Solvay) (Ml  Capsules, orange/clear, enclosing brown-coloured  e/c pellets of pancreatin (pork), providing: protease  (total) 1000 units, lipase 25 000 units, amylase  18 000 units, net price 100-cap pack = £28.25. Coun-  selling, see above and under dose  Dose ADULT and CHILD initially 1 capsule with meals either taken  whole or contents mixed with fluid or soft food (then swallowed  immediately without chewing)    Creon® 40 000 (Solvay) Ml  Capsules, brown/clear, enclosing brown-coloured  e/c granules of pancreatin (pork), providing: protease  (total) 1600 units, lipase 40 000 units, amylase  25 000 units, net price 100-cap pack = £60.00. Coun-  selling, see above and under dose  Dose ADULT and CHILD initially 1-2 capsules with meals either  taken whole or contents mixed with fluid or soft food (then  swallowed immediately without chewing)    Nutrizym 22® (Merck Serono) M  Capsules, red/yellow, enclosing e/c minitablets of  pancreatin (pork), providing minimum of: protease  1100 units, lipase 22 000 units, amylase 19 800 units.  Net price 100-cap pack = £33.33. Counselling, see  above and under dose   Dose ADULT and CHILD over 15 years, 1-2 capsules with meals  and 1 capsule with snacks, swallowed whole or contents taken  with water or mixed with soft food (then swallowed immediately  without chewing)    Pancrease HL® Qanssen-Cilag) (M  Capsules, enclosing light brown e/c minitablets of  pancreatin (pork), providing minimum of: protease  1250 units, lipase 25 000 units, amylase 22 500 units.  Net price 100 = £31.70. Counselling, see above and  under dose   Dose ADULT and CHILD over 15 years, 1-2 capsules during each  meal and 1 capsule with snacks swallowed whole or contents  mixed with slightly acidic liquid or soft food (then swallowed  immediately without chewing)    This chapter also includes advice on the drug man-  agement of the following:  angina, p. 154  arrhythmias, p. 90   Positive inotropic drugs increase the force of contrac-  tion of the myocardium; for sympathomimetics with  inotropic activity see section 2.7.1.   Digoxin is a cardiac glycoside that increases the force of  myocardial contraction and reduces conductivity within  the atrioventricular (AV) node.   Digoxin is most useful for controlling ventricular  response in persistent and permanent atrial fibrillation  and atrial flutter (section 2.3.1). For reference to the role  of digoxin in heart failure, see section 2.5.5.    For management of atrial fibrillation the maintenance  dose of digoxin can usually be determined by the ventri-  cular rate at rest, which should not usually be allowed to  fall persistently below 60 beats per minute.   Digoxin is now rarely used for rapid control of heart rate  (see section 2.3 for the management of supraventricular  arrhythmias). Even with intravenous administration,  response may take many hours; persistence of tachy-  cardia is therefore not an indication for exceeding the  recommended dose. The intramuscular route is not  recommended.   In patients with heart failure who are in sinus rhythm a  loading dose is not required, and a satisfactory plasma-  digoxin concentration can be achieved over a period of  about a week.    Digoxin has a long half-life and maintenance doses need  to be given only once daily (although higher doses may  be divided to avoid nausea); renal function is the most  important determinant of digoxin dosage.   Unwanted effects depend both on the concentration of  digoxin in the plasma and on the sensitivity of the  conducting system or of the myocardium, which is  often increased in heart disease. It can sometimes be  difficult to distinguish between toxic effects and clinical  deterioration because symptoms of both are similar. The  plasma concentration alone cannot indicate toxicity  reliably, but the likelihood of toxicity increases progres-  sively through the range 1.5 to 3 micrograms /litre for  digoxin. Digoxin should be used with special care in the  elderly, who may be particularly susceptible to digitalis  toxicity.    Regular monitoring of plasma-digoxin concentration  during maintenance treatment is not necessary unless  problems are suspected. Hypokalaemia predisposes the  patient to digitalis toxicity; it is managed by giving a  potassium-sparing diuretic or, if necessary, potassium  supplementation.    If toxicity occurs, digoxin should be withdrawn; serious  manifestations require urgent specialist management.  Digoxin-specific antibody fragments are available for  reversal of life-threatening overdosage (see below).   Indications heart failure (see also section 2.5.5),  supraventricular arrhythmias (particularly atrial  fibrillation and atrial flutter; see also section 2.3.2)  Cautions recent myocardial infarction; sick sinus  syndrome; thyroid disease; reduce dose in the elderly;  severe respiratory disease; hypokalaemia, hypo-  magnesaemia, hypercalcaemia, and hypoxia (risk of  digitalis toxicity); monitor serum electrolytes and  renal function; avoid rapid intravenous administration  (risk of hypertension and reduced coronary flow);  interactions: Appendix 1 (cardiac glycosides)  Contra-indications intermittent complete heart block,  second degree AV block; supraventricular arrhyth-  mias associated with accessory conducting pathways  e.g. Wolff-Parkinson-White syndrome; ventricular  tachycardia or fibrillation; hypertrophic cardiomyo-  pathy (unless concomitant atrial fibrillation and heart  failure — but use with caution); myocarditis; constric-  tive pericarditis (unless to control atrial fibrillation or  improve systolic dysfunction — but use with caution)    Renal impairment reduce dose and monitor plasma-  digoxin concentration; toxicity increased by electro-  lyte disturbances   Pregnancy may need dosage adjustment  Breast-feeding amount too small to be harmful  Side-effects see notes above; also nausea, vomiting,  diarrhoea; arrhythmias, conduction disturbances;  dizziness; blurred or yellow vision; rash, eosinophilia;  less commonly depression; very rarely anorexia,  intestinal ischaemia and necrosis, psychosis, apathy,  confusion, headache, fatigue, weakness, gynaeco-  mastia on long-term use, and thrombocytopenia  Dose   • Rapid digitalisation, for atrial fibrillation or flutter, by  mouth, 0.75-1.5 mg over 24 hours in divided doses   • Maintenance, for atrial fibrillation or flutter, by mouth,  according to renal function and initial loading dose;  usual range 125-250 micrograms daily   • Heart failure (for patients in sinus rhythm), by mouth,  62.5-125 micrograms once daily   • Emergency loading dose, for atrial fibrillation or flut-  ter, by intravenous infusion (but rarely necessary),  0.75-1 mg over at least 2 hours (see also Cautions)  then maintenance dose by mouth on the following day   Note The above doses may need to be reduced if digoxin (or  another cardiac glycoside) has been given in the preceding 2  weeks. Digoxin doses in the BNF may differ from those in  product literature. For plasma concentration monitoring, blood  should ideally be taken at least 6 hours after a dose   Digoxin (Non-proprietary) [Ml  Tablets, digoxin 62.5 micrograms, net price 28-tab  pack = £2.03; 125 micrograms, 28-tab pack = £1.12;  250 micrograms, 28-tab pack = £1.13  Injection, digoxin 250micrograms/mL, net price 2-  mL amp = 70p   Tablets, digoxin 125 micrograms, net price 500-tab  pack = £8.09; 250 micrograms (scored), 500-tab pack  = £8.09   Elixir, yellow, digoxin 50 micrograms/mL. Do not  dilute, measure with pipette. Net price 60 mL = £5.35.  Counselling, use of pipette   Digoxin-specific antibody fragments are indicated for  the treatment of known or strongly suspected digoxin or  other cardiac glycoside overdosage when measures  beyond the withdrawal of the cardiac glycoside and  correction of any electrolyte abnormalities are felt to  be necessary (see also notes above).   Injection, powder for preparation of infusion, digoxin-  specific antibody fragments (F(ab)) 38 mg, net price  per vial = £93.97 (hosp. and poisons centres only)  Dose consult product literature   Enoximone and milrinone are phosphodiesterase type-  3 inhibitors that exert most of their effect on the myo-  cardium. Sustained haemodynamic benefit has been  observed after administration, but there is no evidence  of any beneficial effect on survival.   Indications congestive heart failure where cardiac  output reduced and filling pressures increased   Cautions heart failure associated with hypertrophic  cardiomyopathy, stenotic or obstructive valvular dis-  ease or other outlet obstruction; monitor blood pres-  sure, heart rate, ECG, central venous pressure, fluid  and electrolyte status, renal function, platelet count,  hepatic enzymes; avoid extravasation; interactions:  Appendix 1 (phosphodiesterase type-3 inhibitors)   Side-effects ectopic beats; less frequently ventricular  tachycardia or supraventricular arrhythmias (more  likely in patients with pre-existing arrhythmias);  hypotension; also headache, insomnia, nausea and  vomiting, diarrhoea; occasionally, chills, oliguria,  fever, urinary retention; upper and lower limb pain  Dose   • By slow intravenous injection (rate not exceeding  12.5 mg/minute), diluted before use, initially 0.5-   1 mg/kg, then 500 micrograms/kg every 30 minutes  until satisfactory response or total of 3 mg/kg given;  maintenance, initial dose of up to 3 mg/kg may be  repeated every 3-6 hours as required   • By intravenous infusion, initially 90 micrograms/kg/  minute over 10-30 minutes, followed by continuous or  intermittent infusion of 5-20 micrograms /kg/minute  Total dose over 24 hours should not usually exceed  24 mg/kg   Indications short-term treatment of severe congestive  heart failure unresponsive to conventional mainte-  nance therapy (not immediately after myocardial  infarction); acute heart failure, including low output  states following heart surgery  Cautions see under Enoximone; also correct hypo-  kalaemia; interactions: Appendix 1 (phosphodi-  esterase type-3 inhibitors)   Renal impairment reduce dose and monitor response  if eGFR less than 50 mL/minute/ 1.73 m 2 — consult  product literature for details  Pregnancy manufacturer advises use only if potential  benefit outweighs risk   Side-effects ectopic beats, ventricular tachycardia,  supraventricular arrhythmias (more likely in patients  with pre-existing arrhythmias), hypotension; head-  ache; less commonly ventricular fibrillation, chest  pain, tremor, hypokalaemia, thrombocytopenia; very  rarely bronchospasm, anaphylaxis, and rash  Dose   • By intravenous injection over 10 minutes, either  undiluted or diluted before use, 50 micrograms/kg  followed by intravenous infusion at a rate of 375—  750 nanograms/kg/minute, usually for up to 12 hours  following surgery or for 48-72 hours in congestive  heart failure; max. daily dose 1.13 mg/kg   Primacor® (Sanofi-Aventis) (Ml  Injection, milrinone (as lactate) 1 mg/mL, net price  10-mL amp = £16.61   Potassium-sparing diuretics and  aldosterone antagonists  Potassium-sparing diuretics with  other diuretics  Osmotic diuretics  Mercurial diuretics  Carbonic anhydrase inhibitors  Diuretics with potassium   Thiazides (section 2.2.1) are used to relieve oedema  due to chronic heart failure (section 2.5.5) and, in lower  doses, to reduce blood pressure.   Loop diuretics (section 2.2.2) are used in pulmonary  oedema due to left ventricular failure and in patients  with chronic heart failure (section 2.5.5).   Combination diuretic therapy may be effective in  patients with oedema resistant to treatment with one  diuretic. Vigorous diuresis, particularly with loop diur-  etics, may induce acute hypotension; rapid reduction of  plasma volume should be avoided.   Elderly Lower initial doses of diuretics should be used  in the elderly because they are particularly susceptible  to the side-effects. The dose should then be adjusted  according to renal function. Diuretics should not be  used continuously on a long-term basis to treat simple  gravitational oedema (which will usually respond to  increased movement, raising the legs, and support  stockings).   Potassium loss Hypokalaemia can occur with both  thiazide and loop diuretics. The risk of hypokalaemia  depends on the duration of action as well as the potency  and is thus greater with thiazides than with an equipo-  tent dose of a loop diuretic.   Hypokalaemia is dangerous in severe cardiovascular  disease and in patients also being treated with cardiac  glycosides. Often the use of potassium-sparing diuretics  (section 2.2.3) avoids the need to take potassium sup-  plements.   In hepatic failure, hypokalaemia caused by diuretics can  precipitate encephalopathy, particularly in alcoholic    cirrhosis; diuretics can also increase the risk of hypo-  magnesaemia in alcoholic cirrhosis, leading to arrhyth-  mias. Spironolactone, a potassium-sparing diuretic (sec-  tion 2.2.3), is chosen for oedema arising from cirrhosis  of the liver.   Potassium supplements or potassium-sparing diuretics  are seldom necessary when thiazides are used in the  routine treatment of hypertension (see also section  9.2.1. 1).   Thiazides and related compounds are moderately  potent diuretics; they inhibit sodium reabsorption at  the beginning of the distal convoluted tubule. They act  within 1 to 2 hours of oral administration and most have  a duration of action of 12 to 24 hours; they are usually  administered early in the day so that the diuresis does  not interfere with sleep.   In the management of hypertension a low dose of a  thiazide, e.g. bendroflumethiazide 2.5 mg daily, pro-  duces a maximal or near-maximal blood pressure low-  ering effect, with very little biochemical disturbance.  Higher doses cause more marked changes in plasma  potassium, sodium, uric acid, glucose, and lipids, with  little advantage in blood pressure control. For reference  to the use of thiazides in chronic heart failure see section  2.5.5.   Bendroflumethiazide is widely used for mild or mod-  erate heart failure and for hypertension — alone in the  treatment of mild hypertension or with other drugs in  more severe hypertension.   Chlortalidone, a thiazide-related compound, has a  longer duration of action than the thiazides and may  be given on alternate days to control oedema. It is also  useful if acute retention is liable to be precipitated by a  more rapid diuresis or if patients dislike the altered  pattern of micturition caused by other diuretics.   Other thiazide diuretics (including benzthiazide, clop-  amide, cyclopenthiazide, hydrochlorothiazide, and  hydroflumethiazide) do not offer any significant advan-  tage over bendroflumethiazide or chlortalidone.  Metolazone is particularly effective when combined  with a loop diuretic (even in renal failure); profound  diuresis can occur and the patient should therefore be  monitored carefully.   Xipamide and indapamide are chemically related to  chlortalidone. Indapamide is claimed to lower blood  pressure with less metabolic disturbance, particularly  less aggravation of diabetes mellitus.   Cautions See also section 2.2. Thiazides and related  diuretics can exacerbate diabetes, gout, and systemic  lupus erythematosus. Electrolytes should be monitored,  particularly with high doses, long-term use, or in renal  impairment. Thiazides and related diuretics should also  be used with caution in nephrotic syndrome, hyperaldo-  steronism, and malnourishment; interactions: Appen-  dix 1 (diuretics)   Hepatic impairment Thiazides and related diuretics  should be used with caution in mild to moderate impair-  ment and avoided in severe liver disease. Hypokalaemia  may precipitate coma, although hypokalaemia can be  prevented by using a potassium-sparing diuretic. There  is an increased risk of hypomagnesaemia in alcoholic  cirrhosis.   Renal impairment Thiazides and related diuretics are  ineffective if eGFR is less than 30 mL/minute/ 1.73 m 2  and should be avoided; metolazone remains effective  but with a risk of excessive diuresis.   Pregnancy Thiazides and related diuretics should not  be used to treat gestational hypertension. They may  cause neonatal thrombocytopenia, bone marrow sup-  pression, jaundice, electrolyte disturbances, and hypo-  glycaemia; placental perfusion may also be reduced.  Stimulation of labour, uterine inertia, and meconium  staining have also been reported.   Breast-feeding The amount of bendroflumethiazide,  chlortalidone, cyclopenthiazide, and metolazone pre-  sent in milk is too small to be harmful; large doses  may suppress lactation. For indapamide and xipamide  see individual drugs.   Side-effects Side-effects of thiazides and related diur-  etics include mild gastro-intestinal disturbances, postur-  al hypotension, altered plasma-lipid concentrations,  metabolic and electrolyte disturbances including hypo-  kalaemia (see also notes above), hyponatraemia, hypo-  magnesaemia, hypercalcaemia, hyperglycaemia, hypo-  chloraemic alkalosis, hyperuricaemia, and gout. Less  common side-effects include blood disorders such as  agranulocytosis, leucopenia, and thrombocytopenia,  and impotence. Pancreatitis, intrahepatic cholestasis,  cardiac arrhythmias, headache, dizziness, paraesthesia,  visual disturbances, and hypersensitivity reactions  (including pneumonitis, pulmonary oedema, photo-  sensitivity, and severe skin reactions) have also been  reported.   • Oedema, initially 5-10 mg daily in the morning or on  alternate days; maintenance 5-10 mg 1-3 times  weekly   • Hypertension, 2.5 mg daily in the morning; higher  doses rarely necessary (see notes above)    Contra-indications Thiazides and related diuretics  should be avoided in refractory hypokalaemia, hypo-  natraemia and hypercalcaemia, symptomatic hyperuric-  aemia, and Addison’s disease.    Bendroflumethiazide (Non-proprietary) tMl  Tablets, bendroflumethiazide 2.5 mg, net price 28  79p; 5 mg, 28 = 86p  Brands include Aprinox ®   Indications ascites due to cirrhosis in stable patients  (under close supervision), oedema due to nephrotic  syndrome, hypertension (see also notes above), mild  to moderate chronic heart failure; diabetes insipidus  (see section 6.5.2)   Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also rarely jaundice and  allergic interstitial nephritis  Dose   • Hypertension, 25 mg daily in the morning, increased  to 50 mg daily if necessary (but see notes above)   • Heart failure, 25-50 mg daily in the morning,  increased if necessary to 100-200 mg daily (reduce to  lowest effective dose for maintenance)   Tablets, yellow, scored, chlortalidone 50 mg, net price  28-tab pack = £1.64   • Heart failure, 250-500 micrograms daily in the  morning increased if necessary to 1 mg daily (reduce  to lowest effective dose for maintenance)   • Hypertension, initially 250 micrograms daily in the  morning, increased if necessary to 500 micrograms  daily (but see notes above)   • Oedema, up to 500 micrograms daily for a short  period    Side-effects see notes above; also palpitation, diuresis  with doses above 2.5 mg daily   Indapamide (Non-proprietary) (Ml  Tablets, s/c, indapamide 2.5 mg, net price 28-tab  pack = £1.27, 56-tab pack = £2.01   Tablets, f/c, indapamide 2.5 mg. Net price 30-tab  pack = £3.40, 60-tab pack = £6.80   Tablets, m/r, indapamide 1.5 mg, net price 30-tab  pack = £4.05. Label: 25   Tablets, m/r, indapamide 1.5 mg, net price 30-tab  pack = £3.40. Label: 25   • Oedema, 5-10 mg daily in the morning, increased if  necessary to 20 mg daily in resistant oedema, max.  80 mg daily   • Hypertension, initially 5 mg daily in the morning;  maintenance 5 mg on alternate days    Metenix 5® (Sanofi-Aventis) CmD  Tablets, blue, metolazone 5 mg, net price 100-tab  pack = £18.20   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding no information available  Side-effects see notes above  Dose   • Oedema, initially 40 mg daily in the morning,  increased to 80 mg in resistant cases; maintenance  20 mg in the morning   • Hypertension, 20 mg daily in the morning  Diurexan® (Meda) ®   Loop diuretics are used in pulmonary oedema due to  left ventricular failure; intravenous administration pro-  duces relief of breathlessness and reduces pre-load  sooner than would be expected from the time of onset  of diuresis. Loop diuretics are also used in patients with  chronic heart failure. Diuretic-resistant oedema (except  lymphoedema and oedema due to peripheral venous  stasis or calcium-channel blockers) can be treated with a  loop diuretic combined with a thiazide or related diure-  tic (e.g. bendroflumethiazide 5-10 mg daily or meto-  lazone 5-20 mg daily).   If necessary, a loop diuretic can be added to antihyper-  tensive treatment to achieve better control of blood  pressure in those with resistant hypertension, or in  patients with impaired renal function or heart failure.   Loop diuretics inhibit reabsorption from the ascending  limb of the loop of Henle in the renal tubule and are  powerful diuretics.   Furosemide and bumetanide are similar in activity;  both act within 1 hour of oral administration and diur-  esis is complete within 6 hours so that, if necessary, they  can be given twice in one day without interfering with  sleep. Following intravenous administration they have a  peak effect within 30 minutes. The diuresis associated  with these drugs is dose related.   Torasemide has properties similar to those of furose-  mide and bumetanide, and is indicated for oedema and  for hypertension.   Cautions Hypovolaemia and hypotension should be  corrected before initiation of treatment with loop diur-  etics; electrolytes should be monitored during treatment  (see also Potassium Loss, section 2.2). Loop diuretics  can exacerbate diabetes (but hyperglycaemia is less  likely than with thiazides) and gout. If there is an  enlarged prostate, urinary retention can occur, although  this is less likely if small doses and less potent diuretics  are used initially; an adequate urinary output should be  established before initiating treatment; interactions:  Appendix 1 (diuretics).   Contra-indications Loop diuretics should be avoided  in severe hypokalaemia, severe hyponatraemia, anuria,  comatose and precomatose states associated with liver  cirrhosis, and in renal failure due to nephrotoxic or  hepatotoxic drugs.   Hepatic impairment Hypokalaemia induced by loop  diuretics may precipitate hepatic encephalopathy and  coma — potassium-sparing diuretics can be used to pre-  vent this.   Renal impairment High doses of loop diuretics may  occasionally be needed; high doses or rapid intravenous  administration can cause tinnitus and deafness; high  doses of bumetanide can also cause musculoskeletal  pain.   Pregnancy Furosemide and bumetanide should not be  used to treat gestational hypertension because of the  maternal hypovolaemia associated with this condition.   increase in serum-cholesterol and triglyceride concen-  tration, hyperglycaemia (less common than with thi-  azides), acute urinary retention, electrolyte disturbances  (including hyponatraemia, hypokalaemia (see section  2.2), hypocalcaemia, hypochloraemia, and hypo-  magnesaemia), metabolic alkalosis, blood disorders  (including bone-marrow depression, thrombocytopenia,  and leucopenia), hyperuricaemia, visual disturbances,  tinnitus and deafness (usually with high parenteral doses  and rapid administration, and in renal impairment), and  hypersensitivity reactions (including rash, photosensit-  ivity, and pruritus).   Cautions see notes above; also hypoproteinaemia may  reduce diuretic effect and increase risk of side-effects;  hepatorenal syndrome; intravenous administration  rate should not usually exceed 4 mg/minute, however  single doses of up to 80 mg may be administered more  rapidly   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above; also lower rate of  infusion may be necessary  Pregnancy see notes above   • By intramuscular injection or slow intravenous  injection (rate of administration, see Cautions above),  initially 20-50 mg, increased if necessary in steps of  20 mg not less than every 2 hours; doses greater than  50 mg by intravenous infusion only; max. 1.5 g daily;  CHILD under 18 years see BNF for Children   Furosemide (Non-proprietary) (Ml  Tablets, furosemide 20 mg, net price 28 = 81p; 40 mg,  28 = 84p; 500 mg, 28 = £4.05  Brands include Rusyde ®   Oral solution, sugar-free, furosemide, net price  20 mg/5 mL, 150 mL = £13.97; 40 mg/5 mL, 150 mL  = £18.19; 50 mg/5 mL, 150 mL = £19.35  Brands include Frusol ® (contains alcohol 10%)   Injection, furosemide 10 mg/mL, net price 2-mL amp  = 3 Op, 5-mL amp = 38p, 25-mL amp = £2.50    Side-effects Side-effects of loop diuretics include mild Indications oedema (see notes above)  gastro-intestinal disturbances, pancreatitis, hepatic Cautions see notes above  encephalopathy, postural hypotension, temporary Contra-indications see notes above    Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding no information available; may inhibit  lactation   Side-effects see notes above; also gynaecomastia,  breast pain, musculoskeletal pain (associated with  high doses in renal failure)   • By mouth, 1 mg in the morning, repeated after 6-8  hours if necessary; severe cases, 5 mg daily increased  by 5 mg every 12-24 hours according to response;  ELDERLY, 500 micrograms daily may be sufficient   • By intravenous injection, 1-2 mg, repeated after 20  minutes if necessary; ELDERLY, 500 micrograms daily  may be sufficient   • By intravenous infusion, 2-5 mg over 30-60 minutes;  ELDERLY, 500 micrograms daily may be sufficient   • By intramuscular injection, lmg initially then  adjusted according to response; ELDERLY, 500 micr-  ograms daily may be sufficient   Tablets, bumetanide 1 mg, net price 28-tab pack =  £1.12; 5 mg, 28-tab pack = £4.33  Oral liquid, bumetanide lmg/5mL, net price 150 mL  = £128.00   • Oedema, 5 mg once daily, preferably in the morning,  increased if required to 20 mg once daily; usual max.  40 mg daily   • Hypertension, 2.5 mg daily, increased if necessary to  5 mg once daily   Amiloride and triamterene on their own are weak  diuretics. They cause retention of potassium and are  therefore given with thiazide or loop diuretics as a more  effective alternative to potassium supplements. See  section 2.2.4 for compound preparations with thiazides  or loop diuretics.   Potassium supplements must not be given with potas-  sium-sparing diuretics. Administration of a potassium-  sparing diuretic to a patient receiving an ACE inhibitor  or an angiotensin-II receptor antagonist can also cause  severe hyperkalaemia.    Indications oedema; potassium conservation when  used as an adjunct to thiazide or loop diuretics for  hypertension, congestive heart failure, or hepatic  cirrhosis with ascites   Renal impairment monitor plasma-potassium con-  centration (high risk of hyperkalaemia in renal  impairment); manufacturers advise avoid in severe  impairment    Side-effects include gastro-intestinal disturbances,  dry mouth, rashes, confusion, postural hypotension,  hyperkalaemia, hyponatraemia    • Used alone, initially 10 mg daily or 5 mg twice daily,  adjusted according to response; max. 20 mg daily   • With other diuretics, congestive heart failure and  hypertension, initially 5-10 mg daily; cirrhosis with  ascites, initially 5 mg daily   Oral solution, sugar-free, amiloride hydrochloride  5mg/5mL, net price 150 mL =£39.73  Brands include Amilamont® (Excipients include propylene glycol,  see Excipients, p. 2)    Torasemide (Non-proprietary) (Ml  Tablets, torasemide 5 mg, net price 28-tab pack =  £10.36; 10 mg, 28-tab pack = £13.71   Tablets, torasemide 2.5 mg, net price 28-tab pack =  £3.78; 5 mg (scored), 28-tab pack = £5.53; 10 mg  (scored), 28-tab pack = £8.14    Indications oedema, potassium conservation with  thiazide and loop diuretics  Cautions see under Amiloride Hydrochloride; may  cause blue fluorescence of urine  Contra-indications see under Amiloride Hydro-  chloride   Renal impairment monitor plasma-potassium con-  centration (high risk of hyperkalaemia in renal   Side-effects include gastro-intestinal disturbances,  dry mouth, rashes; slight decrease in blood pressure,  hyperkalaemia, hyponatraemia; photosensitivity and  blood disorders also reported; triamterene found in  kidney stones  Dose   • Initially 150-250 mg daily, reducing to alternate days  after 1 week; taken in divided doses after breakfast  and lunch; lower initial dose when given with other  diuretics   Capsules, maroon, triamterene 50 mg, net price 30-  cap pack = £17.35 Label: 14, (see above), 21   Spironolactone potentiates thiazide or loop diuretics by  antagonising aldosterone; it is a potassium-sparing  diuretic. Spironolactone is of value in the treatment of  oedema and ascites caused by cirrhosis of the liver;  furosemide (section 2.2.2) can be used as an adjunct.  Low doses of spironolactone are beneficial in moderate  to severe heart failure, see section 2.5.5.   Spironolactone is also used in primary hyperaldo-  steronism (Conn’s syndrome). It is given before surgery  or if surgery is not appropriate, in the lowest effective  dose for maintenance.   Eplerenone is licensed for use as an adjunct in left  ventricular dysfunction with evidence of heart failure  after a myocardial infarction (see also section 2.5.5 and  section 2.10.1).   Indications adjunct in stable patients with left ventri-  cular dysfunction with evidence of heart failure, fol-  lowing myocardial infarction (start therapy within 3-  14 days of event)   Cautions measure plasma-potassium concentration  before treatment, during initiation, and when dose  changed; elderly; interactions: Appendix 1 (diuretics)  Contra-indications hyperkalaemia; concomitant use  of potassium-sparing diuretics or potassium supple-  ments   Hepatic impairment avoid in severe liver disease  Renal impairment increased risk of hyperkalaemia —  close monitoring required; avoid if eGFR less than  50 mL/minute/1.73 m 2    Side-effects diarrhoea, nausea; hypotension; dizzi-  ness; hyperkalaemia; rash; less commonly flatulence,  vomiting, atrial fibrillation, postural hypotension,  arterial thrombosis, dyslipidaemia, pharyngitis, head-  ache, insomnia, gynaecomastia, pyelonephritis,  hyponatraemia, dehydration, eosinophilia, asthenia,  malaise, back pain, leg cramps, impaired renal func-  tion, azotaemia, sweating and pruritus  Dose   • Initially 25 mg once daily, increased within 4 weeks to  50 mg once daily; CHILD not recommended   Tablets, yellow, f/c, eplerenone 25 mg, net price 28-  tab pack = £42.72; 50 mg, 28-tab pack = £42.72   Indications oedema and ascites in cirrhosis of the  liver, malignant ascites, nephrotic syndrome, conges-  tive heart failure (section 2.5.5); primary hyperaldo-  steronism   Cautions potential metabolic products carcinogenic in  rodents', elderly; monitor electrolytes (discontinue if  hyperkalaemia); acute porphyria (section 9.8.2);  interactions: Appendix 1 (diuretics)   Renal impairment monitor plasma-potassium con-  centration (high risk of hyperkalaemia in renal  impairment); avoid if rapidly deteriorating or severe  impairment   Breast-feeding metabolites present in milk, but  amount probably too small to be harmful   Side-effects gastro-intestinal disturbances, hepato-  toxicity; malaise, headache, confusion, drowsiness,  dizziness; gynaecomastia, benign breast tumour,  breast pain, menstrual disturbances, changes in libido;  hypertrichosis, hyperkalaemia (discontinue), hypo-  natraemia, acute renal failure, hyperuricaemia,  leucopenia, agranulocytosis, thrombocytopenia; leg  cramps; alopecia, hirsutism, rash, and Stevens- John-  son syndrome  Dose   • 100-200 mg daily, increased to 400 mg if required;  CHILD under 18 years, see BNF for Children   Spironolactone (Non-proprietary) £mD  Tablets, spironolactone 25 mg, net price 28 = £1.50;  50 mg, 28 = £2.11; 100 mg, 28 = £2.46. Label: 21  Oral suspensions, spironolactone 5mg/5mL,   10 mg/5 mL, 25 mg/5 mL, 50 mg/5 mL, and 100 mg/  5mL. Label: 21   Aldactone® (Pharmacia) iMl  Tablets, f/c, spironolactone 25 mg (buff), net price  100-tab pack = £8.89; 50 mg (white), 100-tab pack =  £17.78; 100 mg (buff), 28-tab pack = £9.96. Label: 21   Although it is preferable to prescribe thiazides (section  2.2.1) and potassium-sparing diuretics (section 2.2.3)  separately, the use of fixed combinations may be justi-  fied if compliance is a problem. Potassium-sparing diur-  etics are not usually necessary in the routine treatment  of hypertension, unless hypokalaemia develops. For  interactions, see Appendix 1 (diuretics).   ^Amiloride with thiazides  Co-amilozide (Non-proprietary) (Ml  Tablets, co-amilozide 2.5/25 (amiloride hydro-  chloride 2.5 mg, hydrochlorothiazide 25 mg), net price  28-tab pack = £3.73  Brands include Moduret 25®   Dose hypertension, initially 1 tablet daily, increased if necessary  to max. 2 tablets daily   Congestive heart failure, initially 1 tablet daily, increased if  necessary to max. 4 tablets daily   Oedema and ascites in cirrhosis of the liver, initially 2 tablets daily,  increased if necessary to max. 4 tablets daily; reduce for main-  tenance if possible   Tablets, co-amilozide 5/50 (amiloride hydrochloride  5 mg, hydrochlorothiazide 50 mg), net price 28 =  £1.14   Dose hypertension, initially Vi tablet daily, increased if necessary  to max. 1 tablet daily   Congestive heart failure, initially ‘4 tablet daily, increased if  necessary to max. 2 tablets daily   Oedema and ascites in cirrhosis of the liver, initially 1 tablet daily,  increased if necessary to max. 2 tablets daily; reduce for main-  tenance if possible    Navispare® (Goldshield) (Ml  Tablets, f/c, orange, amiloride hydrochloride 2.5 mg,  cyclopenthiazide 250 micrograms, net price 28-tab  pack = £2.70   Tablets, co-amilofruse 2.5/20 (amiloride hydro-  chloride 2.5 mg, furosemide 20 mg), net price 28-tab  pack = £1.18, 56-tab pack = £1.83  Brands include Frumil LS®   Dose oedema, 1 tablet in the morning  Tablets, co-amilofruse 5/40 (amiloride hydrochloride  5 mg, furosemide 40 mg), net price 28-tab pack =  £1.17, 56-tab pack = £1.42  Brands include Frumil ®   Dose oedema, 1-2 tablets in the morning  Tablets, co-amilofruse 10/80 (amiloride hydro-  chloride 10 mg, furosemide 80 mg), net price 28-tab  pack = £11.51    Amiloride with bumetanide (Non-proprietary) (Ml  Tablets, amiloride hydrochloride 5 mg, bumetanide  1 mg, net price 28-tab pack = £29.60  Dose oedema, 1-2 tablets daily   Co-triamterzide (Non-proprietary) (Ml  Tablets, co-triamterzide 50/25 (triamterene 50 mg,  hydrochlorothiazide 25 mg), net price 30-tab pack =  95p. Label: 14, (see above), 21  Dose hypertension, 1 tablet daily after breakfast, increased if  necessary, max. 4 daily   Oedema, 2 tablets daily (1 after breakfast and 1 after midday  meal) increased to 3 daily if necessary (2 after breakfast and 1  after midday meal); usual maintenance in oedema, 1 daily or 2 on  alternate days; max. 4 daily  Brands include Triam-Co ®   Tablets, peach, scored, co-triamterzide 50/25  (triamterene 50 mg, hydrochlorothiazide 25 mg), net  price 30-tab pack = 95p. Label: 14, (see above), 21  Dose hypertension, 1 tablet daily after breakfast, increased if  necessary, max. 4 daily   Oedema, 2 tablets daily (1 after breakfast and 1 after midday  meal) increased to 3 daily if necessary (2 after breakfast and 1  after midday meal); usual maintenance in oedema, 1 daily or 2 on  alternate days; max. 4 daily    Kalspare® (DHP Healthcare) (Ml  Tablets, orange, f/c, scored, triamterene 50 mg,  chlortalidone 50 mg, net price 28-tab pack = £9.90.  Label: 14, (see above), 21  Dose hypertension, oedema, 1-2 tablets in the morning   Tablets, yellow, scored, triamterene 50 mg, furose-  mide 40 mg, net price 56-tab pack = £4.34. Label: 14,  (see above)    ^ Spironolactone with thiazides  Co-flumactone (Non-proprietary) (Ml C^k  Tablets, co-flumactone 25/25 (hydroflumethiazide  25 mg, spironolactone 25 mg), net price 100-tab pack  = £20.23   Dose congestive heart failure, initially 4 tablets daily; range 1-8  tablets daily (but not recommended because spironolactone  generally given in lower dose)   Tablets, co-flumactone 50/50 (hydroflumethiazide  50 mg, spironolactone 50 mg), net price 28-tab pack =  £10.70   Dose congestive heart failure, initially 2 tablets daily; range 1-4  tablets daily (but not recommended because spironolactone  generally given in lower dose)    ^Spironolactone with loop diuretics  Lasilactone® (Sanofi-Aventis) (Ml  Capsules, blue/white, spironolactone 50 mg, furose-  mide 20 mg, net price 28-cap pack = £7.97  Dose resistant oedema, 1-4 capsules daily   Mannitol is an osmotic diuretic that can be used to treat  cerebral oedema and raised intra-ocular pressure.    Indications see notes above; glaucoma (section 11.6)  Cautions extravasation causes inflammation and  thrombophlebitis; monitor fluid and electrolyte bal-  ance, serum osmolality, and pulmonary and renal  function; assess cardiac function before and during  treatment; interactions: Appendix 1 (mannitol)  Contra-indications severe cardiac failure; severe  pulmonary oedema; intracranial bleeding (except  during craniotomy); anuria; severe dehydration  Renal impairment use with caution in severe impair-  ment   Side-effects less commonly hypotension, thrombo-  phlebitis, fluid and electrolyte imbalance; rarely dry  mouth, thirst, nausea, vomiting, oedema, raised  intracranial pressure, arrhythmia, hypertension,  pulmonary oedema, chest pain, headache, con-  vulsions, dizziness, chills, fever, urinary retention,  focal osmotic nephrosis, dehydration, cramp, blurred  vision, rhinitis, skin necrosis, and hypersensitivity  reactions (including urticaria and anaphylaxis); very  rarely congestive heart failure and acute renal failure  Dose    • Cerebral oedema and raised intra-ocular pressure, by  intravenous infusion over 30-60 minutes, 0.25-2 g/kg  repeated if necessary 1-2 times after 4-8 hours  Note For mannitol 20%, an in-line filter is recommended (15-  micron filters have been used)   Intravenous infusion, mannitol 10%, net price 500-  mL Viaflex® bag = £2.26, 500-mL Viaflo® bag =  £2.15; 20%, net price 250-mL Viaflex® bag = £3.27,  250-mL Viaflo® bag = £3.27, 500-mL Viaflex® bag =  £3.29, 500-mL Viaflo® bag = £3.12   Mercurial diuretics are effective but are now almost  never used because of their nephrotoxicity.   The carbonic anhydrase inhibitor acetazolamide is a  weak diuretic and is little used for its diuretic effect. It is  used for prophylaxis against mountain sickness [unli-  censed indication] but is not a substitute for acclimati-  sation.   Acetazolamide and eye drops of dorzolamide and brin-  zolamide inhibit the formation of aqueous humour and  are used in glaucoma (section 11.6).   Many patients on diuretics do not need potassium  supplements (section 9.2. 1.1). For many of those who  do, the amount of potassium in combined preparations   may not be enough, and for this reason their use is to be  discouraged.   Diuretics with potassium and potassium-sparing diur-  etics should not usually be given together.   Counselling Modified-release potassium tablets should be  swallowed whole with plenty of fluid during meals while  sitting or standing   Diumide-K Continus® (Teofarma) (Ml CM  Tablets, white/orange, f/c, furosemide 40 mg, potas-  sium 8 mmol for modified release, net price 30-tab  pack = £3.00. Label: 25, 27, counselling, see above   Tablets, pink/white, f/c, bendroflumethiazide 2.5 mg,  potassium 8.4 mmol for modified release, net price  100 tab-pack = £8.99. Label: 25, 27, counselling, see  above   Management of an arrhythmia requires precise diagno-  sis of the type of arrhythmia, and electrocardiography is  essential; underlying causes such as heart failure require  appropriate treatment.   Ectopic beats If ectopic beats are spontaneous and  the patient has a normal heart, treatment is rarely  required and reassurance to the patient will often suf-  fice. If they are particularly troublesome, beta-blockers  are sometimes effective and may be safer than other  suppressant drugs.   Atrial fibrillation All patients with atrial fibrillation  should be assessed for their risk of stroke and throm-  boembolism, and thromboprophylaxis given if neces-  sary (see below). Atrial fibrillation can be managed by  either controlling the ventricular rate or by attempting  to restore and maintain sinus rhythm.   All haemodynamically unstable patients with acute-  onset atrial fibrillation should undergo electrical cardio-  version. Intravenous amiodarone, or alternatively fle-  cainide, can be used in non-life-threatening cases when  electrical cardioversion is delayed. If urgent ventricular  rate control is required, a beta-blocker, verapamil, or  amiodarone can be given intravenously.   In haemodynamically stable patients, a rhythm-control  treatment strategy is preferred for patients with parox-  ysmal atrial fibrillation; rate-control is preferred for  those with permanent atrial fibrillation. For patients  with persistent atrial fibrillation, the treatment strategy  should be based on criteria such as age, co-morbidities,  presence of symptoms, and the relative advantages and  disadvantages of each treatment.   Ventricular rate can be controlled with a beta-blocker  (section 2.4), or diltiazem [unlicensed indication], or  verapamil. Digoxin is usually only effective for control-  ling the ventricular rate at rest, and should therefore    only be used as monotherapy in predominantly seden-  tary patients. When a single drug fails to adequately  control the ventricular rate, patients should receive  digoxin with either a beta-blocker, diltiazem, or verap-  amil. If ventricular function is diminished, the combina-  tion of a beta-blocker (that is licensed for use in heart  failure) and digoxin is preferred (see section 2.5.5, and  interactions: Appendix 1 (cardiac glycosides)). Digoxin  is also used when atrial fibrillation is accompanied by  congestive heart failure.   Sinus rhythm can be restored by electrical cardio-  version, or pharmacological cardioversion with an oral  or intravenous anti-arrhythmic drug e.g. flecainide or  amiodarone. If necessary, sotalol or amiodarone can be  started 4 weeks before electrical cardioversion to  increase success of the procedure. If atrial fibrillation  has been present for more than 48 hours, cardioversion  should not be attempted until the patient has been fully  anticoagulated (see section 2.8.2) for at least 3 weeks; if  this is not possible, parenteral anticoagulation (section  2.8.1) should be commenced and a left atrial thrombus  ruled out immediately before cardioversion; oral anti-  coagulation should be given after cardioversion and  continued for at least 4 weeks. For atrial fibrillation of  over 48 hours duration, electrical cardioversion is pre-  ferred to pharmacological methods. If drug treatment is  required to maintain sinus rhythm, a beta-blocker is  used. If a standard beta-blocker is not appropriate or  is ineffective, an oral anti-arrhythmic drug such as sota-  lol (section 2.4), flecainide, propafenone, or amiodarone,  is required.   In symptomatic paroxysmal atrial fibrillation, ventri-  cular rhythm is controlled with a beta-blocker. Alterna-  tively, if symptoms persist or a beta-blocker is not  appropriate, an oral anti-arrhythmic drug such as sota-  lol, flecainide, propafenone, or amiodarone can be given  (see also Paroxysmal Supraventricular Tachycardia  below, and Supraventricular Arrhythmias). In selected  patients with infrequent episodes of symptomatic par-  oxysmal atrial fibrillation, sinus rhythm can be restored  using the ‘pill-in-the-pocket’ approach; this involves the  patient taking oral flecainide or propafenone to self-  treat an episode of atrial fibrillation when it occurs.   All patients with atrial fibrillation should be assessed for  their risk of stroke and the need for thromboprophylaxis.  Anticoagulants (section 2.8) are indicated for those with  a history of ischaemic stroke, transient ischaemic  attacks, or thromboembolic events, and those with  valve disease, heart failure, or impaired left ventricular  function; anticoagulants should be considered for those  with cardiovascular disease, diabetes, hypertension, or  thyrotoxicosis, and in the elderly. Anticoagulants are  also indicated during cardioversion procedures (see  above). Aspirin (section 2.9) is less effective than warf-  arin at preventing emboli, but may be appropriate if  there are no other risk factors for stroke, or if warfarin is  contra-indicated.    Atrial flutter Like atrial fibrillation, treatment options  for atrial flutter involve either controlling the ventricular  rate or attempting to restore and maintain sinus rhythm.  However, atrial flutter generally responds less well to  drug treatment than atrial fibrillation.   Control of the ventricular rate is usually an interim  measure pending restoration of sinus rhythm. Ventri-  cular rate can be controlled by administration of a beta-  blocker (section 2.4), diltiazem [unlicensed indication],    or verapamil (section 2.6.2); an intravenous beta-block-  er or verapamil is preferred for rapid control. Digoxin  (section 2.1.1) can be added if rate control remains  inadequate, and may be particularly useful in those  with heart failure.   Conversion to sinus rhythm can be achieved by elec-  trical cardioversion (by cardiac pacing or direct current),  pharmacological cardioversion, or catheter ablation. If  the duration of atrial flutter is unknown, or it has lasted  for over 48 hours, cardioversion should not be  attempted until the patient has been fully anticoagulated  (see section 2.8.2) for at least 3 weeks; if this is not  possible, parenteral anticoagulation (section 2.8.1)  should be commenced and a left atrial thrombus ruled  out immediately before cardioversion; oral anti-  coagulation should be given after cardioversion and  continued for at least 4 weeks.    Direct current cardioversion is usually the treatment of  choice when rapid conversion to sinus rhythm is neces-  sary (e.g. when atrial flutter is associated with haemo-  dynamic compromise); catheter ablation is preferred for  the treatment of recurrent atrial flutter. There is a  limited role for anti-arrhythmic drugs as their use is  not always successful. Flecainide or propafenone can  slow atrial flutter, resulting in 1:1 conduction to the  ventricles, and should therefore be prescribed in con-  junction with a ventricular rate controlling drug such as  a beta-blocker, diltiazem [unlicensed indication], or  verapamil. Amiodarone can be used when other drug  treatments are contra-indicated or ineffective.   All patients should be assessed for their risk of stroke  and the need for thromboprophylaxis; the choice of  anticoagulant is based on the same criteria as for atrial  fibrillation (see notes above).    Paroxysmal supraventricular tachycardia This  will often terminate spontaneously or with reflex vagal  stimulation such as a Valsalva manoeuvre, immersing  the face in ice-cold water, or carotid sinus massage; such  manoeuvres should be performed with ECG monitoring.  If the effects of reflex vagal stimulation are transient or  ineffective, or if the arrhythmia is causing severe symp-  toms, intravenous adenosine (section 2.3.2) should be  given. If adenosine is ineffective or contra-indicated,  intravenous verapamil (section 2.6.2) is an alternative,  but it should be avoided in patients recently treated with  beta-blockers (see p. 133).   Failure to terminate paroxysmal supraventricular tachy-  cardia with reflex vagal stimulation or drug treatment  may suggest an arrhythmia of atrial origin, such as focal  atrial tachycardia or atrial flutter.   Treatment with direct current cardioversion is needed  in haemodynamically unstable patients or when the  above measures have failed to restore sinus rhythm  (and an alternative diagnosis has not been found).   Recurrent episodes of paroxysmal supraventricular  tachycardia can be treated by catheter ablation, or  prevented with drugs such as diltiazem, verapamil,  beta-blockers including sotalol (section 2.4), flecainide,  or propafenone (section 2.3.2).   patients with a paroxysmal tachycardia or rapid irregu-  larity of the pulse it is best not to administer an anti-  arrhythmic until an ECG record has been obtained.  Bradycardia, particularly if complicated by hypotension,    should be treated with 500 micrograms of atropine sul-  phate given intravenously; the dose may be repeated  every 3-5 minutes if necessary up to a maximum total  dose of 3 mg. If there is a risk of asystole, or if the patient  is unstable and has failed to respond to atropine, adr-  enaline should be given by intravenous infusion in a  dose of 2-10 micrograms/minute, adjusted according to  response.   For further advice, refer to the most recent recommen-  dations of the Resuscitation Council (UK) available at  www.resus.org.uk.   Ventricular tachycardia Pulseless ventricular tachy-  cardia or ventricular fibrillation should be treated with  immediate defibrillation (see Cardiopulmonary Resusci-  tation, section 2.7.3).   Patients with unstable sustained ventricular tachycardia,  who continue to deteriorate with signs of hypotension  or reduced cardiac output, should receive direct current  cardioversion to restore sinus rhythm. If this fails, intra-  venous amiodarone (section 2.3.2) should be adminis-  tered and direct current cardioversion repeated.  Patients with sustained ventricular tachycardia who are  haemodynamically stable can be treated with intra-  venous anti-arrhythmic drugs. Amiodarone is the pre-  ferred drug. Flecainide, propafenone (section 2.3.2),  and, although less effective, lidocaine (section 2.3.2)  have all been used. If sinus rhythm is not restored, direct  current cardioversion or pacing should be considered.  Catheter ablation is an alternative if cessation of the  arrhythmia is not urgent. Non-sustained ventricular  tachycardia can be treated with a beta-blocker (section  2.4).   All patients presenting with ventricular tachycardia  should be referred to a specialist. Following restoration  of sinus rhythm, patients who remain at high risk of  cardiac arrest will require maintenance therapy. Most  patients will be treated with an implantable cardioverter  defibrillator. Beta-blockers or sotalol (in place of a  standard beta-blocker), or amiodarone (in combination  with a standard beta-blocker), can be used in addition to  the device in some patients; alternatively, they can be  used alone when use of an implantable cardioverter  defibrillator is not appropriate.   Torsade de pointes is a form of ventricular tachycardia  associated with a long QT syndrome (usually drug-  induced, but other factors including hypokalaemia,  severe bradycardia, and genetic predisposition are  also implicated). Episodes are usually self-limiting, but  are frequently recurrent and can cause impairment or  loss of consciousness. If not controlled, the arrhythmia  can progress to ventricular fibrillation and sometimes  death. Intravenous infusion of magnesium sulphate  (section 9.5. 1.3) is usually effective. A beta-blocker  (but not sotalol) and atrial (or ventricular) pacing can  be considered. Anti-arrhythmics can further prolong the  QT interval, thus worsening the condition.   Anti-arrhythmic drugs can be classified clinically into  those that act on supraventricular arrhythmias (e.g.  verapamil), those that act on both supraventricular  and ventricular arrhythmias (e.g. amiodarone), and  those that act on ventricular arrhythmias (e.g. lidocaine).    Anti-arrhythmic drugs can also be classified according  to their effects on the electrical behaviour of myocardial  cells during activity (the Vaughan Williams classifica-  tion) although this classification is of less clinical sig-  nificance:   Cautions The negative inotropic effects of anti-arrhy-  thmic drugs tend to be additive. Therefore special care  should be taken if two or more are used, especially if  myocardial function is impaired. Most drugs that are  effective in countering arrhythmias can also provoke  them in some circumstances; moreover, hypokalaemia  enhances the arrhythmogenic (pro-arrhythmic) effect of  many drugs.   Adenosine is usually the treatment of choice for termi-  nating paroxysmal supraventricular tachycardia. As it  has a very short duration of action (half-life only about 8  to 10 seconds, but prolonged in those taking dipyrid-  amole), most side-effects are short lived. Unlike verap-  amil, adenosine can be used after a beta-blocker. Verap-  amil may be preferable to adenosine in asthma.  Dronedarone is a multi-channel blocking anti-arrhyth-  mic drug; it is licensed for use in clinically stable  patients with previous or current non-permanent atrial  fibrillation, to prevent recurrence or to lower the ventri-  cular rate.   The Scottish Medicines Consortium (p. 4) has advised  (August 2010) that dronedarone ( Multaq ®) is accepted  for restricted use within NHS Scotland for the preven-  tion of recurrence of atrial fibrillation in patients in  whom conventional first-line anti-arrhythmic drugs are  ineffective, contra-indicated, or not tolerated; treatment  should be initiated on specialist advice only.   Dronedarone for the treatment of non-  permanent atrial fibrillation (August 2010)  Dronedarone is an option for the treatment of non-  permanent atrial fibrillation only in patients who:   • are not controlled on first-line therapy (usually  including beta-blockers), and   • do not have unstable New York Heart Associa-  tion class III or IV heart failure, and   • have at least one cardiovascular risk factor from  the following:   • hypertension managed by at least two dif-  ferent drug classes    Oral administration of a cardiac glycoside (such as  digoxin, section 2.1.1) slows the ventricular response  in cases of atrial fibrillation and atrial flutter. However,  intravenous infusion of digoxin is rarely effective for  rapid control of ventricular rate. Cardiac glycosides are  contra-indicated in supraventricular arrhythmias asso-  ciated with accessory conducting pathways (e.g. Wolff-  Parkinson-White syndrome).   Verapamil (section 2.6.2) is usually effective for supra-  ventricular tachycardias. An initial intravenous dose  (important: serious beta-blocker interaction hazard,  see p. 133) may be followed by oral treatment; hypo-  tension may occur with large doses. It should not be  used for tachyarrhythmias where the QRS complex is  wide (i.e. broad complex) unless a supraventricular  origin has been established beyond reasonable doubt.  It is also contra-indicated in atrial fibrillation or atrial  flutter associated with accessory conducting pathways  (e.g. Wolff-Parkinson- White syndrome). It should not be  used in children with arrhythmias without specialist  advice; some supraventricular arrhythmias in childhood  can be accelerated by verapamil with dangerous con-  sequences.   Intravenous administration of a beta-blocker (section  2.4) such as esmolol or propranolol, can achieve rapid  control of the ventricular rate.   Drugs for both supraventricular and ventricular arrhy-  thmias include amiodarone, beta-blockers (see p. 98),  disopyramide, flecainide, procainamide (available  from ‘special-order’ manufacturers or specialist import-  ing companies, see p. 988), and propafenone, see below  under Supraventricular and Ventricular Arrhythmias.   Indications rapid reversion to sinus rhythm of parox-  ysmal supraventricular tachycardias, including those  associated with accessory conducting pathways (e.g.  Wolff-Parkinson- White syndrome); aid to diagnosis of  broad or narrow complex supraventricular tachy-  cardias   Cautions monitor ECG and have resuscitation facil-  ities available; atrial fibrillation or flutter with acces-  sory pathway (conduction down anomalous pathway  may increase); first-degree A V block; bundle branch  block; left main coronary artery stenosis; uncorrected  hypovolaemia; stenotic valvular heart disease; left to  right shunt; pericarditis; pericardial effusion; auto-  nomic dysfunction; stenotic carotid artery disease  with cerebrovascular insufficiency; recent myocardial  infarction; heart failure; heart transplant (see below);  interactions: Appendix 1 (adenosine)  Contra-indications second- or third-degree AV block  and sick sinus syndrome (unless pacemaker fitted);  long QT syndrome; severe hypotension; decompen-  sated heart failure; chronic obstructive lung disease  (including asthma)   manufacturer advises use only if essential  Breast-feeding no information available — unlikely to  be present in milk owing to short half-life  Side-effects nausea; arrhythmia (discontinue if asys-  tole or severe bradycardia occur), sinus pause, AV  block, flushing, angina (discontinue), dizziness; dys-  pnoea; headache; less commonly metallic taste; pal-  pitation, hyperventilation, weakness, blurred vision,  sweating; very rarely transient worsening of intracra-    nial hypertension, bronchospasm, injection-site reac-  tions; also reported vomiting, syncope, hypotension  (discontinue if severe), cardiac arrest, respiratory  failure (discontinue), and convulsions   • By rapid intravenous injection into central or large  peripheral vein, 6 mg over 2 seconds with cardiac  monitoring; if necessary followed by 12 mg after 1-2  minutes, and then by 12 mg after a further 1-2 min-  utes; increments should not be given if high level AV  block develops at any particular dose  Important Patients with a heart transplant are very sensi-  tive to effects of adenosine and should receive initial dose of  3 mg over 2 seconds, followed if necessary by 6 mg after 1-2  minutes, and then by 12 mg after a further 1-2 minutes.  Also, if essential to give with dipyridamole reduce adenosine  dose to a quarter of the usual dose  Note Adenosine doses in the BNF may differ from those in  product literature   Adenocor® (Sanofi-Aventis) (Ml  Injection, adenosine 3 mg/mL in physiological saline,  net price 2-mL vial = £4.45 (hosp. only)   Note Intravenous infusion of adenosine (Adenoscan® , Sanofi-  Aventis) may be used in conjunction with radionuclide myocardial  perfusion imaging in patients who cannot exercise adequately or  for whom exercise is inappropriate — consult product literature   Cautions heart failure (avoid in patients with a recent  history of moderate heart failure, or with a signifi-  cantly reduced left ventricular function); correct  hypokalaemia and hypomagnesaemia before starting  and during treatment; measure serum creatinine 7  days after initiation; interactions: Appendix 1 (dro-  nedarone)   Contra-indications second- or third-degree AV block  and sick sinus syndrome (unless pacemaker fitted);  bradycardia; prolonged QT interval; haemodynami-  cally unstable patients (including those with moderate  or severe heart failure)   Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2   Side-effects gastro-intestinal disturbances; QT-inter-  val prolongation, bradycardia; fatigue, asthenia; rash,  pruritus; raised serum creatinine; less commonly taste  disturbance; erythema, eczema, dermatitis, photo-  sensitivity    Multaq® (Sanofi-Aventis) ▼ [Ml  Tablets, f/c, dronedarone (as hydrochloride) 400 mg,  net price 20-tab pack = £22.50, 60-tab pack = £67.50.  Label: 21   Amiodarone is used in the treatment of arrhythmias,  particularly when other drugs are ineffective or contra-  indicated. It can be used for paroxysmal supraventricu-    lar, nodal and ventricular tachycardias, atrial fibrillation  and flutter, and ventricular fibrillation. It can also be  used for tachyarrhythmias associated with Wolff-Parkin-  son- White syndrome. It should be initiated only under  hospital or specialist supervision. Amiodarone may be  given by intravenous infusion as well as by mouth, and  has the advantage of causing little or no myocardial  depression. Unlike oral amiodarone, intravenous amio-  darone acts relatively rapidly.   Intravenous injection of amiodarone can be used in  cardiopulmonary resuscitation for ventricular fibrilla-  tion or pulseless tachycardia unresponsive to other  interventions (section 2.7.3).   Amiodarone has a very long half-life (extending to  several weeks) and only needs to be given once daily  (but high doses can cause nausea unless divided). Many  weeks or months may be required to achieve steady-  state plasma-amiodarone concentration; this is particu-  larly important when drug interactions are likely (see  also Appendix 1).   Most patients taking amiodarone develop corneal  microdeposits (reversible on withdrawal of treatment);  these rarely interfere with vision, but drivers may be  dazzled by headlights at night. However, if vision is  impaired or if optic neuritis or optic neuropathy occur,  amiodarone must be stopped to prevent blindness and  expert advice sought. Because of the possibility of  phototoxic reactions, patients should be advised to  shield the skin from light during treatment and for  several months after discontinuing amiodarone; a  wide-spectrum sunscreen (section 13.8.1) to protect  against both long-wave ultraviolet and visible light  should be used.    Amiodarone contains iodine and can cause disorders of  thyroid function; both hypothyroidism and hyper-  thyroidism may occur. Clinical assessment alone is  unreliable, and laboratory tests should be performed  before treatment and every 6 months. Thyroxine (T4)  may be raised in the absence of hyperthyroidism; there-  fore tri-iodothyronine (T3), T4, and thyroid-stimulating  hormone (thyrotrophin, TSH) should all be measured. A  raised T3 and T4 with a very low or undetectable TSH  concentration suggests the development of thyrotoxic-  osis. The thyrotoxicosis may be very refractory, and  amiodarone should usually be withdrawn at least tem-  porarily to help achieve control; treatment with carbim-  azole may be required. Hypothyroidism can be treated  with replacement therapy without withdrawing amio-  darone if it is essential; careful supervision is required.   Pneumonitis should always be suspected if new or  progressive shortness of breath or cough develops in a  patient taking amiodarone. Fresh neurological symp-  toms should raise the possibility of peripheral neuro-  pathy.   Amiodarone is also associated with hepatotoxicity and  treatment should be discontinued if severe liver function  abnormalities or clinical signs of liver disease develop.  Beta-blockers act as anti-arrhythmic drugs principally  by attenuating the effects of the sympathetic system on  automaticity and conductivity within the heart, for  details see section 2.4. For special reference to the  role of sotalol in ventricular arrhythmias, see p. 98.   Disopyramide can be given by intravenous injection to  control arrhythmias after myocardial infarction (includ-  ing those not responding to lidocaine), but it impairs  cardiac contractility. Oral administration of disopyr-    amide is useful, but it has an antimuscarinic effect  which limits its use in patients susceptible to angle-  closure glaucoma or with prostatic hyperplasia.  Flecainide belongs to the same general class as lido-  caine and may be of value for serious symptomatic  ventricular arrhythmias. It may also be indicated for  junctional re-entry tachycardias and for paroxysmal  atrial fibrillation. However, it can precipitate serious  arrhythmias in a small minority of patients (including  those with otherwise normal hearts).   Propafenone is used for the prophylaxis and treatment  of ventricular arrhythmias and also for some supraven-  tricular arrhythmias. It has complex mechanisms of  action, including weak beta-blocking activity (therefore  caution is needed in obstructive airways disease — con-  tra-indicated if severe).   Drugs for supraventricular arrhythmias include aden-  osine, cardiac glycosides, and verapamil; see above  under Supraventricular Arrhythmias. Drugs for ventri-  cular arrhythmias include lidocaine; see under Ventri-  cular Arrhythmias, p. 96.   Mexiletine and procainamide are both available from  ‘special-order’ manufacturers or specialist importing  companies, see p. 988. Mexiletine can be used for life-  threatening ventricular arrhythmias; procainamide is  given by intravenous injection to control ventricular  arrhythmias.   Indications see notes above (should be initiated in  hospital or under specialist supervision)   Cautions liver-function and thyroid-function tests  required before treatment and then every 6 months  (see notes above for tests of thyroid function); hypo-  kalaemia (measure serum-potassium concentration  before treatment); chest x-ray required before treat-  ment; heart failure; elderly; severe bradycardia and  conduction disturbances in excessive dosage; intra-  venous use may cause moderate and transient fall in  blood pressure (circulatory collapse precipitated by  rapid administration or overdosage) or severe hepa-  tocellular toxicity (monitor transaminases closely);  administration by central venous catheter recom-  mended if repeated or continuous infusion required —  infusion via peripheral veins may cause pain and  inflammation; ECG monitoring and resuscitation  facilities must be available during intravenous use;  acute porphyria (section 9.8.2); interactions: Appen-  dix 1 (amiodarone)   Contra-indications (except in cardiac arrest) sinus  bradycardia, sino-atrial heart block; unless pacemaker  fitted avoid in severe conduction disturbances or  sinus node disease; thyroid dysfunction; iodine sen-  sitivity; avoid intravenous use in severe respiratory  failure, circulatory collapse, or severe arterial hypo-  tension; avoid bolus injection in congestive heart  failure or cardiomyopathy   Breast-feeding avoid; present in milk in significant  amounts; theoretical risk of neonatal hypothyroidism  from release of iodine   Side-effects nausea, vomiting, taste disturbances,  raised serum transaminases (may require dose  reduction or withdrawal if accompanied by acute liver  disorders), jaundice; bradycardia (see Cautions);    pulmonary toxicity (including pneumonitis and fibro-  sis); tremor, sleep disorders; hypothyroidism, hyper-  thyroidism; reversible corneal microdeposits (some-  times with night glare); phototoxicity, persistent slate-  grey skin discoloration (see also notes above), injec-  tion-site reactions; less commonly onset or worsening  of arrhythmia, conduction disturbances (see Cau-  tions), peripheral neuropathy and myopathy (usually  reversible on withdrawal); very rarely chronic liver  disease including cirrhosis, sinus arrest, broncho-  spasm (in patients with severe respiratory failure),  ataxia, benign intracranial hypertension, headache,  vertigo, epididymo-orchitis, impotence, haemolytic or  aplastic anaemia, thrombocytopenia, rash (including  exfoliative dermatitis), hypersensitivity including  vasculitis, alopecia, impaired vision due to optic  neuritis or optic neuropathy (including blindness),  anaphylaxis on rapid injection, also hypotension,  respiratory distress syndrome, sweating, and hot  flushes   • By mouth, 200 mg 3 times daily for 1 week reduced to  200 mg twice daily for a further week; maintenance,  usually 200 mg daily or the minimum required to  control the arrhythmia   • By intravenous infusion (see Cautions above), initially  5 mg/kg over 20-120 minutes with ECG monitoring;  subsequent infusion given if necessary according to  response up to max. 1.2 g in 24 hours   • Ventricular fibrillation or pulseless ventricular tachy-  cardia refractory to defibrillation, section 2.7.3    Side-effects ventricular tachycardia, ventricular  fibrillation or torsade de pointes (usually associated  with prolongation of QRS complex or QT interval —  see Cautions above), myocardial depression, hypo-  tension, AV block; antimuscarinic effects include dry  mouth, blurred vision, urinary retention, and very  rarely angle-closure glaucoma; gastro-intestinal irri-  tation; psychosis, cholestatic jaundice, hypoglycaemia  also reported (see Cautions above)   • By slow intravenous injection, 2 mg/kg over at least 5  minutes to a max. of 150 mg, with ECG monitoring,  followed immediately either by 200 mg by mouth,  then 200 mg every 8 hours for 24 hours or   400 micrograms/kg/hour by intravenous infusion;  max. 300 mg in first hour and 800 mg daily   Disopyramide (Non-proprietary) (Ml  Capsules, disopyramide (as phosphate) 100 mg, net  price 84 = £24.38; 150 mg, 84 = £32.57    Amiodarone (Non-proprietary) [Ml  Tablets, amiodarone hydrochloride 100 mg, net price  28-tab pack = £1.75; 200 mg, 28-tab pack = £2.22.  Label: 11   Excipients may include benzyl alcohol (avoid in neonates unless no  safer alternative available, see Excipients, p. 2)   Sterile concentrate, amiodarone hydrochloride  50 mg/mL, net price 3-mL amp = £1.33, 6-mL amp =  £2.86. For dilution and use as an infusion   Excipients may include benzyl alcohol (avoid in neonates unless no  safer alternative available, see Excipients, p. 2)   Cordarone X® (Sanofi-Aventis) fMl  Tablets, scored, amiodarone hydrochloride 100 mg,  net price 28-tab pack = £4.28; 200 mg, 28-tab pack =  £6.99. Label: 11   Excipients include benzyl alcohol (avoid in neonates unless no safer  alternative available, see Excipients, p. 2)   Indications ventricular arrhythmias, especially after  myocardial infarction; supraventricular arrhythmias  Cautions monitor for hypotension, hypoglycaemia,  ventricular tachycardia, ventricular fibrillation or tor-  sade de pointes (discontinue if occur); atrial flutter or  atrial tachycardia with partial block, bundle branch  block, heart failure (avoid if severe); prostatic enlar-  gement; susceptibility to angle-closure glaucoma;  avoid in acute porphyria (section 9.8.2); interactions:  Appendix 1 (disopyramide)   Contra-indications second- and third-degree heart  block and sinus node dysfunction (unless pacemaker    Rythmodan® (Sanofi-Aventis) (Ml  Capsules, disopyramide 100 mg (green/beige), net  price 84-cap pack = £14.14; 150 mg, 84-cap pack =  £18.76   Injection, disopyramide (as phosphate) 10 mg/mL,  net price 5-mL amp = £2.61   Rythmodan Retard® (Sanofi-Aventis) (Ml  Tablets, m/r, scored, f/c, disopyramide (as phos-  phate) 250 mg, net price 60-tab pack = £27.72.   Indications capsules, tablets, and injection: AV nodal  reciprocating tachycardia, arrhythmias associated  with accessory conducting pathways (e.g. Wolff-Par-  kinson-White syndrome), disabling symptoms of par-  oxysmal atrial fibrillation in patients without left  ventricular dysfunction (arrhythmias of recent onset  will respond more readily)   Immediate-release tablets only: symptomatic sus-  tained ventricular tachycardia, disabling symptoms of  premature ventricular contractions or non-sustained  ventricular tachycardia in patients resistant to or  intolerant of other therapy   Cautions patients with pacemakers (especially those  who may be pacemaker dependent because stimula-  tion threshold may rise appreciably); atrial fibrillation  following heart surgery; elderly (accumulation may  occur); ECG monitoring and resuscitation facilities    must be available during intravenous use; interac-  tions: Appendix 1 (flecainide)   Contra-indications heart failure; abnormal left  ventricular function; history of myocardial infarction  and either asymptomatic ventricular ectopics or  asymptomatic non-sustained ventricular tachycardia;  long-standing atrial fibrillation where conversion to  sinus rhythm not attempted; haemodynamically sig-  nificant valvular heart disease; avoid in sinus node  dysfunction, atrial conduction defects, second-degree  or greater A V block, bundle branch block or distal  block unless pacing rescue available   Renal impairment reduce initial oral dose to max.  100 mg daily or reduce intravenous dose by 50%, if  eGFR less than 35 mL/minute/ 1.73 m 2    Pregnancy used in pregnancy to treat maternal and  fetal arrhythmias in specialist centres; toxicity  reported in animal studies; infant hyperbilirubinaemia  also reported   Breast-feeding significant amount present in milk but  not known to be harmful   Side-effects oedema, pro-arrhythmic effects; dys-  pnoea; dizziness, asthenia, fatigue, fever; visual dis-  turbances; rarely pneumonitis, hallucinations,  depression, confusion, amnesia, dyskinesia, con-  vulsions, peripheral neuropathy; also reported gastro-  intestinal disturbances, anorexia, hepatic dysfunction,  flushing, syncope, drowsiness, tremor, vertigo, head-  ache, anxiety, insomnia, ataxia, paraesthesia, anae-  mia, leucopenia, thrombocytopenia, corneal deposits,  tinnitus, increased antinuclear antibodies, hyper-  sensitivity reactions (including rash, urticaria, and  photosensitivity), increased sweating   • By mouth (initiated under direction of hospital con-  sultant), ventricular arrhythmias, initially 100 mg  twice daily (max. 400 mg daily usually reserved for  rapid control or in heavily built patients), reduced  after 3-5 days to the lowest dose that controls  arrhythmia   Supraventricular arrhythmias, 50 mg twice daily,  increased if required to max. 300 mg daily   • By slow intravenous injection (in hospital), 2 mg/kg  over 10-30 minutes, max. 150 mg, with ECG moni-  toring; followed if required by infusion at a rate of  1.5 mg/kg/hour for 1 hour, subsequently reduced to  100-250 micrograms/kg/hour for up to 24 hours;  max. cumulative dose in first 24 hours, 600 mg;  transfer to oral treatment, as above    Flecainide (Non-proprietary) (Ml  Tablets, flecainide acetate 50 mg, net price 60-tab  pack = £6.04; 100 mg, 60-tab pack = £8.95   Tablets, flecainide acetate 50 mg, net price 60-tab  pack = £11.57; 100 mg (scored), 60-tab pack = £16.53  Injection, flecainide acetate lOmg/mL, net price 15-  mL amp = £4.40    M Modified release  Tambocor® XL (Meda) Ml  Capsules, m/r, grey/pink, flecainide acetate 200 mg,  net price 30-cap pack = £14.77. Label: 25  Dose supraventricular arrhythmias, 200 mg once daily  Note Not to be used to control arrhythmias in acute situations;  patients stabilised on 200 mg daily immediate-release flecainide  may be transferred to Tambocor 41 XL   Indications ventricular arrhythmias; paroxysmal  supraventricular tachyarrhythmias which include  paroxysmal atrial flutter or fibrillation and paroxysmal  re-entrant tachycardias involving the AV node or  accessory pathway, where standard therapy ineffec-  tive or contra-indicated   Cautions heart failure; elderly; pacemaker patients;  potential for conversion of paroxysmal atrial fibrilla-  tion to atrial flutter with 2:1 or 1:1 conduction block;  great caution in obstructive airways disease owing to  beta-blocking activity (contra-indicated if severe);  interactions: Appendix 1 (propafenone)   Contra-indications uncontrolled congestive heart  failure, cardiogenic shock (except arrhythmia  induced), severe bradycardia, electrolyte distur-  bances, severe obstructive pulmonary disease,  marked hypotension; myasthenia gravis; unless ade-  quately paced avoid in sinus node dysfunction, atrial  conduction defects, second degree or greater AV  block, bundle branch block or distal block   Side-effects gastro-intestinal disturbances, dry  mouth, bitter taste, anorexia, jaundice, cholestasis,  hepatitis; chest pain, bradycardia, sino-atrial, atrio-  ventricular, or intraventricular blocks, hypotension  (including postural hypotension), dizziness, syncope,  pro-arhythmic effects; anxiety, confusion, ataxia,  restlessness, headache, sleep disorders, paraesthesia,  fatigue, seizures, extrapyramidal symptoms; impo-  tence, reduced sperm count; blood disorders; lupus  syndrome; blurred vision; hypersensitivity (including  skin reactions)   • Body-weight 70 kg and over, initially 150 mg 3 times  daily after food under direct hospital supervision with  ECG monitoring and blood pressure control (if QRS  interval prolonged by more than 20%, reduce dose or  discontinue until ECG returns to normal limits); may  be increased at intervals of at least 3 days to 300 mg  twice daily and, if necessary, to max. 300 mg 3 times  daily; body-weight under 70 kg, reduce dose; ELDERLY  may respond to lower doses   Tablets, f/c, propafenone hydrochloride 150 mg, net  price 90-tab pack = £7.37; 300 mg, 60-tab pack =  £9.34. Label: 21, 25, counselling, driving   Intravenous lidocaine can be used for the treatment of  ventricular tachycardia in haemodynamically stable  patients (section 2.3.1), and ventricular fibrillation and  pulseless ventricular tachycardia in cardiac arrest  refractory to defibrillation (section 2.7.3), however it is  no longer the anti-arrhythmic drug of first choice.  Drugs for both supraventricular and ventricular arrhy-  thmias include amiodarone, beta-blockers, disopyr-  amide, flecainide, procainamide (available from ‘spe-  cial-order’ manufacturers or specialist importing    companies, see p. 988), and propafenone, see above  under Supraventricular and Ventricular Arrhythmias.   Mexiletine is available from ‘special-order’ manufac-  turers or specialist importing companies (see p. 988) for  treatment of life-threatening ventricular arrhythmias.   Indications ventricular arrhythmias, especially after  myocardial infarction; eye (section 11.7); local  anaesthesia (section 15.2)   Cautions lower doses in congestive cardiac failure and  following cardiac surgery; monitor ECG and have  resuscitation facilities available; elderly; interactions:  Appendix 1 (lidocaine)   Contra-indications sino-atrial disorders, all grades of  atrioventricular block, severe myocardial depression;  acute porphyria (section 9.8.2)   Renal impairment possible accumulation of lidocaine  and active metabolite; caution in severe impairment   Pregnancy crosses the placenta but not known to be  harmful in animal studies — use if benefit outweighs  risk   Breast-feeding present in milk but amount too small  to be harmful   Side-effects dizziness, paraesthesia, or drowsiness  (particularly if injection too rapid); other CNS effects  include confusion, respiratory depression and con-  vulsions; hypotension and bradycardia (may lead to  cardiac arrest); rarely hypersensitivity reactions  including anaphylaxis  Dose   • By intravenous injection, in patients without gross  circulatory impairment, 100 mg as a bolus over a few  minutes (50 mg in lighter patients or those whose  circulation is severely impaired), followed immedi-  ately by infusion of 4 mg/minute for 30 minutes,   2 mg/minute for 2 hours, then 1 mg/minute; reduce  concentration further if infusion continued beyond 24  hours (ECG monitoring and specialist advice for  infusion)   Note Following intravenous injection lidocaine has a short  duration of action (lasting for 15-20 minutes). If an intra-  venous infusion is not immediately available the initial  intravenous injection of 50-100 mg can be repeated if  necessary once or twice at intervals of not less than 10  minutes   Lidocaine (Non-proprietary) fMl  Injection 1%, lidocaine hydrochloride lOmg/mL, net  price 2-mL amp = 21p; 5-mL amp = 26p; 10-mL amp  = 39p; 20-mL amp = 78p   Injection 2%, lidocaine hydrochloride 20mg/mL, net  price 2-mL amp = 32p; 5-mL amp = 3 lp; 10-mL amp  = 60p; 20-mL amp = 80p   Infusion, lidocaine hydrochloride 0.1% (1 mg/mL)  and 0.2% (2 mg/mL) in glucose intravenous infusion  5%. 500-mL containers   Minijet® Lignocaine (UCB Pharma) (Ml  Injection, lidocaine hydrochloride 1% (10 mg/mL),  net price 10-mL disposable syringe = £8.48; 2%   Beta-adrenoceptor blocking drugs (beta-blockers) block  the beta-adrenoceptors in the heart, peripheral vascu-  lature, bronchi, pancreas, and liver.   Many beta-blockers are now available and in general  they are all equally effective. There are, however, differ-  ences between them, which may affect choice in treat-  ing particular diseases or individual patients.   Intrinsic sympathomimetic activity (ISA, partial agonist  activity) represents the capacity of beta-blockers to  stimulate as well as to block adrenergic receptors.  Oxprenolol, pindolol, acebutolol, and celiprolol  have intrinsic sympathomimetic activity; they tend to  cause less bradycardia than the other beta-blockers and  may also cause less coldness of the extremities.   Some beta-blockers are lipid soluble and some are water  soluble. Atenolol, celiprolol, nadolol, and sotalol are  the most water-soluble; they are less likely to enter the  brain, and may therefore cause less sleep disturbance  and nightmares. Water-soluble beta-blockers are  excreted by the kidneys and dosage reduction is often  necessary in renal impairment.   Beta-blockers with a relatively short duration of action  have to be given two or three times daily. Many of these  are, however, available in modified-release formulations  so that administration once daily is adequate for hyper-  tension. For angina twice-daily treatment may some-  times be needed even with a modified-release formula-  tion. Some beta-blockers, such as atenolol, bisoprolol,  carvedilol, celiprolol, and nadolol, have an intrinsically  longer duration of action and need to be given only once  daily.   Beta-blockers slow the heart and can depress the myo-  cardium; they are contra-indicated in patients with  second- or third-degree heart block. Beta-blockers  should also be avoided in patients with worsening  unstable heart failure; care is required when initiating  a beta-blocker in those with stable heart failure (see also  section 2.5.5). Sotalol may prolong the QT interval, and  it occasionally causes life-threatening ventricular arrhy-  thmias (important: particular care is required to avoid  hypokalaemia in patients taking sotalol).   Labetalol, celiprolol, carvedilol, and nebivolol are  beta-blockers that have, in addition, an arteriolar vaso-  dilating action, by diverse mechanisms, and thus lower  peripheral resistance. There is no evidence that these  drugs have important advantages over other beta-block-  ers in the treatment of hypertension.   Beta-blockers can precipitate bronchospasm and should  therefore usually be avoided in patients with a history of  asthma. When there is no suitable alternative, it may be  necessary for a patient with well-controlled asthma, or  chronic obstructive pulmonary disease (without signifi-  cant reversible airways obstruction), to receive treat-  ment with a beta-blocker for a co-existing condition (e.g.  heart failure or following myocardial infarction). In this  situation, a cardioselective beta-blocker should be  selected and initiated at a low dose by a specialist; the  patient should be closely monitored for adverse effects.  Atenolol, bisoprolol, metoprolol, nebivolol, and (to a  lesser extent) acebutolol, have less effect on the beta 2  (bronchial) receptors and are, therefore, relatively car-    dioselective, but they are not cardiospecific. They have  a lesser effect on airways resistance but are not free of  this side-effect.   Beta-blockers are also associated with fatigue, coldness  of the extremities (may be less common with those with  ISA, see above), and sleep disturbances with nightmares  (may be less common with the water-soluble beta-  blockers, see above).   Beta-blockers can affect carbohydrate metabolism,  causing hypoglycaemia or hyperglycaemia in patients  with or without diabetes; they can also interfere with  metabolic and autonomic responses to hypoglycaemia,  thereby masking symptoms such as tachycardia. How-  ever, beta-blockers are not contra-indicated in diabetes,  although the cardioselective beta-blockers (see above)  may be preferred. Beta-blockers should be avoided  altogether in those with frequent episodes of hypoglyc-  aemia. Beta-blockers, especially when combined with a  thiazide diuretic, should be avoided for the routine  treatment of uncomplicated hypertension in patients  with diabetes or in those at high risk of developing  diabetes.   Pregnancy Beta-blockers may cause intra-uterine  growth restriction, neonatal hypoglycaemia, and brady-  cardia; the risk is greater in severe hypertension. The  use of labetalol in maternal hypertension is not known  to be harmful, except possibly in the first trimester.  Information on the safety of carvedilol during  pregnancy is lacking. If beta-blockers are used close to  delivery, infants should be monitored for signs of beta-  blockade (and alpha-blockade with labetalol or carve-  dilol). For the treatment of hypertension in pregnancy,  see section 2.5.    Breast-feeding Infants should be monitored as there  is a risk of possible toxicity due to beta-blockade (and  alpha-blockade with labetalol or carvedilol), but the  amount of most beta-blockers present in milk is too  small to affect infants. Acebutolol, atenolol, nadolol, and  sotalol are present in milk in greater amounts than other  beta-blockers. The manufacturers of celiprolol, esmolol,  and nebivolol advise avoidance if breast-feeding.    Hypertension The mode of action of beta-blockers in  hypertension is not understood, but they reduce cardiac  output, alter baroceptor reflex sensitivity, and block  peripheral adrenoceptors. Some beta-blockers depress  plasma renin secretion. It is possible that a central effect  may also partly explain their mode of action.   Beta-blockers are effective for reducing blood pressure  but other antihypertensives (section 2.5) are usually  more effective for reducing the incidence of stroke,  myocardial infarction, and cardiovascular mortality,  especially in the elderly. Other antihypertensives are  therefore preferred for routine initial treatment of  uncomplicated hypertension.   In general, the dose of a beta-blocker does not have to  be high; for example, atenolol is given in a dose of 25-  50 mg daily and it is rarely necessary to increase the  dose to 100 mg.   Beta-blockers can be used to control the pulse rate in  patients with phaeochromocytoma (section 2.5.4).  However, they should never be used alone as beta-  blockade without concurrent alpha-blockade may lead  to a hypertensive crisis. For this reason phenoxybenz-   Angina By reducing cardiac work beta-blockers  improve exercise tolerance and relieve symptoms in  patients with angina (for further details on the manage-  ment of stable angina and acute coronary syndromes,  see section 2.10.1). As with hypertension there is no  good evidence of the superiority of any one drug,  although occasionally a patient will respond better to  one beta-blocker than to another. There is some evi-  dence that sudden withdrawal may cause an exacerba-  tion of angina and therefore gradual reduction of dose is  preferable when beta-blockers are to be stopped. There  is a risk of precipitating heart failure when beta-blockers  and verapamil are used together in established  ischaemic heart disease (important: see p. 133).   Myocardial infarction For advice on the manage-  ment of ST-segment elevation myocardial infarction and  non-ST-segment elevation myocardial infarction, see  section 2.10.1. Several studies have shown that some  beta-blockers can reduce the recurrence rate of myo-  cardial infarction. However, uncontrolled heart failure,  hypotension, bradyarrhythmias, and obstructive air-  ways disease render beta-blockers unsuitable in some  patients following a myocardial infarction. Atenolol and  metoprolol may reduce early mortality after intra-  venous and subsequent oral administration in the  acute phase, while acebutolol, metoprolol, proprano-  lol, and timolol have protective value when started in  the early convalescent phase. The evidence relating to  other beta-blockers is less convincing; some have not  been tested in trials of secondary prevention. Sudden  cessation of a beta-blocker can cause a rebound wor-  sening of myocardial ischaemia.   Arrhythmias Beta-blockers act as anti-arrhythmic  drugs principally by attenuating the effects of the sym-  pathetic system on automaticity and conductivity within  the heart. They can be used in conjunction with digoxin  to control the ventricular response in atrial fibrillation,  especially in patients with thyrotoxicosis. Beta-blockers  are also useful in the management of supraventricular  tachycardias, and are used to control those following  myocardial infarction (see above).   Esmolol is a relatively cardioselective beta-blocker with  a very short duration of action, used intravenously for  the short-term treatment of supraventricular arrhyth-  mias, sinus tachycardia, or hypertension, particularly in  the peri-operative period. It may also be used in other  situations, such as acute myocardial infarction, when  sustained beta-blockade might be hazardous.   Sotalol, a non-cardioselective beta-blocker with addi-  tional class III anti-arrhythmic activity, is used for  prophylaxis in paroxysmal supraventricular arrhyth-  mias. It also suppresses ventricular ectopic beats and  non-sustained ventricular tachycardia. It has been  shown to be more effective than lidocaine in the termi-  nation of spontaneous sustained ventricular tachycardia  due to coronary disease or cardiomyopathy. However, it  may induce torsade de pointes in susceptible patients.   Heart failure Beta-blockers may produce benefit in  heart failure by blocking sympathetic activity.  Bisoprolol and carvedilol reduce mortality in any  grade of stable heart failure; nebivolol is licensed for  stable mild to moderate heart failure in patients over 70    years. Treatment should be initiated by those experi-  enced in the management of heart failure (section 2.5.5).   Thyrotoxicosis Beta-blockers are used in pre-opera-  tive preparation for thyroidectomy. Administration of  propranolol can reverse clinical symptoms of thyro-  toxicosis within 4 days. Routine tests of increased thy-  roid function remain unaltered. The thyroid gland is  rendered less vascular thus making surgery easier (sec-  tion 6.2.2).   Other uses Beta-blockers have been used to alleviate  some symptoms of anxiety, probably patients with  palpitation, tremor, and tachycardia respond best (see  also section 4.1.2 and section 4.9.3). Beta-blockers are  also used in the prophylaxis of migraine (section  4. 7.4.2). Betaxolol, carteolol, levobunolol, metipranolol,  and timolol are used topically in glaucoma (section  11 . 6 ).   Indications see under Dose  Cautions see notes above; also avoid abrupt with-  drawal especially in ischaemic heart disease; first-  degree AV block; portal hypertension (risk of dete-  rioration in liver function); diabetes; history of  obstructive airways disease (introduce cautiously and  monitor lung function — see notes above); myasthenia  gravis; symptoms of hypoglycaemia and thyrotoxic-  osis may be masked (also see notes above); psoriasis;  history of hypersensitivity — may increase sensitivity  to allergens and result in more serious hypersensi-  tivity response, also may reduce response to adrena-  line (epinephrine) (see also section 3.4.3); interac-  tions: Appendix 1 (beta-blockers), important:  verapamil interaction, see also p. 133  Contra-indications asthma (but see notes above),  uncontrolled heart failure, Prinzmetal’s angina,  marked bradycardia, hypotension, sick sinus  syndrome, second- or third- degree AV block,  cardiogenic shock, metabolic acidosis, severe per-  ipheral arterial disease; phaeochromocytoma (apart  from specific use with alpha-blockers, see also notes  above)   Bronchospasm Beta-blockers, including those considered  to be cardioselective, should usually be avoided in patients  with a history of asthma or bronchospasm. However, when  there is no alternative, a cardioselective beta-blocker can be  given to these patients with caution and under specialist  supervision.   Hepatic impairment reduce oral dose  Renal impairment manufacturer advises caution —  dose reduction may be required  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also gastro-intestinal  disturbances; bradycardia, heart failure, hypotension,  conduction disorders, peripheral vasoconstriction  (including exacerbation of intermittent claudication  and Raynaud’s phenomenon); bronchospasm (see  above), dyspnoea; headache, fatigue, sleep distur-  bances, paraesthesia, dizziness, vertigo, psychoses;  sexual dysfunction; purpura, thrombocytopenia;  visual disturbances; exacerbation of psoriasis, alo-  pecia; rarely rashes and dry eyes (reversible on  withdrawal); overdosage: see Emergency Treatment  of Poisoning, p. 37   • By mouth, hypertension, initially 80 mg twice daily,  increased at weekly intervals as required; mainte-  nance 160-320 mg daily   Prophylaxis of variceal bleeding in portal hyper-  tension, initially 40 mg twice daily, increased to 80 mg  twice daily according to heart rate; max. 160 mg twice  daily   60 mg daily for 3 days before surgery or 30 mg daily in  patients unsuitable for surgery  Angina, initially 40 mg 2-3 times daily; maintenance  120-240 mg daily   Arrhythmias, hypertrophic cardiomyopathy, anxiety  tachycardia, and thyrotoxicosis (adjunct), 10-40 mg  3-4 times daily   Anxiety with symptoms such as palpitation, sweating,  tremor, 40 mg once daily, increased to 40 mg 3 times  daily if necessary   daily for 2-3 days, then 80 mg twice daily, beginning 5   • By intravenous injection, arrhythmias and thyrotoxic  crisis, 1 mg over 1 minute; if necessary repeat at 2-  minute intervals; max. total dose 10 mg (5 mg in  anaesthesia)   Note Excessive bradycardia can be countered with intra-  venous injection of atropine sulphate 0.6-2.4mg in divided  doses of 600 micrograms; for overdosage see Emergency  Treatment of Poisoning, p. 37   Propranolol (Non-proprietary) [Ml  Tablets, propranolol hydrochloride 10 mg, net price  28 = 92p; 40 mg, 28 = 93p; 80 mg, 56 = £1.54; 160 mg,  56 = £4.02. Label: 8  Brands include Angilol ®   Oral solution, propranolol hydrochloride 5mg/5mL,  net price 150 mL = £12.50; 10 mg/5 mL, 150 mL =  £16.45; 50 mg/5 mL, 150mL = £19.98. Label: 8  Brands include Syprol ®   Half-lnderal LA® (AstraZeneca) [Ml  Capsules, m/r, lavender/pink, propranolol hydro-  chloride 80 mg, net price 28-cap pack = £5.40.    Inderal-LA® (AstraZeneca) [Ml  Capsules, m/r, lavender/pink, propranolol hydro-  chloride 160 mg, net price 28-cap pack = £1.91.  Label: 8, 25   Note Modified-release capsules containing propranolol hydro-  chloride 160 mg also available; brands include Bedranol SR®,  Beta Program ®, Slo-Pro®   Renal impairment halve dose if eGFR 25-50 mL/  minute/ 1.73 m 2 ; use quarter dose if eGFR less than  25 mL/minute/ 1.73 m 2 ; do not administer more than  once daily   • Hypertension, initially 400 mg once daily or 200 mg  twice daily, increased after 2 weeks to 400 mg twice  daily if necessary   • Angina, initially 400 mg once daily or 200 mg twice  daily; 300 mg 3 times daily in severe angina; up to  1.2 g daily has been used   Sectral® (Sanofi-Aventis) (Ml  Capsules, acebutolol (as hydrochloride) 100 mg  (buff/white), net price 84-cap pack = £14.97; 200 mg  (buff/pink), 56-cap pack = £19.18. Label: 8  Tablets, f/c, acebutolol 400 mg (as hydrochloride),  net price 28-tab pack = £18.62. Label: 8   Tablets, atenolol 25 mg, net price 28-tab pack = 83p;  50 mg, 28-tab pack = 86p; 100 mg, 28-tab pack = 91p.  Label: 8   Co-tenidone (Non-proprietary) (MO  Tablets, co-tenidone 50/12.5 (atenolol 50 mg, chlor-  talidone 12.5 mg), net price 28-tab pack = £1.77; co-  tenidone 100/25 (atenolol 100 mg, chlortalidone  25 mg), 28-tab pack = £1.57. Label: 8  Dose hypertension, 1 tablet daily (but see also under Dose  above)   Capsules, red/ivory, atenolol 50 mg, co-amilozide  2.5/25 (anhydrous amiloride hydrochloride 2.5 mg,  hydrochlorothiazide 25 mg), net price 28-cap pack =  £12.17. Label: 8  Dose hypertension, 1 capsule daily    Indications see under Dose  Cautions see under Propranolol Hydrochloride  Contra-indications see under Propranolol Hydro-  chloride   Renal impairment max. 50 mg daily (10 mg on alter-  nate days intravenously) if eGFR 15-35 mL/minute/  1.73 m 2 ; max. 25 mg daily or 50 mg on alternate days  (10 mg every 4 days intravenously) if eGFR less than  15 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see under Propranolol Hydrochloride  Dose   • By mouth, hypertension, 25-50 mg daily (higher doses  rarely necessary)   Angina, 100 mg daily in 1 or 2 doses  Arrhythmias, 50-100 mg daily  Migraine prophylaxis [unlicensed], 50-200 mg daily in  divided doses   • By intravenous injection, arrhythmias, 2.5 mg at a rate  of 1 mg/minute, repeated at 5-minute intervals to a  max. of 10 mg   Note Excessive bradycardia can be countered with intra-  venous injection of atropine sulphate 0.6-2.4mg in divided  doses of 600 micrograms; for overdosage see Emergency  Treatment of Poisoning, p. 37   • By intravenous infusion, arrhythmias, 150 micr-  ograms/kg over 20 minutes, repeated every 12 hours  if required   Early intervention within 12 hours of myocardial  infarction (section 2.10.1), by intravenous injection  over 5 minutes, 5 mg, then by mouth, 50 mg after 15  minutes, 50 mg after 12 hours, then 100 mg daily    Tenoret 50® (AstraZeneca) (Ml  Tablets, brown, f/c, co-tenidone 50/12.5 (atenolol  50 mg, chlortalidone 12.5 mg), net price 28-tab pack =  £1.15. Label: 8  Dose hypertension, 1 tablet daily   Tenoretic® (AstraZeneca) (Ml  Tablets, brown, f/c, co-tenidone 100/25 (atenolol  100 mg, chlortalidone 25 mg), net price 28-tab pack =  £1.25. Label: 8   Capsules, reddish-brown, atenolol 50 mg, nifedipine  20 mg (m/r), net price 28-cap pack = £9.00. Label: 8,  25   Dose hypertension, 1 capsule daily, increased if necessary to  twice daily; ELDERLY, 1 daily  Angina, 1 capsule twice daily   Capsules, reddish-brown, atenolol 50 mg, nifedipine  20 mg (m/r), net price 28-cap pack = £10.63. Label: 8,  25   Dose hypertension, 1 capsule daily increased if necessary to  twice daily; ELDERLY, 1 daily  Angina, 1 capsule twice daily   Contra-indications see under Propranolol Hydro-  chloride; also acute or decompensated heart failure  requiring intravenous inotropes; sino-atrial block   Renal impairment reduce dose if eGFR less than  20 mL/minute/ 1.73 m 2 (max. 10 mg daily)   Side-effects see under Propranolol Hydrochloride;  also less commonly depression, muscle weakness, and  cramp; rarely hypertriglyceridaemia, syncope, and  hearing impairment; very rarely conjunctivitis  Dose   • Hypertension and angina, usually 10 mg once daily  (5 mg may be adequate in some patients); max. 20 mg  daily   1.25 mg once daily (in the morning) for 1 week then, if  well tolerated, increased to 2.5 mg once daily for 1  week, then 3.75 mg once daily for 1 week, then 5 mg  once daily for 4 weeks, then 7.5 mg once daily for 4  weeks, then 10 mg once daily; max. 10 mg daily   Bisoprolol Fumarate (Non-proprietary) (Ml  Tablets, bisoprolol fumarate 5 mg, net price 28-tab  pack = £1.08; 10 mg, 28-tab pack = £1.14. Label: 8   Cardicor® (Merck Serono) (Ml  Tablets, f/c, bisoprolol fumarate 1.25 mg (white), net  price 28-tab pack = £4.90; 2.5 mg (scored, white), 28-  tab pack = £3.40; 3.75 mg (scored, off-white), 28-tab  pack = £4.90; 5 mg (scored, light yellow), 28-tab pack  = £5.90; 7.5 mg (scored, yellow), 28-tab pack = £5.90;  10 mg (scored, orange), 28-tab pack = £5.90. Label: 8   Emcor® (Merck Serono) (Ml  LS Tablets, yellow, f/c, scored, bisoprolol fumarate  5 mg, net price 28-tab pack = £11.30. Label: 8  Tablets, orange, f/c, scored, bisoprolol fumarate  10 mg, net price 28-tab pack = £12.68. Label: 8   Indications hypertension; angina; adjunct to diuretics,  digoxin, or ACE inhibitors in symptomatic chronic  heart failure   Cautions see under Propranolol Hydrochloride;  monitor renal function during dose titration in  patients with heart failure who also have renal  impairment, low blood pressure, ischaemic heart  disease, or diffuse vascular disease  Contra-indications see under Propranolol Hydro-  chloride; acute or decompensated heart failure  requiring intravenous inotropes  Hepatic impairment avoid  Pregnancy see notes above  Breast-feeding see notes above  Side-effects postural hypotension, dizziness, head-  ache, fatigue, gastro-intestinal disturbances, brady-  cardia; occasionally diminished peripheral circulation,  peripheral oedema and painful extremities, dry    mouth, dry eyes, eye irritation or disturbed vision,  impotence, disturbances of micturition, influenza-like  symptoms; rarely angina, AV block, exacerbation of  intermittent claudication or Raynaud’s phenomenon;  allergic skin reactions, exacerbation of psoriasis, nasal  stuffiness, wheezing, depressed mood, sleep distur-  bances, paraesthesia, heart failure, changes in liver  enzymes, thrombocytopenia, leucopenia also  reported  Dose    • Hypertension, initially 12.5 mg once daily, increased  after 2 days to usual dose of 25 mg once daily; if  necessary may be further increased at intervals of at  least 2 weeks to max. 50 mg daily in single or divided  doses; ELDERLY initial dose of 12.5 mg daily may  provide satisfactory control   • Angina, initially 12.5 mg twice daily, increased after 2  days to 25 mg twice daily   • Adjunct in heart failure (section 2.5.5) initially  3.125 mg twice daily (with food), dose increased at  intervals of at least 2 weeks to 6.25 mg twice daily,  then to 12.5 mg twice daily, then to 25 mg twice daily;  increase to highest dose tolerated, max. 25 mg twice  daily in patients with severe heart failure or body-  weight less than 85 kg and 50 mg twice daily in  patients over 85 kg   Carvedilol (Non-proprietary) (Ml  Tablets, carvedilol 3.125 mg, net price 28-tab pack =  £1.10; 6.25 mg, 28-tab pack = £1.25; 12.5 mg, 28-tab  pack = £1.37; 25 mg, 28-tab pack = £1.84. Label: 8   Tablets, scored, carvedilol 3.125 mg (pink), net price  28-tab pack = £7.13; 6.25 mg (yellow), 28-tab pack =  £7.92; 12.5 mg (peach), 28-tab pack = £8.81; 25 mg,  28-tab pack = £11.00. Label: 8   Indications mild to moderate hypertension  Cautions see under Propranolol Hydrochloride  Contra-indications see under Propranolol Hydro-  chloride   Renal impairment reduce dose by half if eGFR 15-  40mL/minute/1.73m 2 ; avoid if eGFR less than  1 5 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects headache, dizziness, fatigue, nausea and  somnolence; also bradycardia, bronchospasm;  depression and pneumonitis reported rarely  Dose   • 200 mg once daily in the morning, increased to  400 mg once daily if necessary   Celiprolol (Non-proprietary) (Ml  Tablets, celiprolol hydrochloride 200 mg, net price 28-  tab pack = £4.53; 400 mg, 28-tab pack = £24.24.  Label: 8, 22   Tablets, f/c, scored, celiprolol hydrochloride 200 mg  (yellow), net price 28-tab pack = £19.83; 400 mg, 28-  tab pack = £39.65. Label: 8, 22   Indications short-term treatment of supraventricular  arrhythmias (including atrial fibrillation, atrial flutter,  sinus tachycardia); tachycardia and hypertension in  peri-operative period   Cautions see under Propranolol Hydrochloride  Contra-indications see under Propranolol Hydro-  chloride   • By intravenous infusion, usually within range 50-  200 micrograms /kg/minute (consult product litera-  ture for details of dose titration and doses during peri-  operative period)   Injection, esmolol hydrochloride 10 mg/mL, net price  10-mL vial = £7.79, 250-mL infusion bag = £89.69   Indications hypertension (including hypertension in  pregnancy, hypertension with angina, and hyper-  tension following acute myocardial infarction);  hypertensive crises (see section 2.5); controlled  hypotension in anaesthesia   Cautions see under Propranolol Hydrochloride; inter-  feres with laboratory tests for catecholamines; liver  damage (see below)   Liver damage Severe hepatocellular damage reported after  both short-term and long-term treatment. Appropriate  laboratory testing needed at first symptom of liver dys-  function and if laboratory evidence of damage (or if jaundice)  labetalol should be stopped and not restarted  Contra-indications see under Propranolol Hydro-  chloride   Renal impairment dose reduction may be required  Pregnancy see notes above  Breast-feeding see notes above  Side-effects postural hypotension (avoid upright  position during and for 3 hours after intravenous  administration), tiredness, weakness, headache,  rashes, scalp tingling, difficulty in micturition, epi-  gastric pain, nausea, vomiting; liver damage (see  above); rarely lichenoid rash  Dose   • By mouth, initially 100 mg (50 mg in elderly) twice  daily with food, increased at intervals of 14 days to  usual dose of 200 mg twice daily; up to 800 mg daily in  2 divided doses (3-4 divided doses if higher); max.  2.4 g daily   • By intravenous injection, 50 mg over at least 1 minute,  repeated after 5 minutes if necessary; max. total dose  200 mg   Note Excessive bradycardia can be countered with intra-  venous injection of atropine sulphate 0.6-2.4mg in divided  doses of 600 micrograms; for overdosage see Emergency  Treatment of Poisoning, p. 37   • By intravenous infusion, 2 mg/minute until satisfac-  tory response then discontinue; usual total dose 50-  200 mg, (not recommended for phaeochromocytoma,  see under Phaeochromocytoma, section 2.5.4)    Hypertension of pregnancy, 20 mg/hour, doubled  every 30 minutes; usual max. 160 mg/hour  Hypertension following myocardial infarction, 15 mg/  hour, gradually increased to max. 120 mg/hour   Labetalol Hydrochloride (Non-proprietary) (Ml  Tablets, f/c, labetalol hydrochloride 100 mg, net  price, 56 = £7.85; 200 mg, 56 = £11.49; 400 mg, 56 =  £20.60. Label: 8, 21   Tablets, all orange, f/c, labetalol hydrochloride 50 mg,  net price 56-tab pack = £3.64; 100 mg, 56-tab pack =  £4.01; 200 mg, 56-tab pack = £6.51; 400 mg, 56-tab  pack = £9.05. Label: 8, 21   • By mouth, hypertension, initially 100 mg daily,  increased if necessary to 200 mg daily in 1-2 divided  doses; max. 400 mg daily (but high doses rarely  necessary)   Angina, 50-100 mg 2-3 times daily  Arrhythmias, usually 50 mg 2-3 times daily; up to  300 mg daily in divided doses if necessary  Migraine prophylaxis, 100-200 mg daily in divided  doses   • By intravenous injection, arrhythmias, up to 5 mg at  rate 1-2 mg/minute, repeated after 5 minutes if  necessary, total dose 10-15 mg   Note Excessive bradycardia can be countered with intra-  venous injection of atropine sulphate 0.6-2.4mg in divided  doses of 600 micrograms; for overdosage see Emergency  Treatment of Poisoning, p. 37  In surgery, by slow intravenous injection 2-4 mg at  induction or to control arrhythmias developing during  anaesthesia; 2-mg doses may be repeated to a max. of  10 mg   Early intervention within 12 hours of infarction, by  intravenous injection 5 mg every 2 minutes to a max.  of 15 mg, followed after 15 minutes by 50 mg by  mouth every 6 hours for 48 hours; maintenance  200 mg daily in divided doses   Tablets, metoprolol tartrate 50 mg, net price 28 =  £1.31, 56 = £1.74; 100 mg, 28 = £1.59, 56 = £2.51.  Label: 8   Betaloc® (AstraZeneca) (Mi  Injection, metoprolol tartrate 1 mg/mL, net price 5-  mL amp = 42p   Tablets, f/c, scored, metoprolol tartrate 50 mg (pink),  net price 56-tab pack = £2.57; 100 mg (blue), 56-tab  pack = £6.68. Label: 8   Tablets, m/r, yellow, f/c, metoprolol tartrate 200 mg,  net price 28-tab pack = £9.80. Label: 8, 25  Dose hypertension, 200 mg daily; angina, 200-400 mg daily;  migraine prophylaxis, 200 mg daily   Renal impairment increase dosage interval if eGFR  less than 50 mL/minute/ 1.73 m 2   • Hypertension, initially 80 mg once daily, increased in  increments of up to 80 mg at weekly intervals if  required; max. 240 mg daily (higher doses rarely  necessary)   • Angina, initially 40 mg once daily, increased at weekly  intervals if required; usual max. 160 mg daily (rarely  up to 240 mg may be required)   • Arrhythmias, initially 40 mg once daily, increased at  weekly intervals up to 160 mg if required; reduce to  40 mg if bradycardia occurs   • Migraine prophylaxis, initially 40 mg once daily,  increased in 40 mg increments at weekly intervals  according to response; usual maintenance dose 80-  160 mg once daily   Corgard® (Sanofi-Aventis) (Ml  Tablets, blue, scored, nadolol 80 mg, net price 28-tab  pack = £5.00. Label: 8   Indications essential hypertension; adjunct in stable  mild to moderate heart failure in patients over 70  years   Renal impairment for hypertension, initially 2.5 mg  once daily, increased to 5 mg once daily if required; for  heart failure, manufacturer advises avoid if serum  creatinine greater than 250micromol/litre  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see under Propranolol Hydrochloride;   • Hypertension, 5 mg daily; ELDERLY initially 2.5 mg  daily, increased if necessary to 5 mg daily   • Adjunct in heart failure (section 2.5.5), initially  1.25 mg once daily, then if tolerated increased at  intervals of 1-2 weeks to 2.5 mg once daily, then to  5 mg once daily, then to max. 10 mg once daily   Tablets, nebivolol (as hydrochloride) 5 mg, net price  28-tab pack = £3.98. Label: 8   Tablets, scored, nebivolol (as hydrochloride) 5 mg, net  price 28-tab pack = £9.23. Label: 8  Note Also available as Hypoloc ®   • Hypertension, 80-160 mg daily in 2-3 divided doses,  increased as required; max. 320 mg daily   • Angina, 80-160 mg daily in 2-3 divided doses; max.  320 mg daily   • Arrhythmias, 40-240 mg daily in 2-3 divided doses;  max. 240 mg daily   • Anxiety symptoms (short-term use), 40-80 mg daily  in 1-2 divided doses   Tablets, coated, oxprenolol hydrochloride 20 mg, net  price 56 = £1.86; 40 mg, 56 = £3.73; 80 mg, 56 = £6.20;  160 mg, 20 =£2.36. Label: 8   Tablets, f/c, oxprenolol hydrochloride 20 mg (contain  gluten), net price 56-tab pack = £1.86; 40 mg (contain  gluten), 56-tab pack = £3.73; 80 mg (yellow), 56-tab  pack = £6.20. Label: 8   Tablets, m/r, f/c, oxprenolol hydrochloride 160 mg,  net price 28-tab pack = £7.50. Label: 8, 25  Dose hypertension, angina, initially 160 mg once daily; if  necessary may be increased to max. 320 mg daily   Tablets, red, s/c, co-prenozide 160/0.25 (oxprenolol  hydrochloride 160 mg (m/r), cyclopenthiazide  250 micrograms), net price 28-tab pack = £10.66.  Label: 8, 25   Dose hypertension, 1 tablet daily, increased if necessary to 2  daily as a single dose   • Hypertension, initially 5 mg 2-3 times daily or 15 mg  once daily, increased as required at weekly intervals;  usual maintenance 15-30 mg daily; max. 45 mg daily   Pindolol (Non-proprietary) (Ml  Tablets, pindolol 5 mg, net price 100-tab pack = £7.81.  Label: 8   Tablets, scored, pindolol 5 mg, net price 56-tab pack  = £5.85; 15 mg, 28-tab pack = £8.79. Label: 8   4With diuretic  Viskaldix® (Amdipharm) (Ml  Tablets, scored, pindolol 10 mg, clopamide 5 mg, net  price 28-tab pack = £6.70. Label: 8  Dose hypertension, 1 tablet daily in the morning, increased if  necessary to 2 daily; max. 3 daily   Indications life-threatening arrhythmias including  ventricular tachyarrhythmias; symptomatic non-sus-  tained ventricular tachyarrhythmias; prophylaxis of  paroxysmal atrial tachycardia or fibrillation, paroxys-  mal AV re-entrant tachycardias (both nodal and  involving accessory pathways), and paroxysmal  supraventricular tachycardia after cardiac surgery;  maintenance of sinus rhythm following cardioversion  of atrial fibrillation or flutter    Cautions see under Propranolol Hydrochloride; cor-  rect hypokalaemia, hypomagnesaemia, or other  electrolyte disturbances; severe or prolonged diarr-  hoea; interactions: Appendix 1 (beta-blockers),  important: verapamil interaction see also p. 133  Contra-indications see under Propranolol Hydro-  chloride; congenital or acquired long QT syndrome;  torsade de pointes; renal failure  Renal impairment use half normal dose if eGFR 30-  60 mL/minute/1.73 m 2 ; use one-quarter normal dose  if eGFR 10-30 mL/minute/ 1.73 m 2 ; avoid if eGFR  less than 10 mL/minute/ 1.73 m 2    Pregnancy see notes above  Breast-feeding see notes above  Side-effects see under Propranolol Hydrochloride;  arrhythmogenic (pro-arrhythmic) effect (torsade de  pointes — increased risk in women)   • By mouth with ECG monitoring and measurement of  corrected QT interval, arrhythmias, initially 80 mg  daily in 1-2 divided doses increased gradually at  intervals of 2-3 days to usual dose of 160-320 mg  daily in 2 divided doses; higher doses of 480-640 mg  daily for life-threatening ventricular arrhythmias  under specialist supervision    Sotalol (Non-proprietary) (MO  Tablets, sotalol hydrochloride 40 mg, net price 56 =  £1.29; 80 mg, 56 = £1.91; 160 mg, 28 =£2.32. Label: 8    Beta-Cardone® (UCB Pharma) (Ml  Tablets, scored, sotalol hydrochloride 40 mg (green),  net price 56-tab pack = £1.29; 80 mg (pink), 56-tab  pack = £1.91; 200 mg, 28-tab pack = £2.40. Label: 8    Sotacor® (Bristol-Myers Squibb) [Ml  Tablets, scored, sotalol hydrochloride 80 mg, net  price 28-tab pack = £3.06. Label: 8   Indications see under Dose; glaucoma (section 11.6)  Cautions see under Propranolol Hydrochloride  Contra-indications see under Propranolol Hydro-  chloride   • Hypertension, initially 10 mg daily in 1-2 divided  doses; gradually increased if necessary to max. 60 mg  daily, usual maintenance dose 10-30 mg daily (doses  above 30 mg daily given in divided doses)   • Angina, initially 5 mg twice daily increased if neces-  sary by 10 mg daily every 3-4 days; max. 30 mg twice  daily   • Prophylaxis after myocardial infarction, initially 5 mg  twice daily, increased after 2 days to 10 mg twice daily  if tolerated   Tablets, scored, timolol maleate 10 mg, amiloride  hydrochloride 2.5 mg, hydrochlorothiazide 25 mg, net  price 28-tab pack = £29.87. Label: 8  Dose hypertension, 1-2 tablets daily   Tablets, scored, timolol maleate 10 mg, bendroflu-  methiazide 2.5 mg, net price 30-tab pack = £3.49.  Label: 8   Hypertension Lowering raised blood pressure  decreases the risk of stroke, coronary events, heart  failure, and renal impairment. Advice on antihyper-  tensive therapy in this section takes into account the  recommendations of the Joint British Societies (JBS2:  British Societies’ guidelines on prevention of cardiovas-  cular disease in clinical practice. Heart 2005; 91 (Suppl  V): vl-v52).   Possible causes of hypertension (e.g. renal disease,  endocrine causes), contributory factors, risk factors,  and the presence of any complications of hypertension,  such as left ventricular hypertrophy, should be estab-  lished. Patients should be given advice on lifestyle    changes to reduce blood pressure or cardiovascular risk;  these include smoking cessation, weight reduction,  reduction of excessive intake of alcohol, reduction of  dietary salt, reduction of total and saturated fat, increas-  ing exercise, and increasing fruit and vegetable intake.   Thresholds and targets for treatment The follow-  ing thresholds for treatment 1 are recommended:   • Severe hypertension with acute target-organ  damage, or severe hypertension (systolic blood  pressure >180 mmHg or diastolic >110 mmHg)  without acute target-organ damage, treat promptly  (see Hypertensive crises, p. 106)   • When the initial blood pressure is systolic 160-  179mmHg or diastolic 100-109 mmHg, and the  patient has cardiovascular complications, target-  organ damage (e.g. left ventricular hypertrophy,  renal impairment) or diabetes mellitus (type 1 or  2), confirm over 3-4 weeks then treat if these values  are sustained;   • When the initial blood pressure is systolic 160-  179 mmHg or diastolic 100-109 mmHg, but the  patient has no cardiovascular complications, no  target-organ damage, or no diabetes, advise lifestyle  changes, reassess weekly initially and treat if these  values are sustained on repeat measurements over  4-12 weeks;   • When the initial blood pressure is systolic 140—  159 mmHg or diastolic 90-99 mmHg and the  patient has cardiovascular complications, target-  organ damage or diabetes, confirm within 12  weeks and treat if these values are sustained;   • When the initial blood pressure is systolic 140—  159 mmHg or diastolic 90-99 mmHg and no cardi-  ovascular complications, no target-organ damage,  or no diabetes, advise lifestyle changes and reas-  sess monthly; treat persistent mild hypertension if  the 10-year cardiovascular disease risk is 20% or  more. 2   A target systolic blood pressure < 140 mmHg and dia-  stolic blood pressure < 90 mmHg is suggested. A lower  target systolic blood pressure < 130 mmHg and diasto-  lic blood pressure < 80 mmHg should be considered for  those with established atherosclerotic cardiovascular  disease, diabetes, or chronic renal failure. In some  individuals it may not be possible to reduce blood  pressure below the suggested targets despite the use  of appropriate therapy.   Drug treatment of hypertension Response to drug  treatment for hypertension may be affected by the  patient’s age and ethnic background. An ACE inhibitor  (section 2. 5. 5.1) or an angiotensin-II receptor antago-  nist (section 2. 5. 5. 2) may be the most appropriate initial  drug in younger Caucasians; however a beta-blocker  may be considered if an ACE inhibitor or an angio-  tensin-II receptor antagonist is not tolerated or is con-  tra-indicated (see also Hypertension in Pregnancy,   1. Thresholds and targets for treatment based on blood  pressure measured in clinic may not apply to ambulatory  or home blood-pressure monitoring, which usually give  lower values.   2. Cardiovascular disease risk may be determined from the  chart issued by the Joint British Societies ( Heart 2005; 91  (Suppl V): vl-v52) — see inside back cover. The Joint  British Societies’ ‘Cardiac Risk Assessor’ computer pro-  gramme may also be used to determine cardiovascular  disease risk.    p. 106). Afro-Caribbean patients and those aged over  55 years respond less well to ACE inhibitors and angio-  tensin-II receptor antagonists, therefore a thiazide (sec-  tion 2.2.1) or a calcium-channel blocker (section 2.6.2)  may be chosen for initial treatment.   Beta-blockers, especially when combined with a thia-  zide diuretic, should be avoided for the routine treat-  ment of uncomplicated hypertension in patients with  diabetes or in those at high risk of developing diabetes.   A single antihypertensive drug is often not adequate and  other antihypertensive drugs are usually added in a  step-wise manner until control is achieved. Unless it is  necessary to lower the blood pressure urgently, an  interval of at least 4 weeks should be allowed to deter-  mine response.   When two antihypertensive drugs are needed, an ACE  inhibitor or an angiotensin-II receptor antagonist can be  combined with either a thiazide or a calcium-channel  blocker.    If control is inadequate with 2 drugs, a thiazide and a  calcium-channel blocker can be added. The addition of  an alpha-blocker (section 2.5.4), spironolactone,  another diuretic, or a beta-blocker should be considered  in resistant hypertension. In patients with primary  hyperaldosteronism, spironolactone (section 2.2.3) is  effective.   Aspirin (section 2.9) in a dose of 75 mg daily reduces  the risk of cardiovascular events and myocardial infarc-  tion. Unduly high blood pressure must be controlled  before aspirin is given. Unless contra-indicated, aspirin  is recommended for all patients with established cardi-  ovascular disease. Use of aspirin in primary prevention,  in those with or without diabetes, is of unproven benefit  (see also section 2.9).    Lipid-regulating drugs can also be of benefit in cardio-  vascular disease or in those who are at high risk of  developing cardiovascular disease (section 2.12).    Hypertension in the elderly Benefit from antihyper-  tensive therapy is evident up to at least 80 years of age,  but it is probably inappropriate to apply a strict age limit  when deciding on drug therapy. Patients who reach 80  years of age while taking antihypertensive drugs should  continue treatment, provided that it continues to be of  benefit and does not cause significant side-effects. The  thresholds for treatment are diastolic pressure averaging   > 160 mmHg over 3 to 6 months’ observation (despite  appropriate lifestyle interventions). Treatment with a  low dose of a thiazide or a dihydropyridine calcium-  channel blocker is effective. An ACE inhibitor (or an  angiotensin-II receptor antagonist) (section 2.5.5) can  be added if necessary.    Isolated systolic hypertension Isolated systolic  hypertension (systolic pressure > 160 mmHg, diastolic  pressure < 90 mmHg) is associated with an increased  cardiovascular disease risk, particularly in those aged  over 60 years. Systolic blood pressure averaging  160 mmHg or higher over 3 to 6 months (despite appro-  priate lifestyle interventions) should be lowered in those  over 60 years, even if diastolic hypertension is absent.  Treatment with a low dose of a thiazide or a dihydro-  pyridine calcium-channel blocker is effective. An ACE  inhibitor (or an angiotensin-II receptor antagonist) (sec-    tion 2.5.5) can be added if necessary. Patients with  severe postural hypotension should not receive blood  pressure lowering drugs.   Isolated systolic hypertension in younger patients is  uncommon but treatment may be indicated in those  with a threshold systolic pressure of 160 mmHg (or less  if at increased risk of cardiovascular disease, see above).    Hypertension in diabetes For patients with diabetes,  the aim should be to maintain systolic pressure  < 130 mmHg and diastolic pressure < 80 mmHg. How-  ever, in some individuals, it may not be possible to  achieve this level of control despite appropriate therapy.  Most patients require a combination of antihypertensive  drugs.   Hypertension is common in type 2 diabetes, and anti-  hypertensive treatment prevents macrovascular and  microvascular complications. In type 1 diabetes, hyper-  tension usually indicates the presence of diabetic  nephropathy. An ACE inhibitor (or an angiotensin-II  receptor antagonist) may have a specific role in the  management of diabetic nephropathy (section 6.1.5);  in patients with type 2 diabetes, an ACE inhibitor (or  an angiotensin-II receptor antagonist) can delay pro-  gression of microalbuminuria to nephropathy.   Hypertension in renal disease The threshold for  antihypertensive treatment in patients with renal  impairment or persistent proteinuria is a systolic  blood pressure > 140 mmHg or a diastolic blood pres-  sure > 90 mmHg. Optimal blood pressure is a systolic  blood pressure < 130 mmHg and a diastolic pressure  < 80 mmHg, or lower if proteinuria exceeds 1 g in 24  hours. An ACE inhibitor (or an angiotensin-II receptor  antagonist) should be considered for patients with pro-  teinuria; however, ACE inhibitors should be used with  caution in renal impairment, see section 2.5.5. 1. Thia-  zide diuretics may be ineffective and high doses of loop  diuretics may be required. A dihydropyridine calcium  channel blocker can be added.    Hypertension in pregnancy Hypertensive complica-  tions in pregnancy can be hazardous for both the mother  and the fetus, and are associated with a significant risk  of morbidity and mortality; complications can occur in  pregnant women with pre-existing chronic hyper-  tension, or in those who develop hypertension in the  latter half of pregnancy.   Labetalol (section 2.4) is widely used for treating hyper-  tension in pregnancy. Methyldopa (section 2.5.2) is  considered safe for use in pregnancy. Modified-release  preparations of nifedipine [unlicensed] are also used,  but see section 2.6.2 (p. 132) for warnings on use during  pregnancy.   The following advice takes into account the recommen-  dations of NICE Clinical Guideline 107 (August 2010),  Hypertension in Pregnancy.   Pregnant women with chronic hypertension who are  already receiving antihypertensive treatment should  have their drug therapy reviewed. In uncomplicated  chronic hypertension, a target blood pressure of  <150/100 mmHg is recommended; women with tar-  get-organ damage as a result of chronic hypertension,  and in women with chronic hypertension who have  given birth, a target blood pressure of <140/90 mmHg  is advised. Long-term antihypertensive treatment    should be reviewed 2 weeks following the birth.  Women managed with methyldopa during pregnancy  should discontinue treatment and restart their original  antihypertensive medication within 2 days of the birth.   Pregnant women are at high risk of developing pre-  eclampsia if they have chronic kidney disease, diabetes  mellitus, autoimmune disease, chronic hypertension, or  if they have had hypertension during a previous  pregnancy; these women are advised to take aspirin  (section 2.9) in a dose of 75 mg once daily [unlicensed  indication] from week 12 of pregnancy until the baby is  bom. Women with more than one moderate risk factor  (first pregnancy, aged >40 years, pregnancy interval  >10 years, BMI >35 kg/m 2 at first visit, multiple  pregnancy, or family history of pre-eclampsia) for devel-  oping pre-eclampsia are also advised to take aspirin  75 mg once daily [unlicensed indication] from week 12  of pregnancy until the baby is bom.   Women with pre-eclampsia or gestational hypertension  who present with a blood pressure over 150/  100 mmHg, should receive initial treatment with oral  labetalol to achieve a target blood pressure of  <150 mmHg systolic, and diastolic 80-100 mmHg. If  labetalol is unsuitable, methyldopa or modified-release  nifedipine may be considered. Women with gestational  hypertension or pre-eclampsia who have been managed  with methyldopa during pregnancy should discontinue  treatment within 2 days of the birth. Women with a  blood pressure of > 160/ 1 10 mmHg who require critical  care during pregnancy or after birth should receive  immediate treatment with either oral or intravenous  labetalol, intravenous hydralazine (section 2.5.1), or  oral modified-release nifedipine to achieve a target  blood pressure of <150 mmHg systolic, and diastolic  80-100 mmHg.   For use of magnesium sulphate in pre-eclampsia and  eclampsia, see section 9.5. 1.3.    Hypertensive crises If blood pressure is reduced too  quickly in the management of hypertensive crises, there  is a risk of reduced organ perfusion leading to cerebral  infarction, blindness, deterioration in renal function, and  myocardial ischaemia.   A hypertensive emergency is defined as severe hyper-  tension with acute damage to the target organs (e.g.  signs of papilloedema or retinal haemorrhage, or the  presence of clinical conditions such as acute coronary  syndromes, acute aortic dissection, acute pulmonary  oedema, hypertensive encephalopathy, acute cerebral  infarction, intracerebral or subarachnoid haemorrhage,  eclampsia, or rapidly progressing renal failure); prompt  treatment with intravenous antihypertensive therapy is  generally required. Over the first few minutes or within  2 hours, blood pressure should be reduced by 20-25%.  When intravenous therapy is indicated, treatment  options include sodium nitroprusside [unlicensed] (sec-  tion 2.5.1), labetalol (section 2.4), glyceryl trinitrate  (section 2.6.1), phentolamine (section 2.5.4), hydral-  azine (section 2.5.1), or esmolol (section 2.4); choice  of drug is dependent on concomitant conditions and  clinical status of the patient.   Severe hypertension (blood pressure >180/ 1 10 mmHg)  without acute target-organ damage is defined as a  hypertensive urgency, blood pressure should be reduced  gradually over 24-48 hours with oral antihypertensive  therapy, such as labetalol, or the calcium-channel block-    ers (section 2.6.2) amlodipine, felodipine, or isradipine.  Use of sublingual nifedipine is not recommended.   For advice on short-term management of hypertensive  episodes in phaeochromocytoma, see under Phaeo-  chromocytoma, section 2.5.4.   Vasodilators have a potent hypotensive effect, espe-  cially when used in combination with a beta-blocker  and a thiazide. Important: for a warning on the hazards  of a very rapid fall in blood pressure, see Hypertensive  crises, p. 106.   Diazoxide has been used by intravenous injection in  hypertensive emergencies, however alternative treat-  ments are preferred (see section 2.5)   Hydralazine is given by mouth as an adjunct to other  antihypertensives for the treatment of resistant hyper-  tension but is rarely used; when used alone it causes  tachycardia and fluid retention. The incidence of side-  effects is lower if the dose is kept below 100 mg daily,  but systemic lupus erythematosus should be suspected  if there is unexplained weight loss, arthritis, or any other  unexplained ill health.   Sodium nitroprusside [unlicensed] is given by intra-  venous infusion to control severe hypertensive emer-  gencies when parenteral treatment is necessary.   Minoxidil should be reserved for the treatment of  severe hypertension resistant to other drugs. Vasodila-  tation is accompanied by increased cardiac output and  tachycardia and the patients develop fluid retention. For  this reason the addition of a beta-blocker and a diuretic  (usually furosemide, in high dosage) are mandatory.  Hypertrichosis is troublesome and renders this drug  unsuitable for women.   Prazosin, doxazosin, and terazosin (section 2.5.4) have  alpha-blocking and vasodilator properties.  Ambrisentan, bosentan, iloprost, sildenafil, sitaxen-  tan, and tadalafil are licensed for the treatment of  pulmonary arterial hypertension and should be used  under specialist supervision. Epoprostenol (section  2.8.1) can be used in patients with primary pulmonary  hypertension resistant to other treatments. Bosentan is  also licensed to reduce the number of new digital ulcers  in patients with systemic sclerosis and ongoing digital  ulcer disease.   The Scottish Medicines Consortium (p. 4) has advised  (November 2005) that iloprost ( Ventavis ®) is accepted  for restricted use within NHS Scotland in patients in  whom bosentan is ineffective or not tolerated, and  should only be prescribed by specialists in the Scottish  Pulmonary Vascular Unit.   The Scottish Medicines Consortium (p. 4) has advised  (October 2008) that ambrisentan ( Volibris ®) should be  prescribed only by specialists in the Scottish Pulmonary  Vascular Unit or other similar specialists.   The Scottish Medicines Consortium (p. 4) has advised  (January 2010) that sildenafil ( Revatio ®) should be  prescribed only by specialists in the Scottish Pulmonary  Vascular Unit or other similar specialists.   Sitaxentan ( Thelin ®) is to be withdrawn from  worldwide markets due to severe, sometimes fatal,  hepatotoxicity; the benefits of treatment with  sitaxentan no longer outweigh the risks. Patients  currently taking sitaxentan are advised not to stop  until their treatment has been reviewed by their  prescriber; patients should be switched to a suitable  alternative as soon as possible. Patients with  abnormal liver function tests at the time of  sitaxentan discontinuation should be monitored  regularly until liver enzymes return to within the  normal range.    Indications pulmonary arterial hypertension  Cautions not to be initiated in significant anaemia;  monitor haemoglobin concentration or haematocrit  after 1 month and 3 months of starting treatment, and  periodically thereafter (reduce dose or discontinue  treatment if significant decrease in haemoglobin  concentration or haematocrit observed); monitor liver  function before treatment, and monthly thereafter —  discontinue if liver enzymes raised significantly or if  symptoms of liver impairment develop  Hepatic impairment avoid in severe impairment  Renal impairment use with caution if eGFR less than  30 mL/minute/ 1.73 m 2   Pregnancy avoid (teratogenic in animal studies);  exclude pregnancy before treatment and ensure  effective contraception during treatment; monthly  pregnancy tests advised   Side-effects abdominal pain, constipation; palpita-  tion, flushing, peripheral oedema; upper respiratory-  tract disorders; headache; anaemia; less commonly  hypersensitivity reactions (including angioedema and  rash)    • ADULT over 18 years, 5 mg once daily, increased if  necessary to 10 mg once daily   Tablets, f/c, ambrisentan 5 mg (pale pink), net price  30-tab pack = £1618.08; 10 mg (dark pink), 30-tab  pack = £1618.08   Indications pulmonary arterial hypertension; sys-  temic sclerosis with ongoing digital ulcer disease (to  reduce number of new digital ulcers)   Cautions not to be initiated if systemic systolic blood  pressure is below 85 mmHg; monitor haemoglobin  before and during treatment (monthly for first 4  months, then 3-monthly); avoid abrupt withdrawal;  monitor liver function before treatment, at monthly  intervals during treatment, and 2 weeks after dose  increase (reduce dose or suspend treatment if liver  enzymes raised significantly) — discontinue if symp-  toms of liver impairment; interactions: Appendix 1  (bosentan)    Pregnancy avoid (teratogenic in animal studies);  effective contraception required during and for at  least 3 months after administration (hormonal  contraception not considered effective); monthly  pregnancy tests advised   Side-effects gastro-intestinal disturbances, dry  mouth, rectal haemorrhage, hepatic impairment (see  Cautions, above); flushing, hypotension, palpitation,  oedema, chest pain; dyspnoea; headache, dizziness,  fatigue; back pain and pain in extremities; anaemia;  hypersensitivity reactions (including rash, pruritus,  and anaphylaxis)   • Pulmonary arterial hypertension, initially 62.5 mg  twice daily increased after 4 weeks to 125 mg twice  daily; max. 250 mg twice daily; CHILD under 12 years  see BNF for Children   • Systemic sclerosis with ongoing digital ulcer disease,  initially 62.5 mg twice daily increased after 4 weeks to  125 mg twice daily   Tracleer® (Actelion) T [Ml  Tablets, f/c, orange, bosentan (as monohydrate)  62.5 mg, net price 56-tab pack = £1510.21; 125 mg,  56-tab pack = £1510.21   Renal impairment dose reduction may be required  Pregnancy prolonged use may produce alopecia,  hypertrichosis, and impaired glucose tolerance in  neonate; inhibits uterine activity during labour  Side-effects tachycardia, hypotension, hyperglyc-  aemia, sodium and water retention; rarely cardiome-  galy, hyperosmolar non-ketotic coma, leucopenia,  thrombocytopenia, and hirsuitism  Dose   • By rapid intravenous injection (less than 30 seconds),  1-3 mg/kg to max. single dose of 150 mg (see below);  may be repeated after 5-1 5 minutes if required  Note Single doses of 300 mg have been associated with  angina and with myocardial and cerebral infarction   Indications moderate to severe hypertension  (adjunct); heart failure (with long-acting nitrate, but  see section 2.5.5); hypertensive emergencies (includ-  ing during pregnancy) (see section 2.5)   Cautions coronary artery disease (may provoke  angina, avoid after myocardial infarction until stabi-  lised), cerebrovascular disease; occasionally blood  pressure reduction too rapid even with low parenteral  doses; manufacturer advises test for antinuclear factor  and for proteinuria every 6 months and check acet-   Contra-indications idiopathic systemic lupus erythe-  matosus, severe tachycardia, high output heart failure,  myocardial insufficiency due to mechanical obstruc-  tion, cor pulmonale, dissecting aortic aneurysm; acute  porphyria (section 9.8.2)   Renal impairment reduce dose if eGFR less than  30 mL/minute/ 1.73 m 2   Pregnancy neonatal thrombocytopenia reported, but  risk should be balanced against risk of uncontrolled  maternal hypertension; manufacturer advises avoid  before third trimester   Breast-feeding present in milk but not known to be  harmful; monitor infant   Side-effects tachycardia, palpitation, flushing, hypo-  tension, fluid retention, gastro-intestinal disturbances;  headache, dizziness; systemic lupus erythematosus-  like syndrome after long-term therapy with over  100 mg daily (or less in women and in slow acetylator  individuals) (see also notes above); rarely rashes,  fever, peripheral neuritis, polyneuritis, paraesthesia,  arthralgia, myalgia, increased lacrimation, nasal con-  gestion, dyspnoea, agitation, anxiety, anorexia; blood  disorders (including leucopenia, thrombocytopenia,  haemolytic anaemia), abnormal liver function, jaun-  dice, raised plasma creatinine, proteinuria and hae-  maturia reported  Dose   • By mouth, hypertension, 25 mg twice daily, increased  to usual max. 50 mg twice daily (see notes above)  Heart failure (initiated in hospital) 25 mg 3-4 times  daily, increased every 2 days if necessary; usual  maintenance dose 50-75 mg 4 times daily   • By slow intravenous injection, hypertensive emer-  gencies and hypertension with renal complications,  5-10 mg diluted with 10 mL sodium chloride 0.9%;  may be repeated after 20-30 minutes (see Cautions)   • By intravenous infusion, hypertensive emergencies  and hypertension with renal complications, initially  200-300 micrograms/minute; maintenance usually  50-150 micrograms/minute   Hydralazine (Non-proprietary) (Ml  Tablets, hydralazine hydrochloride 25 mg, net price  56 =£9.32; 50 mg, 56 = £16.84   Tablets, yellow, s/c, hydralazine hydrochloride 25 mg,  net price 84-tab pack = £3.38   Cautions unstable pulmonary hypertension with  advanced right heart failure; hypotension (do not  initiate if systolic blood pressure below 85 mmHg);  acute pulmonary infection; chronic obstructive  pulmonary disease; severe asthma; interactions:  Appendix 1 (iloprost)   Contra-indications unstable angina; within 6 months  of myocardial infarction; decompensated cardiac  failure (unless under close medical supervision);    severe arrhythmias; congenital or acquired heart-  valve defects; within 3 months of cerebrovascular  events; pulmonary veno-occlusive disease; conditions  which increase risk of bleeding   Pregnancy manufacturer advises avoid (toxicity in  animal studies); effective contraception must be used  during treatment   Side-effects vasodilatation, hypotension, syncope,  cough, headache, throat or jaw pain; nausea, vomi-  ting, diarrhoea, chest pain, dyspnoea, bronchospasm,  and wheezing also reported   • By inhalation of nebulised solution, initial dose  2.5 micrograms increased to 5 micrograms for second  dose, if tolerated maintain at 5 micrograms 6-9 times  daily according to response; reduce to 2.5 micrograms  6-9 times daily if higher dose not tolerated; CHILD 8-  18 years see BNF for Children   Ventavis® (Bayer Schering) tMO  Nebuliser solution, iloprost (as trometamol)  lOmicrograms/mL, net price 30 x 1-mL (10 micr-  ogram) unit-dose vials = £400.19, 168 x 1-mL =  £2241.08. For use with Prodose ® (SH?I or Venta-Neb®  nebuliser   Indications severe hypertension, in addition to a  diuretic and a beta-blocker  Cautions see notes above; angina; after myocardial  infarction (until stabilised); lower doses in dialysis  patients; acute porphyria (section 9.8.2); interactions:  Appendix 1 (vasodilator antihypertensives)  Contra-indications phaeochromocytoma  Renal impairment use with caution in significant  impairment   Side-effects sodium and water retention; weight gain,  peripheral oedema, tachycardia, hypertrichosis;  reversible rise in creatinine and blood urea nitrogen;  occasionally, gastro-intestinal disturbances, breast  tenderness, rashes  Dose   • Initially 5 mg (ELDERLY, 2.5 mg) daily, in 1-2 divided  doses, increased in steps of 5-10 mg at intervals of at  least 3 days; max. 100 mg daily (seldom necessary to  exceed 50 mg daily)   Loniten® (Pharmacia) (Ml  Tablets, scored, minoxidil 2.5 mg, net price 60-tab  pack = £8.88; 5 mg, 60-tab pack = £15.83; 10 mg, 60-  tab pack = £30.68    Cautions hypotension (avoid if systolic blood pressure  below 90 mmHg); intravascular volume depletion; left  ventricular outflow obstruction; cardiovascular dis-  ease; autonomic dysfunction; pulmonary veno-  occlusive disease; anatomical deformation of the  penis, predisposition to priapism; bleeding disorders  or active peptic ulceration; consider gradual with-  drawal; interactions: Appendix 1 (sildenafil)  Contra-indications recent history of stroke or myo-  cardial infarction, history of non-arteritic anterior  ischaemic optic neuropathy; hereditary degenerative  retinal disorders; avoid concomitant use of nitrates  Hepatic impairment for pulmonary hypertension, if  usual dose not tolerated, reduce oral dose to 20 mg  twice daily, or reduce intravenous dose to 10 mg twice  daily; manufacturer advises avoid in severe impair-  ment    Renal impairment for pulmonary hypertension, if  usual dose not tolerated, reduce oral dose to 20 mg  twice daily, or reduce intravenous dose to 10 mg twice  daily   Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no evidence of harm in ani-  mal studies   Side-effects gastro-intestinal disturbances, dry  mouth; flushing, oedema; bronchitis, cough; head-  ache, migraine, night sweats, paraesthesia, insomnia,  anxiety, tremor, vertigo; fever, influenza-like symp-  toms; anaemia; back and limb pain, myalgia; visual  disturbances, retinal haemorrhage, photophobia,  painful red eyes; nasal congestion, epistaxis; cellulitis,  alopecia; less commonly gynaecomastia, priapism;  also reported rash, retinal vascular occlusion and non-  arteritic anterior ischaemic optic neuropathy (dis-  continue if sudden visual impairment), and sudden  hearing loss (advise patient to seek medical help)   • By intravenous injection, when oral route not appro-  priate, 10 mg three times daily   Tablets, f/c, sildenafil (as citrate), 20 mg, net price 90-  tab pack = £373.50   Injection, sildenafil (as citrate), 800 micrograms/mL,  net price 50-mL vial = £45.28   Cautions test liver function before treatment and  monitor monthly during treatment (discontinue  treatment if liver enzymes significantly raised); mea-  sure haemoglobin concentration before treatment,  after 1-3 months, then every 3 months; interactions:  Appendix 1 (sitaxentan)   Side-effects gastro-intestinal disturbances; peripheral  oedema, flushing; headache, insomnia, fatigue, dizzi-  ness; decreased haemoglobin, prolonged prothrombin  time, increased INR; muscle cramp; nasal congestion,  epistaxis    • Heart failure, by intravenous infusion, initially 10-  15 micrograms /minute, increased every 5-10 min-  utes as necessary; usual range 10-200 micrograms/  minute normally for max. 3 days    Thelin® (Encysive) ▼ tMl  Tablets, f/c, yellow-orange, sitaxentan sodium  100 mg, net price 28-tab pack = £1540.00  Note All orders of Thelin should be based on a prescription  from a specialist in Pulmonary Arterial Hypertension, who has  received appropriate training as part of the Programmed  Access to Sitaxentan Sodium (PASS) scheme. Orders should be  placed with Polarspeed at 01525 217211   Indications hypertensive emergencies (see section  2.5); controlled hypotension in anaesthesia; acute or  chronic heart failure   Cautions hypothyroidism, hyponatraemia, ischaemic  heart disease, impaired cerebral circulation, elderly;  hypothermia; monitor blood pressure and blood-cya-  nide concentration and if treatment exceeds 3 days,  also blood-thiocyanate concentration; avoid sudden  withdrawal — terminate infusion over 15-30 minutes;  protect infusion from light; interactions: Appendix 1  (sodium nitroprusside)   Renal impairment avoid prolonged use — cyanide or  thiocyanate metabolites may accumulate  Pregnancy avoid prolonged use — potential for accu-  mulation of cyanide in fetus  Breast-feeding no information available; caution  advised due to thiocyanate metabolite  Side-effects associated with over rapid reduction in  blood pressure (reduce infusion rate): headache, diz-  ziness, nausea, retching, abdominal pain, perspiration,  palpitation, anxiety, retrosternal discomfort; occa-  sionally reduced platelet count, acute transient phle-  bitis   Cyanide Side-effects caused by excessive plasma concen-  tration of the cyanide metabolite include tachycardia,  sweating, hyperventilation, arrhythmias, marked metabolic  acidosis (discontinue and give antidote, see p. 39)   • Hypertensive emergencies, by intravenous infusion,  initially 0.5-1. 5 micrograms/kg/minute, then  increased in steps of 500 nanograms/kg/minute  every 5 minutes within range 0.5-8 micrograms /kg/  minute (lower doses if already receiving other anti-  hypertensives); stop if response unsatisfactory with  max. dose in 10 minutes    • Maintenance of blood pressure at 30-40% lower than  pretreatment diastolic blood pressure, 20-400 micr-  ograms/minute (lower doses for patients being trea-  ted with other antihypertensives)   • Controlled hypotension in surgery, by intravenous  infusion, max. 1.5 micrograms/kg/minute   Cautions hypotension (avoid if systolic blood pressure  below 90 mmHg); aortic and mitral valve disease;  pericardial constriction; congestive cardiomyopathy;  left ventricular dysfunction; life-threatening arrhyth-  mias; coronary artery disease; uncontrolled hyper-  tension; pulmonary veno-occlusive disease; predis-  position to priapism; anatomical deformation of the  penis; hereditary degenerative retinal disorders;  interactions: Appendix 1 (tadalafil)  Contra-indications acute myocardial infarction in  past 90 days; history of non-arteritic anterior  ischaemic optic neuropathy; avoid concomitant use of  nitrates   Hepatic impairment initially 20 mg once daily in mild  to moderate impairment; avoid in severe impairment  Renal impairment initially 20 mg once daily in mild to  moderate impairment, increased to 40 mg once daily  if tolerated; avoid in severe impairment  Pregnancy manufacturer advises avoid  Breast-feeding manufacturer advises avoid — present  in milk in animal studies   Side-effects nausea, vomiting, dyspepsia, gastro-  oesophageal reflux, chest pain, palpitation, flushing,  hypotension, nasopharyngitis, epistaxis, headache,  myalgia, back and limb pain, increased uterine  bleeding, blurred vision, facial oedema, rash; less  commonly tachycardia, hypertension, seizures,  amnesia, priapism, hyperhidrosis; also reported  unstable angina, arrhythmia, myocardial infarction,  stroke, hearing loss, non-arteritic anterior ischaemic  optic neuropathy, retinal vascular occlusion, visual  field defect, Stevens-Johnson syndrome  Dose   • ADULT over 18 years, 40 mg once daily  Adcirca® (Lilly) ▼ ®   Tablets, f/c, tadalafil 20 mg (orange), net price 56-tab  pack = £491.22   Methyldopa is a centrally acting antihypertensive; it  may be used for the management of hypertension in  pregnancy. Side-effects are minimised if the daily dose is  kept below 1 g.   Clonidine has the disadvantage that sudden withdrawal  of treatment may cause severe rebound hypertension.  Moxonidine, a centrally acting drug, is licensed for mild  to moderate essential hypertension. It may have a role  when thiazides, calcium-channel blockers, ACE inhi-  bitors, and beta-blockers are not appropriate or have  failed to control blood pressure.   Cautions must be withdrawn gradually to avoid severe  rebound hypertension; Raynaud’s syndrome or other  occlusive peripheral vascular disease; history of  depression; interactions: Appendix 1 (clonidine)  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol may be enhanced   Pregnancy may lower fetal heart rate, but risk should  be balanced against risk of uncontrolled maternal  hypertension; avoid intravenous injection   Side-effects dry mouth, sedation, depression, fluid  retention, bradycardia, Raynaud’s phenomenon,  headache, dizziness, euphoria, nocturnal unrest, rash,  nausea, constipation, rarely impotence   • By mouth, 50-100 micrograms 3 times daily,  increased every second or third day; usual max. dose  1.2 mg daily   Catapres® (Boehringer Ingelheim) (M  Tablets, scored, clonidine hydrochloride 100 micr-  ograms, net price 100-tab pack = £5.32; 300 micr-  ograms, 100-tab pack = £12.39. Label: 3, 8   Indications hypertension  Cautions monitor blood counts and liver-function  before treatment and at intervals during first 6-12  weeks or if unexplained fever occurs; history of  depression; positive direct Coombs’ test in up to 20%  of patients (may affect blood cross-matching); inter-  ference with laboratory tests; interactions: Appendix  1 (methyldopa)   Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol may be enhanced   Hepatic impairment manufacturer advises caution in  history of liver disease; avoid in active liver disease  Renal impairment start with small dose; increased  sensitivity to hypotensive and sedative effect  Pregnancy not known to be harmful  Breast-feeding amount too small to be harmful  Side-effects gastro-intestinal disturbances, dry  mouth, stomatitis, sialadenitis; bradycardia, exacer-  bation of angina, postural hypotension, oedema;  sedation, headache, dizziness, asthenia, myalgia,  arthralgia, paraesthesia, nightmares, mild psychosis,  depression, impaired mental acuity, parkinsonism,  Bell’s palsy; hepatitis, jaundice; pancreatitis; haemo-  lytic anaemia; bone-marrow depression, leucopenia,  thrombocytopenia, eosinophilia; hypersensitivity  reactions including lupus erythematosus-like  syndrome, drug fever, myocarditis, pericarditis; rashes  (including toxic epidermal necrolysis); nasal conges-  tion, failure of ejaculation, impotence, decreased libi-  do, gynaecomastia, hyperprolactinaemia, amenor-  rhoea   • Initially 250 mg 2-3 times daily, increased gradually at  intervals of at least 2 days, max. 3 g daily; ELDERLY  initially 125 mg twice daily, increased gradually, max.  2 g daily   Methyldopa (Non-proprietary) Ml  Tablets, coated, methyldopa (anhydrous) 125 mg, net  price 56-tab pack = £16.29; 250 mg, 56-tab pack =  £8.26; 500 mg, 56-tab pack = £11.49. Label: 3, 8   250 mg, net price 60 = £6.15; 500 mg, 30 = £4.55.  Label: 3, 8    Indications mild to moderate essential hypertension  Cautions avoid abrupt withdrawal (if concomitant  treatment with beta-blocker has to be stopped, dis-  continue beta-blocker first, then moxonidine after a  few days); severe coronary artery disease; unstable  angina; first-degree AV block; moderate heart failure;  interactions: see Appendix 1 (moxonidine)  Contra-indications conduction disorders (sick sinus  syndrome, sino-atrial block, second- or third-degree  AV block); bradycardia; severe heart failure  Renal impairment max. single dose 200 micrograms  and max. daily dose 400 micrograms if eGFR 30-  60 mL/minute/ 1.73 m 2 ; avoid if eGFR less than  30 mL/minute/ 1 .73 m 2   Side-effects dry mouth, diarrhoea, nausea, vomiting,  dyspepsia, dizziness, somnolence, insomnia, back  pain, rash, pruritus; less commonly bradycardia, tin-  nitus, angioedema, oedema, nervousness, neck pain    • 200 micrograms once daily in the morning, increased  if necessary after 3 weeks to 400 micrograms daily in  1-2 divided doses; max. 600 micrograms daily in 2  divided doses (max. single dose 400 micrograms)    Moxonidine (Non-proprietary) [Ml  Tablets, f/c, moxonidine 200 micrograms, net price  28-tab pack = £3.76; 300 micrograms, net price 28-tab  pack = £4.82; 400 micrograms, net price 28-tab pack =  £5.01. Label: 3    Physiotens® (Solvay) M  Tablets, f/c, moxonidine 200 micrograms (pink), net  price 28-tab pack = £9.72; 300 micrograms (red), 28-  tab pack = £11.49; 400 micrograms (red), 28-tab pack  = £13.26. Label: 3   Adrenergic neurone blocking drugs prevent the release  of noradrenaline from postganglionic adrenergic neu-  rones. These drugs do not control supine blood pressure  and may cause postural hypotension. For this reason  they have largely fallen from use, but may be necessary  with other therapy in resistant hypertension.    Guanethidine, which also depletes the nerve endings of  noradrenaline, is licensed for rapid control of blood  pressure, however alternative treatments are preferred  (see section 2.5).   Cautions coronary or cerebral arteriosclerosis,  asthma, history of peptic ulceration; interactions:  Appendix 1 (adrenergic neurone blockers)  Contra-indications phaeochromocytoma, heart fail-  ure   Renal impairment reduce dose if eGFR 40-65 mL/  minute/ 1.73 m 2 ; avoid if eGFR less than 40mL/min-  ute/ 1.73 m 2   Pregnancy postural hypotension and reduced utero-  placental perfusion; should not be used to treat  hypertension in pregnancy   Side-effects postural hypotension, failure of ejacula-  tion, fluid retention, nasal congestion, headache,  diarrhoea, drowsiness   • By intramuscular injection, 10-20 mg, repeated after 3  hours if required   Injection, guanethidine monosulphate 10 mg/mL, net  price 1-mL amp = £1.56   Prazosin has post-synaptic alpha-blocking and vasodi-  lator properties and rarely causes tachycardia. It may,  however, reduce blood pressure rapidly after the first  dose and should be introduced with caution. Doxazo-  sin, indoramin, and terazosin have properties similar  to those of prazosin.   Alpha-blockers can be used with other antihypertensive  drugs in the treatment of resistant hypertension (section  2.5).   Prostatic hyperplasia Alfuzosin, doxazosin, indor-  amin, prazosin, tamsulosin, and terazosin are indicated  for benign prostatic hyperplasia (section 7.4.1).   Cautions care with initial dose (postural hypotension);  pulmonary oedema due to aortic or mitral stenosis;  cataract surgery (risk of intra-operative floppy iris  syndrome); heart failure; interactions: Appendix 1  (alpha-blockers)    Pregnancy no evidence of teratogenicity; manufac-  turers advise use only when potential benefit out-  weighs risk   Side-effects see section 7.4.1; also dyspnoea, cough-  ing; fatigue, vertigo, paraesthesia, sleep disturbance,  anxiety; influenza-like symptoms; back pain, myalgia;  less commonly weight changes, angina, myocardial  infarction, hypoaesthesia, tremor, agitation, micturi-  tion disturbance, epistaxis, arthralgia, tinnitus, and  gout; very rarely cholestasis, hepatitis, jaundice,  bradycardia, arrhythmias, bronchospasm, hot flushes,  gynaecomastia, abnormal ejaculation, leucopenia,  thrombocytopenia, and alopecia  Dose   • Hypertension, 1 mg daily, increased after 1-2 weeks  to 2 mg once daily, and thereafter to 4 mg once daily, if  necessary; max. 16 mg daily   Doxazosin (Non-proprietary) (Ml  Tablets, doxazosin (as mesilate) 1 mg, net price 28-  tab pack = 93p; 2 mg, 28-tab pack = 99p; 4 mg, 28-tab  pack = £1.39. Counselling, initial dose, driving  Brands include Doxadura®   Tablets, doxazosin (as mesilate) 1 mg, net price 28-tab  pack = £10.56; 2 mg, 28-tab pack = £14.08. Counsel-  ling, initial dose, driving   ^Modified-release  Doxazosin (Non-proprietary) (Ml  Tablets, m/r, doxazosin (as mesilate) 4 mg, net price  28-tab pack = £6.33. Label: 25, counselling, initial  dose, driving   Dose hypertension, benign prostatic hyperplasia, 4 mg once  daily, increased to 8 mg once daily after 4 weeks if necessary  Brands include Doxadura ® XL, Raporsin ® XL, Slocinx ® XL   Tablets, m/r, doxazosin (as mesilate) 4 mg, net price  28-tab pack = £5.70; 8 mg, 28-tab pack = £9.98.  Label: 25, counselling, driving, initial dose  Dose hypertension, benign prostatic hyperplasia, 4 mg once  daily, increased to 8 mg once daily after 4 weeks if necessary   Cautions avoid alcohol (enhances rate and extent of  absorption); control incipient heart failure before  initiating indoramin; elderly; Parkinson’s disease  (extrapyramidal disorders reported); epilepsy (con-  vulsions in animal studies); history of depression;  cataract surgery (risk of intra-operative floppy iris  syndrome); interactions: Appendix 1 (alpha-blockers)  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol may be enhanced  Contra-indications established heart failure  Hepatic impairment manufacturer advises caution  Renal impairment manufacturer advises caution  Pregnancy no evidence of teratogenicity; manufac-  turers advise use only when potential benefit out-  weighs risk   • Hypertension, initially 25 mg twice daily, increased by  25-50 mg daily at intervals of 2 weeks; max. daily  dose 200 mg in 2-3 divided doses   Indications hypertension (see notes above); conges-  tive heart failure (but see section 2.5.5); Raynaud’s  syndrome (see also section 2.6.4); benign prostatic  hyperplasia (section 7.4.1)   Cautions first dose may cause collapse due to hypo-  tension (therefore should be taken on retiring to bed);  elderly; cataract surgery (risk of intra-operative floppy  iris syndrome); interactions: Appendix 1 (alpha-  blockers)   Contra-indications not recommended for congestive  heart failure due to mechanical obstruction (e.g. aortic  stenosis)   Pregnancy no evidence of teratogenicity; manufac-  turers advise use only when potential benefit out-  weighs risk   Side-effects see section 7.4.1; also dyspnoea; ner-  vousness; urinary frequency; less commonly insom-  nia, paraesthesia, sweating, arthralgia, eye disorders,  tinnitus, and epistaxis; rarely pancreatitis, flushing,  vasculitis, bradycardia, hallucinations, worsening of  narcolepsy, gynaecomastia, urinary incontinence, and  alopecia   • Hypertension (see notes above), 500 micrograms 2-3  times daily for 3-7 days, the initial dose on retiring to  bed at night (to avoid collapse, see Cautions);  increased to 1 mg 2-3 times daily for a further 3-7  days; further increased if necessary to max. 20 mg  daily in divided doses   500 micrograms 2-4 times daily (initial dose at bed-  time, see above), increasing to 4 mg daily in divided  doses; maintenance 4-20 mg daily in divided doses  (but rarely used)   • Raynaud’s syndrome (but efficacy not established, see  section 2.6.4), initially 500 micrograms twice daily  (initial dose at bedtime, see above) increased, if  necessary, after 3-7 days to usual maintenance 1-   Prazosin (Non-proprietary) Ml  Tablets, prazosin (as hydrochloride) 500 micrograms,  net price 56-tab pack = £2.51; 1 mg, 56-tab pack =  £3.23; 2 mg, 56-tab pack = £4.39; 5 mg, 56-tab pack =  £8.75. Counselling, initial dose, driving   Tablets, prazosin (as hydrochloride) 500 micrograms,  net price 60-tab pack = £2.69; 1 mg, scored, 60-tab  pack = £3.46. Counselling, initial dose, driving    Indications mild to moderate hypertension (see notes  above); benign prostatic hyperplasia (section 7.4.1)  Cautions first dose may cause collapse due to hypo-  tension (within 30-90 minutes, therefore should be  taken on retiring to bed) (may also occur with rapid  dose increase); cataract surgery (risk of intra-opera-  tive floppy iris syndrome); interactions: Appendix 1  (alpha-blockers)   Breast-feeding no information available  Side-effects see section 7.4.1; also reported weight  gain, dsypnoea, paraesthesia, nervousness, decreased  libido, thrombocytopenia, back pain, and pain in  extremities  Dose    • Hypertension, 1 mg at bedtime (compliance with  bedtime dose important, see Cautions); dose doubled  after 7 days if necessary; usual maintenance dose 2-  10 mg once daily; more than 20 mg daily rarely  improves efficacy   Terazosin (Non-proprietary) (Ml  Tablets, terazosin (as hydrochloride) 2 mg, net price  28-tab pack = £2.16; 5 mg, 28-tab pack = £2.58; 10 mg,  28-tab pack = £7.88. Counselling, initial dose, driving   Tablets, terazosin (as hydrochloride) 2 mg (yellow),  net price 28-tab pack = £2.29; 5 mg (tan), 28-tab pack  = £4.29; 10 mg (blue), 28-tab pack = £8.57; starter  pack (for hypertension) of 7 x 1-mg tabs with 21x2-  mg tabs = £13.00. Counselling, initial dose, driving   Long-term management of phaeochromocytoma  involves surgery. However, surgery should not take  place until there is adequate blockade of both alpha-  and beta-adrenoceptors; the optimal choice of drug  therapy remains unclear. Alpha-blockers are used in  the short-term management of hypertensive episodes  in phaeochromocytoma. Once alpha blockade is estab-  lished, tachycardia can be controlled by the cautious  addition of a beta-blocker (section 2.4); a cardioselective  beta-blocker is preferred.   Phenoxybenzamine, a powerful alpha-blocker, is effec-  tive in the management of phaeochromocytoma but it  has many side-effects. Phentolamine is a short-acting  alpha-blocker used mainly during surgery of phaeo-  chromocytoma; its use for the diagnosis of phaeo-  chromocytoma has been superseded by measurement  of catecholamines in blood and urine.   Metirosine (available from ‘special-order’ manufac-  turers or specialist importing companies, see p. 988)  inhibits the enzyme tyrosine hydroxylase, and hence  the synthesis of catecholamines. It is rarely used in  the pre-operative management of phaeochromocytoma,  and long term in patients unsuitable for surgery; an    alpha-adrenoceptor blocking drug may also be required.  Metirosine should not be used to treat essential hyper-  tension.   Cautions elderly; congestive heart failure; severe  ischaemic heart disease (see also Contra-indications);  cerebrovascular disease (avoid if history of cerebro-  vascular accident); monitor blood pressure regularly  during infusion; carcinogenic in animals:, avoid in  acute porphyria (section 9.8.2); avoid extravasation  (irritant to tissues)   Contra-indications history of cerebrovascular acci-  dent; during recovery period after myocardial infarc-  tion (usually 3-4 weeks); avoid infusion in hypovol-  aemia   Renal impairment use with caution  Pregnancy hypotension may occur in newborn  Breast-feeding may be present in milk  Side-effects postural hypotension with dizziness and  marked compensatory tachycardia, lassitude, nasal  congestion, miosis, inhibition of ejaculation; rarely  gastro-intestinal disturbances; decreased sweating  and dry mouth after intravenous infusion; idiosyn-  cratic profound hypotension within few minutes of  starting infusion; convulsions following rapid intra-  venous infusion also reported    Phenoxybenzamine (Goldshield) (Ml  Injection concentrate, phenoxybenzamine hydro-  chloride 50 mg/mL. To be diluted before use, net  price 2-mL amp = £57.14 (hosp. only)   Dose by intravenous infusion (preferably through large vein),  adjunct in severe shock (but rarely used) and phaeochromo-  cytoma, 1 mg/kg daily over at least 2 hours; do not repeat within  24 hours (intensive care facilities needed)   Caution Owing to risk of contact sensitisation healthcare profes-  sionals should avoid contamination of hands    Dibenyline® (Goldshield) (Ml  Capsules, red/white, phenoxybenzamine hydro-  chloride 10 mg, net price 30-cap pack = £10.84  Dose phaeochromocytoma, 10 mg daily, increased by 10 mg  daily; usual dose 1-2 mg/kg daily in 2 divided doses   Indications hypertensive episodes due to phaeo-  chromocytoma e.g. during surgery; diagnosis of  phaeochromocytoma (but see notes above)   Cautions monitor blood pressure (avoid in hypo-  tension), heart rate; gastritis, peptic ulcer; elderly;  interactions: Appendix 1 (alpha-blockers)  Contra-indications hypotension; history of myo-  cardial infarction; coronary insufficiency, angina, or  other evidence of coronary artery disease  Renal impairment manufacturer advises caution — no  information available    Side-effects postural hypotension, tachycardia, dizzi-  ness, flushing; nausea and vomiting, diarrhoea, nasal  congestion; also acute or prolonged hypotension,  angina, chest pain, arrhythmias   Rogitine® (Alliance) (Ml  Injection, phentolamine mesilate 10 mg/mL, net  price 1-mL amp = £1.53   Drug treatment of heart failure associated with a  reduced left ventricular ejection fraction (left ventricular  systolic dysfunction) is covered below; optimal manage-  ment of heart failure with a preserved left ventricular  ejection fraction has not been established..   The treatment of chronic heart failure aims to relieve  symptoms, improve exercise tolerance, reduce the inci-  dence of acute exacerbations, and reduce mortality. An  ACE inhibitor, titrated to a ‘target dose’ (or the max-  imum tolerated dose if lower), together with a beta-  blocker, form the basis of treatment for all patients with  heart failure due to left ventricular systolic dysfunction.   An ACE inhibitor (section 2.5.5. 1) is generally advised  for patients with asymptomatic left ventricular systolic  dysfunction or symptomatic heart failure. An angio-  tensin-II receptor antagonist (section 2. 5. 5. 2) may be  a useful alternative for patients who, because of side-  effects such as cough, cannot tolerate ACE inhibitors; a  relatively high dose of the angiotensin-II receptor  antagonist may be required to produce benefit. Cande-  sartan, an angiotensin-II receptor antagonist, can also  be added to ACE inhibitor and beta-blocker therapy in  patients with mild to moderate heart failure who con-  tinue to remain symptomatic.   The beta-blockers bisoprolol and carvedilol (section 2.4)  are of value in any grade of stable heart failure due to left  ventricular systolic dysfunction; nebivolol (section 2.4)  is licensed for stable mild to moderate heart failure in  patients over 70 years. Beta-blocker treatment should  be started by those experienced in the management of  heart failure, at a very low dose and titrated very slowly  over a period of weeks or months. Symptoms may  deteriorate initially, calling for adjustment of concomi-  tant therapy.   The aldosterone antagonist spironolactone (section  2.2.3) can be considered for patients with moderate to  severe heart failure who are already taking an ACE  inhibitor and a beta-blocker; low doses of spirono-  lactone (usually 25 mg daily) reduce symptoms and  mortality in these patients. If spironolactone cannot be    ACE inhibitor can be initiated in the community in  patients who are receiving a low dose of a diuretic or  who are not otherwise at risk of serious hypotension;  nevertheless, care is required and a very low dose of the  ACE inhibitor is given initially    used, eplerenone (section 2.2.3) may be considered for  the management of heart failure after an acute myo-  cardial infarction with evidence of left ventricular sys-  tolic dysfunction. Close monitoring of serum creatinine,  eGFR, and potassium is necessary, particularly follow-  ing any change in treatment or any change in the  patient’s clinical condition.   Patients who cannot tolerate an ACE inhibitor or an  angiotensin-II receptor antagonist, or in whom they are  contra-indicated, may be given isosorbide dinitrate  (section 2.6.1) with hydralazine (section 2.5.1), but  this combination may be poorly tolerated. In patients  of African or Caribbean origin, and those with moderate  to severe heart failure, the combination of isosorbide  dinitrate and hydralazine may be considered in addition  to standard therapy with an ACE inhibitor and a beta-  blocker, if necessary.   Digoxin (section 2.1.1) improves symptoms of heart  failure and exercise tolerance and reduces hospitalisa-  tion due to acute exacerbations but it does not reduce  mortality. Digoxin is reserved for patients with worsen-  ing or severe heart failure due to left ventricular systolic  dysfunction who remain symptomatic despite treatment  with an ACE inhibitor and a beta-blocker in combination  with either an aldosterone antagonist, candesartan, or  isosorbide dinitrate with hydralazine.   Patients with fluid overload should also receive either a  loop or a thiazide diuretic (with salt or fluid restriction  where appropriate). A thiazide diuretic (section 2.2.1)  may be of benefit in patients with mild heart failure and  good renal function; however, thiazide diuretics are  ineffective in patients with poor renal function (eGFR  less than 30 mL/minute/ 1.73 m 2 , see Renal Impair-  ment, section 2.2.1) and a loop diuretic (section 2.2.2)  is preferred. If diuresis with a single diuretic is insuffi-  cient, a combination of a loop diuretic and a thiazide  diuretic may be tried; addition of metolazone (section  2.2.1) may also be considered but the resulting diuresis  may be profound and care is needed to avoid potentially  dangerous electrolyte disturbances.   Angiotensin-converting enzyme inhibitors (ACE inhi-  bitors) inhibit the conversion of angiotensin I to angio-  tensin II. They have many uses and are generally well  tolerated. The main indications of ACE inhibitors are  shown below.   Heart failure ACE inhibitors are used in all grades of  heart failure, usually combined with a beta-blocker  (section 2.5.5). Potassium supplements and potassium-  sparing diuretics should be discontinued before introdu-  cing an ACE inhibitor because of the risk of hyperkal-  aemia. However, a low dose of spironolactone may be  beneficial in severe heart failure (section 2.5.5) and can  be used with an ACE inhibitor provided serum potas-  sium is monitored carefully. Profound first-dose hypo-  tension may occur when ACE inhibitors are introduced  to patients with heart failure who are already taking a  high dose of a loop diuretic (e.g. furosemide 80 mg daily  or more). Temporary withdrawal of the loop diuretic  reduces the risk, but may cause severe rebound pulm-  onary oedema. Therefore, for patients on high doses of  loop diuretics, the ACE inhibitor may need to be  initiated under specialist supervision, see below. An    Hypertension An ACE inhibitor may be the most  appropriate initial drug for hypertension in younger  Caucasian patients; Afro-Caribbean patients, those  aged over 55 years, and those with primary aldosteron-  ism respond less well (see section 2.5). ACE inhibitors  are particularly indicated for hypertension in patients  with type 1 diabetes with nephropathy (see also section  6.1.5). They may reduce blood pressure very rapidly in  some patients particularly in those receiving diuretic  therapy (see Cautions, below); the first dose should  preferably be given at bedtime.   Diabetic nephropathy For comment on the role of  ACE inhibitors in the management of diabetic nephro-  pathy, see section 6.1.5.    Renal effects Renal function and electrolytes should  be checked before starting ACE inhibitors (or increasing  the dose) and monitored during treatment (more fre-  quently if features mentioned below present); hyperkal-  aemia and other side-effects of ACE inhibitors are more  common in those with impaired renal function and the  dose may need to be reduced (see Renal impairment  below and under individual drugs). Although ACE inhi-  bitors now have a specialised role in some forms of renal  disease, including chronic kidney disease, they also  occasionally cause impairment of renal function which  may progress and become severe in other circum-  stances (at particular risk are the elderly). A specialist  should be involved if renal function is significantly  reduced as a result of treatment with an ACE inhibitor.   Concomitant treatment with NSAIDs increases the risk  of renal damage, and potassium-sparing diuretics (or  potassium-containing salt substitutes) increase the risk  of hyperkalaemia.   In patients with severe bilateral renal artery stenosis (or  severe stenosis of the artery supplying a single function-  ing kidney), ACE inhibitors reduce or abolish glomerular  filtration and are likely to cause severe and progressive  renal failure. They are therefore not recommended in    Prophylaxis of cardiovascular events ACE inhi-  bitors are used in the early and long-term management  of patients who have had a myocardial infarction, see  section 2.10.1. ACE inhibitors may also have a role in  preventing cardiovascular events.   Initiation under specialist supervision ACE inhi-  bitors should be initiated under specialist supervision  and with careful clinical monitoring in those with severe  heart failure or in those:   • receiving multiple or high-dose diuretic therapy (e.g.  more than 80 mg of furosemide daily or its equivalent);    patients known to have these forms of critical renovas-  cular disease.   ACE inhibitor treatment is unlikely to have an adverse  effect on overall renal function in patients with severe  unilateral renal artery stenosis and a normal contralat-  eral kidney, but glomerular filtration is likely to be  reduced (or even abolished) in the affected kidney and  the long-term consequences are unknown.   ACE inhibitors are therefore best avoided in patients  with known or suspected renovascular disease, unless  the blood pressure cannot be controlled by other drugs.  If ACE inhibitors are used, they should be initiated only  under specialist supervision and renal function should  be monitored regularly.   ACE inhibitors should also be used with particular  caution in patients who may have undiagnosed and  clinically silent renovascular disease. This includes  patients with peripheral vascular disease or those with  severe generalised atherosclerosis.   Cautions ACE inhibitors need to be initiated with care  in patients receiving diuretics (important: see Conco-  mitant diuretics, below); first doses can cause hypo-  tension especially in patients taking high doses of diur-  etics, on a low-sodium diet, on dialysis, dehydrated, or  with heart failure (see above). They should also be used  with caution in peripheral vascular disease or general-  ised atherosclerosis owing to risk of clinically silent  renovascular disease; for use in pre-existing renovascu-  lar disease, see Renal Effects above. The risk of  agranulocytosis is possibly increased in collagen vascu-  lar disease (blood counts recommended). ACE inhi-  bitors should be used with care in patients with severe  or symptomatic aortic stenosis (risk of hypotension) and  in hypertrophic cardiomyopathy. They should also be  used with care (or avoided) in those with a history of  idiopathic or hereditary angioedema. If jaundice or  marked elevations of hepatic enzymes occur during  treatment then the ACE inhibitor should be discontin-  ued — risk of hepatic necrosis (see also Hepatic impair-  ment, below). Interactions: Appendix 1 (ACE inhi-  bitors).   Anaphylactoid reactions To prevent anaphylactoid  reactions, ACE inhibitors should be avoided during  dialysis with high-flux polyacrylonitrile membranes  and during low-density lipoprotein apheresis with  dextran sulphate; they should also be withheld before  desensitisation with wasp or bee venom.    Hepatic impairment Use of prodrugs such as cilaza-  pril, enalapril, fosinopril, imidapril, moexipril, perindo-  pril, quinapril, ramipril, and trandolapril requires close  monitoring in patients with impaired liver function   Renal impairment ACE inhibitors should be used  with caution and the response monitored (see Renal  effects above); hyperkalaemia and other side effects  more common; the dose may need to be reduced, see  individual drugs.   Pregnancy ACE inhibitors should be avoided in  pregnancy unless essential. They may adversely affect  fetal and neonatal blood pressure control and renal  function; skull defects and oligohydramnios have also  been reported.   Breast-feeding Information on the use of ACE inhi-  bitors in breast-feeding is limited. Cilazapril, fosinopril,  imidapril, lisinopril, moexipril, perindopril, ramipril, and  trandolapril are not recommended; alternative treat-  ment options, with better established safety information  during breast-feeding, are available. Captopril, enalapril,  and quinapril should be avoided in the first few weeks  after delivery, particularly in preterm infants, due to the  risk of profound neonatal hypotension; if essential, they  may be used in mothers breast-feeding older infants —  the infant’s blood pressure should be monitored.   Side-effects ACE inhibitors can cause profound hypo-  tension (see Cautions) and renal impairment (see Renal  effects above), and a persistent dry cough. They can  also cause angioedema (onset may be delayed; higher  incidence reported in Affo-Caribbean patients), rash  (which may be associated with pruritus and urticaria),  pancreatitis, and upper respiratory-tract symptoms such  as sinusitis, rhinitis, and sore throat. Gastro-intestinal  effects reported with ACE inhibitors include nausea,  vomiting, dyspepsia, diarrhoea, constipation, and abdo-  minal pain. Altered liver function tests, cholestatic jaun-  dice, hepatitis, fulminant hepatic necrosis, and hepatic  failure have been reported — discontinue if marked ele-  vation of hepatic enzymes or jaundice. Hyperkalaemia,  hypoglycaemia, and blood disorders including thrombo-  cytopenia, leucopenia, neutropenia, and haemolytic  anaemia have also been reported. Other reported  side-effects include headache, dizziness, fatigue,  malaise, taste disturbance, paraesthesia, bronchospasm,  fever, serositis, vasculitis, myalgia, arthralgia, positive  antinuclear antibody, raised erythrocyte sedimentation  rate, eosinophilia, leucocytosis, and photosensitivity.    Concomitant diuretics ACE inhibitors can cause a very  rapid fall in blood pressure in volume-depleted patients;  treatment should therefore be initiated with very low  doses. If the dose of diuretic is greater than 80 mg  furosemide or equivalent, the ACE inhibitor should be  initiated under close supervision and in some patients  the diuretic dose may need to be reduced or the diuretic  discontinued at least 24 hours beforehand (may not be  possible in heart failure — risk of pulmonary oedema). If  high-dose diuretic therapy cannot be stopped, close  observation is recommended after administration of  the first dose of ACE inhibitor, for at least 2 hours or  until the blood pressure has stabilised.   Contra-indications ACE inhibitors are contra-indi-  cated in patients with hypersensitivity to ACE inhibitors  (including angioedema).    Combination products Products incorporating an  ACE inhibitor with a thiazide diuretic or a calcium-  channel blocker are available for the management of  hypertension. Use of these combination products should  be reserved for patients whose blood pressure has not  responded adequately to a single antihypertensive drug  and who have been stabilised on the individual compo-  nents of the combination in the same proportions.   Indications mild to moderate essential hypertension  alone or with thiazide therapy and severe hyper-  tension resistant to other treatment; congestive heart  failure with left ventricular dysfunction (adjunct — see  section 2.5.5); following myocardial infarction, see    dose; diabetic nephropathy (microalbuminuria greater  than 30 mg/ day) in type 1 diabetes  Cautions see notes above  Contra-indications see notes above  Renal impairment see notes above; reduce dose;  max. initial dose 25 mg daily (do not exceed 100 mg  daily) if eGFR 20-40 mL/minute/1.73 m 2 ; max. initial  dose 12.5 mg daily (do not exceed 75 mg daily) if  eGFR 10-20 mL/minute/1.73 m 2 ; max. initial dose  6.25 mg daily (do not exceed 37.5 mg daily) if eGFR  less than 10 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; tachycardia, serum  sickness, weight loss, stomatitis, maculopapular rash,  photosensitivity, flushing and acidosis  Dose   • Hypertension, used alone, initially 12.5 mg twice  daily; if used in addition to diuretic (see notes above),  or in elderly, initially 6.25 mg twice daily (first dose at  bedtime); usual maintenance dose 25 mg twice daily;  max. 50 mg twice daily (rarely 3 times daily in severe  hypertension)   • Heart failure (adjunct), initially 6.25-12.5 mg 2-3  times daily under close medical supervision (see notes  above), increased gradually at intervals of at least 2  weeks up to max. 150 mg daily in divided doses if  tolerated   • Prophylaxis after infarction in clinically stable patients  with asymptomatic or symptomatic left ventricular  dysfunction (radionuclide ventriculography or echo-  cardiography undertaken before initiation), initially  6.25 mg, starting as early as 3 days after infarction,  then increased over several weeks to 150 mg daily (if  tolerated) in divided doses   • Diabetic nephropathy, 75-100 mg daily in divided  doses; if further blood pressure reduction required,  other antihypertensives may be used in conjunction  with captopril; in severe renal impairment, initially   12.5 mg twice daily (if concomitant diuretic therapy  required, loop diuretic rather than thiazide should be  chosen)   Captopril (Non-proprietary) (Ml  Tablets, captopril 12.5 mg, net price 56-tab pack =  £1.51; 25 mg, 56-tab pack = £1.56; 50 mg, 56-tab pack  = £1.96   Tablets, captopril 25 mg, net price 28-tab pack =  £5.26; 50 mg (scored), 56-tab pack = £17.96   Note For mild to moderate hypertension in patients stabi-  lised on the individual components in the same proportions.  For prescribing information on thiazides, see section 2.2.1   Tablets, co-zidocapt 25/50 (hydrochlorothiazide  25 mg, captopril 50 mg), net price 28-tab pack =  £14.00   LS tablets, scored, co-zidocapt 12.5/25 (hydro-  chlorothiazide 12.5 mg, captopril 25 mg), net price 28-  tab pack = £10.05   Tablets, scored, co-zidocapt 25/50 (hydrochloro-  thiazide 25 mg, captopril 50 mg), net price 28-tab pack  = £7.02   Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above; max. dose  500 micrograms daily in liver cirrhosis; manufacturer  advises avoid in ascites   Renal impairment see notes above; max. initial dose  500 micrograms once daily (do not exceed 2.5 mg  once daily) if eGFR 10-40 mL/minute/1.73 m 2 ; avoid  if eGFR less than 10 mL/minute/1.73 m 2    Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also less commonly dry  mouth, decreased appetite, angina, tachycardia, pal-  pitation, flushing, dyspnoea, impotence, excessive  sweating; rarely glossitis, bronchitis, interstitial lung  disease, gynaecomastia, peripheral neuropathy, Ste-  vens- Johnson syndrome, toxic epidermal necrolysis  Dose   • Hypertension, initially 1 mg once daily (reduced to  500 micrograms daily if used in addition to diuretic  (see notes above), or in cardiac decompensation, in  severe hypertension, in volume depletion, in the  elderly, or in renal impairment), then adjusted  according to response; usual maintenance dose 2.5-  5 mg once daily; max. 5 mg daily   • Heart failure (adjunct), initially 500 micrograms once  daily under close medical supervision (see notes  above), increased at weekly intervals to 1-2.5 mg  once daily if tolerated; max. 5 mg once daily   Tablets, f/c, cilazapril 500 micrograms (white), net  price 30-tab pack = £3.68; 1 mg (yellow), 30-tab pack  = £6.07; 2.5 mg (pink), 28-tab pack = £7.20; 5 mg  (brown), 28-tab pack = £12.51   Indications hypertension; symptomatic heart failure  (adjunct — see section 2.5.5); prevention of sympto-  matic heart failure in patients with asymptomatic left  ventricular dysfunction  Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above; max. initial dose   2.5 mg daily if eGFR less than 30 mL/minute/1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also dyspnoea; depres-  sion, asthenia; blurred vision; less commonly dry  mouth, peptic ulcer, anorexia, ileus; arrhythmias,  palpitation, flushing; confusion, nervousness, drowsi-  ness, insomnia, vertigo; impotence; muscle cramps;  tinnitus; alopecia, sweating; hyponatraemia; rarely    stomatitis, glossitis, Raynaud’s syndrome, pulmonary  infiltrates, allergic alveolitis, dream abnormalities,  gynaecomastia, Stevens- Johnson syndrome, toxic  epidermal necrolysis, exfoliative dermatitis, pemphi-  gus; very rarely gastro-intestinal angioedema   • Hypertension, used alone, initially 5 mg once daily; if  used in addition to diuretic (see notes above), or in  renal impairment, lower initial doses may be required;  usual maintenance dose 20 mg once daily; max.   • Heart failure (adjunct), asymptomatic left ventricular  dysfunction, initially 2.5 mg once daily under close  medical supervision (see notes above), increased  gradually over 2-4 weeks to 10-20 mg twice daily if  tolerated   Tablets, enalapril maleate 2.5 mg, net price 28-tab  pack = £1.05; 5 mg, 28-tab pack = 96p; 10 mg, 28-tab  pack = £1.05; 20 mg, 28-tab pack = £1.24  Brands include Ednyt ®   Tablets, enalapril maleate 2.5 mg, net price 28-tab  pack = £5.35; 5 mg (scored), 28-tab pack = £7.51;   10 mg (red), 28-tab pack = £10.53; 20 mg (peach), 28-  tab pack = £12.51    Note For mild to moderate hypertension in patients stabilised  on the individual components in the same proportions. For  prescribing information on thiazides, see section 2.2.1   Tablets, yellow, scored, enalapril maleate 20 mg,  hydrochlorothiazide 12.5 mg, net price 28-tab pack =  £12.82   Note Non-proprietary tablets containing enalapril maleate  (20 mg) and hydrochlorothiazide (12.5 mg) are available   • Hypertension, initially 10 mg daily, increased if  necessary after 4 weeks; usual dose range 10-40 mg  (doses over 40 mg not shown to increase efficacy); if  used in addition to diuretic see notes above   • Heart failure (adjunct), initially 10 mg once daily  under close medical supervision (see notes above),  increased gradually to 40 mg once daily if tolerated   Fosinopril sodium (Non-proprietary) (Ml  Tablets, fosinopril sodium 10 mg, net price 28-tab  pack = £2.18; 20 mg, 28-tab pack = £2.53    Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above; initial dose  2.5 mg daily if eGFR 30-80 mL/minute/ 1.73 m 2 ;  avoid if eGFR less than 30 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; dry mouth, glossitis,  ileus; bronchitis, dyspnoea; sleep disturbances,  depression, confusion, blurred vision, tinnitus, impo-  tence  Dose   • Initially 5 mg daily before food; if used in addition to  diuretic (see notes above), in elderly, in patients with  heart failure, angina or cerebrovascular disease, or in  renal or hepatic impairment, initially 2.5 mg daily; if  necessary increase dose at intervals of at least 3  weeks; usual maintenance dose 10 mg once daily;  max. 20 mg daily (elderly, 10 mg daily)   Tablets, scored, imidapril hydrochloride 5 mg, net  price 28-tab pack = £6.40; 10 mg, 28-tab pack = £7.22;  20 mg, 28-tab pack = £8.67   Indications hypertension (but see notes above);  symptomatic heart failure (adjunct — see section  2.5.5); short-term treatment following myocardial  infarction in haemodynamically stable patients; renal  complications of diabetes mellitus  Cautions see notes above  Contra-indications see notes above  Renal impairment see notes above; max. initial doses  5-10 mg daily if eGFR 30-80 mL/minute/1. 73 m 2  (max. 40 mg daily); 2.5-5 mg daily if eGFR 10-30 mL/  minute/1.73 m 2 (max. 40 mg daily); 2.5 mg daily if  eGFR less than 10 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also less commonly  tachycardia, palpitation, cerebrovascular accident,  myocardial infarction, Raynaud’s syndrome, confu-  sion, mood changes, vertigo, sleep disturbances,  asthenia, impotence; rarely dry mouth, gynaecomas-  tia, alopecia, psoriasis; very rarely allergic alveolitis,  pulmonary infiltrates, profuse sweating, pemphigus,  Stevens- Johnson syndrome, and toxic epidermal  necrolysis  Dose   • Hypertension, initially 10 mg once daily; if used in  addition to diuretic (see notes above) or in cardiac  decompensation or in volume depletion, initially 2.5-  5 mg once daily; usual maintenance dose 20 mg once  daily; max. 80 mg once daily   • Heart failure (adjunct), initially 2.5 mg once daily  under close medical supervision (see notes above);  increased in steps no greater than 10 mg at intervals  of at least 2 weeks up to max. 35 mg once daily if  tolerated   • Prophylaxis after myocardial infarction, systolic blood  pressure over 120mmHg, 5 mg within 24 hours, fol-  lowed by further 5 mg 24 hours later, then 10 mg after  a further 24 hours, and continuing with 10 mg once  daily for 6 weeks (or continued if heart failure); sys-    tolic blood pressure 100-120 mmHg, initially 2.5 mg  once daily, increased to maintenance dose of 5 mg  once daily   Note Should not be started after myocardial infarction if  systolic blood pressure less than 100 mmHg; temporarily  reduce maintenance dose to 5 mg and if necessary 2.5 mg  daily if systolic blood pressure 100 mmHg or less during  treatment; withdraw if prolonged hypotension occurs (sys-  tolic blood pressure less than 90 mmHg for more than 1  hour)   • Renal complications of diabetes mellitus, initially 2.5-  5 mg once daily adjusted according to response; usual  dose range 10-20 mg once daily   Lisinopril (Non-proprietary) (Ml  Tablets, lisinopril (as dihydrate) 2.5 mg, net price 28-  tab pack = 87p; 5 mg, 28-tab pack = 93p; 10 mg, 28-  tab pack = £1.01; 20 mg, 28-tab pack = £1.19   Tablets, lisinopril (as dihydrate) 2.5 mg, net price 28-  tab pack = £1.78; 5 mg (pink), 28-tab pack = £1.31;   10 mg (pink), 28-tab pack = £2.05; 20 mg (pink), 28-  tab pack = £2.17   Carace 10 Plus tablets, blue, lisinopril 10 mg,  hydrochlorothiazide 12.5 mg, net price 28-tab pack =  £ 10.10   Carace 20 Plus tablets, yellow, scored, lisinopril  20 mg, hydrochlorothiazide 12.5 mg, net price 28-tab  pack = £11.43   Lisicostad 10/12.5 mg tablets, scored, lisinopril (as  dihydrate) 10 mg, hydrochlorothiazide 12.5 mg, net  price 28-tab pack = £10.99  Lisicostad 20/12.5 mg tablets, scored, lisinopril (as  dihydrate) 20 mg, hydrochlorothiazide 12.5 mg, net  price 28-tab pack = £11.99   Zestoretic® (AstraZeneca) (Ml  Zesto retie 10 tablets, peach, lisinopril (as dihydrate)  10 mg, hydrochlorothiazide 12.5 mg, net price 28-tab  pack = £2.27   Zestoretic 20 tablets, lisinopril (as dihydrate) 20 mg,  hydrochlorothiazide 12.5 mg, net price 28-tab pack =  £3.84   Indications essential hypertension  Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above; initial dose  3.75 mg once daily in hepatic cirrhosis  Renal impairment see notes above; if eGFR less than  40mL/minute/1.73m 2 , initial dose 3.75 mg once  daily titrated to max. 1 5 mg once daily  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; arrhythmias, angina,  chest pain, syncope, cerebrovascular accident, myo-  cardial infarction; appetite and weight changes; dry  mouth, photosensitivity, flushing, nervousness, mood  changes, anxiety, drowsiness, sleep disturbance, tin-   • Monotherapy, initially 7.5 mg once daily; if used in  addition to diuretic (see notes above), with nifedipine,  or in elderly, initially 3.75 mg once daily; usual range  7.5-30 mg once daily; doses above 30 mg daily not  shown to increase efficacy   7.5 mg, net price 28-tab pack = £6.04; 15 mg, 28-tab  pack = £6.96    Indications hypertension (but see notes above);  symptomatic heart failure (adjunct — see section  2.5.5); prophylaxis of cardiac events following myo-  cardial infarction or revascularisation in stable cor-  onary artery disease  Cautions see notes above    Hepatic impairment see notes above  Renal impairment see notes above; max. initial dose  2 mg once daily if eGFR 30-60 mL/minute/ 1.73 m 2 ;  2 mg once daily on alternate days if eGFR 15-30 mL/  minute/ 1.73 m 2   Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also asthenia, mood and  sleep disturbances    • Hypertension, initially 4 mg once daily in the morning  for 1 month, subsequently adjusted according to  response; if used in addition to diuretic (see notes  above), in elderly, in renal impairment, in cardiac  decompensation, or in volume depletion, initially 2 mg  once daily; max. 8 mg daily   • Heart failure (adjunct), initially 2 mg once daily in the  morning under close medical supervision (see notes  above), increased after at least 2 weeks to max. 4 mg  once daily if tolerated   • Following myocardial infarction or revascularisation,  initially 4 mg once daily in the morning increased after  2 weeks to 8 mg once daily if tolerated; ELDERLY 2 mg  once daily for 1 week, then 4 mg once daily for 1 week,  thereafter increased to 8 mg once daily if tolerated   2 mg, net price 30-tab pack = £1.72; 4 mg, 30-tab pack  = £1.81; 8 mg, 30-tab pack = £1.94. Label: 22   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above; max. initial dose   2.5 mg once daily if eGFR 30-60 mL/minute/ 1.73 m 2 ;   2.5 mg once daily on alternate days if eGFR 15-  30 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above   • Hypertension, initially 5 mg once daily in the morning  for 1 month, subsequently adjusted according to  response; if used in addition to diuretic (see notes  above), in elderly, in renal impairment, in cardiac  decompensation, or in volume depletion, initially   • Heart failure (adjunct), initially 2.5 mg once daily in  the morning under close medical supervision (see  notes above), increased after 2 weeks to max. 5 mg  once daily if tolerated   • Following myocardial infarction or revascularisation,  initially 5 mg once daily in the morning increased after  2 weeks to 10 mg once daily if tolerated; ELDERLY   2.5 mg once daily for 1 week, then 5 mg once daily for  1 week, thereafter increased to 10 mg once daily if  tolerated   Coversyl® Arginine (Servier) iMl  Tablets, f/c, perindopril arginine 2.5 mg (white), net  price 30-tab pack = £8.27; 5 mg (light green, scored),  30-tab pack = £9.36; 10 mg (green), 30-tab pack =  £11.02. Label: 22   Tablets, f/c, perindopril arginine 5 mg, indapamide  1.25 mg, net price 30-tab pack = £12.65. Label: 22   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above; max. initial dose   2.5 mg once daily if eGFR less than 40 mL/minute/  1.73 m 2   Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; asthenia, chest pain,  oedema, flatulence, nervousness, depression, insom-  nia, blurred vision, impotence, and back pain  Dose   • Hypertension, initially 10 mg once daily; with a  diuretic (see notes above), in elderly, or in renal  impairment initially 2.5 mg daily; usual maintenance  dose 20-40 mg daily in single or 2 divided doses; up to  80 mg daily has been given   • Heart failure (adjunct), initial dose 2.5 mg daily under  close medical supervision (see notes above),  increased gradually to 10-20 mg daily in 1-2 divided  doses if tolerated; max. 40 mg daily   Quinapril (Non-proprietary) tMl  Tablets, quinapril (as hydrochloride) 5 mg, net price  28-tab pack = £2.05; 10 mg, 28-tab pack = £1.91;   20 mg, 28-tab pack = £2.39; 40 mg, 28-tab pack =  £2.81   Tablets, f/c, quinapril (as hydrochloride) 5 mg  (brown), net price 28-tab pack = £8.60; 10 mg (brown),  28-tab pack = £8.60; 20 mg (brown), 28-tab pack =  £10.79; 40 mg (red-brown), 28-tab pack = £9.75   Note For hypertension in patients stabilised on the individual  components in the same proportions. For prescribing infor-  mation on thiazides, see section 2.2.1   Tablets, pink, f/c, scored, quinapril (as hydrochloride)  10 mg, hydrochlorothiazide 12.5 mg, net price 28-tab  pack = £11.75   Indications hypertension; symptomatic heart failure  (adjunct — see section 2.5.5); following myocardial  infarction in patients with clinical evidence of heart  failure; prevention of cardiovascular events in patients  with atherosclerotic cardiovascular disease or with  diabetes mellitus and at least one additional risk factor  for cardiovascular disease; nephropathy (consult pro-  duct literature)   Renal impairment see notes above; max. daily dose  5 mg if eGFR 30-60 mL/minute/ 1.73 m 2 ; max. initial  dose 1.25 mg once daily (do not exceed 5 mg once  daily) if eGFR 10-30 mL/minute/ 1.73 m 2 ; max. initial  dose 1.25 mg once daily (do not exceed 2.5 mg once  daily) if eGFR less than 10 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; arrhythmias, angina,  chest pain, syncope, cerebrovascular accident, myo-  cardial infarction, loss of appetite, stomatitis, dry  mouth, skin reactions including erythema multiforme  and pemphigoid exanthema; precipitation or exacer-  bation of Raynaud’s syndrome; conjunctivitis, ony-  cholysis, confusion, nervousness, depression, anxiety,  impotence, decreased libido, alopecia, bronchitis and  muscle cramps  Dose   • Hypertension, initially 1.25-2.5 mg once daily,  increased at intervals of 2-4 weeks to max. 10 mg  once daily; if used in addition to diuretic see notes  above   • Heart failure (adjunct), initially 1.25 mg once daily  under close medical supervision (see notes above),  increased gradually at intervals of 1-2 weeks to max.  10 mg daily if tolerated (preferably taken in 2 divided  doses)   • Prophylaxis after myocardial infarction (started at  least 48 hours after infarction), initially 2.5 mg twice  daily, increased after 3 days to 5 mg twice daily  Note If initial 2.5-mg dose not tolerated, give 1.25 mg twice  daily for 2 days before increasing to 2.5 mg twice daily, then  5 mg twice daily; withdraw if dose cannot be increased to   • Prophylaxis of cardiovascular events, initially 2.5 mg  once daily, increased after 1-2 weeks to 5 mg once  daily, then increased after a further 2-3 weeks to    • Nephropathy, initially 1.25 mg once daily, increased  after 2 weeks to 2.5 mg once daily, then increased  after a further 2 weeks to 5 mg once daily if tolerated   Ramipril (Non-proprietary) [MI  Capsules, ramipril 1.25 mg, net price 28-cap pack =  £1.10; 2.5 mg, 28-cap pack = £1.18; 5 mg, 28-cap pack  = £1.25; 10 mg, 28-cap pack = £1.41  Tablets, ramipril 1.25 mg, net price 28-tab pack =  £1.71; 2.5 mg, 28-tab pack = £1.42; 5 mg, 28-tab pack  = £1.66; 10 mg, 28-tab pack = £1.89   Tritace® (Sanofi-Aventis) (Ml  Tablets, scored, ramipril 1.25 mg (white), net price 28-  tab pack = £5.09; 2.5 mg (yellow), 28-tab pack = £7.22;  5 mg (red), 28-tab pack = £10.05; 10 mg (white), 28-  tab pack = £13.68   Titration pack, tablets, 35-day starter pack of rami-  pril 7 x 2.5 mg with 21 x 5 mg and 7 x 10 mg, net  price = £13.00   Triapin® (Sanofi-Aventis) (Ml  Triapin® tablets, f/c, brown, ramipril 5 mg, felodipine  5 mg (m/r), net price 28-tab pack = £16.13. Label: 25  Triapin mite® tablets, f/c, orange, ramipril 2.5 mg,  felodipine 2.5 mg (m/r), net price 28-tab pack =  £24.55. Label: 25   Indications mild to moderate hypertension; following  myocardial infarction in patients with left ventricular  dysfunction   Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above; max. 2 mg daily if  eGFR less than 10 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also ileus, dry mouth;  tachycardia, palpitation, arrhythmias, angina, transi-  ent ischaemic attacks, cerebral haemorrhage, myo-  cardial infarction, syncope; dyspnoea, bronchitis;  asthenia, nervousness, sleep disturbances; hot  flushes; alopecia, sweating, skin reactions including  Stevens- Johnson syndrome, toxic epidermal necro-  lysis, and psoriasis-like efflorescence  Dose   • Hypertension, initially 500 micrograms once daily,  increased at intervals of 2-4 weeks; usual range 1-   2 mg once daily; max. 4 mg daily; if used in addition to  diuretic see notes above   • Prophylaxis after myocardial infarction (starting as  early as 3 days after infarction), initially 500 micr-  ograms once daily, gradually increased to max. 4 mg  once daily   Note If symptomatic hypotension develops during titration,  do not increase dose further; if possible, reduce dose of any  adjunctive treatment and if this is not effective or feasible,  reduce dose of trandolapril    Trandolapril (Non-proprietary) Ml  Capsules, trandolapril 500 micrograms, net price 14-  cap pack =£1.49; 1 mg, 28-cap pack = £7.23; 2 mg, 28-  cap pack = £3.75; 4 mg, 28-cap pack = £12.31   Capsules, trandolapril 500 micrograms (red/yellow),  net price 14-cap pack = £1.19; 1 mg (red/orange), 28-  cap pack = £5.81; 2 mg (red/red), 28-cap pack =  £5.81; 4 mg (red/maroon), 28-cap pack = £9.86   Capsules, pink, trandolapril 2 mg, verapamil hydro-  chloride 180 mg (m/r), net price 28 cap-pack =  £10.29. Label: 25   Candesartan, eprosartan, irbesartan, losartan, olme-  sartan, telmisartan, and valsartan are angiotensin-II  receptor antagonists with many properties similar to  those of the ACE inhibitors. However, unlike ACE inhi-  bitors, they do not inhibit the breakdown of bradykinin  and other kinins, and thus are less likely to cause the  persistent dry cough which can complicate ACE inhibi-  tor therapy. They are therefore a useful alternative for  patients who have to discontinue an ACE inhibitor  because of persistent cough.   An angiotensin-II receptor antagonist may be used as an  alternative to an ACE inhibitor in the management of  heart failure (section 2.5.5) or diabetic nephropathy  (section 6.1.5).   Cautions Angiotensin-II receptor antagonists should  be used with caution in renal artery stenosis (see also  Renal Effects under ACE Inhibitors, section 2.5.5. 1).  Monitoring of plasma-potassium concentration is  advised, particularly in the elderly and in patients with  renal impairment; lower initial doses may be appropri-  ate in these patients. Angiotensin-II receptor antago-  nists should be used with caution in aortic or mitral  valve stenosis and in hypertrophic cardiomyopathy.  Those with primary aldosteronism, and Afro-Caribbean  patients (particularly those with left ventricular hyper-  trophy), may not benefit from an angiotensin-II receptor  antagonist. Interactions: Appendix 1 (angiotensin-II  receptor antagonists).   Pregnancy Angiotensin-II receptor antagonists should  be avoided in pregnancy unless essential. They may  adversely affect fetal and neonatal blood pressure con-  trol and renal function; skull defects and oligohydram-  nios have also been reported.   Breast-feeding Information on the use of angio-  tensin-II receptor antagonists in breast-feeding is lim-  ited. They are not recommended in breast-feeding and  alternative treatment options, with better established  safety information during breast-feeding, are available.   Side-effects Side-effects are usually mild. Sympto-  matic hypotension including dizziness may occur, parti-  cularly in patients with intravascular volume depletion    (e.g. those taking high-dose diuretics). Hyperkalaemia  occurs occasionally; angioedema has also been reported  with some angiotensin-II receptor antagonists.    Indications hypertension; heart failure with impaired  left ventricular systolic function in conjunction with  an ACE inhibitor, or when ACE inhibitors are not  tolerated (see also section 2.5.5)   Cautions see notes above  Contra-indications cholestasis  Hepatic impairment initially 4 mg once daily in mild  or moderate impairment; avoid in severe impairment  Renal impairment initially 4 mg daily  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also vertigo, headache;  very rarely nausea, hepatitis, blood disorders, hypo-  natraemia, back pain, arthralgia, myalgia, rash, urti-  caria, pruritus  Dose   • Hypertension, initially 8 mg (intravascular volume  depletion 4 mg) once daily, increased if necessary at  intervals of 4 weeks to max. 32 mg once daily; usual  maintenance dose 8 mg once daily   • Heart failure, initially 4 mg once daily, increased at  intervals of at least 2 weeks to ‘target’ dose of 32 mg  once daily or to max. tolerated dose   Tablets, candesartan cilexetil 2 mg (white), net price  7-tab pack = £3.39; 4 mg (white, scored), 7-tab pack =  £3.68, 28-tab pack = £9.25; 8 mg (pink, scored), 28-tab  pack = £9.89; 16 mg (pink, scored), 28-tab pack =  £12.72; 32 mg (pink, scored), 28-tab pack = £16.13    Cautions see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also nausea, vomiting;  fatigue; musculoskeletal pain; less commonly diarr-  hoea, dyspepsia, flushing, tachycardia, chest pain,  cough, and sexual dysfunction; rarely rash, urticaria;  very rarely headache, myalgia, arthralgia, tinnitus,  taste disturbance, hepatitis, renal dysfunction, and  cutaneous vasculitis  Dose   • Hypertension, initially 150 mg once daily, increased if  necessary to 300 mg once daily (in haemodialysis or  in ELDERLY over 75 years, initial dose of 75 mg once  daily may be used); CHILD not recommended   • Renal disease in hypertensive type 2 diabetes mellitus,  initially 150 mg once daily, increased to 300 mg once  daily if tolerated (in haemodialysis or in ELDERLY over  75 years, consider initial dose of 75 mg once daily);  CHILD not recommended   Aprovel® (Bristol-Myers Squibb, Sanofi-Aventis) (5°M]  Tablets, f/c, irbesartan 75 mg, net price 28-tab pack =  £9.69; 150 mg, 28-tab pack = £11.84; 300 mg, 28-tab  pack = £15.93   CoAprovel® (Bristol-Myers Squibb, Sanofi-Aventis) ImD  Tablets, f/c, irbesartan 150 mg, hydrochlorothiazide  12.5 mg (peach), net price 28-tab pack = £11.84;  irbesartan 300 mg, hydrochlorothiazide 12.5 mg  (peach), 28-tab pack = £15.93; irbesartan 300 mg,  hydrochlorothiazide 25 mg (pink), 28-tab pack =  £15.93   Indications hypertension (see also notes above)  Cautions see notes above  Hepatic impairment halve initial dose in mild or  moderate liver disease; avoid if severe  Renal impairment halve initial dose if eGFR less than  60 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also flatulence, hyper-  triglyceridaemia, arthralgia, rhinitis; rarely headache,  asthenia, anaemia, hypersensitivity reactions (includ-  ing rash, pruritus, urticaria); very rarely nausea  Dose   • 600 mg once daily (elderly over 75 years, mild to  moderate hepatic impairment, renal impairment,  initially 300 mg once daily); if necessary increased  after 2-3 weeks to 800 mg once daily   Tablets, f/c, eprosartan (as mesilate) 300 mg (white),  net price 28-tab pack = £7.31; 400 mg (pink), 56-tab  pack = £15.77; 600 mg (white), 28-tab pack = £14.31.  Label: 21   Indications hypertension; renal disease in hyperten-  sive type 2 diabetes mellitus (see also notes above)   Indications hypertension (including reduction of  stroke risk in hypertension with left ventricular  hypertrophy); chronic heart failure when ACE inhi-  bitors are unsuitable or contra-indicated; diabetic  nephropathy in type 2 diabetes mellitus (see also  notes above)   Cautions see notes above; severe heart failure  Hepatic impairment consider dose reduction in mild  to moderate impairment; manufacturer advises avoid  in severe impairment — no information available  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; asthenia, fatigue,  vertigo; less commonly gastro-intestinal disturbances,  angina, palpitation, oedema, dyspnoea, headache,  sleep disorders, urticaria, pruritus, rash; rarely  hepatitis, atrial fibrillation, cerebrovascular accident,  syncope, paraesthesia; also reported pancreatitis,  anaphylaxis, cough, depression, erectile dysfunction,  anaemia, thrombocytopenia, hyponatraemia, arthr-  algia, myalgia, rhabdomyolysis, tinnitus, photosensit-  ivity, and vasculitis (including Henoch-Schonlein  purpura)   • Hypertension, diabetic nephropathy in type 2 diabetes  mellitus, usually 50 mg once daily (intravascular  volume depletion, initially 25 mg once daily); if    necessary increased after several weeks to 100 mg  once daily; ELDERLY over 75 years initially 25 mg daily  • Chronic heart failure, 12.5 mg once daily, increased at  weekly intervals to 50 mg once daily if tolerated   Tablets, losartan potassium 12.5 mg, net price 28-tab  pack = £7.70; 25 mg, 28-tab pack = £2.64; 50 mg, 28-  tab pack = £2.38; 100 mg, 28-tab pack = £2.84   Tablets, f/c, losartan potassium 12.5 mg (blue), net  price 28-tab pack = £8.09; 25 mg (white), net price 28-  tab pack = £16.18; 50 mg (white, scored), 28-tab pack  = £12.80; 100 mg (white), 28-tab pack = £16.18  Oral suspension, losartan potassium 12.5 mg/5 mL  when reconstituted with solvent provided, net price  200-mL (berry-citrus flavour) = £53.68   Note For hypertension not adequately controlled with losartan  alone. For prescribing information on thiazides, see section  2 . 2.1   Tablets 50/12.5, yellow, f/c, losartan potassium  50 mg, hydrochlorothiazide 12.5 mg, net price 28-tab  pack = £12.80   Tablets 100/12.5, white, f/c, losartan potassium  100 mg, hydrochlorothiazide 12.5 mg, net price 28-tab  pack = £16.18   Tablets 100/25, yellow, f/c, losartan potassium  100 mg, hydrochlorothiazide 25 mg, net price 28-tab  pack = £16.18   Indications hypertension (see also notes above)  Cautions see notes above  Contra-indications biliary obstruction  Hepatic impairment dose should not exceed 20 mg  daily in moderate impairment; manufacturer advises  avoid in severe impairment — no information available  Renal impairment max. 20 mg daily if eGFR 20-  60mL/minute/1.73m 2 ; avoid if eGFR less than  20 mL/minute/1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also gastro-intestinal  disturbances; chest pain, peripheral oedema, hyper-  triglyceridaemia; fatigue; influenza-like symptoms,  cough, pharyngitis, rhinitis; urinary-tract infection;  haematuria, hyperuricaemia; arthritis, musculo-  skeletal pain; less commonly angina, vertigo, rash;  very rarely headache, thrombocytopenia, myalgia,  pruritus, urticaria  Dose   • Initially 10 mg once daily; if necessary increased to  20 mg once daily; max. 40 mg daily    Sevikar® (Daiichi Sankyo) T (Ml  Tablets 20/5, white, f/c, olmesartan medoxomil  20 mg, amlodipine (as besilate) 5 mg, net price 28-tab  pack = £16.95   Tablets 40/5, ivory, f/c, olmesartan medoxomil  40 mg, amlodipine (as besilate) 5 mg, net price 28-tab  pack = £16.95   Tablets 40/10, brownish-red, f/c, olmesartan  medoxomil 40 mg, amlodipine (as besilate) 10 mg, net  price 28-tab pack = £16.95    Olmetec Plus® (Daiichi Sankyo) ▼ [Ml  Tablets, f/c, olmesartan medoxomil 20 mg, hydro-  chlorothiazide 12.5 mg (red-yellow), net price 28-tab  pack = £12.95; olmesartan medoxomil 20 mg, hydro-  chlorothiazide 25 mg (pink), 28-tab pack = £12.95;  olmesartan medoxomil 40 mg, hydrochlorothiazide  12.5 mg (red-yellow), 28-tab pack = £17.50   Indications hypertension (see also notes above); pre-  vention of cardiovascular events in patients with  established atherosclerotic cardiovascular disease, or  type 2 diabetes mellitus with target-organ damage  Cautions see notes above   Hepatic impairment 20-40 mg once daily in mild or  moderate impairment; avoid in severe impairment or  biliary obstruction   Renal impairment manufacturer advises initial dose  of 20 mg once daily in severe impairment  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also gastro-intestinal  disturbances; chest pain; influenza-like symptoms  including pharyngitis and sinusitis; urinary-tract  infection; arthralgia, myalgia, back pain, leg cramps;  eczema; less commonly dry mouth, flatulence,  anxiety, vertigo, tendinitis-like symptoms, abnormal  vision, increased sweating; rarely bradycardia,  tachycardia, dyspnoea, insomnia, depression, blood  disorders, increase in uric acid, eosinophilia, rash, and  pruritus; syncope and asthenia also reported  Dose   • Hypertension, usually 40 mg once daily (but 20 mg  may be sufficient), increased if necessary after at least  4 weeks, to max. 80 mg once daily    Olmetec® (Daiichi Sankyo) (Ml  Tablets, f/c, olmesartan medoxomil 10 mg, net price  28-tab pack = £10.95; 20 mg, 28-tab pack = £12.95;  40 mg, 28-tab pack = £17.50    Micardis® (Boehringer Ingelheim) ▼ [Ml  Tablets, telmisartan 20 mg, net price 28-tab pack =  £8.00; 40 mg, 28-tab pack = £12.50; 80 mg, 28-tab  pack = £17.00   Note For patients with hypertension not adequately controlled  by telmisartan alone. For prescribing information on thiazides,  see section 2.2.1   Micardis Plus® (Boehringer Ingelheim) £mD  Tablets 40/12.5, red/white, telmisartan 40 mg,  hydrochlorothiazide 12.5 mg, net price 28-tab pack =  £12.50   Tablets 80/12.5, red/white, telmisartan 80 mg,  hydrochlorothiazide 12.5 mg, net price 28-tab pack =  £17.00   Tablets 80/25, yellow/white, telmisartan 80 mg,  hydrochlorothiazide 25 mg, net price 28-tab pack =  £17.00    Indications hypertension; heart failure when ACE  inhibitors cannot be used, or in conjunction with an  ACE inhibitor when a beta-blocker cannot be used  (see also section 2.5.5); myocardial infarction with left  ventricular failure or left ventricular systolic dysfunc-  tion (adjunct — see section 2.5.5 and section 2.10.1)  Cautions see notes above   Contra-indications biliary cirrhosis, cholestasis  Hepatic impairment max. dose 80 mg daily in mild to  moderate impairment; avoid if severe  Renal impairment use with caution if eGFR less than  10 mL/minute/ 1.73 m 2 — no information available    Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; renal impairment; less  commonly gastro-intestinal disturbance, syncope,  fatigue, cough, headache, acute renal failure; neutro-  penia, thrombocytopenia, myalgia, and hypersensi-  tivity reactions (including rash, pruritus, vasculitis,  and serum sickness) also reported  Dose   40 mg once daily in intravascular volume depletion); if  necessary increased at intervals of 4 weeks up to max.  320 mg daily   • Heart failure, initially 40 mg twice daily increased at  intervals of at least 2 weeks up to max. 160 mg twice  daily   • Myocardial infarction, initially 20 mg twice daily  increased over several weeks to 160 mg twice daily if  tolerated    Tablets 160/12.5, red, f/c, valsartan 160 mg,  hydrochlorothiazide 12.5 mg, net price 28-tab pack =  £18.41   Tablets 160/25, brown-orange, f/c, valsartan  160 mg, hydrochlorothiazide 25 mg, net price 28-tab  pack = £18.41    Renin inhibitors inhibit renin directly; renin converts  angiotensinogen to angiotensin I. Aliskiren is licensed  for the treatment of hypertension, either alone or in  combination with other antihypertensives. The Scottish  Medicines Consortium (p. 4) has advised (January  2010) that aliskiren ( Rasilez ®) is not recommended  for use within NHS Scotland.   Indications essential hypertension  Cautions patients taking concomitant diuretics, on a  low-sodium diet, or who are dehydrated (first doses  may cause hypotension — initiate with care); renal  artery stenosis; patients at risk of renal impairment;  monitor plasma-potassium concentration and renal  function in diabetes mellitus and heart failure; inter-  actions: Appendix 1 (aliskiren)   Renal impairment caution in renal artery stenosis or  if eGFR less than 30 mL/minute/ 1.73 m 2 — no infor-  mation available; monitor plasma-potassium concen-  tration   Pregnancy manufacturer advises avoid — no informa-  tion available; other drugs acting on the renin-angio-  tensin system have been associated with fetal mal-  formations and neonatal death  Breast-feeding present in milk in animal studies —  manufacturer advises avoid  Side-effects diarrhoea; less commonly rash; rarely  angioedema; acute renal failure (reversible on dis-  continuation of treatment), anaemia, and hyperkal-  aemia also reported  Dose   • ADULT over 18 years, 150 mg once daily, increased if  necessary to 300 mg once daily   Rasilez® (Novartis) ▼ [Ml  Tablets, f/c, aliskiren (as hemifumarate) 150 mg  (pink), net price 28-tab pack = £19.80; 300 mg (red),  net price 28-tab pack = £23.80. Label: 21    Diovan® (Novartis) ▼ 2°M1  Capsules, valsartan 40 mg (grey), net price 28-cap  pack = £13.97; 80 mg (grey/pink), 28-cap pack =  £13.97; 160 mg (dark grey/pink), 28-cap pack =  £18.41   Tablets, f/c, valsartan 40 mg (yellow, scored), net  price 7-tab pack = £3.49; 320 mg (dark grey-violet),  28-tab pack = £20.23   Note For hypertension not adequately controlled by valsartan  alone. For prescribing information on thiazides, see section    Co-Diovan® (Novartis) (Ml  Tablets 80/12.5, orange, f/c, valsartan 80 mg,  hydrochlorothiazide 12.5 mg, net price 28-tab pack =  £13.97    Nitrates, calcium-channel blockers, and potassium-  channel activators have vasodilating effects. Vaso-  dilators can act in heart failure by arteriolar dilatation  which reduces both peripheral vascular resistance and    left ventricular pressure during systole resulting in  improved cardiac output. They can also cause venous  dilatation which results in dilatation of capacitance  vessels, increase of venous pooling, and diminution of  venous return to the heart (decreasing left ventricular  end-diastolic pressure).   For details on the management of stable angina and  acute coronary syndromes, see section 2.10.1.   Nitrates have a useful role in angina (for details on the  management of stable and unstable angina, see section  2.10.1). Although they are potent coronary vasodilators,  their principal benefit follows from a reduction in  venous return which reduces left ventricular work.  Unwanted effects such as flushing, headache, and pos-  tural hypotension may limit therapy, especially when  angina is severe or when patients are unusually sensitive  to the effects of nitrates.   Sublingual glyceryl trinitrate is one of the most effec-  tive drugs for providing rapid symptomatic relief of  angina, but its effect lasts only for 20 to 30 minutes;  the 300-microgram tablet is often appropriate when  glyceryl trinitrate is first used. The aerosol spray pro-  vides an alternative method of rapid relief of symptoms  for those who find difficulty in dissolving sublingual  preparations. Duration of action may be prolonged by  modified-release and transdermal preparations (but tol-  erance may develop, see below).   Isosorbide dinitrate is active sublingually and is a  more stable preparation for those who only require  nitrates infrequently. It is also effective by mouth for  prophylaxis; although the effect is slower in onset, it  may persist for several hours. Duration of action of up to  12 hours is claimed for modified-release preparations.  The activity of isosorbide dinitrate may depend on the  production of active metabolites, the most important of  which is isosorbide mononitrate. Isosorbide mono-  nitrate itself is also licensed for angina prophylaxis;  modified-release formulations (for once daily adminis-  tration) are available.   Glyceryl trinitrate or isosorbide dinitrate may be tried by  intravenous injection when the sublingual form is inef-  fective in patients with chest pain due to myocardial  infarction or severe ischaemia. Intravenous injections  are also useful in the treatment of congestive heart  failure.   Tolerance Many patients on long-acting or transder-  mal nitrates rapidly develop tolerance (with reduced  therapeutic effects). Reduction of blood-nitrate concen-  trations to low levels for 4 to 8 hours each day usually  maintains effectiveness in such patients. If tolerance is  suspected during the use of transdermal patches they  should be left off for several consecutive hours in each  24 hours; in the case of modified-release tablets of  isosorbide dinitrate (and conventional formulations of  isosorbide mononitrate), the second of the two daily  doses should be given after about 8 hours rather than  after 12 hours. Conventional formulations of isosorbide  mononitrate should not usually be given more than  twice daily unless small doses are used; modified-  release formulations of isosorbide mononitrate should  only be given once daily, and used in this way do not  produce tolerance.   Sublingual: prophylaxis and treatment of angina  Buccal: prophylaxis and treatment of angina; adjunct  in unstable angina; acute and congestive heart failure  Injection: control of hypertension and myocardial  ischaemia during and after cardiac surgery; induction  of controlled hypotension during surgery; congestive  heart failure; unstable angina  Transdermal: see under preparations below  Cautions hypothyroidism; malnutrition; hypothermia;  recent history of myocardial infarction; heart failure  due to obstruction; hypoxaemia or other ventilation  and perfusion abnormalities; susceptibility to angle-  closure glaucoma; metal-containing transdermal sys-  tems should be removed before magnetic resonance  imaging procedures, cardioversion, or diathermy;  avoid abrupt withdrawal; monitor blood pressure and  heart rate during intravenous infusion; tolerance (see  notes above); interactions: Appendix 1 (nitrates)  Contra-indications hypersensitivity to nitrates; hypo-  tensive conditions and hypovolaemia; hypertrophic  cardiomyopathy; aortic stenosis; cardiac tamponade;  constrictive pericarditis; mitral stenosis; toxic pulm-  onary oedema; head trauma; cerebral haemorrhage;  cerebrovascular disease; marked anaemia  Hepatic impairment caution in severe impairment  Renal impairment manufacturers advise use with  caution in severe impairment  Pregnancy not known to be harmful  Breast-feeding no information available — manufac-  turers advise use only if potential benefit outweighs  risk   Side-effects postural hypotension, tachycardia (but  paradoxical bradycardia also reported); throbbing  headache, dizziness; less commonly nausea, vomiting,  heartburn, flushing, syncope, temporary hypoxaemia,  rash, application site reactions with transdermal  patches; very rarely angle-closure glaucoma  Injection Specific side-effects following injection (particu-  larly if given too rapidly) include severe hypotension, dia-  phoresis, apprehension, restlessness, muscle twitching, ret-  rosternal discomfort, palpitation, abdominal pain; prolonged  administration has been associated with methaemoglobin-  aemia    • Sublingually, 0.3-1 mg, repeated as required; see also  under preparations   • By intravenous infusion, 10-200 micrograms/minute,  adjusted according to response; max. 400 micr-  ograms/minute; consult product literature for  recommended starting doses specific to indication   Sublingual tablets, glyceryl trinitrate 300 micr-  ograms, net price 100 = £2.71; 500 micrograms, 100 =  £3.27; 600 micrograms, 100 = £12.31. Label: 16  Note Glyceryl trinitrate tablets should be supplied in glass con-  tainers of not more than 100 tablets, closed with a foil-lined cap,  and containing no cotton wool wadding; they should be discarded  after 8 weeks in use   Aerosol spray, glyceryl trinitrate 400 micrograms/  metered dose, net price 200-dose unit = £3.13  Dose treatment or prophylaxis of angina, spray 1-2 doses under  tongue and then close mouth   Aerosol spray, glyceryl trinitrate 400 micrograms/  metered dose, net price 200-dose unit = £3.13  Dose treatment or prophylaxis of angina, spray 1-2 doses under  tongue and then close mouth   Aerosol spray, glyceryl trinitrate 400 micrograms/  metered dose, net price 200-dose unit = £3.29  Dose treatment or prophylaxis of angina, spray 1-2 doses under  tongue and then close mouth  Cautions flammable   Aerosol spray, glyceryl trinitrate 400 micrograms/  metered dose, net price 200-dose unit = £3.44  Dose treatment or prophylaxis of angina, spray 1-2 doses under  tongue and then close mouth   Aerosol spray, glyceryl trinitrate 400 micrograms/  metered dose, net price 180-dose unit = £2.63, 200-  dose unit = £2.71   Buccal tablets, m/r, glyceryl trinitrate 2 mg, net price  100-tab pack = £12.70; 3 mg, 100-tab pack = £18.33;  5 mg, 100-tab pack = £24.96. Counselling, see below  Dose treatment of angina, 2 mg as required, increased to 3 mg if  necessary; prophylaxis 2-3 mg 3 times daily; 5 mg in severe  angina   Unstable angina (adjunct), up to 5 mg with ECG monitoring  Congestive heart failure, 5 mg 3 times daily, increased to 10 mg 3  times daily in severe cases   Acute heart failure, 5 mg repeated until symptoms abate  Counselling Tablets have rapid onset of effect; they are placed  between upper lip and gum, and left to dissolve; vary site to  reduce risk of dental caries   Note Glass or polyethylene apparatus is preferable; loss of  potency will occur if PVC is used   Glyceryl Trinitrate (Non-proprietary) (Ml  Injection, glyceryl trinitrate 1 mg/mL. To be diluted  before use or given undiluted with syringe pump. Net  price 50-mL vial = £15.90   Injection, glyceryl trinitrate 5 mg/mL. To be diluted  before use. Net price 5-mL amp = £6.49; 10-mL amp =  £12.98   Injection, glyceryl trinitrate 1 mg/mL. To be diluted  before use or given undiluted with syringe pump. Net  price 10-mL amp = £5.88; 50-mL bottle = £13.77   Nitronal® (Merck Serono) (Ml  Injection, glyceryl trinitrate 1 mg/mL. To be diluted  before use or given undiluted with syringe pump. Net  price 5-mL vial = £1.80; 50-mL vial = £14.76   Patches, self-adhesive, transparent, glyceryl trinitrate,  ‘5’ patch (releasing approx. 5 mg/24 hours when in  contact with skin), net price 28 = £12.77; ‘10’ patch  (releasing approx. 10 mg/24 hours), 28 = £14.06  Dose prophylaxis of angina, apply one ‘5’ or one TO’ patch to  lateral chest wall, upper arm, thigh, abdomen, or shoulder;  increase to two TO’ patches every 24 hours if necessary; replace  every 24 hours, siting replacement patch on different area; see  also notes above (Tolerance)   Patches, self-adhesive, transparent, glyceryl trinitrate,  ‘5’ patch (releasing approx. 5 mg/24 hours when in  contact with skin), net price 30 = £11.62; ‘10’ patch  (releasing approx. 10 mg/24 hours), 30 = £12.87; ‘15’  patch (releasing approx. 15 mg/24 hours), 30 =  £14.19   ‘0.2 mg /h’ patch (releasing approx. 5 mg/24 hours  when in contact with skin), net price 28 = £10.59;  ‘0.4 mg /h’ patch (releasing approx. 10 mg/24 hours),  28 = £11.72; ‘0.6 mg /h’ patch (releasing  approx. 15 mg/24 hours), 28 = £12.90  Dose prophylaxis of angina, apply one ‘0.2 mg/h’ patch to chest  or outer upper arm; replace every 24 hours, siting replacement  patch on different area: adjust dose according to response; max.  15 mg in 24 hours; see also notes above (Tolerance)   Ointment, glyceryl trinitrate 2%, net price 60 g =  £59.65. Counselling, see administration below   Dose prophylaxis of angina, usual dose 1-2 inches of ointment  measured on to Applirule ® , and applied (usually to chest, arm, or  thigh) without rubbing in and secured with surgical tape, every 3-  4 hours as required; to determine dose, 14 inch on first day then  increased by 14 inch/day until headache occurs, then reduced by  14 inch   Patches, self-adhesive, pink, glyceryl trinitrate, ‘5’  patch (releasing approx. 5 mg/ 24 hours when in  contact with skin), net price 28 = £17.05; ‘10’ patch  (releasing approx. 10 mg/24 hours), 28 = £18.74  Dose prophylaxis of angina, apply one ‘5’ or one TO’ patch to  lateral chest wall; replace every 24 hours, siting replacement  patch on different area; max. two TO’ patches daily; see also notes  above (Tolerance)   Cautions see under Glyceryl Trinitrate  Contra-indications see under Glyceryl Trinitrate  Hepatic impairment see under Glyceryl Trinitrate  Renal impairment see under Glyceryl Trinitrate  Pregnancy may cross placenta — manufacturers  advise avoid unless potential benefit outweighs risk  Breast-feeding see under Glyceryl Trinitrate   • By mouth, daily in divided doses, angina 30-120 mg,  left ventricular failure 40-160 mg, up to 240 mg if  required   • By intravenous infusion, 2-10 mg/hour; higher doses  up to 20 mg/hour may be required   Tablets, isosorbide dinitrate 10 mg, net price 56-tab  pack = £12.24; 20 mg, 56-tab pack = £13.50   Ismo 10 tablets, isosorbide mononitrate 10 mg, net  price 60-tab pack = £3.31. Label: 25  Ismo 20 tablets, scored, isosorbide mononitrate  20 mg, net price 60-tab pack = £4.85. Label: 25   Chemydur® 60XL (Sovereign) (Ml  Tablets, m/r, scored, ivory, isosorbide mononitrate  60 mg, net price 28-tab pack = £3.99. Label: 25  Dose prophylaxis of angina, 1 tablet in the morning (half a tablet  for 2-4 days to minimise possibility of headache), increased if  necessary to 2 tablets   Aerosol spray, isosorbide dinitrate 1.25 mg/metered  dose, net price 200-dose unit = £3.95  Dose treatment or prophylaxis of angina, spray 1-3 doses under  tongue whilst holding breath; allow 30 second interval between  each dose   Retard-20 tablets, m/r, scored, isosorbide dinitrate  20 mg, net price 56-tab pack = £2.58. Label: 25  Retard-40 tablets, m/r, scored, isosorbide dinitrate  40 mg, net price 56-tab pack = £6.36. Label: 25  Dose prophylaxis of angina, 40 mg daily in 1-2 divided doses,  increased if necessary to 60-80 mg daily in 2-3 divided doses   Cautions see under Glyceryl Trinitrate  Contra-indications see under Glyceryl Trinitrate  Hepatic impairment see under Glyceryl Trinitrate  Renal impairment see under Glyceryl Trinitrate  Pregnancy manufacturers advise avoid unless poten-  tial benefit outweighs risk  Breast-feeding see under Glyceryl Trinitrate  Side-effects see under Glyceryl Trinitrate  Dose   • Initially 20 mg 2-3 times daily or 40 mg twice daily  (10 mg twice daily in those who have not previously  received nitrates); up to 120 mg daily in divided doses  if required   Tablets, isosorbide mononitrate 10 mg, net price 56 =  £1.05; 20 mg, 56 =£1.08; 40 mg, 56 =£1.40. Label: 25  Brands include Angeze ®   Elantan 10 tablets, scored, isosorbide mononitrate  10 mg, net price 56-tab pack = £1.32; 84-tab pack =  £4.97. Label: 25   Elantan 20 tablets, scored, isosorbide mononitrate  20 mg, net price 56-tab pack = £1.73; 84-tab pack =  £6.13. Label: 25   Elantan 40 tablets, scored, isosorbide mononitrate  40 mg, net price 56-tab pack = £2.81; 84-tab pack =  £10.56. Label: 25   Elantan LA 25 capsules, m/r, brown/white, enclos-  ing white micropellets, isosorbide mononitrate 25 mg,  net price 28-cap pack = £2.64. Label: 25  Dose prophylaxis of angina, 1 capsule in the morning, increased  if necessary to 2 capsules   Elantan LA 50 capsules, m/r, brown/pink, enclosing  white micropellets, isosorbide mononitrate 50 mg, net  price 28-cap pack = £3.69. Label: 25  Dose prophylaxis of angina, 1 capsule daily in the morning,  increased if necessary to 2 capsules   Dose prophylaxis of angina, 1 tablet in the morning (half a tablet  if headache occurs), increased to 2 tablets in the morning if  required   Tablets, m/r, scored, yellow, isosorbide mononitrate  60 mg, net price 28-tab pack = £8.15. Label: 25  Dose prophylaxis of angina, 1 tablet in the morning (half a tablet  for 2-4 days if headache occurs), increased if necessary to 2  tablets   Isodur 25XL capsules, m/r, brown/white, isosorbide  mononitrate 25 mg, net price 28-cap pack = £5.50.  Label: 25   Isodur 50XL capsules, m/r, brown/red, isosorbide  mononitrate 50 mg, net price 28-cap pack = £6.50.  Label: 25   Dose prophylaxis of angina, 25-50 mg daily in the morning,  increased if necessary to 50-100 mg once daily   Isotard 25XL tablets, m/r, ivory, isosorbide mono-  nitrate 25 mg, net price 28-tab pack = £5.95. Label: 25  Isotard 40XL tablets, m/r, ivory, isosorbide mono-  nitrate 40 mg, net price 28-tab pack = £6.78. Label: 25  Isotard 50XL tablets, m/r, ivory, isosorbide mono-  nitrate 50 mg, net price 28-tab pack = £6.78. Label: 25  Isotard 60XL tablets, m/r, ivory, isosorbide mono-  nitrate 60 mg, net price 28-tab pack = £5.75. Label: 25  Dose prophylaxis of angina, 25-60 mg daily in the morning (if  headache occurs with 60-mg tablet, half a 60-mg tablet may be  given for 2-4 days), increased if necessary to 50-120 mg daily   Tablets, m/r, ivory, isosorbide mononitrate 60 mg, net  price 28-tab pack = £10.36. Label: 25  Dose prophylaxis of angina, 1 tablet daily in the morning (half a  tablet for first 2-4 days to minimise possibility of headache),  increased if necessary to 2 tablets once daily   Monomax® SR, capsules, m/r, isosorbide mono-  nitrate 40 mg, net price 28-cap pack = £6.52; 60 mg,  28-cap pack = £8.86. Label: 25  Dose prophylaxis of angina, 40-60 mg daily in the morning,  increased if necessary to 120 mg daily  Note Also available as Angeze SR ®   Monomax® XL tablets, m/r, isosorbide mononitrate  60 mg, net price 28-tab pack = £5.25. Label: 25  Dose prophylaxis of angina, 1 tablet in the morning (half a tablet  for first 2-4 days to minimise possibility of headache), increased if  necessary to 2 tablets   Tablets, m/r, isosorbide mononitrate 60 mg, net price  28-tab pack = £3.98. Label: 25   Dose prophylaxis of angina, 1 tablet daily in the morning (half a  tablet daily for first 2-4 days to minimise possibility of headache),  increased if necessary to 2 tablets once daily   Monosorb XL 60® (Dexcel) (Ml  Tablets, m/r, f/c, isosorbide mononitrate 60 mg, net  price 28-tab pack = £16.66. Label: 25  Dose prophylaxis of angina, 1 tablet daily in the morning (half a  tablet for first 2-4 days to minimise possibility of headache),  increased if necessary to 2 tablets    Zemon 60XL tablets, scored, m/r, ivory, isosorbide  mononitrate 60 mg, net price 28-tab pack = £11.14.  Label: 25   Dose prophylaxis of angina, 40-60 mg daily in the morning (half  a 60-mg tablet may be given for 2-4 days to minimise possibility  of headache), increased if necessary to 80-120 mg once daily   Calcium-channel blockers (less correctly called ‘cal-  cium-antagonists’) interfere with the inward displace-  ment of calcium ions through the slow channels of  active cell membranes. They influence the myocardial  cells, the cells within the specialised conducting system  of the heart, and the cells of vascular smooth muscle.  Thus, myocardial contractility may be reduced, the  formation and propagation of electrical impulses within  the heart may be depressed, and coronary or systemic  vascular tone may be diminished.   Calcium-channel blockers differ in their predilection for  the various possible sites of action and, therefore, their  therapeutic effects are disparate, with much greater  variation than those of beta-blockers. There are impor-  tant differences between verapamil, diltiazem, and the  dihydropyridine calcium-channel blockers (amlodipine,  felodipine, isradipine, lacidipine, lercanidipine, nicar-  dipine, nifedipine, and nimodipine). Verapamil and dilti-  azem should usually be avoided in heart failure because  they may further depress cardiac function and cause  clinically significant deterioration.   Verapamil is used for the treatment of angina (section  2.10.1), hypertension (section 2.5), and arrhythmias  (section 2.3.2). It is a highly negatively inotropic calcium  channel-blocker and it reduces cardiac output, slows the  heart rate, and may impair atrioventricular conduction.  It may precipitate heart failure, exacerbate conduction  disorders, and cause hypotension at high doses and  should not be used with beta-blockers (see p. 133).  Constipation is the most common side-effect.   Nifedipine relaxes vascular smooth muscle and dilates  coronary and peripheral arteries. It has more influence  on vessels and less on the myocardium than does verap-  amil, and unlike verapamil has no anti-arrhythmic activ-  ity. It rarely precipitates heart failure because any nega-  tive inotropic effect is offset by a reduction in left  ventricular work. Short-acting formulations of nifedipine  are not recommended for angina or long-term manage-  ment of hypertension; their use may be associated with  large variations in blood pressure and reflex tachy-  cardia. Nicardipine has similar effects to those of nife-  dipine and may produce less reduction of myocardial  contractility. Amlodipine and felodipine also resemble  nifedipine and nicardipine in their effects and do not  reduce myocardial contractility and they do not produce  clinical deterioration in heart failure. They have a longer  duration of action and can be given once daily. Nife-  dipine, nicardipine, amlodipine, and felodipine are used  for the treatment of angina (section 2.10.1) or hyper-  tension. All are valuable in forms of angina associated  with coronary vasospasm. Side-effects associated with  vasodilatation such as flushing and headache (which  become less obtrusive after a few days), and ankle  swelling (which may respond only partially to diuretics)  are common.   Isradipine, lacidipine, and lercanidipine have similar  effects to those of nifedipine and nicardipine; they are  indicated for hypertension only.   Nimodipine is related to nifedipine but the smooth  muscle relaxant effect preferentially acts on cerebral  arteries. Its use is confined to prevention and treatment  of vascular spasm following aneurysmal subarachnoid  haemorrhage.   Diltiazem is effective in most forms of angina (section  2.10.1); the longer-acting formulation is also used for  hypertension. It may be used in patients for whom beta-  blockers are contra-indicated or ineffective. It has a less  negative inotropic effect than verapamil and significant  myocardial depression occurs rarely. Nevertheless  because of the risk of bradycardia it should be used  with caution in association with beta-blockers.   Unstable angina Calcium-channel blockers do not  reduce the risk of myocardial infarction in unstable  angina. The use of diltiazem or verapamil should be  reserved for patients resistant to treatment with beta-  blockers.   Withdrawal There is some evidence that sudden  withdrawal of calcium-channel blockers may be asso-  ciated with an exacerbation of angina.   interactions: Appendix 1 (calcium-channel blockers)  Contra-indications cardiogenic shock, unstable  angina, significant aortic stenosis  Hepatic impairment may need dose reduction — half-  life prolonged   • Angina, 60 mg 3 times daily (elderly initially twice  daily); increased if necessary to 360 mg daily    Side-effects abdominal pain, nausea; palpitation,  flushing, oedema; headache, dizziness, sleep distur-  bances, fatigue; less commonly gastro-intestinal dis-  turbances, dry mouth, taste disturbances, hypo-  tension, syncope, chest pain, dyspnoea, rhinitis, mood  changes, asthenia, tremor, paraesthesia, urinary dis-  turbances, impotence, gynaecomastia, weight  changes, myalgia, muscle cramps, back pain, arthr-  algia, visual disturbances, tinnitus, pruritus, rashes  (including isolated reports of erythema multiforme),  sweating, alopecia, purpura, and skin discolouration;  very rarely gastritis, pancreatitis, hepatitis, jaundice,  cholestasis, gingival hyperplasia, myocardial infarc-  tion, arrhythmias, tachycardia, vasculitis, coughing,  peripheral neuropathy, hyperglycaemia, thrombocy-  topenia, angioedema, and urticaria  Dose   • Hypertension or angina, initially 5 mg once daily;  max. 10 mg once daily   Note Tablets from various suppliers may contain different salts  (e.g. amlodipine besilate, amlodipine maleate, and amlodipine  mesilate) but the strength is expressed in terms of amlodipine  (base); tablets containing different salts are considered inter-  changeable   Tablets, amlodipine (as maleate or as mesilate) 5 mg,  net price 28-tab pack = £1.05; 10 mg, 28-tab pack =  £ 1.20   Tablets, amlodipine (as besilate) 5 mg, net price 28-  tab pack = £11.08; 10 mg, 28-tab pack = £16.55   Note For hypertension in patients stabilised on the individual  components in the same proportions. For prescribing infor-  mation on valsartan, see section 2. 5. 5.2   Tablets 5/80, f/c, dark yellow, amlodipine 5 mg,  valsartan 80 mg, net price 28-tab pack = £13.97  Tablets 5/160, f/c, dark yellow, amlodipine 5 mg,  valsartan 160 mg, net price 28-tab pack = £18.41  Tablets 10/160, f/c, light yellow, amlodipine lOmg,  valsartan 160 mg, net price 28-tab pack = £18.41   Cautions heart failure or significantly impaired left  ventricular function, bradycardia (avoid if severe), first  degree AV block, or prolonged PR interval; interac-  tions: Appendix 1 (calcium-channel blockers)  Contra-indications severe bradycardia, left ventri-  cular failure with pulmonary congestion, second- or  third-degree AV block (unless pacemaker fitted), sick  sinus syndrome; acute porphyria (section 9.8.2)  Hepatic impairment reduce dose  Renal impairment start with smaller dose  Pregnancy avoid   Side-effects bradycardia, sino-atrial block, AV block,  palpitation, dizziness, hypotension, malaise, asthenia,  headache, hot flushes, gastro-intestinal disturbances,  oedema (notably of ankles); rarely rashes (including  erythema multiforme and exfoliative dermatitis),  photosensitivity; hepatitis, gynaecomastia, gum   Note These formulations are licensed as generics and there is  no requirement for brand name dispensing. Although their  means of formulation has called for the strict designation  ‘modified-release’ their duration of action corresponds to that  of tablets requiring administration 3 times daily   Tablets, m/r (but see note above), off-white, diltiazem  hydrochloride 60 mg, net price 90-tab pack = £7.96.  Label: 25   Capsules, m/r, diltiazem hydrochloride 120 mg  (pink/blue), net price 28-cap pack = £9.09; 180 mg  (dark pink/blue), 28-cap pack = £10.32; 200 mg  (brown), 28-cap pack = £6.66; 240 mg (red/blue), 28-  cap pack = £11.46; 300 mg (maroon/blue), 28-cap  pack = £9.09. Label: 25   Dose angina and mild to moderate hypertension, initially 240 mg  once daily, increased if necessary to 300 mg once daily; in elderly  and in hepatic or renal impairment, initially 120 mg daily   Capsules, m/r, diltiazem hydrochloride 90 mg  (white), net price 56-cap pack = £7.03; 120 mg  (brown), 56-cap pack = £6.91; 180 mg (brown), 56-cap  pack = £13.27. Label: 25   Dose angina and mild to moderate hypertension, initially 90 mg  twice daily; increased if necessary to 120 mg or 180 mg twice daily   Capsules, m/r, diltiazem hydrochloride 240 mg  (white), net price 28-cap pack = £7.94; 300 mg (yel-  low), 28-cap pack = £6.98. Label: 25  Dose angina and mild to moderate hypertension, initially 240 mg  once daily (elderly and in hepatic and renal impairment, dose  form not appropriate for initial dose titration); increased if  necessary to 300 mg once daily   Note Different versions of modified-release preparations con-  taining more than 60 mg diltiazem hydrochloride may not have  the same clinical effect. To avoid confusion between these  different formulations of diltiazem, prescribes should specify  the brand to be dispensed   Capsules, m/r, diltiazem hydrochloride 90 mg  (white), net price 56-cap pack = £8.45; 120 mg  (brown/white), 56-cap pack = £9.40; 180 mg (brown/  white), 56-cap pack = £14.08. Label: 25  Tablets, m/r, f/c, scored, diltiazem hydrochloride  120 mg, net price 56-tab pack = £14.72. Label: 25  Dose mild to moderate hypertension, usually 120 mg twice daily  (dose form not appropriate for initial dose titration)   Angina, initially 90 mg twice daily (elderly, dose form not appro-  priate for initial dose titration); increased to 180 mg twice daily if  required   Tablets, m/r, both f/c, diltiazem hydrochloride 90 mg,  net price 56-tab pack = £6.33; 120 mg, 56-tab pack =  £7.04. Label: 25   Dose mild to moderate hypertension, initially 90 mg or 120 mg  twice daily; up to 360 mg daily may be required: ELDERLY and in  hepatic and renal impairment, initially 120 mg once daily; up to  240 mg daily may be required   Angina, initially 90 mg or 120 mg twice daily; up to 480 mg daily in  divided doses may be required; ELDERLY and in hepatic and renal  impairment, dose form not appropriate for initial dose titration; up  to 240 mg daily may be required    Dilcardia SR® (Generics) (Ml  Capsules, m/r, diltiazem hydrochloride 60 mg (pink/  white), net price 56-cap pack = £6.03; 90 mg (pink/  yellow), 56-cap pack = £10.33; 120 mg (pink/ orange),  56-cap pack = £11.49. Label: 25  Dose angina and mild to moderate hypertension, initially 90 mg  twice daily; increased if necessary to 180 mg twice daily; ELDERLY  and in hepatic or renal impairment, initially 60 mg twice daily,  max. 90 mg twice daily   Dilzem SR® (Cephalon) (Ml  Capsules, m/r, all beige, diltiazem hydrochloride  60 mg, net price 56-cap pack = £6.03; 90 mg, 56-cap  pack = £11.29; 120 mg, 56-cap pack = £12.89.   Dose angina and mild to moderate hypertension, initially 90 mg  twice daily (elderly 60 mg twice daily); up to 180 mg twice daily  may be required    Dilzem XL® (Cephalon) (Ml  Capsules, m/r, diltiazem hydrochloride 120 mg, net  price 28-cap pack = £7.78; 180 mg, 28-cap pack =  £11.55; 240 mg, 28-cap pack = £11.03. Label: 25  Dose angina and mild to moderate hypertension, initially 180 mg  once daily (elderly and in hepatic and renal impairment, 120 mg  once daily); if necessary may be increased to 360 mg once daily    Slozem® (Merck Serono) (Ml  Capsules, m/r, diltiazem hydrochloride 120 mg  (pink/ clear), net price 28-cap pack = £7.00; 180 mg  (pink/ clear), 28-cap pack = £7.80; 240 mg (red/clear),  28-cap pack = £8.20; 300 mg (red/white), 28-cap pack  = £8.50. Label: 25   Dose angina and mild to moderate hypertension, initially 240 mg  once daily (elderly and in hepatic and renal impairment, 120 mg  once daily); if necessary may be increased to 360 mg once daily    Tildiem LA® (Sanofi-Aventis) (Ml  Capsules, m/r, diltiazem hydrochloride 200 mg  (pink/ grey, containing white pellets), net price 28-cap  pack = £6.27; 300 mg (white/yellow, containing white  pellets), 28-cap pack = £7.22. Label: 25  Dose angina and mild to moderate hypertension, initially 200 mg  once daily before or with food, increased if necessary to 300-  400 mg daily, max. 500 mg daily; ELDERLY and in hepatic or renal  impairment, initially 200 mg daily, increased if necessary to  300 mg daily    Tildiem Retard® (Sanofi-Aventis) (Ml  Tablets, m/r, diltiazem hydrochloride 90 mg, net price  56-tab pack = £7.27; 120 mg, 56-tab pack = £7.15.  Label: 25   Counselling Tablet membrane may pass through gastro-intestinal  tract unchanged, but being porous has no effect on efficacy  Dose mild to moderate hypertension, initially 90 mg or 120 mg  twice daily; increased if necessary to 360 mg daily in divided  doses; ELDERLY and in hepatic or renal impairment, initially  120 mg once daily; increased if necessary to 120 mg twice daily  Angina, initially 90 mg or 120 mg twice daily; increased if neces-  sary to 480 mg daily in divided doses; ELDERLY and in hepatic or  renal impairment, dose form not appropriate for initial titration;  up to 120 mg twice daily may be required    Viazem XL® (Genus) Ml  Capsules, m/r, diltiazem hydrochloride 120 mg  (lavender), net price 28-cap pack = £6.60; 180 mg  (white /blue-green), 28-cap pack = £7.36; 240 mg  (blue-green/lavender), 28-cap pack = £7.74; 300 mg  (white/lavender), 28-cap pack = £8.03; 360 mg (blue-  green), 28-cap pack = £13.85. Label: 25  Dose angina and mild to moderate hypertension, initially 180 mg  once daily, adjusted according to response to 240 mg once daily;  max. 360 mg once daily; ELDERLY and in hepatic or renal impair-  ment, initially 120 mg once daily, adjusted according to response   Dose angina and mild to moderate hypertension, 180-300 mg  once daily, increased if necessary to 360 mg once daily in hyper-  tension and to 480 mg once daily in angina; ELDERLY and in  hepatic or renal impairment, initially 120 mg once daily   Indications hypertension, prophylaxis of angina  Cautions withdraw if ischaemic pain occurs or existing  pain worsens shortly after initiating treatment or if  cardiogenic shock develops; severe left ventricular  dysfunction; avoid grapefruit juice (may affect  metabolism); acute porphyria (but see section 9.8.2);  interactions: Appendix 1 (calcium-channel blockers)  Contra-indications unstable angina, uncontrolled  heart failure; significant aortic stenosis; within 1  month of myocardial infarction  Hepatic impairment reduce dose  Pregnancy avoid; toxicity in animal studies; may  inhibit labour   Breast-feeding present in milk  Side-effects flushing, headache, palpitation, dizziness,  fatigue, gravitational oedema; rarely rash, pruritus,  cutaneous vasculitis, gum hyperplasia, urinary fre-  quency, impotence, fever  Dose   • Hypertension, initially 5 mg (elderly 2.5 mg) daily in  the morning; usual maintenance 5-10 mg once daily;  doses above 20 mg daily rarely needed   • Angina, initially 5 mg daily in the morning, increased if  necessary to 10 mg once daily   Felodipine (Non-proprietary) Ml  Tablets, m/r, felodipine 2.5 mg, net price 28-tab pack  = £6.31; 5 mg, 28-tab pack = £4.21; 10 mg, 28-tab pack  = £5.66, 30-tab pack = £12.87. Label: 25  Brands include Cardioplen XL ®, Felogen XL ®, Felotens XL 9 ,  Keloc SR ®, Neofel XL ®, Parmid XL ®, Vascalpha ®   Plendil® (AstraZeneca) (Ml  Tablets, m/r, f/c, felodipine 2.5 mg (yellow), net price  28-tab pack = £6.31; 5 mg (pink), 28-tab pack = £4.21;  10 mg (brown), 28-tab pack = £5.66. Label: 25   Cautions sick sinus syndrome (if pacemaker not  fitted); avoid grapefruit juice (may affect metabolism);  poor cardiac reserve; interactions: Appendix 1 (cal-  cium-channel blockers)   Contra-indications cardiogenic shock; symptomatic  or tight aortic stenosis; during or within 1 month of  myocardial infarction; unstable angina; acute por-  phyria (section 9.8.2)   Pregnancy may inhibit labour; risk to fetus should be  balanced against risk of uncontrolled maternal  hypertension   Side-effects abdominal discomfort; tachycardia, pal-  pitation, flushing, peripheral oedema; dyspnoea;  headache, fatigue, dizziness; polyuria; rash; less com-  monly hypotension, weight gain; very rarely vomiting,  nausea, gum hyperplasia, anorexia, drowsiness,  arrhythmia, bradycardia, heart failure, cough,  depression, paraesthesia, anxiety, erectile dysfunc-  tion, blood disorders (such as thrombocytopenia,  leucopenia, anaemia), arthralgia, visual disturbance,  hypersensitivity reactions; hepatitis and gynaeco-  mastia also reported  Dose   • 2.5 mg twice daily, increased if necessary after 3-4  weeks to 5 mg twice daily (exceptionally up to 10 mg  twice daily); ELDERLY (or in hepatic or renal impair-  ment) 1.25 mg twice daily, increased if necessary after  3-4 weeks according to response, maintenance dose  of 2.5 mg or 5 mg once daily may be sufficient   Tablets, yellow, scored, isradipine 2.5 mg, net price  56-tab pack = £16.54   Cautions cardiac conduction abnormalities; poor car-  diac reserve; avoid grapefruit juice (may affect  metabolism); interactions: Appendix 1 (calcium-  channel blockers)   Contra-indications cardiogenic shock, unstable  angina, aortic stenosis; avoid within 1 month of  myocardial infarction; acute porphyria (section 9.8.2)   Side-effects flushing, palpitation, oedema; headache,  dizziness; rarely gastro-intestinal disturbances, gum  hyperplasia, aggravation of angina, mood distur-  bances, asthenia, polyuria, muscle cramps, skin rash  (including pruritus and erythema)   • Initially 2 mg as a single daily dose, preferably in the  morning; increased after 3-4 weeks to 4 mg daily, then  if necessary to 6 mg daily    Motens® (Boehringer Ingelheim) (Ml  Tablets, both f/c, lacidipine 2 mg, net price 28-tab  pack = £2.95; 4 mg (scored), 28-tab pack = £3.10    Indications mild to moderate hypertension  Cautions left ventricular dysfunction; sick sinus  syndrome (if pacemaker not fitted); avoid grapefruit  juice (may affect metabolism); interactions: Appen-  dix 1 (calcium-channel blockers)  Contra-indications aortic stenosis; unstable angina,  uncontrolled heart failure; within 1 month of myo-  cardial infarction; acute porphyria (section 9.8.2)  Hepatic impairment avoid in severe disease  Renal impairment avoid if eGFR less than 30 mL/  minute/ 1. 73 m z    Breast-feeding manufacturer advises avoid  Side-effects less commonly flushing, peripheral  oedema, palpitation, tachycardia, headache, dizziness;  rarely gastro-intestinal disturbances, angina, asthenia,  drowsiness, polyuria, myalgia, rash; very rarely gin-  gival hyperplasia, myocardial infarction, hypotension  Dose   • Initially 10 mg once daily; increased, if necessary, after  at least 2 weeks to 20 mg daily   Lercanidipine Hydrochloride (Non-proprietary) Cm]  Tablets, lercanidipine hydrochloride 10 mg, net price  28-tab pack = £5.32; 20 mg, 28-tab pack = £8.56.  Label: 22   Tablets, f/c, lercanidipine hydrochloride 10 mg (yel-  low), net price 28-tab pack = £5.70; 20 mg (pink), 28-  tab pack = £10.82. Label: 22   Cautions withdraw if ischaemic pain occurs or existing  pain worsens within 30 minutes of initiating treatment  or increasing dose; congestive heart failure or signif-  icantly impaired left ventricular function; elderly;  avoid grapefruit juice (may affect metabolism);  interactions: Appendix 1 (calcium-channel blockers)   Contra-indications cardiogenic shock; advanced aor-  tic stenosis; unstable or acute attacks of angina; avoid  within 1 month of myocardial infarction; acute por-  phyria (section 9.8.2)   Pregnancy may inhibit labour; toxicity in animal stu-  dies; manufacturer advises avoid, but risk to fetus  should be balanced against risk of uncontrolled  maternal hypertension   Side-effects dizziness, headache, peripheral oedema,  flushing, palpitation, nausea; also gastro-intestinal  disturbances, drowsiness, insomnia, tinnitus, hypo-  tension, rashes, dyspnoea, paraesthesia, frequency of  micturition; thrombocytopenia, depression and  impotence reported   • Initially 20 mg 3 times daily, increased, after at least  three days, to 30 mg 3 times daily (usual range 60-  120 mg daily)   Nicardipine (Non-proprietary) (5°M1  Capsules, nicardipine hydrochloride 20 mg, net price  56-cap pack = £4.03; 30 mg, 56-cap pack = £5.16   Capsules, nicardipine hydrochloride 20 mg (blue/  white), net price 56-cap pack = £6.00; 30 mg (blue/  pale blue), 56-cap pack = £6.96   Capsules, m/r, nicardipine hydrochloride 30 mg, net  price 56-cap pack = £7.15; 45 mg (blue), 56-cap pack  = £10.40. Label: 25   Dose mild to moderate hypertension, initially 30 mg twice daily;  usual effective dose 45 mg twice daily (range 30-60 mg twice  daily)   Cautions see notes above; also withdraw if ischaemic  pain occurs or existing pain worsens shortly after  initiating treatment; poor cardiac reserve; heart failure  or significantly impaired left ventricular function  (heart failure deterioration observed); severe hypo-  tension; elderly; diabetes mellitus; avoid grapefruit  juice (may affect metabolism); acute porphyria (but  see section 9.8.2); interactions: Appendix 1 (calcium-  channel blockers)    Contra-indications cardiogenic shock; advanced aor-  tic stenosis; within 1 month of myocardial infarction;  unstable or acute attacks of angina  Hepatic impairment dose reduction may be required  in severe liver disease    Pregnancy may inhibit labour; manufacturer advises  avoid before week 20; risk to fetus should be balanced  against risk of uncontrolled maternal hypertension;  use only if other treatment options are not indicated  or have failed   Breast-feeding amount too small to be harmful but  manufacturers advise avoid    Side-effects gastro-intestinal disturbance; hypo-  tension, oedema, vasodilatation, palpitation; head-  ache, dizziness, lethargy, asthenia; less commonly  tachycardia, syncope, chills, nasal congestion, dys-  pnoea, anxiety, sleep disturbance, vertigo, migraine,  paraesthesia, tremor, polyuria, dysuria, nocturia,  erectile dysfunction, epistaxis, myalgia, joint swelling,  visual disturbance, sweating, hypersensitivity reac-  tions (including angioedema, jaundice, pruritus, urti-  caria, and rash); rarely anorexia, gum hyperplasia,  mood disturbances, hyperglycaemia, male infertility,  purpura, and photosensitivity reactions; also reported  dysphagia, intestinal obstruction, intestinal ulcer,  bezoar formation (with some modified-release pre-  parations), gynaecomastia, agranulocytosis, and  anaphylaxis  Dose    Nifedipine (Non-proprietary) (Ml  Capsules, nifedipine 5 mg, net price 84-cap pack =  £2.97; 10 mg, 84-cap pack = £4.00  Dose angina prophylaxis (but not recommended, see notes  above) and Raynaud's phenomenon, initially 5 mg 3 times daily,  adjusted according to response to 20 mg 3 times daily  Hypertension, not recommended therefore no dose stated   Capsules, orange, nifedipine 5 mg, net price 90-cap  pack = £5.73; 10 mg, 90-cap pack = £7.30  Dose angina prophylaxis (but not recommended, see notes  above) and Raynaud’s phenomenon, initially 5 mg 3 times daily,  adjusted according to response to max. 20 mg 3 times daily  Hypertension, not recommended therefore no dose stated   Note Different versions of modified-release preparations may  not have the same clinical effect. To avoid confusion between  these different formulations of nifedipine, prescribers should  specify the brand to be dispensed. Modified-release formula-  tions may not be suitable for dose titration in hepatic disease    Adalat® LA (Bayer Schering) (Ml  LA 20 tablets, m/r, f/c, pink, nifedipine 20 mg, net  price 28-tab pack = £4.97. Label: 25  LA 30 tablets, m/r, f/c, pink, nifedipine 30 mg, net  price 28-tab pack = £6.85. Label: 25  LA 60 tablets, m/r, f/c, pink, nifedipine 60 mg, net  price 28-tab pack = £9.03. Label: 25  Counselling Tablet membrane may pass through gastro-intestinal  tract unchanged, but being porous has no effect on efficacy  Cautions dose form not appropriate for use in hepatic impair-  ment or where there is a history of oesophageal or gastro-intes-  tinal obstruction, decreased lumen diameter of the gastro-intes-  tinal tract, or inflammatory bowel disease (including Crohn’s  disease)   Dose hypertension, 20-30 mg once daily, increased if necessary  to max. 90 mg once daily   Angina prophylaxis, 30 mg once daily, increased if necessary to  max. 90 mg once daily    Adalat® Retard (Bayer Schering) (Ml  Retard 10 tablets, m/r, f/c, grey-pink, nifedipine  10 mg, net price 56-tab pack = £7.34. Label: 25  Retard 20 tablets, m/r, f/c, grey-pink, nifedipine  20 mg, net price 56-tab pack = £8.81. Label: 25  Dose hypertension and angina prophylaxis, 10 mg twice daily,  adjusted according to response to 40 mg twice daily   Tablets, m/r, nifedipine 10 mg (pink), net price 56-tab  pack = £3.73; 20 mg (pink), 56-tab pack = £5.21.  Label: 25   Dose hypertension and angina prophylaxis, 10 mg twice daily,  adjusted according to response to 40 mg twice daily   Tablets, m/r, red, nifedipine 30 mg, net price 28-tab  pack = £4.70; 60 mg, 28-tab pack = £7.10. Label: 25  Dose hypertension and angina prophylaxis, 30 mg once daily,  increased if necessary; max. 90 mg once daily    Coracten SR® (UCB Pharma) (Ml  Capsules, m/r, nifedipine 10 mg (grey /pink, enclos-  ing yellow pellets), net price 60-cap pack = £3.90;   Dose hypertension and angina prophylaxis, initially 10 mg twice  daily, increased if necessary to max. 40 mg twice daily    Coracten XL® (UCB Pharma) Ml  Capsules, m/r, nifedipine 30 mg (brown), net price  28-cap pack = £4.89; 60 mg (orange), 28-cap pack =  £7.34. Label: 25   Dose hypertension and angina prophylaxis, 30 mg once daily,  increased if necessary; max. 90 mg once daily   Dose hypertension and angina prophylaxis, 40 mg once daily,  increased if necessary to 80 mg daily in 1-2 divided doses   Hypolar® Retard 20 (Sandoz) Ml  Tablets, m/r, red, f/c, nifedipine 20 mg, net price 56-  tab pack = £5.75. Label: 25   Dose hypertension and angina prophylaxis, 20 mg twice daily,  increased if necessary to 40 mg twice daily   Nifedipress® MR (Dexcel) (Ml  Tablets, m/r, pink, nifedipine 10 mg, net price 56-tab  pack = £9.23; 20 mg, 56-tab pack = £10.06. Label: 25  Dose hypertension and angina prophylaxis, initially 10 mg twice  daily adjusted according to response to 40 mg twice daily  Note Also available as Calchan ® MR, Kentipine ® MR   Tensipine MR® (Genus) Ml  Tablets, m/r, pink-grey, nifedipine 10 mg, net price  56-tab pack = £4.30; 20 mg, 56-tab pack = £5.49.  Label: 21, 25   Dose hypertension and angina prophylaxis, initially 10 mg twice  daily adjusted according to response to 40 mg twice daily   Tablets, m/r, red, nifedipine 30 mg, net price 28-tab  pack = £7.29; 60 mg, 28-tab pack = £9.13. Label: 25  Cautions dose form not appropriate for use in hepatic impair-  ment, or where there is a history of oesophageal or gastrointes-  tinal obstruction, decreased lumen diameter of the gastrointes-  tinal tract, inflammatory bowel disease, or ileostomy after  proctocolectomy   Dose severe hypertension and prophylaxis of angina, 30 mg  once daily, increased if necessary to max. 90 mg once daily   Indications prevention and treatment of ischaemic  neurological deficits following aneurysmal subarach-  noid haemorrhage   Cautions cerebral oedema or severely raised intra-  cranial pressure; hypotension; avoid concomitant  administration of nimodipine tablets and infusion,  other calcium-channel blockers, or beta-blockers;  concomitant nephrotoxic drugs; avoid grapefruit juice  (may affect metabolism); interactions: Appendix 1  (calcium-channel blockers, alcohol (infusion only))   Contra-indications within 1 month of myocardial  infarction; unstable angina; acute porphyria (section  9.8.2)   Side-effects hypotension, variation in heart-rate,  flushing, headache, gastro-intestinal disorders,  nausea, sweating and feeling of warmth; thrombocy-  topenia and ileus reported   • Prevention, by mouth, 60 mg every 4 hours, starting  within 4 days of aneurysmal subarachnoid haemorr-  hage and continued for 2 1 days   • Treatment, by intravenous infusion via central  catheter, initially 1 mg/hour (up to 500 micrograms/  hour if body-weight less than 70 kg or if blood pres-  sure unstable), increased after 2 hours to 2 mg/hour if  no severe fall in blood pressure; continue for at least 5  days (max. 14 days); if surgical intervention during  treatment, continue for at least 5 days after surgery;  max. total duration of nimodipine use 2 1 days   Nimotop® (Bayer Schering) (Ml  Tablets, yellow, f/c, nimodipine 30 mg, net price 100-  tab pack = £33.60   Note Polyethylene, polypropylene, or glass apparatus should be  used; PVC should be avoided    Indications see under Dose and preparations  Cautions first-degree AV block; acute phase of myo-  cardial infarction (avoid if bradycardia, hypotension,  left ventricular failure); patients taking beta-blockers  (important: see below); avoid grapefruit juice (may  affect metabolism); interactions: Appendix 1 (cal-  cium-channel blockers)   Verapamil and beta-blockers Verapamil injection should  not be given to patients recently treated with beta-blockers  because of the risk of hypotension and asystole. The sug-  gestion that when verapamil injection has been given first, an  interval of 30 minutes before giving a beta-blocker is suffi-  cient has not been confirmed.   It may also be hazardous to give verapamil and a beta-  blocker together by mouth (should only be contemplated if  myocardial function well preserved).   Contra-indications hypotension, bradycardia, sec-  ond- and third-degree AV block, sick sinus syndrome,  cardiogenic shock, sino-atrial block; history of heart  failure or significantly impaired left ventricular func-  tion, even if controlled by therapy; atrial flutter or  fibrillation associated with accessory conducting  pathways (e.g. Wolff-Parkinson- White syndrome);  acute porphyria (section 9.8.2)   Pregnancy may reduce uterine blood flow with fetal  hypoxia; manufacturer advises avoid in first trimester  unless absolutely necessary; may inhibit labour  Breast-feeding amount too small to be harmful  Side-effects constipation; less commonly nausea,  vomiting, flushing, headache, dizziness, fatigue, ankle  oedema; rarely allergic reactions (erythema, pruritus,  urticaria, angioedema, Stevens-Johnson syndrome);  myalgia, arthralgia, paraesthesia, erythromelalgia;  increased prolactin concentration; rarely gynaeco-  mastia and gingival hyperplasia after long-term  treatment; after intravenous administration or high  doses, hypotension, heart failure, bradycardia, heart  block, and asystole  Dose   • By mouth, supraventricular arrhythmias (but see also  Contra-indications), 40-120 mg 3 times daily  Angina, 80-120 mg 3 times daily  Hypertension, 240-480 mg daily in 2-3 divided doses    Prophylaxis of cluster headache [unlicensed] (under  specialist supervision), 240-960 mg daily in 3-4  divided doses   • By slow intravenous injection over 2 minutes (3  minutes in elderly), supraventricular arrhythmias (but  see also Contra-indications), 5-10 mg (preferably with  ECG monitoring); in paroxysmal tachyarrhythmias a  further 5 mg after 5-10 minutes if required   Verapamil (Non-proprietary) [Ml  Tablets, coated, verapamil hydrochloride 40 mg, net  price 84-tab pack = £1.55; 80 mg, 84-tab pack = £1.91;  120 mg, 28-tab pack = £1.54; 160 mg, 56-tab pack =  £28.20   Tablets, yellow, f/c, verapamil hydrochloride 40 mg,  net price 84-tab pack = £1.50; 80 mg, 84-tab pack =  £2.05; 120mg, 28-tab pack = £1.15; 160 mg, 56-tab  pack = £2.80   Dose hypertension, 240 mg daily (new patients initially 120 mg),  increased if necessary to max. 480 mg daily (doses above 240 mg  daily as 2 divided doses)   Angina, 240 mg twice daily (may sometimes be reduced to once  daily)   Prophylaxis after myocardial infarction where beta-blockers not  appropriate (started at least 1 week after infarction), 360 mg daily  in divided doses, given as 240 mg in the morning and 120 mg in  the evening or 120 mg 3 times daily   Capsules, m/r, verapamil hydrochloride 120 mg  (yellow/ dark blue), net price 28-cap pack = £4.86;  180 mg (yellow), 56-cap pack = £11.38; 240 mg (yel-  low/dark blue), 28-cap pack = £7.67. Label: 25  Dose hypertension, 240 mg daily, max. 480 mg daily (new  patients, initial dose 120 mg); angina, 360 mg daily, max. 480 mg  daily   Tablets, m/r, pale green, f/c, verapamil hydrochloride  240 mg, net price 28-tab pack = £6.04. Label: 25  Dose hypertension, 1 tablet daily, increased to twice daily if  necessary: angina, 1 tablet twice daily (may sometimes be  reduced to once daily)   Dose mild to moderate hypertension, 240 mg daily, increased to  twice daily if necessary; angina, 240 mg twice daily (may some-  times be reduced to once daily)   Nicorandil, a potassium-channel activator with a nitrate  component, has both arterial and venous vasodilating  properties and is licensed for the prevention and long-  term treatment of angina (section 2.10.1). Nicorandil  has similar efficacy to other antianginal drugs in con-  trolling symptoms; it may produce additional sympto-  matic benefit in combination with other antianginal  drugs [unlicensed indication].   Ivabradine lowers the heart rate by its action on the  sinus node. It is licensed for the treatment of angina in  patients in normal sinus rhythm in combination with a  beta-blocker, or when beta-blockers are contra-indi-  cated or not tolerated.   Ranolazine is licensed as adjunctive therapy in patients  who are inadequately controlled or intolerant of first-  line antianginal drugs.   Indications treatment of angina in patients in normal  sinus rhythm (see notes above)   Cautions mild heart failure including asymptomatic  left ventricular dysfunction; monitor for atrial fibrilla-  tion or other arrhythmias (treatment ineffective);  hypotension (avoid if severe); retinitis pigmentosa;  elderly; interactions: Appendix 1 (ivabradine)   Contra-indications severe bradycardia (not to be  initiated if heart rate below 60 beats per minute);  cardiogenic shock; acute myocardial infarction;  immediately after cerebrovascular accident; sick-  sinus syndrome; sino-atrial block; moderate to severe  heart failure; patients with pacemaker; unstable  angina; second- and third-degree heart block; conge-  nital QT syndrome   Hepatic impairment manufacturer advises caution in  moderate impairment; avoid in severe impairment   Renal impairment manufacturer advises use with  caution if eGFR less than 15 mL/minute/1.73 m 2 — no  information available   Side-effects bradycardia, first-degree heart block,  ventricular extrasystoles; headache, dizziness; visual  disturbances including phosphenes and blurred  vision; less commonly nausea, constipation, diarr-  hoea, palpitations, supraventricular extrasystoles,  dyspnoea, vertigo, muscle cramps, eosinophilia,  hyperuricaemia, and raised plasma-creatinine con-  centration  Dose   • Initially 5 mg twice daily, increased if necessary after  3-4 weeks to 7.5 mg twice daily (if not tolerated  reduce dose to 2.5-5 mg twice daily); ELDERLY initially  2.5 mg twice daily   Note Ventricular rate at rest should not be allowed to fall  below 50 beats per minute   Procoralan® (Servier) ▼ (Ml  Tablets, pink, f/c, ivabradine (as hydrochloride) 5 mg  (scored), net price 56-tab pack = £39.00; 7.5 mg, 56-  tab pack = £39.00   Cautions hypovolaemia; low systolic blood pressure;  acute pulmonary oedema; acute myocardial infarction  with acute left ventricular failure and low filling  pressures; interactions: Appendix 1 (nicorandil)  Driving Patients should be warned not to drive or operate  machinery until it is established that their performance is  unimpaired   Contra-indications cardiogenic shock; left ventricular  failure with low filling pressures; hypotension   Side-effects headache (especially on initiation,  usually transitory); cutaneous vasodilatation with  flushing; nausea, vomiting, dizziness, weakness also  reported; rarely oral ulceration, myalgia, and rash; at  high dosage, reduction in blood pressure and/or  increase in heart rate; angioedema, hepatic dysfunc-  tion, and anal ulceration also reported   • Initially 10 mg twice daily (if susceptible to headache  5 mg twice daily); usual dose 10-20 mg twice daily; up  to 30 mg twice daily may be used   Tablets, scored, nicorandil 10 mg, net price 60-tab  pack = £7.71; 20 mg, 60-tab pack = £14.64   Indications as adjunctive therapy in the treatment of  stable angina in patients inadequately controlled or  intolerant of first-line antianginal therapies  Cautions moderate to severe congestive heart failure;  QT interval prolongation; elderly; body-weight less  than 60 kg; interactions: Appendix 1 (ranolazine)  Hepatic impairment use with caution in mild impair-  ment; avoid in moderate and severe impairment  Renal impairment use with caution if eGFR 30-  80 mL/minute/1.73 m 2 ; avoid if eGFR less than  3 0 mL /minute /1.73m 2   Side-effects constipation, nausea, vomiting; dizzi-  ness, headache, asthenia; less commonly abdominal  pain, weight loss, dry mouth, dyspepsia, flatulence;  hot flush, hypotension, syncope, prolonged QT  interval, peripheral oedema; dysponea, cough, epis-  taxis; lethargy, hypoaesthesia, drowsiness, tremor,  anxiety, insomnia, anorexia; dysuria, haematuria,  chromaturia; dehydration; pain in extremities, muscle  cramp, joint swelling; visual disturbance; tinnitus;  pruritus, sweating; rarely pancreatitis, erosive duo-  denitis; cold extremities; throat tightness; amnesia,  loss of consciousness, disorientation; erectile dys-  function; parosmia, impaired hearing; allergic  dermatitis, urticaria, rash  Dose   • ADULT over 18 years, initially 375 mg twice daily,  increased after 2-4 weeks to 500 mg twice daily and  then adjusted according to response to max. 750 mg  twice daily (reduce dose to 375-500 mg twice daily if  not tolerated)   Tablets, m/r, ranolazine 375 mg (blue), net price 60-  tab pack = £48.98; 500 mg (orange), 60-tab pack =  £48.98; 750 mg (green), 60-tab pack = £48.98.   Peripheral vascular disease can be either occlusive (e.g.  intermittent claudication ) in which occlusion of the  peripheral arteries is caused by atherosclerosis, or  vasospastic (e.g. Raynaud’s syndrome ).   Peripheral arterial occlusive disease is associated with  an increased risk of cardiovascular events; this risk is  reduced by measures such as smoking cessation (sec-  tion 4.10.2), effective control of blood pressure (section  2.5), regulating blood lipids (section 2.12), optimising  glycaemic control in diabetes (section 6.1), taking  aspirin in a dose of 75 mg daily (section 2.9), and  possibly weight reduction in obesity (section 4.5). Exer-  cise training, treatment with cilostazol or naftidrofuryl  (see below), and possibly statin therapy can improve  symptoms of intermittent claudication.   Cilostazol is licensed for use in intermittent claudica-  tion to improve walking distance in patients without  peripheral tissue necrosis who do not have pain at rest.  Patients receiving cilostazol should be assessed for  improvement after 3 months. The Scottish Medicines  Consortium (p. 4) has advised (October 2005) that cilos-  tazol is not recommended for the treatment of inter-  mittent claudication within NHS Scotland.  Naftidrofuryl can alleviate symptoms of intermittent  claudication and improve pain-free walking distance in  moderate disease. Patients taking naftidrofuryl should  be assessed for improvement after 3-6 months.   Inositol nicotinate, pentoxifylline, and cinnarizine are  not established as being effective for the treatment of  intermittent claudication.   Management of Raynaud’s syndrome includes avoid-  ance of exposure to cold and stopping smoking. More  severe symptoms may require vasodilator treatment,  which is most often successful in primary Raynaud’s  syndrome. Nifedipine (section 2.6.2) is useful for redu-  cing the frequency and severity of vasospastic attacks.  Alternatively, naftidrofuryl may produce symptomatic  improvement; inositol nicotinate (a nicotinic acid deri-  vative) may also be considered. Cinnarizine, pentoxifyl-  line, prazosin, and moxisylyte are not established as  being effective for the treatment of Raynaud’s  syndrome.   Vasodilator therapy is not established as being effective  for chilblains (section 13.13).   Indications intermittent claudication in patients  without rest pain and no peripheral tissue necrosis  Cautions atrial or ventricular ectopy, atrial fibrillation,  atrial flutter; diabetes mellitus (higher risk of intra-  ocular bleeding); concomitant drugs that increase risk  of bleeding; interactions: Appendix 1 (cilostazol)  Contra-indications predisposition to bleeding (e.g.  active peptic ulcer, haemorrhagic stroke in previous 6  months, surgery in previous 3 months, proliferative  diabetic retinopathy, poorly controlled hypertension);    history of ventricular tachycardia, of ventricular  fibrillation and of multifocal ventricular ectopics,  prolongation of QT interval, congestive heart failure  Hepatic impairment avoid in moderate or severe liver  disease   Renal impairment avoid if eGFR less than 25 mL/  minute/ 1.73 m 2   Pregnancy avoid — toxicity in animal studies  Breast-feeding present in milk in animal studies —  manufacturer advises avoid  Side-effects gastro-intestinal disturbances; tachy-  cardia, palpitation, angina, arrhythmia, chest pain,  oedema; rhinitis; dizziness, headache; asthenia; rash,  pruritus, ecchymosis; less commonly gastritis, con-  gestive heart failure, postural hypotension, dyspnoea,  pneumonia, cough, insomnia, abnormal dreams,  anxiety, hyperglycaemia, diabetes mellitus, anaemia,  haemorrhage, myalgia, hypersensitivity reactions  (including Stevens- Johnson syndrome and toxic epi-  dermal necrolysis in rare cases); rarely anorexia,  hypertension, paresis, increased urinary frequency,  bleeding disorders, renal impairment, conjunctivitis,  tinnitus, and jaundice  Dose   • 100 mg twice daily (30 minutes before or 2 hours after  food)   Tablets, cilostazol 50 mg, net price 56-tab pack =  £35.31; 100 mg, 56-tab pack = £35.31   Contra-indications recent myocardial infarction,  acute phase of a cerebrovascular accident  Pregnancy no information available — manufacturer  advises avoid unless potential benefit outweighs risk  Side-effects nausea, vomiting, hypotension, flushing,  syncope, oedema, headache, dizziness, paraesthesia,  rash  Dose   • 3 g daily in 2-3 divided doses; max. 4 g daily  Hexopal® (Genus)   Cautions diabetes mellitus  Contra-indications active liver disease  Pregnancy manufacturer advises avoid  Side-effects nausea, diarrhoea, flushing, headache,  dizziness; hepatic reactions including cholestatic  jaundice and hepatitis reported to CSM  Dose   • Initially 40 mg 4 times daily, increased to 80 mg 4  times daily if poor initial response; discontinue after 2  weeks if no response    Opilon® (Archimedes) (Ml  Tablets, yellow, f/c, moxisylyte 40 mg (as hydro-  chloride), net price 112-tab pack = £75.18. Label: 21   Naftidrofuryl (Non-proprietary) (Ml  Capsules, naftidrofuryl oxalate 100 mg, net price 84-  cap pack = £4.52. Label: 25, 27   Praxilene® (Merck Serono) [MI  Capsules, pink, naftidrofuryl oxalate 100 mg, net  price 84-cap pack = £8.10. Label: 25, 27   Indications peripheral vascular disease; venous leg  ulcers [unlicensed indication] (Appendix A8.2.5)  Cautions hypotension, coronary artery disease; avoid  in acute porphyria (section 9.8.2); interactions:  Appendix 1 (pentoxifylline)   Contra-indications cerebral haemorrhage, extensive  retinal haemorrhage, acute myocardial infarction  Hepatic impairment manufacturer advises reduce  dose in severe impairment  Renal impairment reduce dose by 30-50% if eGFR  less than 30 mL/minute/ 1.73 m 2  Pregnancy manufacturer advises avoid — no informa-  tion available   Breast-feeding present in milk — manufacturer  advises use only if potential benefit outweighs risk  Side-effects gastro-intestinal disturbances, dizziness,  agitation, sleep disturbances, headache; rarely flush-  ing, tachycardia, angina, hypotension, thrombocyto-  penia, intrahepatic cholestasis, hypersensitivity reac-  tions including rash, pruritus and bronchospasm  Dose   Trental® (Sanofi-Aventis) Ml  Tablets, m/r, pink, s/c, pentoxifylline 400 mg, net  price 90-tab pack = £19.68. Label: 21, 25   Rutosides (oxerutins, Paroven ®) are not vasodilators  and are not generally regarded as effective preparations  as capillary sealants or for the treatment of cramps;  side-effects include headache, flushing, rashes, mild  gastro-intestinal disturbances.   Capsules, yellow, oxerutins 250 mg, net price 120-cap  pack = £13.05   Dose relief of symptoms of oedema associated with chronic  venous insufficiency, 500 mg twice daily   The properties of sympathomimetics vary according to  whether they act on alpha or on beta adrenergic recep-  tors. Adrenaline (epinephrine) (section 2.7.3) acts on  both alpha and beta receptors and increases both  heart rate and contractility (betaj effects); it can cause  peripheral vasodilation (a beta 2 effect) or vasoconstric-  tion (an alpha effect).   The cardiac stimulants dobutamine and dopamine act  on beta! receptors in cardiac muscle, and increase  contractility with little effect on rate.   Dopexamine acts on beta 2 receptors in cardiac muscle  to produce its positive inotropic effect; and on periph-  eral dopamine receptors to increase renal perfusion; it is  reported not to induce vasoconstriction.   Shock Shock is a medical emergency associated with a  high mortality. The underlying causes of shock such as  haemorrhage, sepsis, or myocardial insufficiency should  be corrected. The profound hypotension of shock must  be treated promptly to prevent tissue hypoxia and organ  failure. Volume replacement is essential to correct the  hypovolaemia associated with haemorrhage and sepsis  but may be detrimental in cardiogenic shock. Depend-  ing on haemodynamic status, cardiac output may be  improved by the use of sympathomimetic inotropes  such as adrenaline (epinephrine), dobutamine or  dopamine (see notes above). In septic shock, when  fluid replacement and inotropic support fail to maintain  blood pressure, the vasoconstrictor noradrenaline (nor-  epinephrine) (section 2.7.2) may be considered. In  cardiogenic shock peripheral resistance is frequently  high and to raise it further may worsen myocardial  performance and exacerbate tissue ischaemia.   The use of sympathomimetic inotropes and vaso-  constrictors should preferably be confined to the inten-  sive care setting and undertaken with invasive haemo-  dynamic monitoring.   For advice on the management of anaphylactic shock,  see section 3.4.3.   Pregnancy no evidence of harm in animal studies —  manufacturers advise use only if potential benefit  outweighs risk   Side-effects nausea; hypotension, hypertension  (marked increase in systolic blood pressure indicates  overdose), arrhythmias, palpitations, chest pain; dys-  pnoea, bronchospasm; headache; fever; increased  urinary urgency; eosinophilia; rash, phlebitis; very  rarely myocardial infarction, hypokalaemia; coronary  artery spasm and thrombocytopenia also reported   • By intravenous infusion, 2.5-10 micrograms/kg/  minute, adjusted according to response    Dobutamine (Non-proprietary) (Ml  Injection, dobutamine (as hydrochloride) 5mg/mL.  To be diluted before use or given undiluted with  syringe pump. Net price 50-mL vial = £7.50    Concentrate for intravenous infusion, dobutamine  (as hydrochloride) 12.5mg/mL. To be diluted before  use. Net price 20-mL amp = £5.20   Cautions correct hypovolaemia; low dose in shock  due to acute myocardial infarction — see notes above;  hyperthyroidism; interactions: Appendix 1  (sympathomimetics)   Concentrate for intravenous infusion, dopamine  hydrochloride 40 mg/mL, net price 5-mL amp = 90p;  160mg/mL, 5-mL amp = £3.40. To be diluted before  use   Indications inotropic support in infarction, cardiac  surgery, cardiomyopathies, septic shock, and cardio-  genic shock; cardiac stress testing (consult product  literature)   Cautions arrhythmias, acute myocardial infarction,  acute heart failure, severe hypotension, marked  obstruction of cardiac ejection (such as idiopathic  hypertrophic subaortic stenosis); correct hypovol-  aemia before starting treatment; tolerance may  develop with continuous infusions longer than 72   Indications inotropic support and vasodilator in  exacerbations of chronic heart failure and in heart  failure associated with cardiac surgery  Cautions myocardial infarction, recent angina, hypo-  kalaemia, hyperglycaemia; correct hypovolaemia  before starting and during treatment, monitor blood  pressure, pulse, plasma potassium, and blood glucose;  hyperthyroidism; avoid abrupt withdrawal; interac-  tions: Appendix 1 (sympathomimetics)   Side-effects nausea, vomiting; tachycardia, brady-  cardia, arrhythmias, angina, myocardial infarction;  tremor, headache; dyspnoea; reversible thrombocy-  topenia; sweating   • By intravenous infusion into central or large periph-  eral vein, 500 nanograms/kg/minute, may be  increased to 1 microgram/kg/minute and further  increased up to 6 micrograms/kg/minute in incre-  ments of 0.5-1 microgram/kg/minute at intervals of  not less than 15 minutes  Dopacard® (Cephalon) f*i  Concentrate for intravenous infusion, dopexamine  hydrochloride lOmg/mL (1%). To be diluted before  use. Net price 5-mL amp = £19.80  Note Contact with metal in infusion apparatus should be mini-  mised   Vasoconstrictor sympathomimetics raise blood pres-  sure transiently by acting on alpha-adrenergic receptors  to constrict peripheral vessels. They are sometimes  used as an emergency method of elevating blood pres-  sure where other measures have failed (see also section  2.7.1).   The danger of vasoconstrictors is that although they  raise blood pressure they also reduce perfusion of vital  organs such as the kidney.   Spinal and epidural anaesthesia may result in sympa-  thetic block with resultant hypotension. Management  may include intravenous fluids (which are usually given  prophylactically), oxygen (section 3.6), elevation of the  legs, and injection of a pressor drug such as ephedrine.  As well as constricting peripheral vessels ephedrine  also accelerates the heart rate (by acting on beta recep-  tors). Use is made of this dual action of ephedrine to  manage associated bradycardia (although intravenous  injection of atropine sulphate 400 to 600 micrograms  may also be required if bradycardia persists).   Indications see under Dose  Cautions hyperthyroidism, diabetes mellitus,  ischaemic heart disease, hypertension, susceptibility  to angle-closure glaucoma, elderly; may cause acute  urine retention in prostatic hypertrophy; interactions:  Appendix 1 (sympathomimetics)   Side-effects nausea, vomiting, anorexia; tachycardia  (sometimes bradycardia), arrhythmias, anginal pain,  vasoconstriction with hypertension, vasodilation with  hypotension, dizziness and flushing; dyspnoea; head-  ache, anxiety, restlessness, confusion, psychoses,  insomnia, tremor; difficulty in micturition, urine  retention; sweating, hypersalivation; changes in   • Reversal of hypotension from spinal or epidural  anaesthesia, by slow intravenous injection of a solu-  tion containing ephedrine hydrochloride 3 mg/mL, 3-  6 mg (max. 9 mg) repeated every 3-4 minutes  according to response to max. 30 mg   Ephedrine Hydrochloride (Non-proprietary) (Ml  Injection, ephedrine hydrochloride 3 mg/mL, net  price 10-mL amp = £3.25; 30 mg/mL, net price 1-mL  amp = 41p   Indications acute hypotension (see notes above);  priapism (section 7.4.5) [unlicensed indication]   Cautions see under Noradrenaline Acid Tartrate;  longer duration of action than noradrenaline (norepi-  nephrine), see below; cirrhosis  Hypertensive response Metaraminol has a longer duration  of action than noradrenaline, and an excessive vasopressor  response may cause a prolonged rise in blood pressure   Pregnancy may reduce placental perfusion — manu-  facturer advises use only if potential benefit outweighs  risk   • In emergency, by intravenous injection, 0.5-5 mg then  by intravenous infusion, 15-100 mg, adjusted  according to response   Metaraminol (Non-proprietary) (Ml  Injection, metaraminol 10 mg (as tartrate)/mL  Available from ‘special-order’ manufacturers or specialist  importing companies, see p. 988   Cautions coronary, mesenteric, or peripheral vascular  thrombosis; following myocardial infarction, Prinz-  metal’s variant angina, hyperthyroidism, diabetes  mellitus; hypoxia or hypercapnia; uncorrected hypo-  volaemia; elderly; extravasation at injection site may  cause necrosis; interactions: Appendix 1  (sympathomimetics)   • Acute hypotension, by intravenous infusion, via cen-  tral venous catheter, of a solution containing  noradrenaline acid tartrate 80 micrograms/mL  (equivalent to noradrenaline base 40 micrograms/  mL) at an initial rate of 0.16-0.33 mL/minute,  adjusted according to response    • Cardiac arrest, by rapid intravenous or intracardiac  injection, 0.5-0.75 mL of a solution containing  noradrenaline acid tartrate 200 micrograms/mL  (equivalent to noradrenaline base 100 micrograms/  mL)   Noradrenaline/Norepinephrine (Non-proprietary) (Ml  Injection, noradrenaline acid tartrate 2mg/mL  (equivalent to noradrenaline base 1 mg/mL). For  dilution before use. Net price 2-mL amp = £2.40, 4-mL  amp = £4.40, 20-mL amp = £6.35   Indications acute hypotension (see notes above);  priapism (section 7.4.5) [unlicensed indication]   Cautions see under Noradrenaline Acid Tartrate;  longer duration of action than noradrenaline (norepi-  nephrine), see below; coronary disease  Hypertensive response Phenylephrine has a longer dura-  tion of action than noradrenaline, and an excessive vaso-  pressor response may cause a prolonged rise in blood  pressure   Pregnancy avoid if possible; malformations reported  following use in first trimester; fetal hypoxia and  bradycardia reported in late pregnancy and labour   • By subcutaneous or intramuscular injection, 2-5 mg,  followed if necessary by further doses of 1-10 mg   • By slow intravenous injection of a 1 mg/mL solution,  100-500 micrograms repeated as necessary after at  least 15 minutes   • By intravenous infusion, initial rate up to 180 micr-  ograms/minute reduced to 30-60 micrograms/min-  ute according to response   Phenylephrine (Sovereign) (Mi  Injection, phenylephrine hydrochloride 10 mg/mL  (1%), net price 1-mL amp = £5.50    The algorithm for cardiopulmonary resuscitation (see  inside back cover) reflects the most recent recommen-  dations of the Resuscitation Council (UK). These guide-  lines are available at www.resus.org.uk.    Cardiac arrest can be associated with ventricular fibril-  lation, pulseless ventricular tachycardia, asystole, and  pulseless electrical activity (electromechanical dissocia-  tion). Adrenaline (epinephrine) 1 in 10 000 (100 micr-  ograms/mL) is recommended in a dose of 1 mg (10 mL)  by intravenous injection repeated every 3-5 minutes if  necessary. Administration through a central line results  in a faster response than peripheral administration,  however placement of a central line must not interfere  with chest compressions; drugs administered peripher-  ally must be followed by a flush of at least 20 mL Sodium  Chloride 0.9% injection to aid entry into the central  circulation. Intravenous injection of amiodarone  300 mg (from a prefilled syringe or diluted in 20 mL  Glucose 5%) should be considered after adrenaline to  treat ventricular fibrillation or pulseless ventricular  tachycardia in cardiac arrest refractory to defibrillation.  An additional dose of amiodarone 150 mg can be given    by intravenous injection if necessary, followed by an  intravenous infusion of amiodarone 900 mg over 24  hours. Lidocaine, in a dose of 1 mg/kg, is an alternative  if amiodarone is not available; a total dose of 3 mg/kg  lidocaine should not be exceeded during the first hour.  Atropine is no longer recommended in the treatment of  asystole or pulseless electrical activity.   During cardiopulmonary arrest if intravenous access  cannot be obtained, the intraosseous route can be  used instead. Drug administration via the endotracheal  route is no longer recommended.   Indications see notes above  Cautions ischaemic heart disease, severe angina,  obstructive cardiomyopathy, hypertension, arrhyth-  mias, cerebrovascular disease, occlusive vascular  disease, arteriosclerosis, monitor blood pressure and  ECG; cor pulmonale; organic brain damage, psycho-  neurosis; diabetes mellitus, hyperthyroidism, phaeo-  chromocytoma; prostate disorders; hypokalaemia,  hypercalcaemia; susceptibility to angle-closure  glaucoma; elderly; interactions: Appendix 1  (sympathomimetics)   Renal impairment manufacturers advise use with  caution in severe impairment  Pregnancy may reduce placental perfusion and can  delay second stage of labour; manufacturers advise  use only if benefit outweighs risk  Breast-feeding present in milk but unlikely to be  harmful as poor oral bioavailability  Side-effects nausea, vomiting, dry mouth, hypersala-  vation; arrhythmias, syncope, angina, pallor, palpita-  tion, cold extremities, hypertension (risk of cerebral  haemorrhage); dyspnoea, pulmonary oedema (on  excessive dosage or extreme sensitivity); anxiety,  tremor, restlessness, headache, weakness, dizziness,  hallucinations; hyperglycaemia; urinary retention,  difficulty in micturition; metabolic acidosis; hypokal-  aemia; tissue necrosis at injection site and of extre-  mities, liver and kidneys; mydriasis, angle-closure  glaucoma, and sweating  Dose   The main use of anticoagulants is to prevent thrombus  formation or extension of an existing thrombus in the  slower-moving venous side of the circulation, where the    thrombus consists of a fibrin web enmeshed with plate-  lets and red cells.   Anticoagulants are of less use in preventing thrombus  formation in arteries, for in faster-flowing vessels throm-  bi are composed mainly of platelets with little fibrin.  For the uses of anticoagulants see Parenteral  anticoagulants, below and Oral anticoagulants, p. 146   Venous thromboembolism includes deep-vein thrombo-  sis and pulmonary embolism, and occurs as a result of  thrombus formation in a vein.   patients admitted to hospital should undergo a risk  assessment for venous thromboembolism on admission.  Patients considered to be at high risk include those  anticipated to have a substantial reduction in mobility,  those with obesity, malignant disease, history of venous  thromboembolism, thrombophilic disorder, or patients  over 60 years. Patients with risk factors for bleeding  (e.g. acute stroke, thrombocytopenia, acquired or  untreated inherited bleeding disorders) should only  receive pharmacological prophylaxis when the risk of  bleeding does not outweigh the risk of venous throm-  boembolism. A NICE Guideline 1 provides a full list of  risk factors, and gives recommendations for prophy-  laxis. A venous thromboembolism risk assessment  checklist is also available from the Department of  Health (www.dh.gov.uk).    Patients scheduled for surgery should be offered  mechanical prophylaxis (e.g. anti-embolism stockings)  on admission if appropriate; prophylaxis should con-  tinue until the patient is sufficiently mobile. Choice of  mechanical prophylaxis will depend on factors such as  the type of surgery, suitability for the patient, and their  condition.    Patients undergoing general or orthopaedic surgery,  who are considered to be at high risk of venous throm-  boembolism (see above), should be offered pharmacol-  ogical prophylaxis. Choice of prophylaxis will depend on  the type of surgery, suitability for the patient, and local  policy. A low molecular weight heparin is suitable in all  types of general and orthopaedic surgery; unfractio-  nated heparin is preferred for patients in renal failure.  Fondaparinux is an option for patients undergoing hip  or knee replacement surgery, hip fracture surgery, gas-  trointestinal, bariatric, or day surgery procedures. The  oral anticoagulants dabigatran etexilate and rivaroxaban  are indicated for thromboprophylaxis following hip or  knee replacement surgery (see section 2.8.2). Pharma-  cological prophylaxis in general surgery should usually  continue for 5-7 days, or until sufficient mobility has  been re-established. Pharmacological prophylaxis  should be extended to 28 days after major cancer  surgery in the abdomen or pelvis. Hip or knee replace-  ment surgery, and hip fracture surgery, require an  extended duration of pharmacological prophylaxis,  depending on the preparation used (consult product  literature).   General medical patients who are considered to be at  high risk of venous thromboembolism (see above)  should be offered pharmacological prophylaxis on  admission. Choice of prophylaxis will depend on the    1. NICE clinical guideline 92 (January 2010). Venous  thromboembolism: reducing the risk    medical condition, suitability for the patient, and local  policy. Patients should receive either a low molecular  weight heparin, unfractionated heparin (if patient in  renal failure), or fondaparinux. Prophylaxis should con-  tinue until the patient is no longer considered to be at  significant risk of venous thromboembolism. Mechan-  ical prophylaxis (e.g. anti-embolism stockings) can be  offered to medical patients in whom pharmacological  prophylaxis is contra-indicated, and continued until the  patient is sufficiently mobile.   Heparin initiates anticoagulation rapidly but has a short  duration of action. It is often referred to as ‘standard’ or  ‘unfractionated heparin’ to distinguish it from the low  molecular weight heparins (see p. 141), which have a  longer duration of action. Although a low molecular  weight heparin is generally preferred for routine use,  unfractionated heparin can be used in those at high risk  of bleeding because its effect can be terminated rapidly  by stopping the infusion.   Treatment For the initial treatment of deep-vein  thrombosis and pulmonary embolism a low molecular  weight heparin is used; alternatively, unfractionated  heparin is given as an intravenous loading dose, fol-  lowed by continuous intravenous infusion (using an  infusion pump) or by intermittent subcutaneous injec-  tion. Intermittent intravenous injection of unfractio-  nated heparin is no longer recommended. An oral anti-  coagulant (usually warfarin, section 2.8.2) is started at  the same time as unfractionated or low molecular  weight heparin (the heparin needs to be continued for  at least 5 days and until the INR has been in the  therapeutic range for 2 consecutive days). Laboratory  monitoring for unfractionated heparin, preferably on a  daily basis, is essential; determination of the activated  partial thromboplastin time (APTT) is the most widely  used measure (for unffactionated heparin). A low mole-  cular weight heparin or, in some circumstances, unfrac-  tionated heparin is also used in regimens for the man-  agement of myocardial infarction and unstable angina  (section 2.10.1).   Prophylaxis For details on the use of heparins in the  prophylaxis of venous thromboembolism see section  2 . 8 .   Pregnancy Heparins are used for the management of  venous thromboembolism in pregnancy because they  do not cross the placenta. Low molecular weight hepar-  ins are preferred because they have a lower risk of  osteoporosis and of heparin-induced thrombocytopenia.  Low molecular weight heparins are eliminated more  rapidly in pregnancy, requiring alteration of the dosage  regimen for drugs such as dalteparin, enoxaparin, and  tinzaparin; see also under individual drugs. Treatment  should be stopped at the onset of labour and advice  sought from a specialist on continuing therapy after  birth.   Extracorporeal circuits Unfractionated heparin is  also used in the maintenance of extracorporeal circuits  in cardiopulmonary bypass and haemodialysis.    Haemorrhage If haemorrhage occurs it is usually  sufficient to withdraw unfractionated or low molecular  weight heparin, but if rapid reversal of the effects of the  heparin is required, protamine sulphate (section 2.8.3) is  a specific antidote (but only partially reverses the effects  of low molecular weight heparins).   Indications see under Dose  Cautions see notes above; also elderly; concomitant  use of drugs that increase risk of bleeding; interac-  tions: Appendix 1 (heparin)   Heparin-induced thrombocytopenia Clinically important  heparin-induced thrombocytopenia is immune-mediated and  does not usually develop until after 5-10 days; it can be  complicated by thrombosis. Platelet counts should be mea-  sured just before treatment with unfractionated or low  molecular weight heparin, and regular monitoring of platelet  counts is recommended if given for longer than 4 days. Signs  of heparin-induced thrombocytopenia include a 50% reduc-  tion of platelet count, thrombosis, or skin allergy. If heparin-  induced thrombocytopenia is strongly suspected or con-  firmed, the heparin should be stopped and an alternative  anticoagulant, such as lepirudin or danaparoid, should be  given. Ensure platelet counts return to normal range in those  who require warfarin   Hyperkalaemia Inhibition of aldosterone secretion by  unfractionated or low molecular weight heparin can result  in hyperkalaemia; patients with diabetes mellitus, chronic  renal failure, acidosis, raised plasma potassium or those  taking potassium-sparing drugs seem to be more susceptible.  The risk appears to increase with duration of therapy, and  plasma-potassium concentration should be measured in  patients at risk of hyperkalaemia before starting the heparin  and monitored regularly thereafter, particularly if treatment  is to be continued for longer than 7 days  Contra-indications haemophilia and other haemor-  rhagic disorders, thrombocytopenia (including history  of heparin-induced thrombocytopenia), recent cere-  bral haemorrhage, severe hypertension; peptic ulcer;  after major trauma or recent surgery to eye or ner-  vous system; acute bacterial endocarditis; spinal or  epidural anaesthesia with treatment doses of unfrac-  tionated or low molecular weight heparin; hyper-  sensitivity to unfractionated or low molecular weight  heparin   Side-effects haemorrhage (see notes above), throm-  bocytopenia (see Cautions), rarely rebound hyper-  lipidaemia following unfractionated heparin with-  drawal, priapism, hyperkalaemia (see Cautions),  osteoporosis (risk lower with low molecular weight  heparins), alopecia on prolonged use, injection-site  reactions, skin necrosis, and hypersensitivity reac-  tions (including urticaria, angioedema, and anaphy-  laxis)   • Treatment of deep-vein thrombosis, pulmonary  embolism, unstable angina, and acute peripheral  arterial occlusion, by intravenous injection, loading  dose of 5000 units or 75 units/kg (10 000 units in    severe pulmonary embolism), followed by continuous  intravenous infusion of 18 units/kg/hour or treat-  ment of deep-vein thrombosis, by subcutaneous  injection of 15 000 units every 12 hours (laboratory  monitoring essential — preferably on a daily basis, and  dose adjusted accordingly); CHILD under 18 years see  BNF for Children   • Prophylaxis in surgery (see also notes above), by  subcutaneous injection, 5000 units 2 hours before  surgery, then every 8-12 hours (monitoring not  needed); during pregnancy (with monitoring), 5000-  10 000 units every 12 hours (important: prevention of  prosthetic heart-valve thrombosis in pregnancy calls  for specialist management)   • Haemodialysis by intravenous injection initially  1000-5000 units, followed by continuous intravenous  infusion of 250-1000 units/hour   Doses above reflect the guidelines of the British  Society for Haematology; for doses of the low mole-  cular weight heparins, see below    Heparin Sodium (Non-proprietary) (Ml  Injection, heparin sodium lOOOunits/mL, net price 1-  mL amp = 99p, 5-mL amp = £2.50, 5-mL vial = £2.50,  10-mL amp = £4.31, 20-mL amp = £7.09; 5000 units/  mL, 1-mL amp = £1.94, 5-mL amp = £5.06, 5-mL vial  = £5.64; 25 OOOunits/mL, 0.2-mL amp = £2.49, 1-mL  amp = £5.13, 5-mL vial = £11.11   Excipients may include benzyl alcohol (avoid in neonates, see Excipi-  ents, p. 2)   Low molecular weight heparins (bemiparin,  dalteparin, enoxaparin, and tinzaparin) are usually  preferred over unfractionated heparin in the prevention  of venous thromboembolism because they are as effec-  tive and they have a lower risk of heparin-induced  thrombocytopenia; see Prophylaxis of Venous Throm-  boembolism, p. 140. The standard prophylactic regimen  does not require monitoring. The duration of action of  low molecular weight heparins is longer than that of  unfractionated heparin and once-daily subcutaneous  administration is possible for some indications, making  them convenient to use.   Low molecular weight heparins are also used in the  treatment of deep-vein thrombosis, pulmonary embo-  lism (see also Treatment, above), myocardial infarction  (section 2.10.1), unstable coronary artery disease (sec-  tion 2.10.1) and for the prevention of clotting in extra-  corporeal circuits.   Dalteparin is also licensed for the extended treatment  and prophylaxis of venous thromboembolism in patients  with solid tumours; treatment is recommended for a  duration of 6 months.   Routine monitoring of anti-Factor Xa activity is not  usually required during treatment with low molecular  weight heparins, but may be necessary in patients at    increased risk of bleeding (e.g. in renal impairment and  those who are underweight or overweight).   Indications see notes above and under preparations  Cautions see under Heparin and notes above  Contra-indications see under Heparin  Hepatic impairment manufacturer advises use with  caution and avoid in severe impairment  Renal impairment risk of bleeding may be  increased — use with caution; monitoring of anti-Fac-  tor Xa may be required; use of unfractionated heparin  may be preferable   Zibor® (Archimedes) T (Ml  Injection, bemiparin sodium 12 500units/mL, net  price 2500-unit (0.2-mL) prefilled syringe = £1.86;   Dose prophylaxis of deep-vein thrombosis, by subcutaneous  injection, moderate risk, 2500 units 2 hours before or 6 hours after  surgery then 2500 units every 24 hours; high risk, 3500 units 2  hours before or 6 hours after surgery then 3500 units every 24  hours   Injection, bemiparin sodium 25 000 units /mL, net  price 0.2-mL (5000-unit) prefilled syringe = £4.22, 0.3-  mL (7500-unit) prefilled syringe = £5.34, 0.4-mL  (10 000-unit) prefilled syringe = £4.39  Dose treatment of deep-vein thrombosis (with or without  pulmonary embolism), by subcutaneous injection, 115 units/kg  every 24 hours until adequate oral anticoagulation established   Contra-indications see under Heparin  Hepatic impairment dose reduction may be required  in severe impairment   Renal impairment risk of bleeding may be  increased — dose reduction, and monitoring of anti-  Factor Xa, may be required; use of unffactionated  heparin may be preferable   Fragmin® (Pharmacia) ▼ (Ml  Injection (single-dose syringe), dalteparin sodium  12 500units/mL, net price 2500-unit (0.2-mL) syringe  = £1.86; 25 000 units/mL, 5000-unit (0.2-mL) syringe  = £2.82, 7500-unit (0.3-mL) syringe = £4.23, 10 000-    unit (0.4-mL) syringe = £5.65, 12 500-unit (0.5-mL)  syringe = £7.06, 15 000-unit (0.6-mL) syringe = £8.47,  18 000-unit (0.72-mL) syringe = £10.16  Dose prophylaxis of deep-vein thrombosis, in surgical patients,  by subcutaneous injection, moderate risk, 2500 units 1-2 hours  before surgery then 2500 units every 24 hours; high risk,   2500 units 1-2 hours before surgery, then 2500 units 8-12 hours  later (or 5000 units on the evening before surgery, then 5000 units  on the following evening), then 5000 units every 24 hours  Prophylaxis of deep-vein thrombosis in medical patients, by  subcutaneous injection, 5000 units every 24 hours  Treatment of deep-vein thrombosis and of pulmonary embolism,  by subcutaneous injection, as a single daily dose, ADULT body-  weight under 46 kg, 7500 units daily; body-weight 46-56 kg,   10 000 units daily; body-weight 57-68 kg, 12 500 units daily; body-  weight 69-82 kg, 15 000 units daily; body-weight 83 kg and over,  18 000 units daily, with oral anticoagulant treatment until ade-  quate oral anticoagulation established; monitoring of anti-Factor  Xa not usually required; for patients at increased risk of  haemorrhage, see below   Treatment of venous thromboembolism in pregnancy [unlicensed  indication], by subcutaneous injection, early pregnancy body-  weight under 50 kg, 5000 units twice daily; body-weight 50-70 kg,  6000 units twice daily; body-weight 70-90 kg, 8000 units twice  daily; body-weight over 90 kg, 10 000 units twice daily  Extended treatment and prophylaxis of venous thromboembolism  in patients with solid tumours, by subcutaneous injection, once  daily for 30 days, ADULT body-weight 40-45 kg, 7500 units daily;  body-weight 46-56 kg, 10 000 units daily; body-weight 57-68 kg,  12 500 units daily; body-weight 69-82 kg, 15 000 units daily; body-  weight 83 kg and over, 18 000 units daily; then once daily for a  further 5 months, by subcutaneous injection, ADULT body-weight  40-56 kg, 7500 units daily; body-weight 57-68 kg, 10 000 units  daily; body-weight 69-82 kg, 12 500 units daily; body-weight 83-  98 kg, 15 000 units daily; body-weight 99 kg and over, 18 000 units  daily; interrupt treatment or reduce dose in chemotherapy-  induced thrombocytopenia — consult product literature  Injection, dalteparin sodium 2500 units/mL (for sub-  cutaneous or intravenous use), net price 4-mL  (10 000-unit) amp = £5.12; 10 000-units/mL (for sub-  cutaneous or intravenous use), 1-mL (10 000-unit)  amp = £5.12; 25 000 units/mL (for subcutaneous use  only), 4-mL (100 000-unit) vial = £48.66   Excipients include benzyl alcohol (in 100 000-unit/4 mL multidose vial)  (avoid in neonates, see Excipients, p. 2)   Dose treatment of deep-vein thrombosis and of pulmonary  embolism, by subcutaneous injection, 200 units/kg (max.   18 000 units) as a single daily dose (or 100 units/kg twice daily if  increased risk of haemorrhage) until adequate oral anti-  coagulation established   Note For monitoring, blood should be taken 3-4 hours after a dose  (recommended plasma concentration of anti-Factor Xa 0.5-  1 unit/mL); monitoring not required for once-daily treatment  regimen and not generally necessary for twice-daily regimen  Unstable coronary artery disease, by subcutaneous injection,   120 units/kg every 12 hours (max. 10 000 units twice daily) for 5-  8 days   Injection (graduated syringe), dalteparin sodium  10 000 units/mL, net price 1-mL (10 000-unit) syringe  = £5.65   Dose unstable coronary artery disease (including non-ST-seg-  ment-elevation myocardial infarction), by subcutaneous injec-  tion, 120 units/kg every 12 hours (max. 10 000 units twice daily)  for up to 8 days; beyond 8 days (if awaiting angiography or  revascularisation) women body-weight less than 80 kg and men  less than 70 kg, 5000 units every 12 hours, women body-weight  greater than 80 kg and men greater than 70 kg, 7500 units every  12 hours, until day of procedure (max. 45 days)   Indications see notes above and under preparations  Cautions see under Heparin and notes above; low  body-weight (increased risk of bleeding)   Renal impairment risk of bleeding increased; reduce  dose if eGFR less than 30 mL/minute/ 1.73 m 2 —  consult product literature for details; monitoring of  anti-factor Xa may be required; use of unfractionated  heparin may be preferable   Clexane® (Sanofi-Aventis) £mD  Injection, enoxaparin sodium lOOmg/mL, net price  20-mg (0.2-mL, 2000-units) syringe = £3.03, 40-mg  (0.4-mL, 4000-units) syringe = £4.04, 60-mg (0.6-mL,  6000-units) syringe = £4.57, 80-mg (0.8-mL, 8000-  units) syringe = £6.49, 100-mg (1-mL, 10 000-units)  syringe = £8.04; 300 mg (3-mL, 30 000-units) vial  ( Clexane ® Multidose) = £21.33; 150mg/mL  (Clexane® Forte), 120-mg (0.8-mL, 12 000-units)  syringe = £9.77, 150-mg (1-mL, 15 000-units) syringe  = £ 11.10   Excipients include benzyl alcohol (in 300 mg multidose vials) (avoid in  neonates, see Excipients, p. 2)   Dose prophylaxis of deep-vein thrombosis especially in surgical  patients, by subcutaneous injection, moderate risk, 20 mg  (2000 units) approx. 2 hours before surgery then 20 mg  (2000 units) every 24 hours; high risk (e.g. orthopaedic surgery),  40 mg (4000 units) 12 hours before surgery then 40 mg  (4000 units) every 24 hours   Prophylaxis of deep-vein thrombosis in medical patients, by  subcutaneous injection, 40 mg (4000 units) every 24 hours  Treatment of deep-vein thrombosis or pulmonary embolism, by  subcutaneous injection, 1.5 mg/kg (150 units/kg) every 24 hours  until adequate oral anticoagulation established  Treatment of acute ST-segment elevation myocardial infarction,  ADULT under 75 years, by intravenous injection, 30 mg  (3000 units) followed by subcutaneous injection, 1 mg/kg  (100 units/kg), then by subcutaneous injection, 1 mg/kg every 12  hours for up to 8 days (max. 100 mg (10 000 units) for first two  subcutaneous doses only); ELDERLY over 75 years, by subcuta-  neous injection only, 750 micrograms/kg (75 units/kg) every 12  hours (max. 75 mg (7500 units) for first two doses only); patients  undergoing percutaneous coronary intervention, additional dose,  by intravenous injection, 300 micrograms/kg (30 units/kg) at  time of procedure if last subcutaneous dose given more than 8  hours previously   Note When administered in conjunction with a thrombolytic,  enoxaparin should be given between 15 minutes before and 30  minutes after the start of thrombolytic therapy  Unstable angina and non-ST-segment-elevation myocardial  infarction, by subcutaneous injection, 1 mg/kg (100 units/kg)  every 12 hours usually for 2-8 days (minimum 2 days)  Prevention of clotting in extracorporeal circuits, consult product  literature   Treatment of venous thromboembolism in pregnancy [unlicensed  indication], by subcutaneous injection, early pregnancy body-  weight under 50 kg, 40 mg (4000 units) twice daily; body-weight  50-70 kg, 60 mg (6000 units) twice daily; body-weight 70-90 kg,  80 mg (8000 units) twice daily; body-weight over 90 kg, 100 mg  (10 000 units) twice daily    Factor Xa may be required; use with caution in elderly  and avoid if age over 90 years; unfractionated heparin  may be preferable   Injection, tinzaparin sodium lOOOOunits/mL, net  price 2500-unit (0.25-mL) syringe = £1.98, 3500-unit  (0.35-mL) syringe = £2.77, 4500-unit (0.45-mL)  syringe = £3.56, 20 000-unit (2-mL) vial = £10.56   Excipients include benzyl alcohol (in vial) (avoid in neonates, see Exci-  pients, p. 2)   Dose prophylaxis of deep-vein thrombosis, by subcutaneous  injection, general surgery, 3500 units 2 hours before surgery, then  3500 units every 24 hours; orthopaedic surgery, 50 units/kg 2  hours before surgery, then 50 units/kg every 24 hours or  4500 units 12 hours before surgery, then 4500 units every 24 hours  Prevention of clotting in extracorporeal circuits, consult product  literature    Injection, tinzaparin sodium 20 000 units/mL, net  price 0.5-mL (10 000-unit) syringe = £8.46, 0.7-mL  (14 000-unit) syringe = £11.85, 0.9-mL (18 000-unit)  syringe = £15.23, 2-mL (40 000-unit) vial = £34.20   Excipients include benzyl alcohol (in vial) (avoid in neonates, see Exci-  pients, p. 2), sulphites (in 20 000 units/mL vial and syringe)   Dose treatment of deep-vein thrombosis and of pulmonary  embolism, by subcutaneous injection, 175 units/kg once daily  until adequate oral anticoagulation established  Treatment of venous thromboembolism in pregnancy [unlicensed  indication], by subcutaneous injection, 175 units/kg once daily  (based on early pregnancy body-weight)   Danaparoid is a heparinoid used for prophylaxis of  deep-vein thrombosis in patients undergoing general  or orthopaedic surgery. Providing there is no evidence  of cross-reactivity, it also has a role in patients who  develop heparin-induced thrombocytopenia.   Indications prevention of deep-vein thrombosis in  general or orthopaedic surgery; thromboembolic dis-  ease in patients with history of heparin-induced  thrombocytopenia   Cautions recent bleeding or risk of bleeding; conco-  mitant use of drugs that increase risk of bleeding;  antibodies to heparins (risk of antibody-induced  thrombocytopenia); body-weight over 90 kg (monitor  anti factor Xa activity)   Contra-indications haemophilia and other haemor-  rhagic disorders, thrombocytopenia (unless patient  has heparin-induced thrombocytopenia), recent  cerebral haemorrhage, severe hypertension, active  peptic ulcer (unless this is the reason for operation),  diabetic retinopathy, acute bacterial endocarditis,  spinal or epidural anaesthesia with treatment doses of  danaparoid   Hepatic impairment caution in moderate impairment  (increased risk of bleeding); avoid in severe impair-  ment unless patient has heparin-induced thrombocy-  topenia and no alternative available    Renal impairment caution in moderate impairment;  increased risk of bleeding (monitor anti-Factor Xa  activity); avoid in severe impairment unless patient  has heparin-induced thrombocytopenia and no alter-  native available   Pregnancy manufacturer advises avoid — limited  information available but not known to be harmful  Breast-feeding amount probably too small to be  harmful but manufacturer advises avoid  Side-effects bleeding; hypersensitivity reactions  (including rash)   • Prevention of deep-vein thrombosis, by subcuta-  neous injection, 750 units twice daily for 7-10 days;  initiate treatment before operation (with last pre-  operative dose 1-4 hours before surgery)   • Thromboembolic disease in patients with history of  heparin-induced thrombocytopenia, by intravenous  injection, 2500 units (1250 units if body- weight under  55 kg, 3750 units if over 90 kg), followed by intra-  venous infusion of 400 units/hour for 2 hours, then  300 units/hour for 2 hours, then 200 units/hour for 5  days   Injection, danaparoid sodium 1250units/mL, net  price 0.6-mL amp (750 units) = £26.68   Lepirudin, a recombinant hirudin, is licensed for anti-  coagulation in patients with Type II (immune) heparin-  induced thrombocytopenia who require parenteral anti-  thrombotic treatment. The dose of lepirudin is adjusted  according to activated partial thromboplastin time  (APTT). Bivalirudin, a hirudin analogue, is a thrombin  inhibitor which is licensed for acute coronary syn-  dromes in patients planned for urgent or early interven-  tion, and as an anticoagulant for patients undergoing  percutaneous coronary intervention (see also section  2.10.1); bivalirudin should be administered in combina-  tion with aspirin and clopidogrel. The Scottish Medi-  cines Consortium (p. 4) has advised (November 2008)  that bivalirudin (Angiox®) is accepted for restricted use  within NHS Scotland for patients with acute coronary  syndromes planned for urgent or early intervention who  would have been considered for treatment with   unffactionated heparin in combination with a glycopro-  tein Ilb/IIIa inhibitor; it should not be used as an  alternative to heparin alone. The Scottish Medicines  Consortium (p. 4) has advised (August 2010) that  bivalirudin (Angiox®) is accepted for restricted use  within NHS Scotland as an anticoagulant in patients  undergoing percutaneous coronary intervention who  would have been considered for treatment with   unffactionated heparin in combination with a glycopro-  tein Ilb/IIIa inhibitor; it should not be used as an  alternative to heparin alone.   Indications acute coronary syndromes in patients  planned for urgent or early intervention; anti-  coagulation for patients undergoing percutaneous  coronary intervention (PCI)   Cautions exposure to lepirudin (theoretical risk from  lepirudin antibodies); brachytherapy procedures;   Contra-indications severe hypertension; subacute  bacterial endocarditis; active bleeding; bleeding dis-  orders   Renal impairment for percutaneous coronary inter-  vention, reduce rate of infusion to 1.4 mg/kg/hour if  eGFR 30-60 mL/minute/ 1.73 m 2 and monitor blood  clotting parameters; for acute coronary syndromes  and percutaneous coronary intervention, avoid if  eGFR less than 30 mL/minute/ 1.73 m 2   Side-effects bleeding (discontinue), thrombosis,  ecchymosis; less commonly nausea, vomiting, tachy-  cardia, bradycardia, hypotension, angina, dyspnoea,  allergic reactions (including isolated reports of  anaphylaxis), headache, thrombocytopenia, anaemia,  back and chest pain, and injection-site reactions  Dose   • Acute coronary syndromes (in addition to aspirin and  clopidogrel), initially by intravenous injection,   100 micrograms/kg then by intravenous infusion  250 micrograms/kg/hour (for up to 72 hours in  medically managed patients); patients proceeding to  percutaneous coronary intervention or coronary  artery bypass surgery without cardiopulmonary  bypass, additional bolus dose by intravenous injection  500 micrograms/kg, then by intravenous infusion  1.75 mg/kg/hour for duration of procedure; following  percutaneous coronary intervention, reduce infusion  rate to 250 micrograms /kg/hour for 4-12 hours as  necessary; patients proceeding to coronary artery  bypass surgery with cardiopulmonary bypass, dis-  continue intravenous infusion 1 hour before proce-  dure and treat with unfractionated heparin   • Anticoagulation in patients undergoing percutaneous  coronary intervention (in addition to aspirin and clo-  pidogrel), initially by intravenous injection, 750 micr-  ograms/kg then by intravenous infusion 1.75 mg/kg/  hour for up to 4 hours after procedure; a reduced  infusion rate of 250 micrograms/kg/hour may be  continued for a further 4-12 hours if necessary   Angiox® (The Medicines Company) ▼ [Ml  Injection, powder for reconstitution, bivalirudin, net  price 250-mg vial = £310.00   Indications thromboembolic disease requiring par-  enteral anticoagulation in patients with heparin-  induced thrombocytopenia type II  Cautions recent bleeding or risk of bleeding including  recent puncture of large vessels, organ biopsy, recent  major surgery, stroke, bleeding disorders, severe  hypertension, bacterial endocarditis; concomitant use  of drugs that increase risk of bleeding; determine  activated partial thromboplastin time 4 hours after  start of treatment (or after infusion rate altered) and at  least once daily thereafter   Hepatic impairment no information — manufacturer  advises that cirrhosis may affect renal excretion  Renal impairment reduce initial intravenous injection  dose to 200 micrograms/kg and reduce subsequent  infusion dose by 50-85% if eGFR less than 60 mL/    minute/ 1.73m 2 , but avoid or stop infusion if eGFR  less than 15 mL/minute/ 1.73 m 2 (consult product lit-  erature)   Side-effects bleeding; reduced haemoglobin concen-  tration without obvious source of bleeding; fever,  hypersensitivity reactions (including rash); injection-  site reactions   • Initially by slow intravenous injection (of 5mg/mL  solution), 400 micrograms/kg followed by continuous  intravenous infusion of 150 micrograms/kg/hour  (max. 16.5 mg/hour), adjusted according to activated  partial thromboplastin time, for 2-10 days (longer if  necessary)   The use of heparin flushes should be kept to a minimum.  For maintaining patency of peripheral venous catheters,  sodium chloride injection 0.9% is as effective as heparin  flushes. The role of heparin flushes in maintaining  patency of arterial and central venous catheters is  unclear.   Heparin Sodium (Non-proprietary) fMO  Solution, heparin sodium lOunits/mL, net price 5-  mL amp = £1.00; lOOunits/mL, 2-mL amp = £1.05  Dose to maintain patency of catheters, cannulas, etc. 10-  200 units flushed through every 4-8 hours. Not for therapeutic use  Excipients may include benzyl alcohol (avoid in neonates, see Excipi-  ents, p. 2)   Epoprostenol (prostacyclin) can be given to inhibit  platelet aggregation during renal dialysis when heparins  are unsuitable or contra-indicated. It is also licensed for  the treatment of primary pulmonary hypertension resis-  tant to other treatment, usually with oral anti-  coagulation. Since its half-life is only about 3 minutes  it must be given by continuous intravenous infusion. It is  a potent vasodilator and therefore its side-effects  include flushing, headache, and hypotension.   Indications see notes above  Cautions anticoagulant monitoring required when  given with anticoagulants; haemorrhagic diathesis;  dose titration for pulmonary hypertension should be  in hospital (risk of pulmonary oedema); concomitant  use of drugs that increase risk of bleeding  Contra-indications severe left ventricular dysfunction  Pregnancy manufacturer advises caution — no infor-  mation available   Side-effects see notes above; also bradycardia,  tachycardia, pallor, sweating with higher doses; gas-  trointestinal disturbances; lassitude, anxiety, agita-  tion; dry mouth, jaw pain, chest pain; also reported,  hyperglycaemia and injection-site reactions  Dose   Infusion, powder for reconstitution, epoprostenol (as  sodium salt), net price 500-microgram vial (with  diluent) = £62.05; 1.5-mg vial (▼) (with diluent) =  £125.00   Fondaparinux sodium is a synthetic pentasaccharide  that inhibits activated factor X.   For details on the use of fondaparinux in the prophylaxis  of venous thromboembolism, see section 2.8, p. 140.    Indications prophylaxis of venous thromboembolism  in medical patients immobilised because of acute  illness, and patients undergoing major orthopaedic  surgery of the hip or leg, or abdominal surgery;  treatment of deep-vein thrombosis, superficial-vein  thrombosis, and pulmonary embolism; treatment of  unstable angina or non-ST-segment elevation myo-  cardial infarction; treatment of ST-segment elevation  myocardial infarction   Cautions bleeding disorders, active gastro-intestinal  ulcer disease; recent intracranial haemorrhage; brain,  spinal, or ophthalmic surgery; spinal or epidural  anaesthesia (risk of spinal haematoma — avoid if using  treatment doses); risk of catheter thrombus during  percutaneous coronary intervention; low body-  weight; elderly patients; concomitant use of drugs that  increase risk of bleeding   Renal impairment increased risk of bleeding; for  treatment of acute coronary syndromes avoid if eGFR  less than 20 mL/minute/ 1.73 m 2 ; for treatment of  venous thromboembolism use with caution if eGFR  30-50 mL/minute/1. 73 m 2 , avoid if eGFR less than  30mL/minute/1.73m 2 ; for prophylaxis of venous  thromboembolism and treatment of superficial-vein  thrombosis reduce dose to 1.5 mg daily if eGFR 20-  50 mL/minute/1. 73 m 2 , avoid if eGFR less than  20 mL/minute/ 1 .73 m 2    Side-effects bleeding, purpura, anaemia; less com-  monly gastro-intestinal disturbances, oedema, hepatic  impairment, chest pain, dyspnoea, thrombocytopenia,  thrombocythaemia, rash, pruritus; rarely hypo-  tension, flushing, cough, vertigo, dizziness, anxiety,  drowsiness, confusion, headache, hypokalaemia,  hyperbilirubinaemia, injection-site reactions; also  reported atrial fibrillation, tachycardia, and pyrexia  Dose    • Prophylaxis of venous thromboembolism after sur-  gery, by subcutaneous injection, 2.5 mg 6 hours  after surgery then 2.5 mg once daily; CHILD under  17 years not recommended   Prophylaxis of venous thromboembolism in medi-  cal patients, by subcutaneous injection, 2.5 mg  once daily; CHILD under 17 years not recommended  Treatment of superficial-vein thrombosis, by sub-  cutaneous injection, ADULT body-weight over 50 kg,   2.5 mg once daily for at least 30 days (max. 45 days  if high risk of thromboembolic complications); treat-  ment should be stopped 24 hours before surgery  and restarted at least 6 hours post operatively; CHILD  under 1 7 years not recommended  Unstable angina and non-ST-segment elevation  myocardial infarction, by subcutaneous injection,   2.5 mg once daily for up to 8 days (or until hospital  discharge if sooner); treatment should be stopped  24 hours before coronary artery bypass graft sur-  gery (where possible) and restarted 48 hours post  operatively; CHILD under 17 years not recommended  ST-segment elevation myocardial infarction, initi-  ally by intravenous injection or infusion, 2.5 mg for  first day, thereafter by subcutaneous injection   2.5 mg once daily for up to 8 days (or until hospital  discharge if sooner); treatment should be stopped  24 hours before coronary artery bypass graft sur-  gery (where possible) and restarted 48 hours post  operatively; CHILD under 17 years not recommended  Treatment of deep-vein thrombosis and of pulm-  onary embolism, by subcutaneous injection, ADULT  body-weight under 50 kg, 5 mg every 24 hours;  body-weight 50-100 kg, 7.5 mg every 24 hours;  body-weight over 100 kg, 10 mg every 24 hours;  continue until adequate oral anticoagulation estab-  lished; CHILD under 17 years not recommended   0.3-mL (1.5-mg) prefilled syringe = £6.28; 0.5-mL (2.5-  mg) prefilled syringe = £6.28  Injection, fondaparinux sodium 12.5mg/mL, net  price 0.4-mL (5-mg) prefilled syringe = £11.66, 0.6-mL  (7.5-mg) prefilled syringe = £11.66, 0.8-mL (10-mg)  prefilled syringe = £11.66   The oral anticoagulants warfarin, acenocoumarol and  phenindione, antagonise the effects of vitamin K, and  take at least 48 to 72 hours for the anticoagulant effect  to develop fully; warfarin is the drug of choice. If an  immediate effect is required, unfractionated or low  molecular weight heparin must be given concomitantly.   Uses Indications for these oral anticoagulants include  deep-vein thrombosis, pulmonary embolism, atrial  fibrillation in those who are at risk of embolisation  (see also section 2.3.1), and mechanical prosthetic  heart valves (to prevent emboli developing on the  valves).   These oral anticoagulants should not be used in cerebral  artery thrombosis or peripheral artery occlusion as first-  line therapy; aspirin is more appropriate for reduction of  risk in transient ischaemic attacks (see p. 151). Unfrac-  tionated or a low molecular weight heparin (section    2.8.1) is usually preferred for the prophylaxis of venous  thromboembolism in patients undergoing surgery; alter-  natively, warfarin can be continued in selected patients  currently taking long-term warfarin and who are at high  risk of thromboembolism (seek expert advice).   Dose The base-line prothrombin time should be deter-  mined but the initial dose should not be delayed whilst  awaiting the result.   For patients who require rapid anticoagulation the usual  adult induction dose of warfarin is 5-10 mg 1 on the first  day; subsequent doses depend upon the prothrombin  time, reported as INR (international normalised ratio).  For patients who do not require rapid anticoagulation, a  lower loading dose can be used over 3-4 weeks. The  daily maintenance dose of warfarin is usually 3-9 mg  (taken at the same time each day). The following  indications and target INRs 2 take into account recom-  mendations of the British Society for Haematology 3 :   • INR 2.5 for treatment of deep-vein thrombosis and  pulmonary embolism (including those associated  with antiphospholipid syndrome or for recurrence  in patients no longer receiving warfarin), for atrial  fibrillation, cardioversion (higher target values, such  as an INR of 3, can be used for up to 4 weeks before  the procedure to avoid cancellations due to low  INR; anticoagulation should continue for at least 4  weeks following the procedure), dilated cardiomyo-  pathy, mural thrombus, symptomatic inherited  thrombophilia, coronary artery thrombosis (if anti-  coagulated), and paroxysmal nocturnal haemoglo-  binuria;   • INR 3.5 for recurrent deep-vein thrombosis and  pulmonary embolism (in patients currently receiv-  ing warfarin with INR above 2);   • For mechanical prosthetic heart valves, the recom-  mended target INR depends on the type and loca-  tion of the valve. Generally, a target INR of 3 is  recommended for mechanical aortic valves, and 3.5  for mechanical mitral valves.   Monitoring It is essential that the INR be determined  daily or on alternate days in early days of treatment,  then at longer intervals (depending on response 4 ) then  up to every 12 weeks.   Haemorrhage The main adverse effect of all oral  anticoagulants is haemorrhage. Checking the INR and  omitting doses when appropriate is essential; if the  anticoagulant is stopped but not reversed, the INR  should be measured 2-3 days later to ensure that it is  falling. The following recommendations are based on  the result of the INR and whether there is major or   1. First dose reduced if base-line prothrombin time pro-  longed, if liver-function tests abnormal, or if patient in  cardiac failure, on parenteral feeding, less than average  body weight, elderly, or receiving other drugs known to  potentiate oral anticoagulants.   2. An INR which is within 0.5 units of the target value is  generally satisfactory; larger deviations require dosage  adjustment. Target values (rather than ranges) are now  recommended.   3. Guidelines on Oral Anticoagulation (warfarin): third  edition — 2005 update. Br J Haematol 2005; 132: 277-285.   4. Change in patient’s clinical condition, particularly asso-  ciated with liver disease, intercurrent illness, or drug  administration, necessitates more frequent testing. See also  interactions, Appendix 1 (warfarin). Major changes in diet  (especially involving salads and vegetables) and in alcohol  consumption may also affect warfarin control.   • Major bleeding — stop warfarin; give phytomena-  dione (vitamin KJ 5-10 mg by slow intravenous  injection; give dried prothrombin complex (factors  II, VII, IX, and X — section 2.11) 30-50 units/kg (if  dried prothrombin complex unavailable, fresh fro-  zen plasma 15mL/kg can be given but is less  effective)   • INR>8.0, no bleeding or minor bleeding — stop  warfarin and give phytomenadione (vitamin KJ  2.5-5 mg by mouth using the intravenous prepara-  tion orally [unlicensed use], or 0.5-1 mg by slow  intravenous injection (if complete reversal required  5-10 mg by slow intravenous injection); repeat dose  of phytomenadione if INR still too high after 24  hours; restart warfarin when INR <5.0   • INR 5. 0-8.0, no bleeding — stop warfarin; minor  bleeding — stop warfarin and give phytomenadione  (vitamin KJ 1-2.5 mg by mouth using the intra-  venous preparation orally [unlicensed use]; restart  warfarin when INR <5.0   • Unexpected bleeding at therapeutic levels — always  investigate possibility of underlying cause e.g.  unsuspected renal or gastro-intestinal tract pathol-  ogy   Hepatic impairment Warfarin, acenocoumarol, and  phenindione should be avoided in severe impairment,  especially if prothrombin time is already prolonged.   Renal impairment Warfarin, acenocoumarol, and  phenindione should be used with caution in mild to  moderate impairment and avoided in severe impair-  ment.   Pregnancy Warfarin, acenocoumarol, and phenindi-  one are teratogenic and should not be given in the first  trimester of pregnancy. Women of child-bearing age  should be warned of this danger since stopping these  drugs before the sixth week of gestation may largely  avoid the risk of fetal abnormality. These oral anticoa-  gulants cross the placenta with risk of congenital mal-  formations, and placental, fetal, or neonatal haemorr-  hage, especially during the last few weeks of pregnancy  and at delivery. Therefore, if at all possible, they should  be avoided in pregnancy, especially in the first and third  trimesters. Difficult decisions may have to be made,  particularly in women with prosthetic heart valves, atrial  fibrillation, or with a history of recurrent venous  thrombosis or pulmonary embolism.   Breast-feeding With warfarin, acenocoumarol, and  phenindione there is a risk of haemorrhage which is  increased by vitamin-K deficiency. Warfarin is not pre-  sent in milk in significant amounts, and appears safe, but  phenindione should be avoided; the manufacturer of  acenocoumarol recommends prophylactic vitamin K  for the infant (consult product literature).   Treatment booklets Anticoagulant treatment book-  lets should be issued to patients, and are available for  distribution to local healthcare professionals from  Health Authorities and from:    These booklets include advice for patients on anti-  coagulant treatment, an alert card to be carried by the  patient at all times, and a section for recording of INR  results and dosage information. Electronic copies and  further advice are also available at www.npsa.nhs.uk/  nrls/alerts-and-directives/alerts/anticoagulant.    Indications prophylaxis of embolisation in rheumatic  heart disease and atrial fibrillation; prophylaxis after  insertion of prosthetic heart valve; prophylaxis and  treatment of venous thrombosis and pulmonary  embolism; transient ischaemic attacks  Cautions see notes above; also recent surgery; recent  ischaemic stroke; history of gastro-intestinal bleeding;  peptic ulcer; concomitant use of drugs that increase  risk of bleeding; bacterial endocarditis (increased risk  of bleeding; use only if warfarin otherwise indicated);  avoid cranberry juice; interactions: Appendix 1  (coumarins)   Contra-indications haemorrhagic stroke; significant  bleeding; avoid use within 48 hours postpartum  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects haemorrhage — see notes above; also  nausea, vomiting, diarrhoea, jaundice, hepatic dys-  function, pancreatitis, pyrexia, alopecia, purpura,  rash, ‘purple toes’, skin necrosis (increased risk in  patients with protein C or protein S deficiency)   Tablets, warfarin sodium 500 micrograms (white), net  price 28-tab pack = £1.49; 1 mg (brown), 28-tab pack  = 93p; 3 mg (blue), 28-tab pack = 95p; 5 mg (pink), 28-  tab pack = £1.03. Label: 10, anticoagulant card  Brands include Marevan ®   • 4 mg on first day, 4-8 mg on second day; maintenance  dose usually 1-8 mg daily adjusted according to  response   Sinthrome® (Alliance) (Ml  Tablets, acenocoumarol 1 mg, net price 100-tab pack  = £4.27. Label: 10, anticoagulant card   Indications prophylaxis of embolisation in rheumatic  heart disease and atrial fibrillation; prophylaxis after  insertion of prosthetic heart valve; prophylaxis and  treatment of venous thrombosis and pulmonary  embolism   Contra-indications see under Warfarin Sodium  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see under Warfarin Sodium; also hyper-  sensitivity reactions including exfoliative dermatitis,  exanthema, fever, leucopenia, agranulocytosis,  eosinophilia, and renal damage; micro-adenopathy  and urine coloured pink or orange  Dose   • 200 mg on day 1; 100 mg on day 2, then adjusted  according to response; maintenance dose usually 50-  150 mg daily   Phenindione (Non-proprietary) (Ml  Tablets, phenindione 10 mg, net price 28-tab pack =  £21.10; 25 mg, 28-tab pack = £27.36; 50 mg, 28-tab  pack = £32.33. Label: 10, anticoagulant card, 14,  (urine pink or orange)   Dabigatran etexilate, a direct thrombin inhibitor, is  given orally for prophylaxis of venous thromboembo-  lism in adults after total hip replacement or total knee  replacement surgery; see Prophylaxis of Venous Throm-  boembolism, p. 140. Dabigatran etexilate has a rapid  onset of action and does not require therapeutic mon-  itoring. The most common side-effect is haemorrhage  and patients should be monitored for signs of bleeding  or anaemia; treatment should be stopped if severe  bleeding occurs.   Dabigatran etexilate for the prevention of  venous thromboembolism after hip or knee  replacement surgery in adults (September  2008)   Dabigatran etexilate is an option for the prophylaxis  of venous thromboembolism in adults after total hip  replacement or total knee replacement surgery.   Indications see notes above  Cautions see notes above; also elderly; body-weight  less than 50 kg; recent surgery; anaesthesia with  postoperative indwelling epidural catheter (risk of  paralysis — give initial dose at least 2 hours after  catheter removal and monitor neurological signs);  bacterial endocarditis (increased risk of bleeding);  bleeding disorders; active gastro-intestinal ulceration;  concomitant use of drugs that increase risk of bleed-  ing; interactions: Appendix 1 (dabigatran etexilate)  Contra-indications active bleeding; impaired hae-  mostasis   Hepatic impairment avoid in severe liver disease,  especially if prothrombin time already prolonged    Renal impairment reduce initial dose to 75 mg and  subsequent doses to 150 mg once daily if eGFR 30-  50 mL/minute/ 1.73 m 2 ; reduce dose to 75 mg once  daily if eGFR 30-50 mL/minute/ 1.73 m 2 and patient  receiving concomitant treatment with verapamil;  avoid if eGFR less than 30 mL/minute/ 1.73 m 2   • Prophylaxis of venous thromboembolism following  total knee replacement surgery, ADULT over 18 years,   1 10 mg (ELDERLY over 75 years, 75 mg) 1-4 hours after  surgery, then 220 mg (ELDERLY over 75 years, 150 mg)  once daily for 9 days   • Prophylaxis of venous thromboembolism following  total hip replacement surgery, ADULT over 18 years,   1 10 mg (ELDERLY over 75 years, 75 mg) 1-4 hours after  surgery, then 220 mg (ELDERLY over 75 years, 150 mg)  once daily for 27-34 days   Pradaxa® (Boehringer Ingelheim) ▼ (Ml  Capsules, blue/ivory, dabigatran etexilate (as mesi-  late) 75 mg, net price 10-cap pack = £21.00, 60-cap  pack = £126.00; 110 mg 10-cap pack = £21.00, 60-cap  pack = £126.00. Label: 25   Rivaroxaban, a direct inhibitor of activated factor X, is  given orally for prophylaxis of venous thromboembo-  lism in adults after hip or knee replacement surgery; see  Prophylaxis of Venous Thromboembolism, p. 140. Riv-  aroxaban does not require therapeutic monitoring. The  common side-effects are nausea and haemorrhage, and  patients should be monitored for signs of bleeding or  anaemia; treatment should be stopped if severe bleeding  occurs.   Rivaroxaban for the prevention of venous  thromboembolism after total hip or total  knee replacement in adults (April 2009)  Rivaroxaban is an option for the prophylaxis of  venous thromboembolism in adults after total hip  replacement or total knee replacement surgery.   Indications see notes above  Cautions see notes above; also bleeding disorders;  concomitant use of drugs that increase risk of bleed-  ing; severe hypertension; active or recent gastro-  intestinal ulceration; vascular retinopathy; anaes-  thesia with postoperative indwelling epidural catheter  (risk of paralysis — monitor neurological signs and  wait at least 18 hours after rivaroxaban dose before  removing catheter and do not give next dose until at  least 6 hours after catheter removal); recent surgery;  interactions: Appendix 1 (rivaroxaban)  Contra-indications active bleeding    Hepatic impairment manufacturer advises caution in  cirrhotic patients with moderate hepatic impairment;  avoid in liver disease with coagulopathy   Renal impairment use with caution if eGFR 15-  29 mL/minute/ 1.73 m 2 or if eGFR 30-49 mL/min-  ute/ 1.73 m 2 and concomitant use of drugs that  increase plasma-rivaroxaban concentration (consult  product literature); avoid if eGFR less than 15 mL/  minute /1.73m 2   Side-effects nausea; haemorrhage (see notes above);  less commonly constipation, diarrhoea, dyspepsia,  dry mouth, vomiting, hypotension, oedema, tachy-  cardia, thrombocythaemia, syncope, dizziness, head-  ache, renal impairment, pain in extremities, pruritus,  and rash; jaundice also reported  Dose   • Prophylaxis of venous thromboembolism following  knee replacement surgery, ADULT over 18 years, 10 mg  once daily for 2 weeks starting 6-10 hours after  surgery   • Prophylaxis of venous thromboembolism following  hip replacement surgery, ADULT over 18 years, 10 mg  once daily for 5 weeks starting 6-10 hours after  surgery   Tablets, red, f/c, rivaroxaban 10 mg, net price 10-tab  pack = £44.15, 30-tab pack = £132.44, 100-tab pack =  £441.45   Protamine sulphate is used to treat overdosage of  unfractionated or low molecular weight heparin. The  long half-life of low molecular weight heparins should  be taken into consideration when determining the dose  of protamine sulphate; the effects of low molecular  weight heparins can persist for up to 24 hours after  administration. Excessive doses of protamine sulphate  can have an anticoagulant effect.   Cautions see above; also monitor activated partial  thromboplastin time or other appropriate blood clot-  ting parameters; increased risk of allergic reaction to  protamine (including previous treatment with prot-  amine or protamine insulin, allergy to fish, men who  are infertile or who have had a vasectomy)  Side-effects nausea, vomiting, lassitude, flushing,  hypotension, hypertension, bradycardia, dyspnoea,  rebound bleeding, back pain; hypersensitivity reac-  tions (including angioedema, anaphylaxis) and pulm-  onary oedema reported  Dose   • Overdosage with intravenous injection of unfractio-  nated heparin, by intravenous injection (rate not  exceeding 5 mg/minute), 1 mg neutralises 80-  100 units heparin when given within 15 minutes of  heparin; if longer than 15 minutes since heparin, less  protamine required (consult product literature for  details) as heparin rapidly excreted; max. 50 mg    • Overdosage with intravenous infusion of unfractio-  nated heparin, by intravenous injection (rate not  exceeding 5 mg/minute), 25-50 mg once heparin  infusion stopped   • Overdosage with subcutaneous injection of unfrac-  tionated heparin, lmg neutralises 100 units heparin;  give 25-50 mg by intravenous injection (rate not  exceeding 5 mg/minute) then any remaining dose  given by intravenous infusion over 8-16 hours; max.  total dose 50 mg   • Overdosage with subcutaneous injection of low  molecular weight heparin, by intermittent intravenous  injection (rate not exceeding 5 mg/minute) or by  continuous intravenous infusion, 1 mg neutralises  approx. 100 units low molecular weight heparin  (consult product literature of low molecular weight  heparin for details); max. 50 mg   Protamine Sulphate (Non-proprietary) (Ml  Injection, protamine sulphate 10 mg /mL, net price 5-  mL amp = £1.43, 10-mL amp = £4.15   Antiplatelet drugs decrease platelet aggregation and  inhibit thrombus formation in the arterial circulation,  because in faster-flowing vessels, thrombi are com-  posed mainly of platelets with little fibrin.   Use of aspirin in primary prevention of cardiovascular  events, in patients with or without diabetes, is of unpro-  ven benefit. Long-term use of aspirin, in a dose of 75 mg  daily, is of benefit in established cardiovascular disease  (secondary prevention); unduly high blood pressure  must be controlled before aspirin is given. If the patient  is at a high risk of gastro-intestinal bleeding, a proton  pump inhibitor (section 1.3.5) can be added.   Aspirin in a dose of 75-300 mg daily is given following  coronary bypass surgery. For details on the use of  aspirin in atrial fibrillation see section 2.3.1; for inter-  mittent claudication see section 2.6.4; for stable angina  and acute coronary syndromes see section 2.10.1; for  use following placement of coronary stents see below;  for use in stroke see also below.   Clopidogrel is licensed for the prevention of ischaemic  events in patients with a history of symptomatic  ischaemic disease. Clopidogrel, in combination with  low-dose aspirin, is also licensed for acute coronary  syndrome without ST-segment elevation (section  2.10.1); in these circumstances the combination is  given for up to 12 months (most benefit occurs during  the first 3 months; there is no evidence of benefit  beyond 12 months). Clopidogrel, in combination with  low-dose aspirin, is also licensed for acute myocardial  infarction with ST-segment elevation (section 2.10.1);  the combination is licensed for at least 4 weeks, but the  optimum treatment duration has not been established.  In patients undergoing percutaneous coronary interven-  tion, clopidogrel is used as an adjunct with aspirin (see  also below). Patients, who are not already taking clopi-  dogrel, should receive a 300 mg loading dose prior to  the procedure; alternatively, a 600 mg [unlicensed] load-  ing dose may produce a greater and more rapid inhibi-  tion of platelet aggregation. Use of clopidogrel with  aspirin increases the risk of bleeding. Clopidogrel mono-  therapy is an alternative when aspirin is contra-indi-    cated, for example in those with aspirin hypersensitivity,  or when aspirin is not tolerated despite the addition of a  proton pump inhibitor.   For details on the use of clopidogrel in stroke, see below.  The Scottish Medicines Consortium (p. 4) has advised  (February 2004) that clopidogrel be accepted for  restricted use for the treatment of confirmed acute  coronary syndrome (without ST-segment elevation), in  combination with aspirin. Clopidogrel should be  initiated in hospital inpatients only. The Scottish Med-  icines Consortium has also advised (July 2007) that  clopidogrel be accepted for restricted use for patients  with ST-segment elevation acute myocardial infarction  in combination with aspirin; treatment with clopidogrel  is restricted to 4 weeks only.   Dipyridamole is used by mouth as an adjunct to oral  anticoagulation for prophylaxis of thromboembolism  associated with prosthetic heart valves. Modified-  release preparations are licensed for secondary preven-  tion of ischaemic stroke and transient ischaemic attacks  (see also Long-term Management, under Ischaemic  Stroke, below).   Clopidogrel and modified-release  dipyridamole in the prevention of occlusive  vascular events (December 2010)   The guidance applies to patients who have had an  occlusive vascular event, or who have established  peripheral arterial disease. The guidance does not  apply to patients who have had, or are at risk of,  stroke associated with atrial fibrillation, or who need  prophylaxis for occlusive events following coronary  revascularisation or carotid artery procedures.  Clopidogrel monotherapy is recommended as an  option to prevent occlusive vascular events in  patients who have had:   • an ischaemic stroke, or who have peripheral  arterial disease or multivascular disease, or   • a myocardial infarction, only if aspirin is contra-  indicated or not tolerated.   Modified-release dipyridamole, in combination with  aspirin, is recommended as an option to prevent  occlusive vascular events in patients who have had:   • an ischaemic stroke, only if clopidogrel is con-  tra-indicated or not tolerated.   Modified-release dipyridamole monotherapy is  recommended as an option to prevent occlusive  vascular events in patients who have had:   • an ischaemic stroke, only if aspirin and clopido-  grel are contra-indicated or not tolerated, or   • a transient ischaemic attack, only if aspirin is  contra-indicated or not tolerated.    Prasugrel, in combination with aspirin, is licensed for  the prevention of atherothrombotic events in patients  with acute coronary syndrome undergoing percuta-  neous coronary intervention (section 2.10.1); the com-  bination is usually given for up to 12 months.   The Scottish Medicines Consortium (p. 4) has advised  (August 2009) that prasugrel ( Efient ®), in combination  with aspirin, be accepted for restricted use within NHS  Scotland for the prevention of atherothrombotic events  in patients with acute coronary syndrome undergoing  percutaneous coronary intervention who are eligible to  receive the 10 mg dose of prasugrel.   Prasugrel for the treatment of acute  coronary syndromes with percutaneous  coronary intervention (October 2009)  Prasugrel, in combination with aspirin, is an option  for the prevention of atherothrombotic events in  patients with acute coronary syndromes undergoing  percutaneous coronary intervention, only when:   • immediate primary percutaneous coronary  intervention is necessary for ST-segment eleva-  tion myocardial infarction, or    Patients selected for percutaneous coronary interven-  tion, with the placement of a coronary stent, will require  dual antiplatelet therapy with aspirin and clopidogrel, or  aspirin and prasugrel. Aspirin therapy should continue  indefinitely. Clopidogrel is recommended for 1 month  following elective percutaneous coronary intervention  with placement of a bare-metal stent, and for 12 months  if percutaneous coronary intervention with placement  of a bare-metal stent was for an acute coronary  syndrome; clopidogrel should be given for 12 months  following placement of a drug-eluting stent. Clopidogrel  should not be discontinued prematurely in patients with  a drug-eluting stent — there is an increased risk of stent  thrombosis as a result of the eluted drug slowing the re-  endothelialisation process. Patients considered to be at  high risk of developing late stent thrombosis with a  drug-eluting stent may require a longer duration of  treatment with clopidogrel. Prasugrel is an alternative  to clopidogrel in certain patients undergoing percuta-  neous coronary intervention (see notes above).   Glycoprotein llb/llla inhibitors Glycoprotein lib/  Ilia inhibitors prevent platelet aggregation by blocking  the binding of fibrinogen to receptors on platelets.  Abciximab is a monoclonal antibody which binds to  glycoprotein Ilb/IIIa receptors and to other related  sites; it is licensed as an adjunct to unfractionated hep-  arin and aspirin for the prevention of ischaemic com-  plications in high-risk patients undergoing percutaneous  transluminal coronary intervention. Abciximab should  be used once only (to avoid additional risk of thrombo-  cytopenia). Eptifibatide and tirofiban also inhibit gly-  coprotein Ilb/IIIa receptors; they are licensed for use  with unfractionated heparin and aspirin to prevent early  myocardial infarction in patients with unstable angina or  non-ST-segment-elevation myocardial infarction (sec-  tion 2.10.1). Abciximab, eptifibatide and tirofiban should  be used by specialists only.   Stroke is associated with a significant risk of morbidity  and mortality. Patients presenting with acute symptoms  should be immediately transferred to hospital for accu-  rate diagnosis of stroke type, and urgent initiation of  appropriate treatment; patients should be managed by a  specialist multidisciplinary stroke team.   The following notes give an overview of the initial and  long-term management of transient ischaemic attack,  ischaemic stroke, and intracerebral haemorrhage.   Patients suspected of having a transient ischaemic  attack should immediately receive aspirin 300 mg  once daily (patients with aspirin hypersensitivity, or  those intolerant of aspirin despite the addition of a  proton pump inhibitor, should receive clopidogrel  75 mg once daily [unlicensed use] as an alternative).  Following a confirmed diagnosis, patients should  receive treatment for secondary prevention (see Long-  term Management, under Ischaemic Stroke, below).   Initial management Alteplase (section 2.10.2) is  recommended in the treatment of acute ischaemic  stroke if it can be administered within 3 hours of  symptom onset; it should be given by medical staff  experienced in the administration of thrombolytics  and the treatment of acute stroke, preferably within a  specialist stroke centre. Treatment with aspirin 300 mg  once daily for 14 days should be initiated 24 hours after  thrombolysis (or as soon as possible within 48 hours of  symptom onset in patients not receiving thrombolysis);  patients with aspirin hypersensitivity, or those intolerant  of aspirin despite the addition of a proton pump inhi-  bitor, should receive clopidogrel 75 mg once daily [unli-  censed use] as an alternative.   Anticoagulants are not recommended as an alternative  to antiplatelet drugs in acute ischaemic stroke in  patients who are in sinus rhythm. However, parenteral  anticoagulants (section 2.8.1) may be indicated in  patients who are symptomatic of, or at high risk of  developing, deep vein thrombosis or pulmonary embo-  lism; warfarin should not be commenced in the acute  phase of ischaemic stroke.   Anticoagulants (section 2.8.2) should be considered  after cardio-embolic ischaemic stroke in patients with  atrial fibrillation, however patients presenting with atrial  fibrillation following a disabling ischaemic stroke should  receive aspirin 300 mg once daily for 14 days, before  being considered for warfarin treatment. Patients  already receiving anticoagulation for a prosthetic heart  valve who experience a disabling ischaemic stroke and  are at significant risk of haemorrhagic transformation,  should have their anticoagulant treatment stopped for 7  days and substituted with aspirin 300 mg once daily.  Treatment of hypertension in the acute phase of  ischaemic stroke can result in reduced cerebral perfu-  sion, and should therefore only be instituted in the event  of a hypertensive emergency (see section 2.5), or in  those patients considered for thrombolysis.   Long-term management Patients should receive  long-term treatment following a transient ischaemic  attack or an ischaemic stroke to reduce the risk of  further cardiovascular events. Following a transient  ischaemic attack, long-term treatment with modified-  release dipyridamole in combination with aspirin is  recommended; if patients are intolerant of aspirin, or  it is contra-indicated, then modified-release dipyrid-  amole alone is recommended. Clopidogrel 75 mg once  daily is recommended as long-term treatment following  an ischaemic stroke (not associated with atrial fibrilla-  tion (see below)); if clopidogrel is contra-indicated or  not tolerated, patients should receive modified-release  dipyridamole in combination with aspirin; modified-    release dipyridamole alone can be considered for  patients with contra-indications to, or intolerance of,  aspirin and clopidogrel. Patients with stroke associated  with atrial fibrillation should be reviewed for long-term  treatment with aspirin or warfarin (see Initial Manage-  ment under Ischaemic Stroke, above, and section 2.3).   Anticoagulants are not routinely recommended in the  long-term prevention of recurrent stroke, except in  patients with atrial fibrillation (section 2.3).   A statin (section 2.12) should be initiated 48 hours after  stroke symptom onset, irrespective of the patient’s  serum-cholesterol concentration.   Following the acute phase of ischaemic stroke, blood  pressure should be measured and treatment initiated to  achieve a target blood pressure of <130/80 mmHg (see  section 2.5). Beta-blockers should not be used in the  management of hypertension following a stroke, unless  they are indicated for a co-existing condition.   All patients should be advised to make lifestyle mod-  ifications that include beneficial changes to diet, exer-  cise, weight, alcohol intake, and smoking.   Initial management Surgical intervention may be  required following intracerebral haemorrhage to  remove the haematoma and relieve intracranial pres-  sure. Patients taking anticoagulants should have this  treatment stopped and reversed (see section 2.8.2);  anticoagulant therapy has, however, been used in  patients with intracerebral haemorrhage who are symp-  tomatic of deep vein thrombosis or pulmonary embo-  lism; placement of a caval filter is an alternative in this  situation.   Long-term management Aspirin therapy should only  be given to patients at a high risk of a cardiac ischaemic  event. Blood pressure should be measured and treat-  ment initiated where appropriate (see section 2.5), tak-  ing care to avoid hypoperfusion. Statins should be  avoided following intracerebral haemorrhage, however  they can be used with caution when the risk of a  vascular event outweighs the risk of further haemorr-  hage.   Indications prevention of ischaemic cardiac compli-  cations in patients undergoing percutaneous coronary  intervention; short-term prevention of myocardial  infarction in patients with unstable angina not  responding to conventional treatment and who are  scheduled for percutaneous coronary intervention  (use under specialist supervision)   Cautions measure baseline prothrombin time, acti-  vated clotting time, activated partial thromboplastin  time, platelet count, haemoglobin and haematocrit;  monitor haemoglobin and haematocrit 12 hours and  24 hours after start of treatment and platelet count 2-  4 hours and 24 hours after start of treatment; con-  comitant use of drugs that increase risk of bleeding;  discontinue if uncontrollable serious bleeding occurs  or emergency cardiac surgery needed; consult pro-  duct literature for details of procedures to minimise  bleeding; elderly    Contra-indications active internal bleeding; major  surgery, intracranial or intraspinal surgery or trauma  within last 2 months; stroke within last 2 years;  intracranial neoplasm, arteriovenous malformation or  aneurysm, severe hypertension, haemorrhagic dia-  thesis, thrombocytopenia, vasculitis, hypertensive  retinopathy   Side-effects bleeding manifestations; nausea, vomi-  ting, hypotension, bradycardia, chest pain, back pain,  headache, fever, puncture site pain, thrombocytope-  nia; rarely cardiac tamponade, adult respiratory dis-  tress, hypersensitivity reactions  Dose   • ADULT initially by intravenous injection over 1 minute,  250 micrograms/kg, then by intravenous infusion,  125 nanograms/kg/minute (max. 10 micrograms/  minute); for prevention of ischaemic complications  start 10-60 minutes before percutaneous coronary  intervention and continue infusion for 12 hours; for  unstable angina start up to 24 hours before possible  percutaneous coronary intervention and continue  infusion for 12 hours after intervention    utero and possibly persistent pulmonary hypertension  of newborn; kemicterus in jaundiced neonates   Breast-feeding avoid — possible risk of Reye’s  syndrome; regular use of high doses could impair  platelet function and produce hypoprothrombinaemia  in infant if neonatal vitamin K stores low   Side-effects bronchospasm; gastro-intestinal irrita-  tion, gastro-intestinal haemorrhage (occasionally  major), also other haemorrhage (e.g. subconjunctival)  Dose   Dispersible tablets, aspirin 75 mg, net price 28 =  83p; 300 mg, see section 4.7.1. Label: 13, 21, 32  Tablets, e/c, aspirin 75 mg, net price 28-tab pack =  93p; 56-tab pack = £1.03; 300 mg, see section 4.7.1.  Label: 5, 25, 32  Brands include Micropirin ®   Tablets, e/c, pink, aspirin 75 mg, net price 28-tab  pack = £1.51, 56-tab pack = £2.52, 100-tab pack =  £5.24; 300 mg, see section 4.7.1. Label: 5, 25, 32   Nu-Seals® Aspirin (Alliance) (Ml  Tablets, e/c, aspirin 75 mg, net price 56-tab pack =  £3.12; 300 mg, see section 4.7.1. Label: 5, 25, 32  Note Tablets may be chewed at diagnosis for rapid absorption   Indications secondary prevention of thrombotic  cerebrovascular or cardiovascular disease, and fol-  lowing by-pass surgery (see also section 2.10.1 and  notes above)   Cautions asthma; uncontrolled hypertension; previous  peptic ulceration (but manufacturers may advise  avoidance of low-dose aspirin in history of peptic  ulceration); concomitant use of drugs that increase  risk of bleeding; G6PD deficiency (section 9.1.5);  interactions: Appendix 1 (aspirin)   Contra-indications use other than as an antiplatelet in  children and adolescents under 16 years (Reye’s  syndrome, section 4.7.1); active peptic ulceration;  haemophilia and other bleeding disorders  Hypersensitivity Aspirin and other NSAIDs are contra-  indicated in history of hypersensitivity to aspirin or any  other NSAID — which includes those in whom attacks of  asthma, angioedema, urticaria, or rhinitis have been preci-  pitated by aspirin or any other NSAID   Renal impairment use with caution; avoid in severe  impairment; sodium and water retention; deteriora-  tion in renal function; increased risk of gastro-intes-  tinal bleeding   Pregnancy use with caution during third trimester;  impaired platelet function and risk of haemorrhage;  delayed onset and increased duration of labour with  increased blood loss; avoid analgesic doses if possible  in last few weeks (low doses probably not harmful);  with high doses, closure of fetal ductus arteriosus in    Indications prevention of atherosclerotic events in  peripheral arterial disease, or within 35 days of myo-  cardial infarction, or within 6 months of ischaemic  stroke; prevention of artherosclerotic events in acute  coronary syndrome without ST-segment elevation  (given with aspirin — see notes above) and in acute  myocardial infarction with ST-segment elevation  (given with aspirin — see notes above)   Cautions patients at risk of increased bleeding from  trauma, surgery or other pathological conditions;  concomitant use of drugs that increase risk of bleed-  ing; discontinue 7 days before elective surgery if  antiplatelet effect not desirable; interactions:  Appendix 1 (clopidogrel)   Contra-indications active bleeding  Hepatic impairment manufacturer advises caution  (risk of bleeding); avoid in severe impairment  Renal impairment manufacturer advises caution  Pregnancy manufacturer advises avoid — no informa-  tion available   Breast-feeding manufacturer advises avoid  Side-effects dyspepsia, abdominal pain, diarrhoea;  bleeding disorders (including gastro-intestinal and  intracranial); less commonly nausea, vomiting, gastri-  tis, flatulence, constipation, gastric and duodenal  ulcers, headache, dizziness, paraesthesia, leucopenia,  decreased platelets (very rarely severe thrombocyto-  penia), eosinophilia, rash, and pruritus; rarely vertigo;  very rarely colitis, pancreatitis, hepatitis, acute liver  failure, vasculitis, confusion, hallucinations, taste dis-  turbance, stomatitis, bronchospasm, interstitial pneu-  monitis, blood disorders (including thrombocytopenic   1. Aspirin tablets 75 mg may be sold to the public in packs of  up to 100 tablets; for details relating to other strengths see  section 4.7.1 and Medicines, Ethics and Practice, No. 34,  London, Pharmaceutical Press, 2010 (and subsequent  editions as available)    purpura, agranulocytosis and pancytopenia), and  hypersensitivity-like reactions (including fever, glo-  merulonephritis, arthralgia, Stevens- Johnson  syndrome, toxic epidermal necrolysis, lichen planus)   • Prevention of artherosclerotic events in peripheral  arterial disease or after myocardial infarction or  ischaemic stroke, 75 mg once daily   • Acute myocardial infarction (with ST-segment eleva-  tion), initially 300 mg then 75 mg daily (with aspirin —  see notes above); initial dose omitted if patient over  75 years   75 mg, net price 28-tab pack = £3.17, 30-tab pack =  £3.40   Plavix® (Sanofi-Aventis) (Ml  Tablets, pink, f/c, clopidogrel (as hydrogen sulphate)  75 mg, net price 30-tab pack = £35.64; 300 mg, 30-tab  pack = £142.54   Cautions rapidly worsening angina, aortic stenosis,  recent myocardial infarction, left ventricular outflow  obstruction, heart failure; may exacerbate migraine;  hypotension; myasthenia gravis (risk of exacerbation);  coagulation disorders; concomitant use of drugs that  increase risk of bleeding; interactions: Appendix 1  (dipyridamole)   Side-effects gastro-intestinal effects, dizziness, myal-  gia, throbbing headache, hypotension, hot flushes and  tachycardia; worsening symptoms of coronary heart  disease; hypersensitivity reactions such as rash, urti-  caria, severe bronchospasm and angioedema;  increased bleeding during or after surgery; thrombo-  cytopenia reported  Dose   • By mouth, 300-600 mg daily in 3-4 divided doses  Modified-release preparations, see under preparation  below   Dipyridamole (Non-proprietary) (Ml  Tablets, coated, dipyridamole 25 mg, net price 84 =  £3.11; 100 mg, 84 = £2.80. Label: 22  Oral suspension, dipyridamole 50 mg/5 mL, net  price 150 mL = £40.63   Persantin® (Boehringer Ingelheim) (Ml  Tablets, s/c, dipyridamole 25 mg (orange), net price  84-tab pack = £1.49; 100 mg, 84-tab pack = £4.16.  Label: 22   Persantin® Retard (Boehringer Ingelheim) [Ml  Capsules, m/r, red/orange containing yellow pellets,  dipyridamole 200 mg, net price 60-cap pack = £9.00.  Label: 21, 25   Dose secondary prevention of ischaemic stroke and transient  ischaemic attacks (used alone or with aspirin), adjunct to oral  anticoagulation for prophylaxis of thromboembolism associated  with prosthetic heart valves, 200 mg twice daily preferably with  food   Note Dispense in original container (pack contains a desiccant)  and discard any capsules remaining 6 weeks after opening   Asasantin® Retard (Boehringer Ingelheim) (Ml  Capsules, red/ivory, aspirin 25 mg, dipyridamole  200 mg (m/r), net price 60-cap pack = £7.79.   Dose secondary prevention of ischaemic stroke and transient  ischaemic attacks, 1 capsule twice daily  Note Dispense in original container (pack contains a desiccant)  and discard any capsules remaining 6 weeks after opening    Indications prevention of early myocardial infarction  in patients with unstable angina or non-ST-segment-  elevation myocardial infarction and with last episode  of chest pain within 24 hours (use under specialist  supervision)   Cautions risk of bleeding, concomitant drugs that  increase risk of bleeding — discontinue immediately if  uncontrolled serious bleeding; measure baseline  prothrombin time, activated partial thromboplastin  time, platelet count, haemoglobin, haematocrit and  serum creatinine; monitor haemoglobin, haematocrit  and platelets within 6 hours after start of treatment  then at least once daily; discontinue if thrombolytic  therapy, intra-aortic balloon pump or emergency  cardiac surgery necessary  Contra-indications abnormal bleeding within 30  days, major surgery or severe trauma within 6 weeks,  stroke within last 30 days or any history of haemor-  rhagic stroke, intracranial disease (aneurysm, neo-  plasm or arteriovenous malformation), severe hyper-  tension, haemorrhagic diathesis, increased  prothrombin time or INR, thrombocytopenia  Hepatic impairment avoid in severe liver disease —  increased risk of bleeding   Renal impairment reduce infusion to 1 microgram/  kg/minute if eGFR 30-50 mL/minute/ 1.73 m 2 ; avoid  if eGFR less than 30 mL/minute/ 1.73 m 2  Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding manufacturer advises avoid — no  information available   • Initially by intravenous injection, 180 micrograms/kg,  then by intravenous infusion, 2 micrograms /kg/min-  ute for up to 72 hours (up to 96 hours if percutaneous  coronary intervention during treatment)   Injection, eptifibatide 2mg/mL, net price 10-mL (20-  mg) vial = £13.61   Indications in combination with aspirin for the pre-  vention of atherothrombotic events in patients with  acute coronary syndrome undergoing percutaneous  coronary intervention   Cautions patients at increased risk of bleeding (e.g.  from recent trauma, surgery, gastro-intestinal bleed-  ing, or active peptic ulcer disease); concomitant use of  drugs that increase risk of bleeding; discontinue at  least 7 days before elective surgery if antiplatelet  effect not desirable; elderly; body-weight less than  60 kg; interactions: Appendix 1 (prasugrel)  Contra-indications active bleeding; history of stroke  or transient ischaemic attack  Hepatic impairment use with caution — increased risk  of bleeding; avoid in severe impairment  Renal impairment use with caution — increased risk  of bleeding   • ADULT over 18 years, (with aspirin — see notes above)  initially 60 mg as a single dose then body- weight over  60 kg, 10 mg once daily or body-weight under 60 kg or  ELDERLY over 75 years, 5 mg once daily   Tablets, f/c, prasugrel (as hydrochloride) 5 mg (yel-  low), net price 28-tab pack = £47.56; 10 mg (beige),  28-tab pack = £47.56   Indications prevention of early myocardial infarction  in patients with unstable angina or non-ST-segment-  elevation myocardial infarction and with last episode  of chest pain within 12 hours (use under specialist  supervision)   Cautions major surgery or severe trauma within 3  months (avoid if within 6 weeks); traumatic or pro-  tracted cardiopulmonary resuscitation, organ biopsy  or lithotripsy within last 2 weeks; risk of bleeding  including active peptic ulcer within 3 months; acute  pericarditis, aortic dissection, haemorrhagic retino-  pathy, vasculitis, haematuria, faecal occult blood;  severe heart failure, cardiogenic shock, anaemia;  puncture of non-compressible vessel within 24 hours;  concomitant drugs that increase risk of bleeding  (including within 48 hours of thrombolytic adminis-  tration); monitor platelet count, haemoglobin and  haematocrit before treatment, 2-6 hours after start of  treatment and then at least once daily; discontinue if  thrombolytic therapy, intra-aortic balloon pump or  emergency cardiac surgery necessary; discontinue  immediately if serious bleeding uncontrolled by  pressure occurs; interactions: Appendix 1 (tirofiban)   Contra-indications abnormal bleeding within 30  days, stroke within 30 days or any history of hae-  morrhagic stroke, intracranial disease (aneurysm,  neoplasm or arteriovenous malformation), severe  hypertension, haemorrhagic diathesis, increased  prothrombin time or INR, thrombocytopenia    Hepatic impairment caution in mild to moderate liver  disease; avoid in severe liver disease — increased risk  of bleeding   Renal impairment increased risk of bleeding; monitor  carefully if eGFR less than 60 mL/minute/1.73 m 2 ;  use half normal dose if eGFR less than 30 mL/min-  ute/1.73 m 2   • By intravenous infusion, initially 400 nanograms/kg/  minute for 30 minutes, then 100 nanograms/kg/  minute for at least 48 hours (continue during and for  12-24 hours after percutaneous coronary interven-  tion); max. duration of treatment 108 hours   Concentrate for intravenous infusion, tirofiban (as  hydrochloride) 250micrograms/mL. For dilution  before use, net price 50-mL (12.5-mg) vial = £146.11  Intravenous infusion, tirofiban (as hydrochloride)   It is important to distinguish stable angina from unstable  angina. Stable angina usually results from atherosclero-  tic plaques in the coronary arteries and is often pre-  cipitated by exertion and relieved by rest. Treatment  involves management of acute anginal pain, and long-  term management to prevent angina attacks and to  reduce the risk of cardiovascular events.   Acute attacks of stable angina should be managed with  sublingual glyceryl trinitrate (section 2.6.1); sublingual  glyceryl trinitrate can also be taken before performing  activities that are known to bring on an attack. If attacks  occur more than twice a week, regular drug therapy is  required and should be introduced in a step-wise man-  ner according to response.    Patients with mild or moderate stable angina should be  given a beta-blocker (section 2.4). In those with left-  ventricular dysfunction, beta-blocker treatment should  be started at a very low dose and titrated very slowly  over a period of weeks or months (section 2.5.5).   For those patients in whom beta-blockers are not toler-  ated or are contra-indicated, a long-acting nitrate (sec-  tion 2.6.1) or a rate-limiting calcium-channel blocker  (diltiazem or verapamil, section 2.6.2) can be used; in  patients with left-ventricular dysfunction, diltiazem and  verapamil are contra-indicated because heart failure  may be precipitated (important: see p. 128); however,  a long-acting dihydropyridine calcium-channel blocker,  such as amlodipine or felodipine, is suitable. Nicorandil  or ivabradine (section 2.6.3) are alternatives.   When a single drug fails to control symptoms, combina-  tion treatment can be used. A calcium-channel blocker  can be added to a beta-blocker, although combining  verapamil with a beta-blocker should be avoided (see  p. 133); combinations including diltiazem and a beta-  blocker should be used with caution. Long-acting  nitrates can also be used with a beta-blocker or a cal-  cium-channel blocker, if appropriate. Combinations that  include nicorandil or ranolazine (section 2.6.3) can also  be considered.   Patients should be referred to a specialist if a combina-  tion of two drugs fails to control symptoms. Revascular-  isation procedures may be appropriate; see section 2.9  for the use of antiplatelet drugs in patients undergoing  coronary stenting.   For long-term prevention of cardiovascular events, see  Prevention of cardiovascular events, p. 156.   Acute coronary syndromes encompass a spectrum of  conditions which include unstable angina, and myo-  cardial infarction with or without ST-segment elevation.  Patients with different acute coronary syndromes may  present similarly; definitive diagnosis is made on the  basis of clinical presentation, ECG changes, and mea-  surement of biochemical cardiac markers.   Unstable angina and non-ST-segment elevation  myocardial infarction (NSTEMI) are related acute  coronary syndromes that fall between the classifications  of stable angina and ST-segment elevation myocardial  infarction (STEMI). They usually occur as a result of  atheromatous plaque rupture, and are often charac-  terised by stable angina that suddenly worsens, recur-  ring or prolonged angina at rest, or new onset of severe  angina. Patients with unstable angina have no evidence  of myocardial necrosis, whereas in NSTEMI, myocardial  necrosis (less significant than with STEMI) will be  evident. There is a risk of progression to STEMI or  sudden death, particularly in patients who experience  pain at rest.   ST-segment elevation myocardial infarction  (STEMI) is an acute coronary syndrome where ather-  omatous plaque rupture leads to thrombosis and myo-  cardial ischaemia, with irreversible necrosis of the heart  muscle, often leading to long-term complications.  STEMI can also occasionally occur as a result of cor-  onary spasm or embolism, arteritis, spontaneous  thrombosis, or sudden severe elevation in blood pres-  sure.   These conditions are managed similarly; the aims of  management are to provide supportive care and pain  relief during the acute attack and to prevent further  cardiac events and death. For advice on the manage-  ment of patients with acute ST-segment elevation myo-  cardial infarction (STEMI), see below.    Initial management Oxygen (section 3.6) should be  administered if there is evidence of hypoxia, pulmonary  oedema, or continuing myocardial ischaemia; hyperoxia  should be avoided and particular care is required in  patients with chronic obstructive airways disease.   Nitrates (section 2.6.1) are used to relieve ischaemic  pain. If sublingual glyceryl trinitrate is not effective,  intravenous or buccal glyceryl trinitrate or intravenous  isosorbide dinitrate is given. If pain continues, diamor-  phine or morphine (section 4.7.2) can be given by slow  intravenous injection; an antiemetic such as metoclo-  pramide should also be given (section 4.6).    Aspirin (chewed or dispersed in water) is given for its  antiplatelet effect in a dose of 300 mg (section 2.9). If  aspirin is given before arrival at hospital, a note saying  that it has been given should be sent with the patient.  Clopidogrel in a dose of 300 mg (or 600 mg [unlicensed]  if used prior to percutaneous coronary intervention)  should also be given (see section 2.9). Prasugrel, in a  dose of 60 mg, is an alternative to clopidogrel in certain  patients undergoing percutaneous coronary interven-  tion (see NICE guidance, p. 150). Patients should also  receive either unfractionated heparin, a low molecular  weight heparin, or fondaparinux (section 2.8.1).   Patients without contra-indications should receive beta-  blockers (section 2.4) which should be continued inde-  finitely. In patients without left ventricular dysfunction  and in whom beta-blockers are inappropriate, diltiazem  or verapamil can be given (section 2.6.2).    The glycoprotein Ilb/IIIa inhibitors eptifibatide and  tirofiban (section 2.9) can be used (with aspirin and  unfractionated heparin) for unstable angina or for non-  ST-segment elevation myocardial infarction in patients  at a high risk of either myocardial infarction or death.    In intermediate- and high-risk patients, abciximab, epti-  fibatide, or tirofiban can also be used with aspirin and  unfractionated heparin in patients undergoing percuta-  neous coronary intervention, to reduce the immediate  risk of vascular occlusion. In intermediate- and high-risk  patients in whom early intervention is planned, bivalir-  udin (section 2.8.1) can be considered as an alternative  to the combination of a glyocprotein Ilb/IIIa inhibitor  plus a heparin.   Revascularisation procedures are often appropriate for  patients with unstable angina or non-ST-segment eleva-  tion myocardial infarction (NSTEMI); see section 2.9 for  the use of antiplatelet drugs in patients undergoing  coronary stenting.    Long-term management The need for long-term  angina treatment or for coronary angiography should  be assessed. Most patients will require standard angina  treatment (see management of stable angina, above) to  prevent recurrence of symptoms.    Prevention of cardiovascular events Patients with  stable and unstable angina should be given advice and  treatments to reduce their cardiovascular risk. The  importance of life-style changes, especially stopping  smoking, should be emphasised. Patients should take  aspirin indefinitely in a dose of 75 mg daily. In patients  with non-ST-segment elevation acute coronary  syndrome, a combination of aspirin and clopidogrel  (section 2.9) is given for up to 12 months; most benefit  occurs during the first 3 months. An ACE inhibitor  (section 2. 5. 5.1) and a statin (section 2.12) should also  be given.    Local guidelines for the management of myocardial  infarction should be followed where they exist   These notes give an overview of the initial and long-  term management of myocardial infarction with ST-  segment elevation. For advice on the management of  non-ST-segment elevation myocardial infarction and  unstable angina, see above. The aims of management  of ST-segment elevation myocardial infarction are to  provide supportive care and pain relief, to promote  reperfusion and to reduce mortality. Oxygen, nitrates,  and diamorphine or morphine can provide initial sup-  port and pain relief; aspirin and percutaneous coronary  intervention or thrombolytics promote reperfusion; anti-  coagulants help to reduce re-occlusion and systemic  embolisation; long-term use of aspirin, beta-blockers,  ACE inhibitors, and statins help to reduce mortality  further.    Initial management Oxygen (section 3.6) should be  administered if there is evidence of hypoxia, pulmonary  oedema, or continuing myocardial ischaemia; hyperoxia  should be avoided and particular care is required in  patients with chronic obstructive airways disease.   The pain (and anxiety) of myocardial infarction is man-  aged with slow intravenous injection of diamorphine or  morphine (section 4.7.2); an antiemetic such as meto-  clopramide (or, if left ventricular function is not com-  promised, cyclizine) by intravenous injection should  also be given (section 4.6).   Aspirin (chewed or dispersed in water) is given for its  antiplatelet effect (section 2.9); a dose of 300 mg is  suitable. If aspirin is given before arrival at hospital, a  note saying that it has been given should be sent with  the patient. Clopidogrel, in a dose of 300 mg (or 600 mg  [unlicensed] if used prior to percutaneous coronary  intervention), should also be given (section 2.9). Prasu-  grel, in a dose of 60 mg, is an alternative to clopidogrel  in certain patients undergoing percutaneous coronary  intervention (see NICE guidance, p. 150).   Patency of the occluded artery can be restored by  percutaneous coronary intervention or by giving a  thrombolytic drug (section 2.10.2), unless contra-indi-  cated. Percutaneous coronary intervention is the pre-  ferred method; a glycoprotein Ilb/IIIa inhibitor (sec-  tion 2.9) can be used to reduce the risk of immediate  vascular occlusion in intermediate- and high-risk  patients. Patients undergoing percutaneous coronary  intervention should also receive either unfractionated  heparin or a low molecular weight heparin (e.g. enoxa-    parin); bivalirudin (section 2.8.1) is an alternative to the  combination of a glycoprotein Ilb/IIIa inhibitor plus a  heparin. In patients who cannot be offered percuta-  neous coronary intervention within 90 minutes of diag-  nosis, a thrombolytic drug should be administered along  with either unffactionated heparin (for maximum 2  days), a low molecular weight heparin (e.g. enoxaparin),  or fondaparinux. See section 2.9 for the use of anti-  platelet drugs in patients undergoing coronary stenting.   Patients who do not receive reperfusion therapy (with  percutaneous coronary intervention or a thrombolytic)  should be treated with either fondaparinux, enoxaparin,  or unfractionated heparin. Prescribes should consult  product literature and local protocols (where they exist)  for details of anticoagulant dose and duration.   Nitrates (section 2.6.1) are used to relieve ischaemic  pain. If sublingual glyceryl trinitrate is not effective,  intravenous glyceryl trinitrate or isosorbide dinitrate is  given.   Early administration of some beta-blockers (section  2.4) has been shown to be of benefit and should be  given to patients without contra-indications.   ACE inhibitors (section 2. 5. 5.1), and angiotensin-II  receptor antagonists (section 2. 5. 5. 2) if an ACE inhibitor  cannot be used, are also of benefit to patients who have  no contra-indications; in hypertensive and normoten-  sive patients treatment with an ACE inhibitor, or an  angiotensin-II receptor antagonist, can be started within  24 hours of the myocardial infarction and continued for  at least 5-6 weeks (see below for long-term treatment).   All patients should be closely monitored for hyperglyc-  aemia; those with diabetes or raised blood-glucose  concentration should receive insulin.    Long-term management Long-term management  following ST-segment elevation myocardial infarction  involves the use of several drugs which should ideally  be started before the patient is discharged from hospital.   Aspirin (section 2.9) should be given to all patients,  unless contra-indicated, at a dose of 75 mg daily. The  addition of clopidogrel (section 2.9) has been shown to  reduce morbidity and mortality. For those intolerant of  clopidogrel, and who are at low risk of bleeding, the  combination of warfarin (section 2.8.2) and aspirin  should be considered. In those intolerant of both aspirin  and clopidogrel, warfarin alone can be used. Warfarin  should be continued for those who are already being  treated for another indication, such as atrial fibrillation,  with the addition of aspirin if there is a low risk of  bleeding. The combination of aspirin with clopidogrel  or warfarin increases the risk of bleeding. See section 2.9  for details of antiplatelet drug duration following cor-  onary stenting.   Beta-blockers (section 2.4) should be given to all  patients in whom they are not contra-indicated. Ace-  butolol, metoprolol, propranolol, and timolol are suita-  ble; for patients with left ventricular dysfunction, carve-  dilol, bisoprolol, or long-acting metoprolol may be  appropriate (section 2.5.5).   Diltiazem [unlicensed] or verapamil (section 2.6.2) can  be considered if a beta-blocker cannot be used; how-  ever, they are contra-indicated in those with left ventri-  cular dysfunction. Other calcium-channel blockers have  no place in routine long-term management after a myo-  cardial infarction.    An ACE inhibitor (section 2.5.5. 1) should be considered  for all patients, especially those with evidence of left  ventricular dysfunction. If an ACE inhibitor cannot be  used, an angiotensin-II receptor antagonist may be used  for patients with heart failure. A relatively high dose of  either the ACE inhibitor or angiotensin-II receptor  antagonist may be required to produce benefit.   Eplerenone (section 2.2.3) is licensed for use following  a myocardial infarction in those with left ventricular  dysfunction and evidence of heart failure.   For the role of statins in preventing recurrent cardio-  vascular events, see section 2.12.   Fibrinolytic drugs act as thrombolytics by activating  plasminogen to form plasmin, which degrades fibrin  and so breaks up thrombi.   The value of thrombolytic drugs for the treatment of  myocardial infarction has been established (section  2.10.1). Streptokinase and alteplase have been  shown to reduce mortality. Reteplase and tenecteplase  are also licensed for acute myocardial infarction.  Thrombolytic drugs are indicated for any patient with  acute myocardial infarction for whom the benefit is  likely to outweigh the risk of treatment. Trials have  shown that the benefit is greatest in those with ECG  changes that include ST segment elevation (especially in  those with anterior infarction) and in patients with  bundle branch block. Patients should not be denied  thrombolytic treatment on account of age alone  because mortality in the elderly is high and the reduc-  tion in mortality is the same as in younger patients.   Alteplase, reteplase and streptokinase need to be given  within 12 hours of symptom onset, ideally within 1 hour;  use after 12 hours requires specialist advice. Tenecte-  plase should be given as early as possible and usually  within 6 hours of symptom onset.   Alteplase, streptokinase, and urokinase can be used for  other thromboembolic disorders such as deep-vein  thrombosis and pulmonary embolism. Alteplase is also  used for acute ischaemic stroke (see section 2.9).   Urokinase is also licensed to restore the patency of  occluded intravenous catheters and cannulas blocked  with fibrin clots.   Cautions Thrombolytic drugs should be used with  caution if there is a risk of bleeding including that  from venepuncture or invasive procedures. They should  also be used with caution in external chest compression,  elderly, hypertension, conditions in which thrombolysis  might give rise to embolic complications such as  enlarged left atrium with atrial fibrillation (risk of dis-  solution of clot and subsequent embolisation), and  recent or concurrent use of drugs that increase the  risk of bleeding.   Contra-indications Thrombolytic drugs are contra-  indicated in recent haemorrhage, trauma, or surgery  (including dental extraction), coagulation defects, bleed-  ing diatheses, aortic dissection, aneurysm, coma, his-  tory of cerebrovascular disease especially recent events  or with any residual disability, recent symptoms of   possible peptic ulceration, heavy vaginal bleeding,  severe hypertension, active pulmonary disease with  cavitation, acute pancreatitis, pericarditis, bacterial  endocarditis, and oesophageal varices; also in the case  of streptokinase, previous allergic reactions to either  streptokinase or anistreplase (no longer available).   Prolonged persistence of antibodies to streptokinase  and anistreplase (no longer available) can reduce the  effectiveness of subsequent treatment; therefore,  streptokinase should not be used again beyond 4 days  of first administration of either streptokinase or  anistreplase.   Hepatic impairment Thrombolytic drugs should be  avoided in severe hepatic impairment as there is an  increased risk of bleeding.   Pregnancy Thrombolytic drugs can possibly lead to  premature separation of the placenta in the first 18  weeks of pregnancy. There is also a risk of maternal  haemorrhage throughout pregnancy and post-partum,  and also a theoretical risk of fetal haemorrhage through-  out pregnancy.    Side-effects Side-effects of thrombolytics are mainly  nausea and vomiting and bleeding. When thrombolytics  are used in myocardial infarction, reperfusion arrhyth-  mias and recurrent ischaemia and angina may occur.  Reperfusion may also cause cerebral and pulmonary  oedema. Hypotension can also occur and can usually be  controlled by elevating the patient’s legs, or by reducing  the rate of infusion or stopping it temporarily. Back pain,  fever, and convulsions have been reported. Bleeding is  usually limited to the site of injection, but intracerebral  haemorrhage or bleeding from other sites can occur.  Serious bleeding calls for discontinuation of the throm-  bolytic and may require administration of coagulation  factors and antifibrinolytic drugs (e.g. tranexamic acid).  Rarely further embolism may occur (either due to clots  that break away from the original thrombus or to cho-  lesterol crystal emboli). Thrombolytics can cause aller-  gic reactions (including rash, flushing and uveitis) and  anaphylaxis has been reported (for details of manage-  ment see Allergic Emergencies, section 3.4.3). Guillain-  Barre syndrome has been reported rarely after strepto-  kinase treatment.   Indications acute myocardial infarction (see notes  above and section 2.10.1); pulmonary embolism;  acute ischaemic stroke (treatment under specialist  neurology physician only)   Cautions see notes above; in acute stroke, monitor for  intracranial haemorrhage, monitor blood pressure  (antihypertensive recommended if systolic above  180mmHg or diastolic above 105mmHg)  Contra-indications see notes above; in acute stroke,  convulsion accompanying stroke, severe stroke, his-  tory of stroke in patients with diabetes, stroke in last 3  months, hypoglycaemia, hyperglycaemia  Hepatic impairment see notes above  Pregnancy see notes above  Side-effects see notes above; also risk of cerebral  bleeding increased in acute stroke   • Myocardial infarction, accelerated regimen (initiated  within 6 hours of symptom onset), 15 mg by intra-  venous injection, followed by intravenous infusion of  50 mg over 30 minutes, then 35 mg over 60 minutes  (total dose 100 mg over 90 minutes); in patients less  than 65 kg, 15 mg by intravenous injection, followed  by intravenous infusion of 0.75 mg/kg over 30 min-  utes, then 0.5 mg/kg over 60 minutes (max. total dose  100 mg over 90 minutes)   • Myocardial infarction, initiated within 6-12 hours of  symptom onset, 10 mg by intravenous injection, fol-  lowed by intravenous infusion of 50 mg over 60  minutes, then 4 infusions each of 10 mg over 30  minutes (total dose 100 mg over 3 hours; max.   • Pulmonary embolism, 10 mg by intravenous injection  over 1-2 minutes, followed by intravenous infusion of  90 mg over 2 hours; max. 1.5 mg/kg in patients less  than 65 kg   • Acute stroke (treatment must begin within 3 hours of  symptom onset), by intravenous administration over  60 minutes, 900 micrograms/kg (max. 90 mg); initial  10% of dose by intravenous injection, remainder by  intravenous infusion; ELDERLY over 80 years not  recommended   Actilyse® (Boehringer Ingelheim) (Mi  Injection, powder for reconstitution, alteplase 10 mg  (5.8 million units) /vial, net price per vial (with diluent)  = £120.00; 20 mg (11.6 million units)/vial (with diluent  and transfer device) = £180.00; 50 mg (29 million -  units) /vial (with diluent, transfer device, and infusion  bag) = £300.00   Contra-indications see notes above  Hepatic impairment see notes above  Pregnancy see notes above  Breast-feeding manufacturer advises avoid breast-  feeding for 24 hours after dose (express and discard  milk during this time)   • By intravenous injection (initiated within 12 hours of  symptom onset), 10 units over not more than 2 min-  utes, followed after 30 minutes by a further 10 units   Injection, powder for reconstitution, reteplase  10 units/ vial, net price pack of 2 vials (with 2 prefilled  syringes of diluent and transfer device) = £627.97   Indications acute myocardial infarction (see notes  above and section 2.10.1); deep-vein thrombosis,  pulmonary embolism, acute arterial thromboembo-  lism, and central retinal venous or arterial thrombosis  Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Pregnancy see notes above  Side-effects see notes above   • Myocardial infarction (initiated within 12 hours of  symptom onset), by intravenous infusion, 1.5 million  units over 60 minutes   • Deep-vein thrombosis, pulmonary embolism, acute  arterial thromboembolism, central retinal venous or  arterial thrombosis, by intravenous infusion,   250 000 units over 30 minutes, then 100 000 units  every hour for up to 12-72 hours according to con-  dition with monitoring of clotting parameters (consult  product literature)   Injection, powder for reconstitution, streptokinase,  net price 250 000-unit vial = £15.91; 750 000-unit vial  = £41.72; 1.5 million-unit vial = £83.44 (hosp. only)   Contra-indications see notes above  Hepatic impairment see notes above  Pregnancy see notes above  Breast-feeding manufacturer advises avoid breast-  feeding for 24 hours after dose (express and discard  milk during this time)   • By intravenous injection over 10 seconds (initiated  within 6 hours of symptom onset), 30-50 mg accord-  ing to body-weight — consult product literature; max.  50 mg   Injection, powder for reconstitution, tenecteplase, net  price 40-mg (8000-unit) vial = £502.25; 50-mg  (10 000-unit) vial = £502.25 (both with prefilled  syringe of water for injection)   Indications thromboembolic occlusive vascular dis-  ease including deep-vein thrombosis, pulmonary  embolism, and peripheral vascular occlusion;  occluded intravenous catheters and cannulas blocked  by fibrin clots  Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Pregnancy see notes above  Breast-feeding manufacturer advises avoid — no  information available  Side-effects see notes above  Dose   • Deep-vein thrombosis, by intravenous infusion, initi-  ally 4400 units/kg in 15mL sodium chloride 0.9%  over 10 minutes, followed by 4400 units/kg/hour for  12-24 hours   • Pulmonary embolism, by intravenous infusion, initi-  ally 4400 units/kg in 15mL sodium chloride 0.9%  over 10 minutes, followed by 4400 units/kg/hour for  12 hours or by injection into pulmonary artery, initially  15 000 units/kg, subsequent doses adjusted according  to response; max. 3 doses in 24 hours   • Occluded catheters and cannulas, by injection directly  into catheter or cannula, 5000-25 000 units dissolved  in suitable volume of sodium chloride 0.9% to fill the  catheter or cannula lumen; leave for 20-60 minutes  then aspirate the lysate; repeat if necessary   Syner-KINASE® (Syner-Med) [Ml  Injection, powder for reconstitution, urokinase, net  price 10 000-unit vial = £35.95; 25 000-unit vial =  £45.95; 100 000-unit vial = £112.95  Note 50 000-unit vial and 250 000-unit vial also available from  ‘special-order’ manufacturers or specialist importing companies,  see p. 988   Fibrin dissolution can be impaired by the administration  of tranexamic acid, which inhibits fibrinolysis. It can be  used to prevent bleeding or to treat bleeding associated  with excessive fibrinolysis (e.g. in prostatectomy,  bladder surgery, in dental extraction in patients with  haemophilia, in conisation of the cervix, and in trau-  matic hyphaema) and in the management of menorr-  hagia. Tranexamic acid may also be used in hereditary  angioedema, epistaxis, and in thrombolytic overdose.   Desmopressin (section 6.5.2) is used in the manage-  ment of mild to moderate haemophilia and von Will-  ebrand’s disease. It is also used for fibrinolytic response  testing.   Etamsylate reduces capillary bleeding in the presence  of a normal number of platelets; it does not act by fibrin  stabilisation, but probably by correcting abnormal adhe-  sion. Etamsylate is less effective than other treatments  in the management of heavy menstrual bleeding and its  use is no longer recommended.   Cautions exclude structural or histological causes of  menorrhagia, or fibroids causing distortion of the  uterine cavity, before initiating treatment   Dicynene® (Sanofi-Aventis) (Ml  Tablets, scored, etamsylate 500 mg, net price 100-tab  pack = £8.44   Cautions massive haematuria (avoid if risk of ureteric  obstruction); not for use in disseminated intravascular  coagulation; irregular menstrual bleeding (exclude    structural or histological causes of menorrhagia, or  fibroids causing distortion of the uterine cavity, before  initiating treatment); regular liver function tests in  long-term treatment of hereditary angioedema  Contra-indications thromboembolic disease  Renal impairment reduce dose — consult product lit-  erature for details    Pregnancy no evidence of teratogenicity in animal  studies; manufacturer advises use only if potential  benefit outweighs risk — crosses the placenta  Breast-feeding small amount present in milk — anti-  fibrinolytic effect in infant unlikely  Side-effects nausea, vomiting, diarrhoea (reduce  dose); rarely disturbances in colour vision (discon-  tinue), thromboembolic events, convulsions, allergic  skin reactions; dizziness and hypotension on rapid  intravenous injection   • By mouth, local fibrinolysis, 1-1.5 g (or 15-25 mg/kg)  2-3 times daily   Menorrhagia (initiated when menstruation has  started), 1 g 3 times daily for up to 4 days; max. 4 g  daily   Hereditary angioedema, 1-1.5 g 2-3 times daily  Epistaxis, 1 g 3 times daily for 7 days   • By slow intravenous injection, local fibrinolysis, 0.5-  1 g 3 times daily   • By continuous intravenous infusion, local fibrinolysis,  following initial treatment by intravenous injection,  25-50 mg/kg over 24 hours   Tranexamic acid (Non-proprietary) tMl  Tablets, tranexamic acid 500 mg, net price 60-tab  pack = £5.27    Cyklokapron® (Meda) (Ml  Tablets, f/c, scored, tranexamic acid 500 mg, net  price 60-tab pack = £14.30   Dried prothrombin complex is prepared from human  plasma by a suitable fractionation technique, and  contains factor IX, together with variable amounts of  factors II, VII, and X   Indications treatment and peri-operative prophylaxis  of haemorrhage in patients with congenital deficiency  of factors II, VII, IX, or X if purified specific coagu-  lation factors not available; treatment and peri-  operative prophylaxis of haemorrhage in patients with  acquired deficiency of factors II, VII, IX, or X (e.g.  during warfarin treatment — see section 2.8.2)  Cautions risk of thrombosis; disseminated intravascu-  lar coagulation; history of myocardial infarction or  coronary heart disease; postoperative use  Contra-indications angina; recent myocardial infarc-  tion (except in life-threatening haemorrhage following  overdosage of oral anticoagulants, and before induc-  tion of fibrinolytic therapy); history of heparin-  induced thrombocytopenia   Side-effects thrombotic events (including dissemi-  nated intravascular coagulation); rarely headache;  very rarely pyrexia, antibody formation, hypersensi-  tivity reactions (including anaphylaxis); nephrotic  syndrome also reported   Indications adjunctive treatment of severe sepsis with  multiple organ failure — start treatment within 24  hours (and no later than 48 hours) after onset of organ  failure   Cautions increased risk of bleeding, concomitant use  of drugs that increase risk of bleeding; interactions:  Appendix 1 (drotrecogin alfa)   Contra-indications internal bleeding; intracranial  neoplasm or cerebral herniation; thrombocytopenia;  not recommended for use in children under 18 years  or in single organ failure   Drotrecogin alfa (activated) should be considered for  adults with severe sepsis that has resulted in the failure  of two or more major organs and who are receiving  optimum intensive care support. Drotrecogin alfa  (activated) should be initiated and supervised only  by a specialist consultant with intensive care skills  and experience in the care of patients with sepsis.   Indications treatment and prophylaxis of haemorr-  hage in patients with haemophilia A or B with inhi-  bitors to factors VIII or IX, acquired haemophilia,  factor VII deficiency, or Glanzmann’s thrombasthenia   Side-effects very rarely nausea, thrombotic events  (including myocardial infarction and cerebrovascular  accident), coagulation disorders, fever, pain, and  allergic reactions including rash   Dried factor VIII fraction is prepared from human  plasma by a suitable fractionation technique   Indications treatment and prophylaxis of haemorr-  hage in congenital factor VIII deficiency (haemophilia  A), acquired factor VIII deficiency, von Willebrand’s  disease    Cautions monitor for development of factor VIII inhi-  bitors; intravascular haemolysis after large or fre-  quently repeated doses in patients with blood groups  A, B, or AB — less likely with high potency concen-  trates   Side-effects gastro-intestinal disturbances, taste dis-  turbances; flushing, palpitation; dyspnoea, coughing;  headache, dizziness, paraesthesia, drowsiness; blurred  vision; antibody formation; hypersensitivity reactions  including hypotension, angioedema, chills, fever,  urticaria, and anaphylaxis  Available from Biotest UK (Haemoctin® Y), CSL Behring  (Haemate® P), BPL ( Optivate ®, High Purity Factor VIII and  von Willebrand factor concentrate; 8Y®), Grifols (Alphanate ® ;  Fanhdi ®), Octapharma (Octanate®; Wilate® ▼)   Note Preparation of recombinant human coagulation factor  VIII (octocog alfa) available from CSL Behring ( Helixate ®  NexGen), Baxter (Advate®), Bayer Schering ( Kogenate ®  Bayer); preparation of recombinant human coagulation factor  VIII (moroctocog alfa) available from Wyeth ( ReFacto AF® ▼);  octocog alfa and moroctocog alfa are not indicated for use in  von Willebrand’s disease   Preparations with factor VIII inhibitor bypassing  activity are prepared from human plasma   Indications treatment and prophylaxis of haemorr-  hage in patients with congenital factor VIII deficiency  (haemophilia A) and factor VIII inhibitors; treatment  of haemorrhage in non-haemophiliac patients with  acquired factor VIII inhibitors   Side-effects thrombosis, disseminated intravascular  coagulation, myocardial infarction; paraesthesia;  pyrexia; hypersensitivity reactions including hypo-  tension, flushing, urticaria, rash, and anaphylaxis  Available from Baxter ( FEIBA ®)   Dried factor IX fraction is prepared from human  plasma by a suitable fractionation technique; it may  also contain clotting factors II, VII, and X   Indications treatment and prophylaxis of haemorr-  hage in congenital factor IX deficiency (haemophilia   Side-effects gastro-intestinal disturbances; headache,  dizziness; allergic reactions, including chills, fever  Available from CSL Behring (Mononine®), BPL ( Replenine ®-  VF, Dried Factor IX Fraction), Grifols ( AlphaNine ®)   Note Preparation of recombinant coagulation factor IX (non-  acog alfa) available from Wyeth ( BeneFIX ®)   Fresh frozen plasma is prepared from the supernatant  liquid obtained by centrifugation of one donation of  whole blood   Indications to replace coagulation factors or other  plasma proteins where their concentration or func-  tional activity is critically reduced  Cautions need for compatibility  Contra-indications circulatory overload; avoid use as  a volume expander   Side-effects allergic reactions including chills, fever,  bronchospasm; adult respiratory distress syndrome  Available from Regional Blood Transfusion Services  Note A preparation of solvent/detergent treated human  plasma (frozen) from pooled donors is available from Octa-  pharma ( Octaplas ®)   Indications congenital protein C deficiency  Cautions hypersensitivity to heparins  Side-effects very rarely fever, bleeding, dizziness, and  hypersensitivity reactions  Available from Baxter ( Ceprotin ®)    Preventative measures should be taken in individuals  with a high risk of developing cardiovascular disease  (primary prevention) and to prevent recurrence of  events in those with established cardiovascular disease  (secondary prevention).   Individuals at high risk include those who already have  atherosclerotic disease, those with diabetes mellitus  aged over 40 years, and those with familial hyper-  cholesterolaemia. The risk also increases with age;  those over 75 years are at particularly high risk, espe-  cially if they smoke or have hypertension.   Preventative measures are also required for other indi-  viduals who may be at high risk of developing athero-  sclerotic cardiovascular disease; those with a 10-year  risk of cardiovascular disease 1 of 20% or more stand to  benefit most from drug treatment. The risk is assessed  on the basis of lipid concentration as well as smoking  status, blood pressure, gender, and age; other risk fac-  tors, such as premature menopause, ethnicity, obesity,  triglyceride concentration, chronic kidney disease,  impaired glucose tolerance, and a family history of  premature cardiovascular disease, should also be  taken into account when assessing risk in individual  patients.   Patients with hypothyroidism should receive adequate  thyroid replacement therapy before assessing the  requirement for lipid-regulating treatment because cor-  recting hypothyroidism itself may resolve the lipid    1. Cardiovascular disease risk may be determined from the  chart issued by the Joint British Societies (Heart 2005; 91  (Suppl V): vl-v52) — see inside back cover. The Joint  British Societies’ ‘Cardiac Risk Assessor’ computer pro-  gramme may also be used to determine cardiovascular  disease risk.    abnormality. Untreated hypothyroidism increases the  risk of myositis with lipid-regulating drugs.   Lowering the concentration of low-density lipoprotein  (LDL) cholesterol and raising high-density lipoprotein  (HDL) cholesterol slows the progression of athero-  sclerosis and may even induce regression. All patients  at high risk of cardiovascular disease should be advised  to make lifestyle modifications that include beneficial  changes to diet, exercise, weight management, alcohol  consumption, and smoking cessation. Lipid-regulating  drug treatment must be combined with advice on diet  and lifestyle measures, lowering of raised blood pres-  sure (section 2.5), the use of low-dose aspirin (section  2.9), and management of diabetes (section 6.1).    A statin (see p. 162) reduces the risk of cardiovascular  disease events, irrespective of serum cholesterol con-  centration, and is the drug of first choice for primary  and secondary prevention of cardiovascular disease. If  statins are contra-indicated or not tolerated, a fibrate  (p. 166) or a bile acid sequestrant (p. 164) may be  considered for primary or secondary prevention; nico-  tinic acid (p. 168) is also an option for secondary  prevention. Fibrates, bile acid sequestrants, or nicotinic  acid should not be used in combination with a statin for  primary prevention of cardiovascular disease. In sec-  ondary prevention of cardiovascular events, if a total  cholesterol concentration of less than 4 mmol/litre or a  LDL-cholesterol concentration of less than 2 mmol/litre  is not achieved with initial treatment, consider treating  patients with a ‘high-intensity’ statin (e.g. simvastatin or  atorvastatin) — a ‘high-intensity’ statin is one that pro-  duces a greater LDL-cholesterol reduction than simva-  statin 40 mg; see also risk of Muscle Effects, p. 162.  Patients with an acute coronary syndrome should also  receive treatment with a ‘high-intensity’ statin where  appropriate.   A statin is also the drug of first choice for treating  hypercholesterolaemia and moderate hypertriglyceri-  daemia. Severe hyperlipidaemia not adequately con-  trolled with a maximal dose of a statin may require  the use of an additional lipid-regulating drug such as  ezetimibe or colestyramine; such treatment should  generally be supervised by a specialist.    A number of conditions, some familial, are characterised  by very high LDL-cholesterol concentration, high trigly-  ceride concentration, or both. Fenofibrate may be  added to statin therapy if triglycerides remain high  even after the LDL-cholesterol concentration has been  reduced adequately; nicotinic acid may also be used to  further lower triglyceride or LDL-cholesterol concentra-  tion.    Combination of a statin with a fibrate or with nicotinic  acid carries an increased risk of side-effects (including  rhabdomyolysis — see Muscle Effects below) and should  be used under specialist supervision; monitoring of liver  function and creatine kinase should also be considered.  The concomitant administration of gemfibrozil with a  statin increases the risk of rhabdomyolysis consider-  ably — this combination should not be used.   A statin is recommended for all patients with familial  hypercholesterolaemia. A ‘high-intensity’ statin (e.g.  rosuvastatin (initiated by a specialist), simvastatin, or  atorvastatin) should be considered in order to achieve  the recommended reduction in LDL-cholesterol con-  centration of greater than 50% from baseline; a ‘high-  intensity’ statin is one that produces a greater LDL-  cholesterol reduction than simvastatin 40 mg — see also    risk of Muscle Effects, below. Patients with heterozygous  familial hypercholesterolaemia who have contra-indica-  tions to, or are intolerant of, statins should receive  ezetimibe. The combination of a statin and ezetimibe  can be considered if a statin alone fails to provide  adequate control (or if intolerance limits dose titration),  and when a switch to an alternative statin is being  considered. Patients for whom statins and ezetimibe  are inappropriate, should be referred to a specialist for  the consideration of treatment with a bile acid seques-  trant, nicotinic acid, or a fibrate.   The prescribing of drug therapy in homozygous familial  hypercholesterolaemia should be undertaken in a spe-  cialist centre.   The statins (atorvastatin, fluvastatin, pravastatin,  rosuvastatin, and simvastatin) competitively inhibit  3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)  reductase, an enzyme involved in cholesterol synthesis,  especially in the liver. Statins are more effective than  other lipid-regulating drugs at lowering LDL-cholesterol  concentration but they are less effective than the  fibrates in reducing triglyceride concentration. How-  ever, statins reduce cardiovascular disease events and  total mortality irrespective of the initial cholesterol  concentration.    Statins should be considered for all patients, including  the elderly, with symptomatic cardiovascular disease  such as those with coronary heart disease (including  history of angina or acute myocardial infarction), occlu-  sive arterial disease (including peripheral vascular dis-  ease, non-haemorrhagic stroke, or transient ischaemic  attacks).   In patients with diabetes mellitus, the risk of developing  cardiovascular disease depends on the duration and  complications of diabetes, age, and concomitant risk  factors. Statin therapy should be considered for all  patients over 40 years with diabetes mellitus (type 1  and 2). In younger patients with diabetes, treatment  with a statin should be considered if there is target-  organ damage, poor glycaemic control (HbA lc greater  than 9%), low HDL-cholesterol and raised triglyceride  concentration, hypertension, or a family history of pre-  mature cardiovascular disease.   Statins are also used for the prevention of cardiovascu-  lar disease events in asymptomatic individuals who are  at increased risk (see p. 161). Statin treatment should  also be considered if the total cholesterol concentration  to HDL-cholesterol ratio exceeds 6.    Cautions Hypothyroidism should be managed ade-  quately before starting treatment with a statin (see  p. 161). Statins should be used with caution in those  with a history of liver disease or with a high alcohol  intake — see also Hepatic impairment, below. There is  little information available on a rational approach to  liver-function monitoring; however, a NICE guideline 1  suggests that liver enzymes should be measured before  treatment, and repeated within 3 months and at 12  months of starting treatment, unless indicated at other   1. NICE clinical guideline 67 (May 2008). Lipid Modifica-  tion — Cardiovascular risk assessment and the modification  of blood lipids for the primary and secondary prevention of  cardiovascular disease    times by signs or symptoms suggestive of hepatotoxi-  city. Those with serum transaminases that are raised,  but less than 3 times the upper limit of the reference  range, should not be routinely excluded from statin  therapy. Those with serum transaminases of more  than 3 times the upper limit of the reference range  should discontinue statin therapy. Statins should be  used with caution in those with risk factors for myo-  pathy or rhabdomyolysis; patients should be advised to  report unexplained muscle pain (see Muscle Effects  below). Statins should be avoided in acute porphyria  (section 9.8.2) but rosuvastatin is thought to be safe.  Interactions: Appendix 1 (statins).   Hepatic impairment Statins should be used with  caution in those with a history of liver disease and  avoided in active liver disease or when there are unex-  plained persistent elevations in serum transaminases.    Pregnancy Statins should be avoided in pregnancy as  congenital anomalies have been reported and the  decreased synthesis of cholesterol possibly affects  fetal development. Adequate contraception is required  during treatment and for 1 month afterwards.   Breast-feeding The manufacturers of atorvastatin,  fluvastatin, rosuvastatin, and simvastatin advise avoid-  ing use in mothers who are breast-feeding as there is no  information available. The manufacturers of pravastatin  advise against use in breast-feeding mothers as a small  amount of drug is present in breast milk.    Side-effects The statins can cause various muscular  side-effects, including myositis, which can lead to rhab-  domyolysis. Muscular effects are rare but often signifi-  cant (see Muscle Effects below). Statins can cause  gastro-intestinal disturbances, and very rarely pancreat-  itis. They can also cause altered liver function tests, and  rarely hepatitis and jaundice; hepatic failure has been  reported very rarely. Other side-effects include sleep  disturbance, headache, dizziness, depression, paraes-  thesia, asthenia, peripheral neuropathy, amnesia, fati-  gue, sexual dysfunction, thrombocytopenia, arthralgia,  visual disturbance, alopecia, and hypersensitivity reac-  tions (including rash, pruritus, urticaria, and very rarely  lupus erythematosus-like reactions). In very rare cases,  statins can cause interstitial lung disease; if patients  develop symptoms such as dyspnoea, cough, and  weight loss, they should seek medical attention.   Muscle effects Myalgia, myositis, myopathy and rarely rhab-  domyolysis have been reported with the statins; if myopathy is  suspected and creatine kinase is markedly elevated (more than  5 times upper limit of normal), or muscular symptoms are  severe, treatment should be discontinued; in patients at  increased risk of muscle effects, a statin should not be started if  creatine kinase is elevated. Patients at increased risk of myo-  pathy include those with a personal or family history of  muscular disorders, previous history of muscular toxicity, those  with a high alcohol intake, renal impairment, hypothyroidism,  women, and the elderly. There is also an increased incidence of  myopathy if a statin is given at a high dose or given with a  fibrate, with lipid-lowering doses of nicotinic acid, or with drugs  that increase the plasma-statin concentration, such as ciclos-  porin; close monitoring of liver function and, if symptomatic, of  creatine kinase is required in patients receiving these drugs.  Rhabdomyolysis with acute renal impairment secondary to  myoglobinuria has also been reported.    Counselling Advise patient to report promptly unex-  plained muscle pain, tenderness, or weakness.   Indications primary hypercholesterolaemia, hetero-  zygous familial hypercholesterolaemia, homozygous  familial hypercholesterolaemia or combined (mixed)  hyperlipidaemia in patients who have not responded  adequately to diet and other appropriate measures;  prevention of cardiovascular events in patients with  type 2 diabetes and at least one additional risk factor  for cardiovascular disease   Cautions see notes above; also haemorrhagic stroke  Hepatic impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also chest pain; back  pain; less commonly anorexia, malaise, weight gain,  hypoglycaemia, hyperglycaemia, tinnitus; rarely cho-  lestatic jaundice, peripheral oedema; very rarely taste  disturbances, gynaecomastia, hearing loss, Stevens-  Johnson Syndrome, and toxic epidermal necrolysis  Dose   • Primary hypercholesterolaemia and combined  hyperlipidaemia, usually 10 mg once daily; if neces-  sary, may be increased at intervals of at least 4 weeks  to max. 80 mg once daily; CHILD 10-17 years usually  10 mg once daily (limited experience with doses  above 20 mg daily)   • Familial hypercholesterolaemia, initially 10 mg daily,  increased at intervals of at least 4 weeks to 40 mg  once daily; if necessary, further increased to max.   80 mg once daily (or 40 mg once daily combined with  anion-exchange resin in heterozygous familial hyper-  cholesterolaemia); CHILD 10-17 years initially 10 mg  daily, increased if necessary after at least 4 weeks to  20 mg once daily (limited experience with higher  doses)   • Prevention of cardiovascular events in type 2 dia-  betes, 10 mg once daily   Note Max. 10 mg daily with concomitant ciclosporin; max.  20 mg daily (or temporarily discontinue atorvastatin) with  concomitant clarithromycin; max. 40 mg daily (or temporarily  discontinue atorvastatin) with concomitant itraconazole   Tablets, all f/c, atorvastatin (as calcium trihydrate)  10 mg, net price 28-tab pack = £13.00; 20 mg, 28-tab  pack = £24.64; 40 mg 28-tab pack = £24.64; 80 mg, 28-  tab pack = £28.21. Counselling, muscle effects, see  notes above   Note The Scottish Medicines Consortium (p. 4) has advised  (February 2004) that fluvastatin is accepted for restricted use  for the secondary prevention of coronary events after percu-  taneous coronary angioplasty; if the patient has previously  been receiving another statin, then there is no need to change  the statin   Indications adjunct to diet in primary hyper-  cholesterolaemia or combined (mixed) hyperlipid-  aemia (types Ha and lib); adjunct to diet to slow  progression of coronary atherosclerosis in primary  hypercholesterolaemia and concomitant coronary  heart disease; prevention of coronary events after  percutaneous coronary intervention  Cautions see notes above  Hepatic impairment see notes above  Renal impairment manufacturer advises doses above  40 mg daily should be initiated with caution if eGFR  less than 30 mL/minute/ 1.73 m 2   • Hypercholesterolaemia or combined hyperlipidaemia,  initially 20-40 mg daily in the evening, adjusted at  intervals of at least 4 weeks; up to 80 mg daily may be  required; CHILD under 18 years, see BNF for Children   • Prevention of progression of coronary atherosclerosis,  40 mg daily in the evening   Fluvastatin (Non-proprietary) (Ml  Capsules, fluvastatin (as sodium salt) 20 mg, net price  28-cap pack = £5.03; 40 mg, 28-cap pack = £5.36.  Counselling, muscle effects, see notes above   Capsules, fluvastatin (as sodium salt) 20 mg (brown/  yellow), net price 28-cap pack = £15.26; 40 mg  (brown/orange), 28-cap pack = £15.26, 56-cap pack =  £30.53. Counselling, muscle effects, see notes above    Indications adjunct to diet for primary hyper-  cholesterolaemia or combined (mixed) hyperlipidae-  mias in patients who have not responded adequately  to dietary control; adjunct to diet to prevent cardio-  vascular events in patients with hypercholesterol-  aemia; prevention of cardiovascular events in patients  with previous myocardial infarction or unstable  angina; reduction of hyperlipidaemia in patients  receiving immunosuppressive therapy following solid-  organ transplantation  Cautions see notes above  Hepatic impairment see notes above  Renal impairment manufacturer advises initial dose  of 10 mg once daily in moderate to severe impairment  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; less commonly abnor-  mal urination (including dysuria, nocturia and fre-  quency); very rarely fulminant hepatic necrosis  Dose   • Hypercholesterolaemia or combined hyperlipidae-  mias, 10-40 mg once daily at night, adjusted at inter-  vals of at least 4 weeks   • Familial hypercholesterolaemia, CHILD 8-14 years 10-  20 mg once daily at night, 14-18 years 10-40 mg once  daily at night   • Prevention of cardiovascular events, 40 mg once daily  at night   • Post-transplantation hyperlipidaemia, initially 20 mg  once daily at night, increased if necessary (under  close medical supervision) to max. 40 mg once daily  at night    4 Modified release  Lescol® XL (Novartis) (Ml  Tablets, m/r, yellow, fluvastatin (as sodium salt)   80 mg, net price 28-tab pack = £19.20. Label: 25,  counselling, muscle effects, see notes above  Dose 80 mg once daily (dose form not appropriate for initial dose  titration in hypercholesterolaemia or combined hyperlipidaemia)    Pravastatin (Non-proprietary) (Ml  Tablets, pravastatin sodium 10 mg, net price 28-tab  pack = £1.72; 20 mg, 28-tab pack = £2.02; 40 mg, 28-  tab pack = £2.78. Counselling, muscle effects, see  notes above   Tablets, all yellow, pravastatin sodium 10 mg, net  price 28-tab pack = £14.18; 20 mg, 28-tab pack =  £26.01; 40 mg, 28-tab pack = £26.01. Counselling,  muscle effects, see notes above   Indications primary hypercholesterolaemia (type Ha  including heterozygous familial hypercholesterol-  aemia), mixed dyslipidaemia (type lib), or homozy-  gous familial hypercholesterolaemia in patients who  have not responded adequately to diet and other  appropriate measures; prevention of cardiovascular  events in patients at high risk of a first cardiovascular  event   Cautions see notes above; patients of Asian origin (see  under Dose); max. dose 20 mg in patients with risk  factors for myopathy or rhabdomyolysis (including  personal or family history of muscular disorders or  toxicity)   Renal impairment initially 5 mg once daily (do not  exceed 20 mg daily) if eGFR 30-60 mL/minute/   1.73 m 1 2 ; avoid if eGFR less than 30 mL/minute/   Side-effects see notes above; also diabetes mellitus;  proteinuria; very rarely haematuria   • Hypercholesterolaemia, initially 5-10 mg once daily  increased if necessary at intervals of at least 4 weeks  to 20 mg once daily, increased after further 4 weeks to  40 mg daily only in severe hypercholesterolaemia with  high cardiovascular risk and under specialist super-  vision; ELDERLY initially 5 mg once daily; patient of  ASIAN origin, initially 5 mg once daily increased if  necessary to max. 20 mg daily   Crestor® (AstraZeneca) T (Ml  Tablets, f/c, rosuvastatin (as calcium salt) 5 mg (yel-  low), net price 28-tab pack = £18.03; 10 mg (pink), 28-  tab pack = £18.03; 20 mg (pink), 28-tab pack = £26.02;  40 mg (pink), 28-tab pack = £29.69. Counselling,  muscle effects, see notes above   Indications primary hypercholesterolaemia, homozy-  gous familial hypercholesterolaemia or combined  (mixed) hyperlipidaemia in patients who have not  responded adequately to diet and other appropriate  measures; prevention of cardiovascular events in  patients with atherosclerotic cardiovascular disease or  diabetes mellitus   Cautions see notes above; also 80-mg dose only for  those with severe hypercholesterolaemia and at high  risk of cardiovascular complications    Renal impairment doses above 10 mg daily should be  used with caution if eGFR less than 30 mL/minute/   • Primary hypercholesterolaemia, combined hyper-  lipidaemia, 10-20 mg daily at night, adjusted at  intervals of at least 4 weeks; usual range 10-80 mg  once daily at night   • Homozygous familial hypercholesterolaemia, 40 mg  daily at night or 80 mg daily in 3 divided doses (with  largest dose at night)   40 mg once daily at night, adjusted at intervals of at  least 4 weeks; max. 80 mg once daily at night  Note Max. 10 mg daily with concomitant ciclosporin, danazol,  or fibrate (except fenofibrate). Max. 20 mg daily with conco-  mitant amiodarone or verapamil. Max. 40 mg daily with dilti-  azem or amlodipine   1 Simvastatin (Non-proprietary) T [Ml  Tablets, simvastatin 10 mg, net price 28-tab pack =  90p, 20 mg, 28-tab pack = £1.01; 40 mg, 28-tab pack =  £1.32; 80 mg, 28-tab pack = £2.29. Counselling,  muscle effects, see notes above  Brands include Simvador *   Oral suspension, simvastatin 20 mg/5 mL, net price  150 mL = £99.50, 40 mg/5 mL, 150 mL = £152.00.  Counselling, muscle effects, see notes above   Tablets, all f/c, simvastatin 10 mg (peach), net price  28-tab pack = £18.03; 20 mg (tan), 28-tab pack =  £29.69; 40 mg (red), 28-tab pack = £29.69; 80 mg (red),  28-tab pack = £29.69. Counselling, muscle effects, see  notes above   Note For homozygous familial hypercholesterolaemia, primary  hypercholesterolaemia, and mixed hyperlipidaemia in patients  stabilised on the individual components in the same propor-  tions, or for patients not adequately controlled by statin alone.  For prescribing information on ezetimibe, see Ezetimibe   Inegy® (MSD, Schering-Plough) (Ml  Tablets, simvastatin 20 mg, ezetimibe 10 mg, net price  28-tab pack = £33.42; simvastatin 40 mg, ezetimibe  10 mg, 28-tab pack = £38.98; simvastatin 80 mg, eze-  timibe 10 mg, 28-tab pack = £41.21. Counselling,  muscle effects, see notes above   Colesevelam, colestipol, and colestyramine are bile  acid sequestrants used in the management of hyper-  cholesterolaemia. They act by binding bile acids, pre-  venting their reabsorption; this promotes hepatic con-  version of cholesterol into bile acids; the resultant  increased LDL-receptor activity of liver cells increases  the clearance of LDL-cholesterol from the plasma. Bile   1. Simvastatin 10 mg tablets can be sold to the public to   reduce risk of first coronary event in individuals at  moderate risk of coronary heart disease (approx. 10-15%  risk of major event in 10 years), max. daily dose 10 mg and  pack size of 28 tablets; treatment should form part of a  programme to reduce risk of coronary heart disease   Cautions Bile acid sequestrants interfere with the  absorption of fat-soluble vitamins; supplements of vita-  mins A, D, K, and folic acid may be required when  treatment is prolonged. Interactions: Appendix 1 (bile  acid sequestrants)   Pregnancy and breast-feeding Bile acid seques-  trants should be used with caution as although the drugs  are not absorbed, they may cause fat-soluble vitamin  deficiency on prolonged use.   Side-effects As bile acid sequestrants are not  absorbed, gastro-intestinal side-effects predominate.  Constipation is common, but diarrhoea has occurred,  as have nausea, vomiting, and gastro-intestinal discom-  fort. Hypertriglyceridaemia may be aggravated. An  increased bleeding tendency has been reported due to  hypoprothrombinaemia associated with vitamin K defi-  ciency.   Counselling Other drugs should be taken at least 1  hour before (4 hours before colesevelam), or 4-6 hours  after bile acid sequestrants to reduce possible interfer-  ence with absorption. Colesevelam can be taken at the  same time as a statin or ezetimibe.   Indications primary hypercholesterolaemia as an  adjunct to dietary measures, either alone or with a  statin; primary and familial hypercholesterolaemia, in  combination with ezetimibe, either with or without a  statin   Cautions see notes above; also gastro-intestinal moti-  lity disorders, major gastro-intestinal surgery,  inflammatory bowel disease; patients receiving  ciclosporin should have their blood-ciclosporin con-  centration monitored before, during, and after treat-  ment with colesevelam; interactions: Appendix 1  (colesevelam)   • Monotherapy, 3.75 g daily in 1-2 divided doses; max.  4.375 g daily   • Combination therapy with a statin, or ezetimibe, or  both, 2.5-3.75 g daily in 1-2 divided doses   Cholestagel® (Genzyme) T [Ml  Tablets, f/c, colesevelam hydrochloride 625 mg, net  price 180-cap pack = £87.36. Label: 21, counselling,  avoid other drugs at same time (see notes above)   Indications hyperlipidaemias, particularly type Ila, in  patients who have not responded adequately to diet  and other appropriate measures; primary prevention  of coronary heart disease in men aged 35-59 years  with primary hypercholesterolaemia who have not  responded to diet and other appropriate measures;    pruritus associated with partial biliary obstruction and  primary biliary cirrhosis (section 1.9.2); diarrhoeal  disorders (section 1.9.2)   Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; intestinal obstruction  reported rarely and hyperchloraemic acidosis  reported on prolonged use  Dose   • Lipid reduction, initially 4 g daily increased by 4 g at  weekly intervals to 12-24 g daily in 1-4 divided doses,  then adjusted as required; max. 36 g daily   Note The contents of each sachet should be mixed with at least  150 mL of water or other suitable liquid such as fruit juice,  skimmed milk, thin soups, and pulpy fruits with a high moisture  content    Colestyramine (Non-proprietary) (5°M1  Powder, sugar-free, colestyramine (anhydrous) 4g/  sachet, net price 50-sachet pack = £18.34. Label: 13,  counselling, avoid other drugs at same time (see notes  above)   Questran® (Bristol-Myers Squibb) (MI  Powder, colestyramine (anhydrous) 4g/sachet, net  price 50-sachet pack = £10.76. Label: 13, counselling,  avoid other drugs at same time (see notes above)   Questran Light® (Bristol-Myers Squibb) (Ml  Powder, sugar-free, colestyramine (anhydrous) 4g/  sachet, net price 50-sachet pack = £16.15. Label: 13,  counselling, avoid other drugs at same time (see notes  above)   Indications hyperlipidaemias, particularly type Ila, in  patients who have not responded adequately to diet  and other appropriate measures  Cautions see notes above; interactions: Appendix 1  (colestipol)   Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above   • Initially 5 g 1-2 times daily in liquid increased if  necessary in 5-g increments at intervals of 1 month to  max. 30 g daily (in 1-2 divided doses)   Note The contents of each sachet should be mixed with at least  100 mL of water or other suitable liquid such as fruit juice,  skimmed milk, thin soups, yoghurt, and pulpy fruits with a high  moisture content   Colestid® (Pharmacia) £mD  Granules, yellow, colestipol hydrochloride 5 g/sachet,  net price 30 sachets = £15.05. Label: 13, counselling,  avoid other drugs at same time (see notes above)  Colestid Orange, granules, yellow/ orange, colestipol  hydrochloride 5 g/sachet, with aspartame, net price  30 sachets = £15.05. Label: 13, counselling, avoid  other drugs at same time (see notes above)   Ezetimibe inhibits the intestinal absorption of choles-  terol. It is licensed as an adjunct to dietary manipulation  in patients with primary hypercholesterolaemia in com-  bination with a statin or alone (if a statin is inappropri-  ate), in patients with homozygous familial hyper-  cholesterolaemia in combination with a statin, and in  patients with homozygous familial sitosterolaemia (phy-  tosterolaemia). If ezetimibe is used in combination with  a statin, there is an increased risk of rhabdomyolysis  (see also Muscle Effects, p. 162)   Ezetimibe for the treatment of primary  hypercholesterolaemia (November 2007)  Ezetimibe, used in accordance with the licensed  indications for Ezetrol®, is an option for the  treatment of adults with primary hypercholesterol-  aemia.   Indications adjunct to dietary measures and statin  treatment in primary hypercholesterolaemia and  homozygous familial hypercholesterolaemia (ezeti-  mibe alone in primary hypercholesterolaemia if statin  inappropriate or not tolerated); adjunct to dietary  measures in homozygous sitosterolaemia  Cautions interactions: Appendix 1 (ezetimibe)  Hepatic impairment avoid in moderate and severe  impairment — may accumulate  Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding manufacturer advises avoid — present  in milk in animal studies    Side-effects gastro-intestinal disturbances; headache,  fatigue; myalgia; rarely arthralgia, hypersensitivity  reactions (including rash, angioedema, and anaphy-  laxis), hepatitis; very rarely pancreatitis, cholelithiasis,  cholecystitis, thrombocytopenia, raised creatine  kinase, myopathy, and rhabdomyolysis  Dose    • ADULT and CHILD over 10 years, 10 mg once daily    Ezetrol® (MSD, Schering-Plough) (Ml  Tablets, ezetimibe 10 mg, net price 28-tab pack =  £26.31   act mainly by decreasing serum triglycerides; they have  variable effects on LDL-cholesterol. Although a fibrate  can reduce the risk of coronary heart disease events in  those with low HDL-cholesterol or with raised tri-  glycerides, a statin should be used first. Fibrates are  first-line therapy only in those whose serum-triglyceride  concentration is greater than 10 mmol/litre or in those  who cannot tolerate a statin. In type 2 diabetes a fibrate  can be added to a statin for those with a serum-trigly-  ceride concentration exceeding 2.3 mmol/litre, despite  6 months of treatment with a statin and optimal glycae-  mic control.    Fibrates can cause a myositis-like syndrome, especially  if renal function is impaired. Also, combination of a  fibrate with a statin increases the risk of muscle effects  (especially rhabdomyolysis) and should be used with  caution (see Muscle Effects, p. 162) and monitoring of  liver function and creatine kinase should be considered;  gemfibrozil and statins should not be used concomi-  tantly.   Indications hyperlipidaemias of types Ha, lib, III, IV,  and V in patients who have not responded adequately  to diet and other appropriate measures; also see notes  above   Cautions correct hypothyroidism before initiating  treatment (see p. 161); interactions: Appendix 1  (fibrates)   Hepatic impairment avoid in severe liver disease  Renal impairment reduce dose to 400 mg daily if  eGFR 40-60 mL/minute/ 1.73 m 2 ; reduce dose to  200 mg every 1-2 days if eGFR 15-40 mL/minute/  1.73 m 2 ; avoid if eGFR less than 15 mL/minute/   1.73 m 2 ; avoid modified-release preparations if eGFR  less than 60 mL/minute/ 1.73 m 2  Myotoxicity Special care needed in patients with renal  disease, as progressive increases in serum creatinine con-  centration or failure to follow dosage guidelines may result in  myotoxicity (rhabdomyolysis); discontinue if myotoxicity  suspected or creatine kinase concentration increases signif-  icantly   Side-effects gastro-intestinal disturbances, anorexia;  less commonly cholestasis, weight gain, dizziness,  headache, fatigue, drowsiness, renal impairment,  raised serum creatinine (unrelated to renal impair-  ment), erectile dysfunction, myotoxicity (with myas-  thenia or myalgia) — special risk in renal impairment  (see Cautions), urticaria, pruritus, photosensitivity  reactions; very rarely gallstones, hypoglycaemia,  anaemia, leucopenia, thrombocytopenia, increased  platelet count, alopecia, Stevens-Johnson syndrome,  and toxic epidermal necrolysis  Dose   Tablets, bezafibrate 200 mg, net price 100-tab pack =  £6.86 Label: 21   Dose 200 mg 3 times daily; CHILD over 10 years, see BNF for  Children   Tablets, f/c, bezafibrate 200 mg, net price 100-tab  pack = £8.63. Label: 21   Dose 200 mg 3 times daily; CHILD over 10 years, see BNF for  Children   4 Modified release  Bezafibrate (Non-proprietary) (Ml  Tablets, m/r, bezafibrate 400 mg, net price 28-tab  pack = £3.25. Label: 21, 25   Dose 400 mg once daily (dose form not appropriate in patients  with renal impairment)    Bezalip® Mono (Actavis) (Ml  Tablets, m/r, f/c, bezafibrate 400 mg, net price 30-tab  pack = £7.63. Label: 21, 25   Dose 400 mg once daily (dose form not appropriate in patients  with renal impairment)   Indications hyperlipidaemias of types Ha, lib, III, and  IV in patients who have not responded adequately to  diet; also see notes above   Renal impairment manufacturer advises reduce dose  to 100 mg on alternate days in moderate impairment;  avoid in severe impairment; see also Myotoxicity  under Bezafibrate   Ciprofibrate (Non-proprietary) (Ml  Tablets, ciprofibrate 100 mg, net price 28-tab pack =  £28.00   Indications hyperlipidaemias of types Ha, lib, III, IV,  and V in patients who have not responded adequately  to diet and other appropriate measures; also see notes  above   Cautions see under Bezafibrate; liver function tests  recommended every 3 months for first year (discon-  tinue treatment if significantly raised)   Contra-indications gall bladder disease; pancreatitis  (unless due to severe hypertriglyceridemia); photo-  sensitivity to ketoprofen   Renal impairment reduce dose to 134 mg daily if  eGFR less than 60 mL/minute/ 1.73 m 2 ; reduce dose  to 67 mg daily if eGFR less than 20 mL/minute/   1.73 m 2 ; avoid if eGFR less than 15 mL/minute/   Side-effects see under Bezafibrate; also very rarely  hepatitis, pancreatitis, and interstitial pneumopathies   Fenofibrate (Non-proprietary) CmD  Capsules, fenofibrate (micronised) 200 mg, net price  28-cap pack = £3.53. Label: 21   Dose 1 capsule daily (dose form not appropriate for children or  in renal impairment)   Capsules, fenofibrate (micronised) 267 mg, net price  28-cap pack = £11.69. Label: 21  Dose severe hyperlipidaemia, 1 capsule daily (dose form not  appropriate for children or in renal impairment)   Dose initially 3 capsules daily in divided doses; usual range 2-4  capsules daily; CHILD 4-15 years 1 capsule/20 kg daily   Dose initially 1 capsule daily (dose form not appropriate for  children or in renal impairment)   Dose severe hyperlipidaemia, 1 capsule daily (dose form not  appropriate for children or in renal impairment)   Tablets, f/c, fenofibrate (micronised) 160 mg, net  price 28-tab pack = £6.69. Label: 21  Dose 160 mg daily (dose form not appropriate for children or in  renal impairment)    Indications hyperlipidaemias of types Ha, lib, III, IV  and V in patients who have not responded adequately  to diet and other appropriate measures; primary pre-  vention of cardiovascular disease in men with hyper-  lipidaemias that have not responded to diet and other  appropriate measures; also see notes above  Cautions lipid profile, blood counts, and liver-function  tests before initiating long-term treatment; preferably  avoid use with statins (high risk of rhabdomyolysis);  correct hypothyroidism before initiating treatment  (see p. 161); elderly; interactions: Appendix 1  (fibrates)   Contra-indications alcoholism, biliary-tract disease  including gallstones; photosensitivity to fibrates  Hepatic impairment avoid in liver disease  Renal impairment initially 900 mg daily if eGFR 30-  80mL/minute/1.73m 2 ; avoid if eGFR less than  30 mL/minute/ 1.73 m 2 ; see also Myotoxicity under  Bezafibrate   Side-effects gastro-intestinal disturbances; headache,  fatigue, vertigo; eczema, rash; less commonly atrial  fibrillation; rarely pancreatitis, appendicitis, distur-  bances in liver function including hepatitis and cho-  lestatic jaundice, dizziness, paraesthesia, sexual dys-  function, thrombocytopenia, anaemia, leucopenia,  eosinophilia, bone-marrow suppression, myalgia,  myopathy, myasthenia, myositis accompanied by  increase in creatine kinase (discontinue if raised sig-  nificantly), blurred vision, exfoliative dermatitis, alo-  pecia, and photosensitivity)   • 1.2 g daily, usually in 2 divided doses; range 0.9-1. 2 g  daily; CHILD not recommended    Gemfibrozil (Non-proprietary) (Ml  Capsules, gemfibrozil 300 mg, net price 112-cap pack  = £35.57. Label: 22   Tablets, gemfibrozil 600 mg, net price 30-tab pack =  £13.88, 56-tab pack = £31.43. Label: 22   ‘300’ capsules, white/maroon, gemfibrozil 300 mg,  net price 112-cap pack = £35.57. Label: 22  ‘600’ tablets, f/c, gemfibrozil 600 mg, net price 56-  tab pack = £35.57. Label: 22   The value of nicotinic acid is limited by its side-effects,  especially vasodilatation. In doses of 1.5 to 3 g daily it  lowers both cholesterol and triglyceride concentrations  by inhibiting synthesis; it also increases HDL-cholester-  ol. Nicotinic acid is licensed for use with a statin if the  statin alone cannot adequately control dyslipidaemia  (raised LDL-cholesterol, triglyceridaemia, and low  HDL-cholesterol); it can be used alone if the patient is  intolerant of statins (for advice on treatment of dyslipi-  daemia, including use of combination treatment, see   A preparation combining laropiprant with nicotinic acid  ( Tredaptive ®) is available; laropiprant has no lipid-  regulating effect, but reduces the symptoms of flushing  associated with nicotinic acid.   Acipimox seems to have fewer side-effects than nico-  tinic acid but may be less effective in its lipid-regulating  capabilities.   Indications hyperlipidaemias of types lib and IV in  patients who have not responded adequately to diet  and other appropriate measures  Contra-indications peptic ulcer  Renal impairment reduce dose if eGFR 30-60 mL/  minute/ 1.73m 2 ; avoid if eGFR less than 30mL/min-  ute/ 1.73 m 2   Pregnancy manufacturer advises avoid  Breast-feeding manufacturer advises avoid  Side-effects vasodilatation, flushing, itching, rashes,  urticaria, erythema; heartburn, epigastric pain,  nausea, diarrhoea, headache, malaise, dry eyes; rarely  angioedema, bronchospasm, anaphylaxis  Dose   Olbetam® (Pharmacia) (Ml  Capsules, brown/pink, acipimox 250 mg, net price  90-cap pack = £46.33. Label: 21   Indications adjunct to statin in dyslipidaemia or used  alone if statin not tolerated (see also p. 161)  Cautions unstable angina, acute myocardial infarction,  diabetes mellitus, gout, history of peptic ulceration;  interactions: Appendix 1 (nicotinic acid)  Contra-indications arterial bleeding; active peptic  ulcer disease   Hepatic impairment manufacturer advises monitor  liver function in mild to moderate impairment and  avoid in severe impairment; discontinue if severe  abnormalities in liver function tests  Renal impairment manufacturer advises use with  caution — no information available  Pregnancy no information available — manufacturer  advises avoid unless potential benefit outweighs risk   Side-effects diarrhoea, nausea, vomiting, abdominal  pain, dyspepsia; flushing; pruritus, rash; less com-  monly tachycardia, palpitation, shortness of breath,  peripheral oedema, headache, dizziness, increase in  uric acid, hypophosphataemia, prolonged prothrom-  bin time, and reduced platelet count; rarely hypo-  tension, syncope, rhinitis, insomnia, reduced glucose  tolerance, myalgia, myopathy, myasthenia; very rarely  anorexia, rhabdomyolysis, visual disturbance, and  jaundice also reported   Note Prostaglandin-mediated symptoms (such as flushing)  can be reduced by low initial doses taken with meals or, if  patient taking aspirin, aspirin dose should be taken 30  minutes before nicotinic acid   Tablets, m/r, nicotinic acid 500 mg, net price 56-tab  pack = £18.98; 750 mg, 56-tab pack = £28.88; 1 g, 56-  tab pack = £38.23; 21-day starter pack of 7 x 375-mg  tab with 7 x 500-mg tab and 7 x 750-mg tab = £15.40.  Label: 21, 25   Dose 375 mg once daily at night (after a low-fat snack) for 1  week, then 500 mg once daily at night for 1 week, then 750 mg  once daily at night for 1 week, then 1 g once daily at night for 4  weeks, increased if necessary in steps of 500 mg at intervals of at  least 4 weeks to max. 2 g daily; usual maintenance dose 1-2 g  once daily at night   Tredaptive® (MSD) ▼ (Ml  Tablets, m/r, nicotinic acid 1 g, laropiprant 20 mg, net  price 28-tab pack = £16.73; 56-tab pack = £33.46.  Label: 21, 25   Dose 1 tablet once daily at night, increased after 4 weeks to 2  tablets once daily at night   The omega-3 fatty acid compounds comprise omega-3-  acid ethyl esters ( Omacor ®) and omega-3-marine  triglycerides (Maxepa®). Omega-3 fatty acid com-  pounds may be used to reduce triglycerides, as an  alternative to a fibrate and in addition to a statin, in  patients with combined (mixed) hyperlipidaemia not  adequately controlled with a statin alone. A triglyceride  concentration exceeding 10 mmol/litre is associated  with acute pancreatitis and lowering the concentration  reduces this risk. The fat content of omega-3 fatty acid  compounds (including excipients in the preparations)  should be taken into consideration when treating  hypertriglyceridaemia. There is little clinical trial  evidence that the triglyceride lowering effect decreases  the risk of cardiovascular disease.   The Scottish Medicines Consortium (p. 4) has advised  (November 2002) that omega-3-acid ethyl esters  [Omacor®) is not recommended for use within NHS  Scotland for the treatment of hypertriglyceridaemia.   Indications adjunct to diet and statin in type lib or III  hypertriglyceridaemia; adjunct to diet in type IV  hypertriglyceridaemia; adjunct in secondary preven-  tion in those who have had a myocardial infarction in  the preceding 3 months   Side-effects gastro-intestinal disturbances; less com-  monly taste disturbances, dizziness, and hypersensi-  tivity reactions; rarely hepatic disorders, headache,  hyperglycaemia, acne, and rash; very rarely hypo-  tension, nasal dryness, urticaria, and increased white  cell count  Dose   Capsules, 1 g of omega-3-acid ethyl esters 90 con-  taining eicosapentaenoic acid 460 mg and docosa-  hexaenoic acid 380 mg, net price 28-cap pack =  £14.24, 100-cap pack = £50.84. Label: 21  Dose hypertriglyceridaemia, initially 2 capsules daily with food,  increased if necessary to 4 capsules daily  Secondary prevention after myocardial infarction, 1 capsule daily  with food    Ethanolamine Oleate (UCB Pharma) (Ml  Injection, ethanolamine oleate 5%, net price 2-mL  amp = £3.19, 5-mL amp = £5.98  Dose by slow injection into empty isolated segment of vein, 2-  5 mL divided between 3-4 sites; repeated at weekly intervals   Indications sclerotherapy of varicose veins  Cautions see under Ethanolamine Oleate  Contra-indications see under Ethanolamine Oleate  Side-effects see under Ethanolamine Oleate   Fibro-Vein® (STD Pharmaceutical) (Ml  Injection, sodium tetradecyl sulphate 0.2%, net price  5-mL amp = £5.51; 0.5%, 2-mL amp = £2.87; 1%, 2-  mL amp = £3.31; 3%, 2-mL amp = £4.07, 5-mL vial =  £10.25   Indications adjunct in the reduction of plasma tri-  glycerides in severe hypertriglyceridaemia  Cautions haemorrhagic disorders, anticoagulant  treatment; aspirin-sensitive asthma; type 2 diabetes  Side-effects occasional nausea and belching  Dose   Capsules, 1 g (approx. 1.1 mL) concentrated fish oils  containing eicosapentaenoic acid 170 mg, docosa-  hexaenoic acid 115 mg. Vitamin A content less than  lOOunits/g, vitamin D content less than lOunits/g,  net price 200-cap pack = £29.28. Label: 21  Dose 5 capsules twice daily with food  Liquid, golden-coloured, concentrated fish oils con-  taining eicosapentaenoic acid 170 mg, docosahexae-  noic acid 115mg/g (1.1 mL). Vitamin A content less  than lOOunits/g, vitamin D content less than  lOunits/g, net price 150 mL = £21.59. Label: 21  Dose 5 mL twice daily with food    Ethanolamine oleate and sodium tetradecyl sulphate are  used in sclerotherapy of varicose veins, and phenol is  used in haemorrhoids (section 1.7.3).   Indications sclerotherapy of varicose veins  Cautions extravasation may cause necrosis of tissues  Contra-indications inability to walk, acute phlebitis,  oral contraceptive use, obese legs  Side-effects allergic reactions (including anaphylaxis)    This chapter also includes advice on the drug man-  agement of the following:   severe acute asthma, p. 171  anaphylaxis, p. 197  angioedema, p. 199  chronic asthma, p. 172   Drugs used in the management of asthma include beta 2  agonists (section 3.1.1), antimuscarinic bronchodilators  (section 3.1.2), theophylline (section 3.1.3), corticoster-  oids (section 3.2), cromoglicate and nedocromil (section  3.3.1), leukotriene receptor antagonists (section 3.3.2),  and, in specialist centres, omalizumab (section 3.4.2).  For tables outlining the management of chronic and  acute asthma, see p. 172 and p. 173. For advice on the  management of medical emergencies in dental practice,  see p. 27.   Inhalation This route delivers the drug directly to the  airways; the dose required is smaller than when given by  mouth and side-effects are reduced. See also Inhaler  devices, section 3.1.5.   Solutions for nebulisation are available for use in severe  acute asthma. They are administered over 5-10 minutes  from a nebuliser, usually driven by oxygen in hospital.  See also Nebulisers, section 3.1.5.   Oral The oral route is used when administration by  inhalation is not possible. Systemic side-effects occur  more frequently when a drug is given orally rather than  by inhalation. Drugs given by mouth for the treatment of  asthma include beta 2 agonists, corticosteroids, theo-  phylline, and leukotriene receptor antagonists.   Parenteral Drugs such as beta 2 agonists, corticoster-  oids, and aminophylline can be given by injection in  acute severe asthma when administration by nebulisa-  tion is inadequate or inappropriate. If the patient is  being treated in the community, urgent transfer to  hospital should be arranged.   It is particularly important that asthma should be well  controlled during pregnancy; when this is achieved  asthma has no important effects on pregnancy, labour,  or on the fetus. Drugs for asthma should preferably be  administered by inhalation to minimise exposure of the  fetus. Inhaled drugs, theophylline, and prednisolone (see  section 6.3.2) can be taken as normal during pregnancy  and breast-feeding. Women planning to become preg-  nant should be counselled about the importance of  taking their asthma medication regularly to maintain  good control.   Severe acute exacerbations of asthma can have an  adverse effect on pregnancy and should be treated    promptly in hospital with conventional therapy, includ-  ing nebulisation of a beta 2 agonist and oral or parenteral  administration of a corticosteroid; prednisolone is the  preferred corticosteroid for oral administration since  very little of the drug reaches the fetus. Oxygen should  be given immediately to maintain arterial oxygen  saturation of 94-98% and prevent maternal and fetal  hypoxia. An intravenous beta 2 agonist, aminophylline,  or magnesium sulphate can be used during pregnancy if  necessary; parenteral beta 2 agonists can affect the myo-  metrium (see section 7.1.3).   Regard each emergency consultation as being for  severe acute asthma until shown otherwise.   Failure to respond adequately at any time requires  immediate transfer to hospital.    Severe acute asthma can be fatal and must be treated  promptly and energetically. All patients with severe  acute asthma should be given high-flow oxygen (if  available) and an inhaled short-acting beta 2 agonist  via a large-volume spacer or nebuliser; give 2-10 puffs  of salbutamol 100 micrograms /metered inhalation,  each puff inhaled separately via a large-volume spacer,  and repeat at 10-20 minute intervals or as necessary. If  there are life-threatening features, give salbutamol or  terbutaline via an oxygen-driven nebuliser every 20-30  minutes or as necessary, see p. 177 and p. 179. In all  cases, a systemic corticosteroid (section 6.3.2) should  be given. For adults, give prednisolone 40-50 mg by  mouth for at least 5 days, or intravenous hydrocortisone  (preferably as sodium succinate) 100 mg every 6 hours  until conversion to oral prednisolone is possible. For  children, give prednisolone 1-2 mg/kg by mouth (max.  40 mg) for up to 3 days, or longer if necessary, or  intravenous hydrocortisone (preferably as sodium  succinate) 4 mg/kg (CHILD under 2 years max. 25 mg,  2-5 years max. 50 mg, 6-12 years max. 100 mg) every 6  hours until conversion to oral prednisolone is possible. If  the child has been taking an oral corticosteroid for more  than a few days, then give prednisolone 2 mg/kg (max.  60 mg). In severe or life-threatening asthma, also con-  sider initial treatment with ipratropium by nebuliser,  500 micrograms every 4-6 hours (CHILD under 12 years  250 micrograms repeated every 20-30 minutes for the  first 2 hours, then every 4-6 hours as necessary).   Most patients do not require and do not benefit from the  addition of intravenous aminophylline or of intra-  venous beta 2 agonist; both cause more adverse effects  than nebulised beta 2 agonists. Nevertheless, an occa-  sional patient who has not been taking theophylline may  benefit from aminophylline infusion (see p. 181).  Magnesium sulphate [unlicensed indication] 1.2-2 g  by intravenous infusion over 20 minutes can be used  for patients with severe acute asthma, but evidence of  benefit is limited.   Treatment of severe acute asthma is safer in hospital  where resuscitation facilities are immediately available.  Treatment should never be delayed for investigations,  patients should never be sedated, and the possibility of  a pneumothorax should be considered.    For a table outlining the management of acute asthma,  see p. 173.   Follow up in all cases Episodes of acute asthma  should be regarded as a failure of preventative therapy.  A careful history should be taken to establish the reason  for the exacerbation. Inhaler technique should be  checked and regular treatment should be reviewed in  accordance with the Management of Chronic Asthma  table, p. 172. Patients should be given a written asthma  action plan aimed at preventing relapse, optimising  treatment, and preventing delay in seeking assistance  in future exacerbations. Follow-up within 48 hours  should be arranged with the general practitioner or  appropriate primary care health professional. Patients  should also be reviewed by a respiratory specialist  within one month of the exacerbation.    Smoking cessation (section 4.10.2) reduces the progres-  sive decline in lung function in chronic obstructive  pulmonary disease (COPD, chronic bronchitis, or  emphysema). Infection can complicate chronic obstruc-  tive pulmonary disease and may be prevented by  vaccination (pneumococcal vaccine and influenza  vaccine, section 14.4).   A trial of a high-dose inhaled corticosteroid or an oral  corticosteroid is recommended for patients with mod-  erate or severe airflow obstruction if the diagnosis is in  doubt.   Symptoms of chronic obstructive pulmonary disease  may be alleviated by an inhaled short-acting beta 2  agonist (section 3. 1.1.1) or a short-acting anti-  muscarinic bronchodilator (section 3.1.2) used as  required.   When the airways obstruction is more severe, regular  inhaled therapy should be used, see also Use of Inhaled  Therapies in Chronic Obstructive Pulmonary Disease,  p. 174.   If the Forced Expiratory Volume in 1 second (FEV,), is  50% of predicted or more, either a long-acting anti-  muscarinic bronchodilator (section 3.1.2) or a long-act-  ing beta 2 agonist (section 3. 1.1.1) should be used. Short-  acting antimuscarinic bronchodilators should be discon-  tinued when a long-acting antimuscarinic bronchodila-  tor is started. A long-acting beta 2 agonist with a cortico-  steroid (section 3.2) in a combination inhaler can be  used for patients who remain symptomatic despite  regular treatment with a long-acting beta 2 agonist.   If FEVJ is less than 50% of predicted, either a long-  acting antimuscarinic bronchodilator or a long-acting  beta 2 agonist with a corticosteroid in a combination  inhaler should be used.    In any patient who remains breathless or continues to  have exacerbations, triple therapy with a long-acting  beta 2 agonist and a corticosteroid in a combination  inhaler plus a long-acting antimuscarinic bronchodilator  should be used.    If an inhaled corticosteroid is not appropriate, a long-  acting antimuscarinic bronchodilator can be used with a  long-acting beta 2 agonist.    If the patient’s condition deteriorates despite pharma-  cological treatment, intermittent positive pressure ven-  tilation may be needed.    If symptoms persist or if the patient is unable to use an  inhaler, oral modified-release aminophylline or theo-  phylline (section 3.1.3) can be used.    Important Start at step most appropriate to initial severity; before initiating a new drug consider whether  diagnosis is correct, check compliance and inhaler technique, and eliminate trigger factors for acute exacerbations   Note Move to step 2 if needed more than twice a week, or if  night-time symptoms more than once a week, or if exacerbation  in the last 2 years    Step 2: regular inhaled preventer therapy  Inhaled short-acting beta 2 agonist as required  plus   Increase dose of inhaled corticosteroid to upper end of  standard dose range 1   Either stop long-acting beta 2 agonist if of no benefit  Or continue long-acting beta 2 agonist if of some benefit  If asthma still not controlled and long-acting beta 2 agonist  stopped, add one of   Leukotriene receptor antagonist  Modified-release oral theophylline  Modified-release oral beta 2 agonist; CHILD under 12  years not recommended   In adults 6-week sequential therapeutic trial of one or more  of   Leukotriene receptor antagonist  Modified-release oral theophylline  Modified-release oral beta 2 agonist   Step 5: regular corticosteroid tablets  Refer to a respiratory specialist  Inhaled short-acting beta 2 agonist as required  with   Note In addition to regular prednisolone, continue high-dose  inhaled corticosteroid (in exceptional cases may exceed  licensed doses); these patients should normally be referred to an  asthma clinic   Review treatment every 3 months; if control achieved,  stepwise reduction maybe possible; reduce dose of inhaled  corticosteroid slowly (consider reduction every 3 months,  decreasing dose by up to 50% each time)    Step 1: occasional relief bronchodilator  Short-acting beta 2 agonist as required (not more than once  daily)   Note Preferably by inhalation (less effective and more side-  effects when given by mouth)   Move to step 2 if needed more than twice a week, or if night-  time symptoms more than once a week, or if exacerbation in the  last 2 years    Step 2: regular preventer therapy  Inhaled short-acting beta 2 agonist as required  plus   Either regular standard-dose 1 inhaled corticosteroid  Or (if inhaled corticosteroid cannot be used) leukotriene  receptor antagonist   Beclometasone dipropionate or budesonide 100-  400 micrograms twice daily; CHILD under 12 years 100-  200 micrograms twice daily   Fluticasone propionate 50-200 micrograms twice daily;  CHILD 4-12 years 50-100 micrograms twice daily    2. Alternatives to inhaled corticosteroid are leukotriene receptor  antagonists, theophylline, inhaled cromoglicate, or inhaled  nedocromil   Beclometasone dipropionate or budesonide 0.4-1 mg  twice daily; CHILD 5—12 years 200-400 micrograms twice  daily   Fluticasone propionate 200-500 micrograms twice daily;  CHILD 5-12 years 100-200 micrograms twice daily   Note. Dose adjustments may be required for some inhaler  devices, see under individual preparations, section 3.2.  Failure to achieve control with these doses is unusual, see  also Side-effects of Inhaled Corticosteroids, section 3.2    4. Lung-function measurements cannot be used to guide  management in those under 5 years    Advice on the management of chronic asthma is based on the recommendations of the British Thoracic Society and Scottish  Intercollegiate Guidelines Network (updated June 2009); updates available at www.brit-thoracic.org.uk    Important Patients with severe or life-threatening acute asthma may not be distressed and may not have all of these  abnormalities; the presence of any should alert the doctor. Regard each emergency consultation as being for severe  acute asthma until shown otherwise   • Respiration (breaths/minute) < 25;  CHILD 2-5 years < 40, 5-12 years  <30   • Pulse (beats/minute) < 110; CHILD  2-5 years < 140, 5-12 years < 125   • Peak flow > 50% of predicted or  best; CHILD 5-12 years > 50%   Treat at home or in surgery and  assess response to treatment   • Inhaled short-acting beta 2 ago-  nist via a large-volume spacer or  oxygen-driven nebuliser (if avail-  able); give 2-10 puffs of salbut-  amol 100 micrograms / metered  inhalation each inhaled separately,  and repeat at 10-20 minute inter-  vals if necessary or give nebulised  salbutamol 5 mg (CHILD under 5  years 2.5 mg, 5-12 years 2.5-5 mg)  or terbutaline 10 mg (CHILD under  5 years 5 mg, 5-12 years 5-10 mg),  and repeat at 20-30 minute inter-  vals if necessary   • Prednisolone 40-50 mg by mouth  for at least 5 days; CHILD 1-2 mg/  kg (max. 40 mg) for up to 3 days, or  longer if necessary; if the child has  been taking an oral corticosteroid  for more than a few days, give  prednisolone 2 mg/kg (max.   If response is poor or a relapse  occurs in 3-4 hours, send immedi-  ately to hospital for assessment and  further treatment   • Respiration (breaths/minute) > 25;  CHILD 2-5 years > 40; 5-12 years  >30   • Pulse (beats/minute) > 110; CHILD  2-5 years > 140; 5-12 years > 125   • Arterial oxygen saturation > 92%;  CHILD under 12 years < 92%   • Peak flow 33-50% of predicted or  best; CHILD 5-12 years 33-50%   • Inhaled short-acting beta 2 agonist  via a large-volume spacer or oxy-  gen-driven nebuliser (if available) as  for moderate acute asthma   • Prednisolone by mouth as for  moderate acute asthma or intra-  venous hydrocortisone (preferably  as sodium succinate) 100 mg every  6 hours until conversion to oral  prednisolone is possible; CHILD   4 mg/kg (CHILD under 2 years max.  25 mg, 2-5 years max. 50 mg, 6-12  years max. 100 mg)   • Inhaled ipratropium bromide via  oxygen-driven nebuliser (if avail-  able) 500 micrograms every 4-6  hours (CHILD under 12 years   250 micrograms repeated every  20-30 minutes for the first 2 hours,  then every 4-6 hours as necessary)   Refer those who fail to respond and  require ventilatory support to an  intensive care or high-dependency  unit   • Consider intravenous beta 2 ago-  nists, aminophylline (p. 181) or  magnesium sulphate [unlicensed  indication] (p. 171) only after con-  sultation with senior medical staff   • Hypotension, bradycardia,  arrhythmia, exhaustion, agitation  (in children), or reduced level of  consciousness   • Peak flow < 33% of predicted or  best; CHILD 5-12 years <33%   Start treatment below and send  immediately to hospital; consult with  senior medical staff and refer to  intensive care   • Short-acting beta 2 agonist via  oxygen-driven nebuliser (if avail-  able); give salbutamol 5 mg (CHILD  under 5 years 2.5 mg, 5-12 years  2.5-5 mg) or terbutaline 10 mg  (CHILD under 5 years 5 mg, 5-12  years 5-10 mg), and repeat at 20-  30 minute intervals or as neces-  sary; reserve intravenous beta 2  agonists for those in whom inhaled  therapy cannot be used reliably   • Prednisolone by mouth as for  moderate acute asthma or intra-  venous hydrocortisone as for  severe acute asthma   • Inhaled ipratropium bromide via  oxygen-driven nebuliser (if avail-  able) as for severe acute asthma   • Consider intravenous aminophyl-  line (p. 181) or magnesium sul-  phate [unlicensed indication]   Monitor symptoms and peak flow. Set up asthma action plan and check inhaler technique   Review by general practitioner or appropriate primary care health professional within 48 hours, see also p. 171   Advice on the management of acute asthma is based on the recommendations of the British Thoracic Society and  Scottish Intercollegiate Guidelines Network (updated June 2009); updates available at www.brit-thoracic.org.uk   Advice on the use of inhaled therapies in chronic obstructive pulmonary disease is based on the recommendations of the National Institute for Health and Clinical  Excellence (2010). Management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: NICE.    Indacaterol (section 3. 1.1.1) is a long-acting beta 2 ago-  nist licensed for the maintenance treatment of chronic  obstructive pulmonary disease.   In patients with severe chronic obstructive pulmonary  disease associated with chronic bronchitis and a history  of frequent exacerbations, roflumilast (section 3.3.3) is  licensed as an adjunct to existing bronchodilator treat-  ment.   A mucolytic drug (section 3.7) may be considered for a  patient with a chronic productive cough.   Long-term oxygen therapy (section 3.6) prolongs survi-  val in patients with severe chronic obstructive pulm-  onary disease and hypoxaemia.   During an exacerbation of chronic obstructive pulm-  onary disease, bronchodilator therapy can be adminis-  tered through a nebuliser if necessary and oxygen given  if appropriate. Aminophylline can be given intrave-  nously if response to nebulised bronchodilators is  poor. A short course of oral corticosteroid (section  6.3.2), such as prednisolone 30 mg daily for 7-14 days,  should be given if increased breathlessness interferes  with daily activities. Antibacterial treatment (Table 1,  section 5.1) is required when sputum becomes purulent  or if there are other signs of infection.   Patients who have had an episode of hypercapnic resp-  iratory failure should be given a 24% or 28% Venturi    mask and an oxygen alert card (see below) endorsed  with the oxygen saturations required during previous  exacerbations. Patients and their carers should be  instructed to show the card to emergency healthcare  providers in the event of an exacerbation, see also  section 3.6.   I am at risk of type II respiratory failure with a raised C0 2  level.   Use compressed air to drive nebulisers (with nasal oxygen  at 2 litres/minute). If compressed air not available, limit  oxygen-driven nebulisers to 6 minutes.    Oxygen alert card based on British Thoracic Society guideline  for emergency oxygen use in adult patients (October 2008);  available at www.brit-thoracic.org.uk   Mild croup is largely self-limiting, but treatment with a  single dose of a corticosteroid (e.g. dexamethasone  150 micrograms/kg) by mouth may be of benefit.    More severe croup (or mild croup that might cause  complications) calls for hospital admission; a single  dose of a corticosteroid (e.g. dexamethasone 150 micr-  ograms/kg or prednisolone 1-2 mg/kg by mouth, sec-  tion 6.3.2) should be administered before transfer to  hospital. In hospital, dexamethasone 150 micrograms/  kg (by mouth or by injection) or budesonide 2 mg (by  nebulisation, section 3.2) will often reduce symptoms;  the dose may need to be repeated after 12 hours if  necessary.   For severe croup not effectively controlled with cortico-  steroid treatment, nebulised adrenaline solution 1 in  1000 (lmg/mL) should be given with close clinical  monitoring in a dose of 400 micrograms/kg (max.  5 mg) repeated after 30 minutes if necessary; the effects  of nebulised adrenaline last 2-3 hours and the child  needs to be monitored carefully for recurrence of the  obstruction.   The selective beta 2 agonists (selective beta 2 -adreno-  ceptor agonists, selective beta 2 stimulants) (section  3. 1.1.1) such as salbutamol or terbutaline are the safest  and most effective short-acting beta 2 agonists for  asthma. Less selective beta 2 agonists such as ephedrine  (section 3. 1.1.2) should be avoided whenever possible.  Adrenaline (epinephrine) (which has both alpha- and  beta-adrenoceptor agonist properties) is used in the  emergency management of allergic and anaphylactic  reactions (section 3.4.3) and in the management of  croup (see above).    Selective beta 2 agonists produce bronchodilation. A  short-acting beta 2 agonist is used for immediate relief  of asthma symptoms while some long-acting beta 2  agonists are added to an inhaled corticosteroid in  patients requiring prophylactic treatment.    Management of Chronic Asthma table, see p. 172  Management of Acute Asthma table, see p. 173    Short-acting beta 2 agonists Mild to moderate  symptoms of asthma respond rapidly to the inhalation  of a selective short-acting beta 2 agonist such as salbut-  amol or terbutaline. If beta 2 agonist inhalation is  needed more often than once daily, prophylactic treat-  ment should be considered, using a stepped approach as  outlined in the Management of Chronic Asthma table,  p. 172. Regular treatment with an inhaled short-acting  beta 2 agonist is less effective than ‘as required’ inhala-  tion and is not appropriate prophylactic treatment.   A short-acting beta 2 agonist inhaled immediately before  exertion reduces exercise-induced asthma, however,  frequent exercise-induced asthma probably reflects  poor overall control and calls for reassessment of  asthma treatment.   Long-acting beta 2 agonists Formoterol (eformo-  terol) and salmeterol are longer-acting beta 2 agonists    which are administered by inhalation. They should be  used for asthma only in patients who regularly use an  inhaled corticosteroid (see CHM advice below). They  have a role in the long-term control of chronic asthma  (see Management of Chronic Asthma table, p. 172) and  they can be useful in nocturnal asthma. Salmeterol  should not be used for the relief of an asthma attack;  it has a slower onset of action than salbutamol or ter-  butaline. Formoterol is licensed for short-term symptom  relief and for the prevention of exercise-induced bron-  chospasm; its speed of onset of action is similar to that  of salbutamol.   Combination inhalers that contain a long-acting beta 2  agonist and a corticosteroid (section 3.2) ensure that  long-acting beta 2 agonists are not used without conco-  mitant corticosteroids, but reduce the flexibility to  adjust the dose of each component.   To ensure safe use, the CHM has advised that for the  management of chronic asthma, long-acting beta 2  agonists (formoterol and salmeterol) should:   • be added only if regular use of standard-dose  inhaled corticosteroids has failed to control  asthma adequately;   • be introduced at a low dose and the effect  properly monitored before considering dose  increase;   • not be used for the relief of exercise-induced  asthma symptoms unless regular inhaled corti-  costeroids are also used;   • be reviewed as clinically appropriate: stepping  down therapy should be considered when good  long-term asthma control has been achieved.   A daily dose of 24 micrograms of formoterol should  be sufficient for the majority of children, particularly  for younger age-groups; higher doses should be used  rarely, and only when control is not maintained on  the lower dose.   Patients should be advised to report any deteriora-  tion in symptoms following initiation of treatment  with a long-acting beta 2 agonist, see Management of  Chronic Asthma table, p. 172.   Indacaterol is a long-acting beta 2 agonist recently  licensed for chronic obstructive pulmonary disease; it  is not indicated for the relief of acute bronchospasm.    Inhalation Pressurised-metered dose inhalers are an  effective and convenient method of drug administration  in mild to moderate asthma. A spacer device (section  3.1.5) may improve drug delivery. At recommended  inhaled doses the duration of action of salbutamol,  terbutaline and fenoterol is about 3 to 5 hours and for  salmeterol and formoterol 12 hours. The dose, the  frequency, and the maximum number of inhalations in  24 hours of the beta 2 agonist should be stated explicitly  to the patient. The patient should be advised to seek  medical advice when the prescribed dose of beta 2  agonist fails to provide the usual degree of symptomatic  relief because this usually indicates a worsening of the  asthma and the patient may require a prophylactic drug  such as an inhaled corticosteroid (see Management of  Chronic Asthma table, p. 172).    Nebuliser (or respirator) solutions of salbutamol and  terbutaline are used for the treatment of severe acute  asthma in hospital or in general practice. Patients with a  severe attack of asthma should preferably have oxygen  during nebulisation since beta 2 agonists can increase  arterial hypoxaemia. For the use of nebulisers in chronic  obstructive pulmonary disease, see section 3.1.5. The  dose given by nebuliser is substantially higher than that  given by inhaler. Patients should therefore be warned  that it is dangerous to exceed the prescribed dose and  they should seek medical advice if they fail to respond to  the usual dose of the respirator solution, see also section  3.1.5.    Oral Oral preparations of beta 2 agonists may be used  by patients who cannot manage the inhaled route. They  are sometimes used for children and the elderly, but  inhaled beta 2 agonists are more effective and have fewer  side-effects. The longer-acting oral preparations, includ-  ing bambuterol, may be of value in nocturnal asthma but  they have a limited role and inhaled long-acting beta 2  agonists are usually preferred.    Parenteral Salbutamol or terbutaline can be given  intravenously for severe or life-threatening acute  asthma; patients should be carefully monitored and  the dose adjusted according to response and heart  rate. The regular use of beta 2 agonists by the subcuta-  neous route is not recommended since the evidence of  benefit is uncertain and it may be difficult to withdraw  such treatment once started. Beta 2 agonists may also be  given by intramuscular injection.    Children Selective beta 2 agonists are useful even in  children under the age of 18 months. They are most  effective by the inhaled route; a pressurised metered-  dose inhaler should be used with a spacer device in  children under 5 years (see NICE guidance, section  3.1.5). A beta 2 agonist may also be given by mouth  but administration by inhalation is preferred; a long-  acting inhaled beta 2 agonist may be used where appro-  priate (see Management of Chronic Asthma table,  p. 172). In severe attacks nebulisation using a selective  beta 2 agonist or ipratropium is advisable (see also  Management of Chronic Asthma table and Management  of Acute Asthma table, p. 172 and p. 173).    Cautions Beta 2 agonists should be used with caution in  hyperthyroidism, cardiovascular disease, arrhythmias,  susceptibility to QT-interval prolongation, and hyper-  tension. Beta 2 agonists should be used with caution in  diabetes — monitor blood glucose (risk of ketoacidosis,  especially when beta 2 agonist given intravenously).  Interactions: Appendix 1 (sympathomimetics, beta 2 ).    Hypokalaemia Potentially serious hypokalaemia may  result from beta 2 agonist therapy. Particular caution is  required in severe asthma, because this effect may be  potentiated by concomitant treatment with theophylline  and its derivatives, corticosteroids, and diuretics, and by  hypoxia. Plasma-potassium concentration should there-  fore be monitored in severe asthma.   Side-effects Side-effects of the beta 2 agonists include  fine tremor (particularly in the hands), nervous tension,  headache, muscle cramps, and palpitation. Other side-  effects include tachycardia, arrhythmias, peripheral  vasodilation, myocardial ischaemia, and disturbances  of sleep and behaviour. Paradoxical bronchospasm  (occasionally severe), urticaria, angioedema, hypo-  tension, and collapse have also been reported. High    doses of beta 2 agonists are associated with hypokal-  aemia (see Hypokalaemia above).   Note Bambuterol is a pro-drug of terbutaline  Indications asthma and other conditions associated  with reversible airways obstruction  Cautions see notes above  Hepatic impairment avoid in severe impairment  Renal impairment reduce initial dose by half if eGFR  less than 50 mL/minute/ 1.73m 2  Pregnancy manufacturer advises avoid — no informa-  tion available; see also p. 170  Breast-feeding see p. 170  Side-effects see notes above  Dose   • 20 mg once daily at bedtime if patient has previously  tolerated beta 2 agonists; other patients, initially 10 mg  once daily at bedtime, increased if necessary after 1-2  weeks to 20 mg once daily; CHILD not recommended   Bam bee® (AstraZeneca) (Ml  Tablets, both scored, bambuterol hydrochloride  10 mg, net price 28-tab pack = £12.05; 20 mg, 28-tab  pack = £13.14   Pregnancy see p. 170  Breast-feeding see p. 170  Side-effects see notes above   Indications reversible airways obstruction (including  nocturnal asthma and prophylaxis of exercise-induced  bronchospasm) in patients requiring long-term regu-  lar bronchodilator therapy, see also Management of  Chronic Asthma table, p. 172; chronic obstructive  pulmonary disease   Note For use in asthma only in patients who regularly use an  inhaled corticosteroid, see notes above   Side-effects see notes above; very rarely QT- interval  prolongation; taste disturbances, nausea, dizziness,  rash, and pruritus also reported   • See under preparations below  Counselling Advise patients not to exceed prescribed dose,  and to follow manufacturer’s directions; if a previously  effective dose of inhaled formoterol fails to provide adequate  relief, a doctor’s advice should be obtained as soon as  possible   Formoterol (Non-proprietary) (S  Dry powder for inhalation, formoterol fumarate  12 micrograms /metered inhalation, net price 120-  dose unit = £23.75. Counselling, administration  Brands include Easyhaler ® Formoterol  Dose by inhalation of powder, asthma, ADULT and CHILD over 6  years, 12 micrograms twice daily, increased to 24micr-   Atimos Modulite® (Chiesi) ▼ (Ml  Aerosol inhalation, formoterol fumarate 12 micr-  ograms/metered inhalation, net price 100-dose unit =  £30.06. Counselling, administration  Dose by aerosol inhalation, asthma, ADULT and CHILD over 12  years, 12 micrograms twice daily, increased to max. 24 micr-  ograms twice daily in more severe airways obstruction  Chronic obstructive pulmonary disease, ADULT over 18 years,   12 micrograms twice daily; for symptom relief additional doses  may be taken to total max. 48 micrograms daily (max. single dose  24 micrograms)    Onbrez Breezhaler® (Novartis) ▼ (Ml  Inhalation powder, hard capsule (for use with  Onbrez Breezhaler ® device), indacaterol (as maleate)  150 micrograms, net price 30-cap pack with Onbrez  Breezhaler® device = £29.26; 300 micrograms, net  price 30-cap pack with Onbrez Breezhaler® device =  £29.26. Counselling, administration   Dry powder for inhalation, formoterol fumarate  12 micrograms /capsule, net price 60-cap pack (with  inhaler device) = £23.38. Counselling, administration  Dose by inhalation of powder, asthma, ADULT and CHILD over 12  years, 12 micrograms twice daily, increased to max. 24 micr-  ograms twice daily in more severe airways obstruction; CHILD 5-  12 years 12 micrograms twice daily  Chronic obstructive pulmonary disease, 12 micrograms twice  daily   Turbohaler® (= dry powder inhaler), formoterol  fumarate 6 micrograms/metered inhalation, net price  60-dose unit = £24.80; 12 micrograms /metered inha-  lation, 60-dose unit = £24.80. Counselling, adminis-  tration   Dose by inhalation of powder, chronic asthma, 6-12 micrograms  1-2 times daily, increased up to 24 micrograms twice daily if  necessary; occasionally up to 72 micrograms daily may be needed  (max. single dose 36 micrograms); reassess treatment if additional  doses required on more than 2 days a week; CHILD 6-18 years, 6-  12 micrograms 1-2 times daily; occasionally up to 48 micrograms  daily may be needed (max. single dose 12 micrograms) (see also  CHM advice above)   Relief of bronchospasm, ADULT and CHILD over 6 years, 6-  12 micrograms   Prophylaxis of exercise-induced bronchospasm, 12 micrograms  before exercise; CHILD 6-18 years, 6-12 micrograms before  exercise   Chronic obstructive pulmonary disease, 12 micrograms 1-2 times  daily; for symptom relief additional doses can be taken to total  max. 48 micrograms daily (max. single dose 24 micrograms)   Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — present in milk in  animal studies   Side-effects see notes above; also peripheral oedema,  cough, pharyngolaryngeal pain, nasopharyngitis,  sinusitis, rhinorrhoea; less commonly atrial fibrillation,  non-cardiac chest pain, paraesthesia    Indications asthma and other conditions associated  with reversible airways obstruction; premature labour  (section 7.1.3)   • By mouth (but use by inhalation preferred), 4 mg  (elderly and sensitive patients initially 2 mg) 3-4 times  daily; max. single dose 8 mg (but unlikely to provide  much extra benefit or to be tolerated); CHILD under 2  years see BNF for Children ; 2-6 years 1-2 mg 3-4  times daily, 6-12 years 2 mg 3-4 times daily   • By intravenous infusion (but see also Management of  Acute Asthma table, p. 173), initially 5 micrograms/  minute, adjusted according to response and heart-rate  usually in range 3-20 micrograms/minute, or more if  necessary; CHILD under 18 years see BNF for Children   • By aerosol inhalation (but see also Management of  Acute Asthma table, p. 173, or Management of  Chronic Asthma table, p. 172), 100-200 micrograms  (1-2 puffs); for persistent symptoms up to 4 times  daily; CHILD 100 micrograms (1 puff), increased to  200 micrograms (2 puffs) if necessary; for persistent  symptoms up to 4 times daily   Prophylaxis of allergen- or exercise-induced bron-  chospasm, 200 micrograms (2 puffs); CHILD 100 micr-  ograms (1 puff), increased to 200 micrograms (2 puffs)  if necessary   • By inhalation of powder (but see also Management of  Chronic Asthma table, p. 172), 200-400 micrograms;  for persistent symptoms up to 4 times daily; CHILD  over 5 years 200 micrograms; for persistent symp-  toms up to 4 times daily (for Asmasal Clickhaler ® ,  Salbulin Novolizer® , and Ventolin Accuhaler® doses,  see under preparations)   Prophylaxis of allergen- or exercise-induced bron-  chospasm, 400 micrograms; CHILD 200 micrograms   • By inhalation of nebulised solution, ADULT and CHILD  over 5 years 2.5-5 mg, repeated up to 4 times daily or  more frequently in severe cases; CHILD under 5 years  2.5 mg, repeated up to 4 times daily or more fre-  quently in severe cases; see also Management of  Acute Asthma table, p. 173 and Management of  Chronic Asthma table, p. 172   Salbutamol (Non-proprietary) (M  Tablets, salbutamol (as sulphate) 2 mg, net price 28-  tab pack = £17.74; 4 mg, 28-tab pack = £16.40  Oral solution, salbutamol (as sulphate) 2mg/5mL,  net price 150 mL = £1.55  Brands include Salapin ® (sugar-free)   Ventmax® SR (Chiesi) (Ml  Capsules, m/r, salbutamol (as sulphate) 4 mg (green/  grey), net price 56-cap pack = £8.08; 8 mg (white), 56-  cap pack = £9.69. Label: 25  Dose 8 mg twice daily; CHILD 3-12 years 4 mg twice daily   Syrup, sugar-free, salbutamol (as sulphate) 2 mg/  5mL, net price 150 mL = 60p   Injection, salbutamol (as sulphate) 500 micrograms/  mL, net price 1-mL amp = 38p  Solution for intravenous infusion, salbutamol (as  sulphate) 1 mg/mL. Dilute before use. Net price 5-mL  amp = £2.48   Counselling Advise patients not to exceed prescribed dose  and to follow manufacturer’s directions; if a previously  effective dose of inhaled salbutamol fails to provide at least 3  hours relief, a doctor’s advice should be obtained as soon as  possible.    Dry powder for inhalation, salbutamol 100 micr-  ograms/metered inhalation, net price 200-dose unit =  £3.31; 200 micrograms/metered inhalation, 100-dose  unit = £4.85, 200-dose unit = £6.63. Counselling,  administration   Inhalation powder, hard capsule (for use with  Cyclohaler ® device), salbutamol 200 micrograms, net  price 120-cap pack = £8.99; 400 micrograms, 120-cap  pack = £12.99. Counselling, administration  Brands include Salbutamol Cyclocaps ®   Nebuliser solution, salbutamol (as sulphate) 1 mg/  mL, net price 20 x 2.5 mL (2.5 mg) = £1.91; 2 mg/mL,  20 x 2.5 mL (5 mg) = £3.82. May be diluted with  sterile sodium chloride 0.9%   100 micrograms/metered inhalation, net price 200-  dose unit = £1.97. Counselling, administration  Autohaler (breath-actuated aerosol inhalation), sal-  butamol (as sulphate) 100 micrograms /metered  inhalation, net price 200-dose unit = £6.02. Counsel-  ling, administration   Asmasal Clickhaler® (UCB Pharma) (Ml  Dry powder for inhalation, salbutamol (as sulphate)  95 micrograms /metered inhalation, net price 200-  dose unit = £5.65. Counselling, administration  Dose acute bronchospasm, by inhalation of powder, ADULT and  CHILD over 5 years, 1-2 puffs; for persistent symptoms up to 4  times daily (but see also Management of Chronic Asthma table,  P- 172)   Prophylaxis of allergen- or exercise-induced bronchospasm, by  inhalation of powder, ADULT and CHILD over 5 years, 1-2 puffs   Salbulin Novolizer® (Meda) (M  Dry powder for inhalation, salbutamol (as sulphate)  100 micrograms/metered inhalation, net price refill-  able 200-dose unit = £4.95; 200-dose refill = £2.75.  Counselling, administration   Dose acute bronchospasm, by inhalation of powder, ADULT 100-  200 micrograms; for persistent symptoms up to 800 micrograms  daily (but see also Management of Chronic Asthma table, p. 172);  CHILD 6-12 years 100-200 micrograms; for persistent symptoms  up to 400 micrograms daily (but see also Management of Chronic  Asthma table, p. 172)   Prophylaxis of allergen- or exercise-induced bronchospasm, by  inhalation of powder, ADULT 200 micrograms; CHILD 6-12 years  100-200 micrograms   Accuhaler® (dry powder for inhalation), disk con-  taining 60 blisters of salbutamol (as sulphate)   200 micrograms/blister with Accuhaler -® device, net  price = £4.92. Counselling, administration  Dose acute bronchospasm, by inhalation of powder, ADULT and  CHILD over 5 years, 200 micrograms; for persistent symptoms up  to 4 times daily (but see also Management of Chronic Asthma  table, p. 172)   Prophylaxis of allergen- or exercise-induced bronchospasm, by  inhalation of powder, ADULT and CHILD over 5 years, 200 micr-  ograms   Evohaler® (aerosol inhalation), salbutamol (as sul-  phate) 100 micrograms/metered inhalation, net price  200-dose unit = £1.50. Counselling, administration  Nebules® (for use with nebuliser), salbutamol (as  sulphate) 1 mg/mL, net price 20 x 2.5 mL (2.5 mg) =  £1.65; 2 mg/mL, 20 x 2.5 mL (5 mg) = £2.78. May be  diluted with sterile sodium chloride 0.9% if adminis-  tration time in excess of 10 minutes is required  Respirator solution (for use with a nebuliser or  ventilator), salbutamol (as sulphate) 5 mg/mL, net  price 20 mL = £2.18 (hosp. only). May be diluted with  sterile sodium chloride 0.9%   Management of Chronic Asthma table, see p. 172  Management of Acute Asthma table, see p. 173   Indications reversible airways obstruction (including  nocturnal asthma and prevention of exercise-induced  bronchospasm) in patients requiring long-term regu-  lar bronchodilator therapy, see also Management of  Chronic Asthma table, p. 172; chronic obstructive  pulmonary disease   Note Not for immediate relief of acute asthma attacks; for  use in asthma only in patients who regularly use an inhaled  corticosteroid, see notes above   Side-effects see notes above; nausea, dizziness,  arthralgia, and rash also reported   • By inhalation, asthma, 50 micrograms (2 puffs or 1  blister) twice daily; up to 100 micrograms (4 puffs or 2  blisters) twice daily in more severe airways obstruc-    tion; CHILD 5-12 years, 50 micrograms (2 puffs or 1  blister) twice daily   Chronic obstructive pulmonary disease 50 micr-  ograms (2 puffs or 1 blister) twice daily  Counselling Advise patients that salmeterol should not be  used for relief of acute attacks, not to exceed prescribed  dose, and to follow manufacturer’s directions; if a previously  effective dose of inhaled salmeterol fails to provide adequate  relief, a doctor’s advice should be obtained as soon as  possible   Accu haler® (dry powder for inhalation), disk con-  taining 60 blisters of salmeterol (as xinafoate)   50 micrograms/blister with Accuhaler® device, net  price = £29.26. Counselling, administration  Evohaler® aerosol inhalation T, salmeterol (as  xinafoate) 25 micrograms/metered inhalation, net  price 120-dose unit = £29.26. Counselling, adminis-  tration   Diskhaler® (dry powder for inhalation), disks con-  taining 4 blisters of salmeterol (as xinafoate)   50 micrograms /blister, net price 15 disks with Dis-  khaler ® device = £35.79, 15-disk refill = £35.15.  Counselling, administration   Indications asthma and other conditions associated  with reversible airways obstruction; premature labour  (section 7.1.3)   • By mouth (but use by inhalation preferred), initially  2.5 mg 3 times daily for 1-2 weeks, then up to 5 mg 3  times daily; CHILD 1 month-7 years 75 micrograms/kg  3 times daily; 7-15 years 2.5 mg 2-3 times daily   • By subcutaneous or slow intravenous injection, 250-  500 micrograms up to 4 times daily; CHILD 2-15 years  10 micrograms/kg to a max. of 300 micrograms   • By continuous intravenous infusion as a solution  containing 3-5 micrograms/mL, 90-300 micr-  ograms/hour for 8-10 hours; CHILD 1 month-18 years,  initially 2-4 micrograms /kg as a loading dose, then 1-  10 micrograms/kg/hour according to response and  heart rate (max. 300 micrograms/hour); high doses  with close monitoring   • By inhalation of powder (Turbohaler®), ADULT and  CHILD over 5 years, 500 micrograms (1 inhalation); for  persistent symptoms up to 4 times daily (but see  Management of Chronic Asthma table, p. 172)   • By inhalation of nebulised solution (but see also  Management of Acute Asthma table, p. 173), 5-10 mg  2-4 times daily; additional doses may be necessary in  severe acute asthma; CHILD under 5 years 5 mg 2-4  times daily, 5-12 years 5-10 mg 2-4 times daily  [unlicensed dose]   Bricanyl® (AstraZeneca) (Ml  Tablets, scored, terbutaline sulphate 5 mg, net price  100- tab pack= £4.09   Syrup, sugar-free, terbutaline sulphate 1.5 mg/ 5 mL,  net price 100 mL = £2.00    Injection, terbutaline sulphate 500 micrograms/mL,  net price 1-mL amp = 30p; 5-mL amp = £1.40   Counselling Advise patients not to exceed prescribed dose  and to follow manufacturer’s directions; if a previously  effective dose of inhaled terbutaline fails to provide at least 3  hours relief, a doctor’s advice should be obtained as soon as  possible   Turbohaler® (= dry powder inhaler), terbutaline  sulphate 500 micrograms/metered inhalation, net  price 100-dose unit = £6.92. Counselling, administra-  tion   Respules® (= single-dose units for nebulisation),  terbutaline sulphate 2.5 mg/mL, net price 20 x 2-mL  units (5-mg) = £4.04   Ephedrine is less suitable and less safe for use as a  bronchodilator than the selective beta 2 agonists,  because it is more likely to cause arrhythmias and  other side-effects; it should be avoided whenever pos-  sible.   Adrenaline (epinephrine) injection (1 in 1000) is used  in the emergency treatment of acute allergic and ana-  phylactic reactions (section 3.4.3), in angioedema (sec-  tion 3.4.3), and in cardiopulmonary resuscitation (sec-  tion 2.7.3). Adrenaline solution (1 in 1000) is used by  nebulisation in the management of severe croup (sec-  tion 3.1).   Cautions hyperthyroidism; diabetes mellitus;  ischaemic heart disease; hypertension; elderly; pro-  static hypertrophy (risk of acute retention); interac-  tions: Appendix 1 (sympathomimetics)   Renal impairment use with caution  Pregnancy manufacturer advises avoid  Breast-feeding present in milk; manufacturer advises  avoid — irritability and disturbed sleep reported  Side-effects tachycardia; anxiety, restlessness,  insomnia; tremor, arrhythmias, dry mouth, and cold  extremities also reported  Dose   • 15-60 mg 3 times daily; CHILD up to 1 year 7.5 mg 3  times daily, 1-5 years 15 mg 3 times daily, 6-12 years  30 mg 3 times daily   Ephedrine Hydrochloride (Non-proprietary) (m\L^  Tablets, ephedrine hydrochloride 15 mg, net price 28  = £6.62; 30 mg, 28 =£10.01  1. For exemptions see Medicines, Ethics and Practice, No. 34,  London, Pharmaceutical Press, 2010 (and subsequent  editions as available)   Ipratropium can provide short-term relief in chronic  asthma, but short-acting beta 2 agonists act more quickly  and are preferred. Ipratropium by nebulisation can be  added to other standard treatment in life-threatening  asthma or if acute asthma fails to improve with standard   The aerosol inhalation of ipratropium can be used for  short-term relief in mild chronic obstructive pulmonary  disease in patients who are not using a long-acting  antimuscarinic drug. Its maximal effect occurs 30-60  minutes after use; its duration of action is 3 to 6 hours  and bronchodilation can usually be maintained with  treatment 3 times a day.   Tiotropium, a long-acting antimuscarinic bronchodila-  tor, is effective for the management of chronic obstruc-  tive pulmonary disease; it is not suitable for the relief of  acute bronchospasm.   Cautions Antimuscarinic bronchodilators should be  used with caution in patients with prostatic hyperplasia,  bladder outflow obstruction, and those susceptible to  angle-closure glaucoma (see below); interactions:  Appendix 1 (antimuscarinics).   Glaucoma Acute angle-closure glaucoma reported  with nebulised ipratropium, particularly when given  with nebulised salbutamol (and possibly other beta 2  agonists); care needed to protect patient’s eyes from  nebulised drug or from drug powder.   Side-effects Dry mouth is the most common side-  effect of antimuscarinic bronchodilators; also constipa-  tion, cough, paradoxical bronchospasm, headache, diz-  ziness; less commonly nausea, tachycardia, palpitation,  atrial fibrillation, urinary retention, angle-closure glauc-  oma, and blurred vision occur. Raised intra-ocular pres-  sure has occurred rarely.   Aerocaps® (dry powder for inhalation; for use with  Atrovent Aerohaler®), green, ipratropium bromide  40 micrograms, net price pack of 100 caps with  Aerohaler ® =£14.53; 100 caps =£10.53. Counselling,  administration   Note One Atrovent Aerocap ® is equivalent to 2 puffs of  Atrovent? metered aerosol inhalation  Aerosol inhalation Y, ipratropium bromide 20 micr-  ograms/metered inhalation, net price 200-dose unit =  £5.05. Counselling, administration  Nebuliser solution, isotonic, ipratropium bromide  250micrograms/mL, net price 20 x 1-mL unit-dose  vials = £4.14, 60 x 1-mL vials = £12.44; 20 x 2-mL  vials = £4.87, 60 x 2-mL vials = £14.59. If dilution is  necessary use only sterile sodium chloride 0.9%   Ipratropium Steri-Neb® (IVAX) (Ml  Nebuliser solution, isotonic, ipratropium bromide  250micrograms/mL, net price 20 x 1-mL (250-  microgram) unit-dose vials = £8.72; 20 x 2-mL (500-  microgram) = £9.94. If dilution is necessary use only  sterile sodium chloride 0.9%   Nebuliser solution, isotonic, ipratropium bromide  250micrograms/mL, net price 20 x 1-mL (250-  microgram) unit-dose vials = £4.78; 20 x 2-mL (500-  microgram) = £5.60. If dilution is necessary use only  sterile sodium chloride 0.9%   Indications reversible airways obstruction, particu-  larly in chronic obstructive pulmonary disease; rhin-  itis (section 12.2.2)   Side-effects see notes above; also vomiting, diarr-  hoea, local irritation; rarely laryngospasm, eye pain,  mydriasis   • By aerosol inhalation, 20-40 micrograms, 3-4 times  daily; CHILD up to 6 years 20 micrograms 3 times daily,  6-12 years 20-40 micrograms 3 times daily   • By inhalation of powder, ADULT and CHILD over 12  years, 40 micrograms 3-4 times daily (may be  doubled in less responsive patients)   • By inhalation of nebulised solution, reversible air-  ways obstruction in chronic obstructive pulmonary  disease, 250-500 micrograms 3-4 times daily  Acute bronchospasm (but see also Management of  Acute Asthma table, p. 173), 500 micrograms  repeated as necessary; CHILD under 5 years 125—   Ipratropium Bromide (Non-proprietary) (Ml  Nebuliser solution, ipratropium bromide 250micr-  ograms/mL, net price 20 x 1-mL (250-microgram)  unit-dose vials = £6.75, 60 x 1-mL = £21.78; 20 x 2-  mL (500-microgram) = £7.43, 60 x 2-mL = £26.97. If  dilution is necessary use only sterile sodium chloride  0.9%   Renal impairment plasma-tiotropium concentration  raised; use with caution if eGFR less than 50 mL/  minute/ 1.73 m 2   Side-effects see notes above; less commonly taste  disturbance, stomatitis, gastro-oesophageal reflux  disease, pharyngitis, dysphonia, dysphagia, dysuria,  epistaxis, oropharyngeal candidiasis; rarely intestinal  obstruction (including paralytic ileus), laryngitis,  insomnia, urinary-tract infection, skin infection,  sinusitis, dental caries, gingivitis, glossitis, skin ulcer;  also reported dehydration, joint swelling, dry skin  Dose   Spiriva® (Boehringer Ingelheim) (Ml  Inhalation powder, hard capsule (for use with  HandiHaler® device), green, tiotropium (as tiotro-  pium bromide monohydrate) 18 micrograms, net price  30-cap pack with HandiHaler ® device = £34.87, 30-  cap refill = £31.89. Counselling, administration  Dose by inhalation of powder, ADULT over 18 years, 18 micr-  ograms once daily   Respimat® (solution for inhalation) ▼, tiotropium (as  tiotropium bromide monohydrate) 2.5 micrograms/  metered inhalation, net price 60-dose unit = £36.27.  Counselling, administration   Dose by inhalation, ADULT over 18 years, 5 micrograms (2 puffs)  once daily   Note The Scottish Medicines Consortium has advised (November  2007) that Spiriva Respimat? is restricted for use in chronic  obstructive pulmonary disease in patients who have poor manual  dexterity and difficulty using the Handihaler * device    CNS stimulation, insomnia, and convulsions; over-  dosage: see Emergency Treatment of Poisoning, p. 39   Theophylline is a xanthine used as a bronchodilator in  asthma (see Management of Chronic Asthma table,  p. 172) and stable chronic obstructive pulmonary dis-  ease, (see p. 171); it is not generally effective in exacer-  bations of chronic obstructive pulmonary disease. Theo-  phylline may have an additive effect when used in  conjunction with small doses of beta 2 agonists; the  combination may increase the risk of side-effects,  including hypokalaemia (see p. 176).   Theophylline is metabolised in the liver. The plasma-  theophylline concentration is increased in heart failure,  hepatic impairment, viral infections, in the elderly, and  by drugs that inhibit its metabolism. The plasma-theo-  phylline concentration is decreased in smokers, by  alcohol consumption, and by drugs that induce its  metabolism. For interactions: see Appendix 1 (theo-  phylline).   Differences in the half-life of theophylline are important  because the toxic dose is close to the therapeutic dose.  In most individuals, satisfactory bronchodilation is asso-  ciated with a plasma-theophylline concentration of 10-  20 mg/litre (see Note below), although a lower plasma-  theophylline concentration may be effective. Adverse  effects can occur within the range 10-20 mg/litre and  both the frequency and severity increase at concentra-  tions above 20 mg/litre.   Theophylline is given by injection as aminophylline, a  mixture of theophylline with ethylenediamine, which is  20 times more soluble than theophylline alone. Amino-  phylline injection is needed rarely for severe acute  asthma, see Management of Acute Asthma table,  p. 173. It must be given by very slow intravenous  injection (over at least 20 minutes); it is too irritant for  intramuscular use. Measurement of plasma-theo-  phylline concentration may be helpful, and is essential  if aminophylline is to be given to patients who are  already taking theophylline, because serious side-effects  such as convulsions and arrhythmias can occasionally  precede other symptoms of toxicity.   Caffeine is a xanthine derivative used as a respiratory  stimulant in neonatal apnoea, see BNF for Children  section 3.5.1.   Indications reversible airways obstruction, severe  acute asthma; see also Management of Chronic  Asthma table p. 172 and Management of Acute  Asthma table p. 173   Cautions see notes above, also cardiac disease;  hypertension; hyperthyroidism; peptic ulcer; epilepsy;  elderly; fever; hypokalaemia risk, see p. 176; avoid in  acute porphyria (section 9.8.2); monitor plasma-  theophylline concentration (see notes above); dose  adjustment may be necessary if smoking started or  stopped during treatment  Hepatic impairment reduce dose  Pregnancy neonatal irritability and apnoea have been  reported; see also p. 170   Side-effects nausea, vomiting, gastric irritation,  diarrhoea; palpitation, tachycardia, arrhythmias,  hypotension; anxiety, dizziness, tremor, headache,    • See under preparations below  Note Plasma-theophylline concentration for optimum  response 10-20 mg/litre (55-110 micromol/litre); 4-6  hours after a dose and at least 5 days after starting treatment;  narrow margin between therapeutic and toxic dose, see also  notes above   Note The rate of absorption from modified-release prepara-  tions can vary between brands. If a prescription for a modified-  release oral theophylline preparation does not specify a brand  name, the pharmacist should contact the prescriber and agree  the brand to be dispensed. Additionally, it is essential that a  patient discharged from hospital should be maintained on the  brand on which that patient was stabilised as an in-patient.   Dose 175-350 mg every 12 hours; CHILD 6-12 years 175 mg  every 12 hours   SA 250 tablets, m/r, scored, theophylline 250 mg, net  price 60-tab pack = £4.46. Label: 21, 25  Dose 250-500 mg every 12 hours; CHILD 6-12 years 125-250 mg  every 12 hours   Note Aminophylline is a stable mixture or combination of  theophylline and ethylenediamine; the ethylenediamine con-  fers greater solubility in water   Cautions see under Theophylline  Hepatic impairment see under Theophylline  Pregnancy see under Theophylline  Breast-feeding see under Theophylline  Side-effects see under Theophylline; also allergy to  ethylenediamine can cause urticaria, erythema, and  exfoliative dermatitis; hypotension, arrhythmias, and  convulsions especially if given rapidly by intravenous  injection  Dose   • See under preparations, below  Note Plasma-theophylline concentration for optimum  response 10-20 mg/litre (55-1 10 micromol/litre); measure  plasma-theophylline concentration 4-6 hours after dose by   Capsules, m/r, theophylline 60 mg (white/clear,  enclosing white pellets), net price 56-cap pack =  £2.76; 125 mg (brown/clear, enclosing white pellets),  56-cap pack = £3.48; 250 mg (blue/clear, enclosing  white pellets), 56-cap pack = £4.34. Label: 25, or  counselling, see below   Dose 250-500 mg every 12 hours; CHILD 2-6 years 60-120 mg  every 12 hours, 6-12 years 125-250 mg every 12 hours  Counselling Swallow whole with fluid or swallow enclosed gran-  ules with soft food (e.g. yoghurt)   Tablets, m/r, scored, theophylline 200 mg, net price  56-tab pack = £2.94; 300 mg, 56-tab pack = £4.77;  400 mg, 56-tab pack = £5.32. Label: 25  Dose 200 mg every 1 2 hours, increased according to response to  400 mg every 12 hours; CHILD 2-12 years, 9 mg/kg (up to 200 mg)  every 12 hours; some children with chronic asthma may require  10-16 mg/kg (max. 400 mg) every 12 hours  Note May be appropriate to give larger evening or morning dose  to achieve optimum therapeutic effect when symptoms most  severe; in patients whose night or daytime symptoms persist  despite other therapy, who are not currently receiving theo-  phylline, total daily requirement may be added as single evening  or morning dose    mouth and at least 5 days after starting oral treatment;  measure plasma-theophylline concentration 4-6 hours after  the start of intravenous infusion; narrow margin between  therapeutic and toxic dose, see also notes above   To avoid excessive dosage in obese patients, dose  should be calculated on the basis of ideal weight for  height    Aminophylline (Non-proprietary) [MI  Injection, aminophylline 25mg/mL, net price 10-mL  amp = 84p   Dose severe acute asthma or acute exacerbation of chronic  obstructive pulmonary disease in patients not previously treated  with theophylline, by slow intravenous injection over at least 20  minutes (with close monitoring), 250-500 mg (5 mg/kg), then see  below; CHILD under 12 years 5 mg/kg, then see below  Severe acute asthma or acute exacerbation of chronic obstructive  pulmonary disease by intravenous infusion (with close monitor-  ing), 500-700 micrograms/kg/hour, adjusted according to  plasma-theophylline concentration; ELDERLY 300 micrograms/  kg/hour; CHILD under 12 years 1 mg/kg/hour, adjusted according  to plasma-theophylline concentration  Note Patients taking oral theophylline or aminophylline should not  normally receive a loading dose of intravenous aminophylline;  plasma-theophylline concentration should be measured in all  patients receiving intravenous aminophylline (see note above)   Note Advice about modified-release theophylline preparations  (see p. 181) also applies to modified-release aminophylline  preparations   Tablets, m/r, yellow, f/c, aminophylline hydrate  225 mg, net price 56-tab pack = £2.39. Label: 25  Dose ADULT and CHILD body-weight over 40 kg initially 1 tablet  twice daily, increased after 1 week to 2 tablets twice daily  according to plasma-theophylline concentration    Forte tablets, m/r, yellow, f/c, aminophylline hydrate  350 mg, net price 56-tab pack = £4.22. Label: 25  Dose initially 1 tablet twice daily, increased after 1 week to 2  tablets twice daily if necessary   Note Phyllocontin Continus ® Forte tablets are for smokers and  other patients with shorter theophylline half-life (see notes above)   In general, patients are best treated with single-ingre-  dient preparations, such as a selective beta 2 agonist  (section 3. 1.1.1) or ipratropium bromide (section  3.1.2), so that the dose of each drug can be adjusted.  This flexibility is lost with compound bronchodilator  preparations. However, a combination product may be  appropriate for patients stabilised on individual compo-  nents in the same proportion.   Nebuliser solution, ipratropium bromide 500 micr-  ograms, salbutamol (as sulphate) 2.5 mg/2. 5-mL vial,  net price 60 unit-dose vials = £23.75  Brands include Salipraneb, Ipramol   Dose bronchospasm in chronic obstructive pulmonary disease,  by inhalation of nebulised solution, ADULT and CHILD over 12  years, 1 vial (2.5 mL) 3-4 times daily   Nebuliser solution, isotonic, ipratropium bromide  500 micrograms, salbutamol (as sulphate) 2.5 mg/2. 5-  mL vial, net price 60 unit-dose vials = £24.10  Dose bronchospasm in chronic obstructive pulmonary disease,  by inhalation of nebulised solution, ADULT and CHILD over 12  years, 1 vial (2.5 mL) 3-4 times daily   Nebuliser solution, isotonic, fenoterol hydrobromide  1.25 mg, ipratropium bromide 500micrograms/4-mL  vial, net price 20 unit-dose vials = £8.00  Dose acute severe asthma or acute exacerbation of chronic  asthma, by inhalation of nebulised solution, ADULT and CHILD  over 14 years, 1 vial (4 mL); may be repeated up to max. 4 vials in  24 hours   Measurement of peak flow is particularly helpful for  patients who are ‘poor perceivers’ and hence slow to  detect deterioration in their asthma, and for those with  moderate or severe asthma.   Standard-range peak flow meters are suitable for both  adults and children; low-range peak flow meters are  appropriate for severely restricted airflow in adults and  children. Patients must be given clear guidelines as to  the action they should take if their peak flow falls below  a certain level. Patients can be encouraged to adjust  some of their own treatment (within specified limits)  according to changes in peak flow rate.   Standard Range Peak Flow Meter  Conforms to standard EN ISO 23747:2007  AirZone®, range 60-720 litres/minute, net price = £4.50,  replacement mouthpiece = 38p (Clement Clarke)   MicroPeak®, range 60-800 litres/minute, net price = £6.50,  replacement mouthpiece = 38p (Micro Medical)  Mini-Wright®, range 60-800 litres/minute, net price = £6.86,  replacement mouthpiece = 38p (Clement Clarke)   Personal Best®, range 60-800 litres /minute, net price =  £6.86, replacement mouthpiece = 25p (Respironics)   Piko-1®, range 15-999 litres/minute, net price = £9.50,  replacement mouthpiece = 38p (nSPIRE Health)   Pocketpeak®, range 60-800 litres /minute, net price = £6.53,  replacement mouthpiece = 38p (nSPIRE Health)  Vitalograph®, range 50-800 litres/minute, net price = £4.75  (children’s coloured version also available), replacement  mouthpiece = 40p (Vitalograph)   Note Readings from new peak flow meters are often lower than  those obtained from old Wright-scale peak flow meters and the  correct recording chart should be used    Mini-Wright®, range 30-400 litres/minute, net price = £6.90,  replacement mouthpiece = 38p (Clement Clarke)   Pocketpeak® , range 50-400 litres /minute, net price = £6.53,  replacement mouthpiece = 38p (nSPIRE Health)   Note Readings from new peak flow meters are often lower than  those obtained from old Wright-scale peak flow meters and the  correct recording chart should be used   Inhaler devices These include pressurised metered-  dose inhalers, breath-actuated inhalers, and dry pow-  der inhalers. Many patients can be taught to use a  pressurised metered-dose inhaler effectively but some  patients, particularly the elderly and children, find them  difficult to use. Spacer devices (see below) can help such  patients because they remove the need to coordinate  actuation with inhalation. Dry powder inhalers may be  useful in adults and children over 5 years who are  unwilling or unable to use a pressurised metered-dose  inhaler. Alternatively, breath-actuated inhalers are sui-  table for adults and older children provided they can use  the device effectively.   On changing from a pressurised metered-dose inhaler to  a dry powder inhaler, patients may notice a lack of  sensation in the mouth and throat previously associated  with each actuation. Coughing may also occur.   The patient should be instructed carefully on the use of  the inhaler and it is important to check that the inhaler  continues to be used correctly because inadequate  inhalation technique may be mistaken for a lack of  response to the drug.   Inhaler devices for children with chronic  asthma (children under 5 years, August  2000; children 5-15 years, March 2002)   A child’s needs, ability to develop and maintain  effective technique, and likelihood of good compli-  ance should govern the choice of inhaler and spacer  device; only then should cost be considered.   • corticosteroid and bronchodilator therapy  should be delivered by pressurised metered-  dose inhaler and spacer device, with a facemask  if necessary;   • if this is not effective, and depending on the  child’s condition, nebulised therapy may be con-  sidered and, in children over 3 years, a dry  powder inhaler may also be considered [but  see notes above].   • corticosteroid therapy should be routinely deliv-  ered by a pressurised metered-dose inhaler and  spacer device;   • children and their carers should be trained in the  use of the chosen device; suitability of the device  should be reviewed at least annually. Inhaler  technique and compliance should be monitored.    Spacer devices Spacer devices remove the need for  coordination between actuation of a pressurised  metered-dose inhaler and inhalation. The spacer device  reduces the velocity of the aerosol and subsequent  impaction on the oropharynx and allows more time  for evaporation of the propellant so that a larger propor-  tion of the particles can be inhaled and deposited in the    lungs. Spacer devices are particularly useful for patients  with poor inhalation technique, for children, for patients  requiring high doses of inhaled corticosteroids (see  Management of Chronic Asthma table, p. 172), for  nocturnal asthma, and for patients prone to candidiasis  with inhaled corticosteroids. The size of the spacer is  important, the larger spacers with a one-way valve  (Volumatic®) being most effective. It is important to  prescribe a spacer device that is compatible with the  metered-dose inhaler, see devices below. Spacer devices  should not be regarded as interchangeable; patients  should be advised not to switch between spacer devices.   Use and care of spacer devices Patients should  inhale from the spacer device as soon as possible after  actuation because the drug aerosol is very short-lived;  single-dose actuation is recommended. Tidal breathing  is as effective as single breaths. The device should be  cleaned once a month by washing in mild detergent and  then allowed to dry in air without rinsing; the mouth-  piece should be wiped clean of detergent before use.  Some manufacturers recommend more frequent clean-  ing, but this should be avoided since any electrostatic  charge may affect drug delivery. Spacer devices should  be replaced every 6-12 months.   Spacer device, small-volume device. For use with all pres-  surised (aerosol) inhalers, net price standard device = £4.20;  with infant, child or adult mask = £6.86   Spacer device, medium-volume device. For use with all  pressurised (aerosol) inhalers, net price standard device  (blue) = £4.53, with mask (blue) = £7.56; infant device  (orange) with mask = £7.56; child device (yellow) with mask  = £7.56   Spacer device, for paediatric use with Flixotide ®, and  Ventolin ® inhalers, net price = £11.34   Inhalation aid, device to place over pressurised (aerosol)  inhalers to aid when strength in hands is impaired (e.g. in  arthritis). For use with Flixotide ®, Seretide ®, Serevent ®, and  Ventolin ® inhalers. Available as Haleraid® -120 for 120-dose  inhalers and Haleraid® -200 for 200-dose inhalers, net price   Spacer device, for use with Pulmicort® aerosol inhalers, net  price = £8.56   Spacer device, for use with all pressurised (aerosol) inhalers,  net price = £4.28; with small, medium or large mask = £7.00   Spacer device, medium-volume device. For use with all  pressurised (aerosol) inhalers, net price with mouthpiece =  F6-07fliH?l; with mask for infant or child = £7.91; with adult  mask = £9.97lS?l   Spacer device, small-volume device. For use with all pres-  surised (aerosol) inhalers, net price = £4.18; with infant,  small, medium, or large mask = £9.75   Spacer inhaler, large-volume device. For use with Clenil  Modulite ®, Flixotide ®, Seretide ® , Serevent®, and Ventolin®  inhalers, net price = £2.81; with paediatric mask = £2.81   In England and Wales nebulisers and compressors  are not available on the NHS (but they are free of  VAT); some nebulisers (but not compressors) are  available on form GP10A in Scotland (for details  consult Scottish Drug Tariff).    A nebuliser converts a solution of a drug into an aerosol  for inhalation. It is used to deliver higher doses of drug  to the airways than is usual with standard inhalers. The  main indications for use of a nebuliser are to deliver:    • a beta 2 agonist or ipratropium to a patient with an  acute exacerbation of asthma or of chronic obstruc-  tive pulmonary disease;   • a beta 2 agonist, corticosteroid, or ipratropium on a  regular basis to a patient with severe asthma or  reversible airways obstruction when the patient is  unable to use other inhalational devices;    • an antibiotic (such as colistin) or a mucolytic to a  patient with cystic fibrosis;   The use of nebulisers in chronic persistent asthma and  chronic obstructive pulmonary disease should be con-  sidered only:    • after review of therapy (see Management of Chronic  Asthma, p. 172 and Chronic Obstructive Pulmonary  Disease, p. 171) and the patient’s ability to use  hand-held devices;    • after increased doses of inhaled therapy from hand-  held inhalers (with a spacer if necessary) have been  tried for 2 weeks;    • if the patient remains breathless, despite correctly  using optimal therapy    Before prescribing a nebuliser, a home trial should  preferably be undertaken to monitor response for up  to 2 weeks on standard treatment and up to 2 weeks on  nebulised treatment. If prescribed, patients must:   • have clear instructions from a doctor, specialist  nurse or pharmacist on the use of the nebuliser  (including maintenance and cleaning) and on peak-  flow monitoring;   • be instructed not to treat acute attacks at home  without also seeking help;   • have regular follow up by a doctor, specialist nurse  or physiotherapist after about 1 month and annually  thereafter    The proportion of a nebuliser solution that reaches the  lungs depends on the type of nebuliser and although it  can be as high as 30%, it is more frequently close to 10%  and sometimes below 10%. The remaining solution is  left in the nebuliser as residual volume or is deposited in  the mouthpiece and tubing. The extent to which the  nebulised solution is deposited in the airways or alveoli  depends on the droplet size, pattern of breath inhalation,  and condition of the lung. Droplets with a mass median  diameter of 1-5 microns are deposited in the airways  and are therefore appropriate for asthma, whereas a  particle size of 1-2 microns is needed for alveolar  deposition of pentamidine to combat pneumocystis  infection. The type of nebuliser is therefore chosen    according to the deposition required and according to  the viscosity of the solution (antibiotic solutions usually  being more viscous).   Jet nebulisers are more widely used than ultrasonic  nebulisers. Most jet nebulisers require an optimum gas  flow rate of 6-8 litres/minute and in hospital can be  driven by piped air or oxygen; in acute asthma the  nebuliser should be driven by oxygen. Domiciliary oxy-  gen cylinders do not provide an adequate flow rate  therefore an electrical compressor is required for dom-  iciliary use.   For patients at risk of hypercapnia, such as those with  chronic obstructive pulmonary disease, oxygen can be  dangerous and the nebuliser should be driven by air (see  section 3.1). If oxygen is required, it should be given  simultaneously by nasal cannula.   The Department of Health has reminded users of the  need to use the correct grade of tubing when con-  necting a nebuliser to a medical gas supply or  compressor.    Ultrasonic nebulisers produce an aerosol by ultrasonic  vibration of the drug solution and therefore do not  require a gas flow; they are not suitable for the nebulisa-  tion of some drugs, such as domase alfa and nebulised  suspensions.   Nebulisation may be carried out using an undiluted  nebuliser solution or it may require dilution beforehand.  The usual diluent is sterile sodium chloride 0.9%  (physiological saline).   Sodium Chloride (Non-proprietary) (Ml  Nebuliser solution, sodium chloride 0.9%, net price  20 x 2.5 mL = £11.50   Corticosteroids are used for the management of rever-  sible and irreversible airways disease. An inhaled  corticosteroid used for 3-4 weeks may help to distin-  guish asthma from chronic obstructive pulmonary dis-  ease; clear improvement over 3-4 weeks suggests  asthma.   Asthma Corticosteroids are effective in asthma, they  reduce airway inflammation (and hence reduce oedema  and secretion of mucus into the airway).   An inhaled corticosteroid is used regularly for prophy-  laxis of asthma when patients require a beta 2 agonist  more than twice a week, or if symptoms disturb sleep  more than once a week, or if the patient has suffered  exacerbations in the last 2 years requiring a systemic  corticosteroid or a nebulised bronchodilator (see Man-  agement of Chronic Asthma table, p. 172). Regular use  of inhaled corticosteroids reduces the risk of exacerba-  tion of asthma.   Current and previous smoking reduces the effectiveness  of inhaled corticosteroids and higher doses may be  necessary.   Corticosteroid inhalers must be used regularly for max-  imum benefit; alleviation of symptoms usually occurs 3    Doses for corticosteroid CFC-free pressurised metered-  dose inhalers may be different from traditional CFC-  containing inhalers and may differ between brands, see  MHRA/CHM advice below.   • Beclometasone dipropionate CFC-free pres-  surised metered-dose inhalers (Qvar® and  Clenil Modulite ®) are not interchangeable and  should be prescribed by brand name; Qvar® has  extra-fine particles, is more potent than tradi-  tional beclometasone dipropionate CFC-con-  taining inhalers, and is approximately twice as  potent as Clenil Modulite ®;   • Fostair ® is a combination beclometasone  dipropionate and formoterol fumarate CFC-  free pressurised metered-dose inhaler; Fostair®  has extra-fine particles and is more potent than  traditional beclometasone dipropionate CFC-  free inhalers.    Side-effects of inhaled corticosteroids Inhaled  corticosteroids have considerably fewer systemic  effects than oral corticosteroids (section 6.3.2), but  adverse effects have been reported.   High doses of inhaled corticosteroids (see Management  of Chronic Asthma table, p. 172) used for prolonged  periods can induce adrenal suppression. Inhaled corti-  costeroids have been associated with adrenal crisis and  coma in children; excessive doses should be avoided.  Patients using high doses of inhaled corticosteroids  should be given a ‘steroid card’ (section 6.3.2) and  specific written advice to consider corticosteroid repla-  cement during an episode of stress, such as severe  intercurrent illness or an operation.   High doses of inhaled corticosteroid have been asso-  ciated with lower respiratory tract infections, including  pneumonia, in older patients with chronic obstructive  pulmonary disease.   Bone mineral density may be reduced following long-  term inhalation of higher doses of corticosteroids, pre-  disposing patients to osteoporosis (section 6.6). It is  therefore sensible to ensure that the dose of an inhaled  corticosteroid is no higher than necessary to keep a  patient’s asthma under good control.    to 7 days after initiation. Beclometasone dipropionate,  budesonide, fluticasone propionate, and mometa-  sone furoate appear to be equally effective. Prepara-  tions that combine a corticosteroid with a long-acting  beta 2 agonist may be helpful for patients stabilised on  the individual components in the same proportion.   In adults using an inhaled corticosteroid and a long-  acting beta 2 agonist for the prophylaxis of asthma, but  who are poorly controlled, (see step 3 of the Manage-  ment of Chronic Asthma table, p. 172) Symbicort®  (budesonide with formoterol) can be used as a reliever  (instead of a short-acting beta 2 agonist), in addition to its  regular use for the prophylaxis of asthma. Symbicort®  can also be used in this way in adults using an inhaled  corticosteroid with a dose greater than beclometasone  dipropionate 400 micrograms daily 1 , but who are poorly  controlled (see step 2 of the Management of Chronic  Asthma table, p. 172). When starting this treatment, the  total regular daily dose of inhaled corticosteroid should  not be reduced. Patients must be carefully instructed on  the appropriate dose and management of exacerbations  before initiating this therapy, see Symbicort® p. 188.  Patients using budesonide with formoterol as a reliever  once a day or more should have their treatment  reviewed regularly. This management approach is also  used by some specialists in children 12-18 years  [unlicensed]. It has not been investigated with combina-  tion inhalers containing other corticosteroids and long-  acting beta 2 agonists.   High doses of inhaled corticosteroid can be prescribed  for patients who respond only partially to standard  doses with a long-acting beta 2 agonist or another  long-acting bronchodilator (see Management of Chronic  Asthma table, p. 172). High doses should be continued  only if there is clear benefit over the lower dose. The  recommended maximum dose of an inhaled cortico-  steroid should not generally be exceeded. However, if a  higher dose is required, then it should be initiated and  supervised by a specialist. The use of high doses of  inhaled corticosteroid can minimise the requirement for  an oral corticosteroid.   Systemic corticosteroid therapy may be necessary dur-  ing episodes of stress, such as severe infection, or if the  asthma is worsening, when higher doses are needed and  access of inhaled drug to small airways may be reduced;  patients may need a reserve supply of corticosteroid  tablets.   Chronic obstructive pulmonary disease In chronic  obstructive pulmonary disease inhaled corticosteroid  therapy may reduce exacerbations when given in com-  bination with an inhaled long-acting beta 2 agonist, see  section 3.1, p. 171.   Paradoxical bronchospasm The potential for paradox-  ical bronchospasm (calling for discontinuation and alter-  native therapy) should be borne in mind — mild bron-  chospasm may be prevented by inhalation of a short-  acting beta 2 agonist beforehand (or by transfer from an  aerosol inhalation to a dry powder inhalation).   CFC-free inhalers Chlorofluorocarbon (CFC) propel-  lants in pressurised aerosol inhalers have been replaced  by hydrofluoroalkane (HFA) propellants.   1. For standard doses of other inhaled corticosteroids, see  Management of Chronic Asthma table, p. 172.    In children, growth restriction associated with systemic  corticosteroid therapy does not seem to occur with  recommended doses of inhaled therapy; although initial  growth velocity may be reduced, there appears to be no  effect on achieving normal adult height. However, the  height of children receiving prolonged treatment of  inhaled corticosteroid should be monitored; if growth  is slowed, referral to a paediatrician should be consid-  ered. Large-volume spacer devices should be used for  administering inhaled corticosteroids in children under  5 years (see NICE guidance, section 3.1.5); they are also  useful in older children and adults, particularly if high  doses are required. Spacer devices increase airway  deposition and reduce oropharyngeal deposition.   A small risk of glaucoma with prolonged high doses of  inhaled corticosteroids has been reported; cataracts  have also been reported with inhaled corticosteroids.  Hoarseness and candidiasis of the mouth or throat have  been reported, usually only with large doses (see also  below). Hypersensitivity reactions (including rash and    angioedema) have been reported rarely. Other side-  effects that have been reported very rarely include  paradoxical bronchospasm, anxiety, depression, sleep  disturbances, and behavioural changes including hyper-  activity, irritability, and aggression (particularly in chil-  dren); skin thinning and bruising have also been  reported.   Candidiasis The risk of oral candidiasis can be reduced  by using a spacer device with the corticosteroid inhaler;  rinsing the mouth with water (or cleaning a child’s teeth)  after inhalation of a dose may also be helpful. Antifungal  oral suspension or lozenges (section 12.3.2) can be used  to treat oral candidiasis without discontinuing therapy.    Oral An acute attack of asthma should be treated with a  short course of an oral corticosteroid starting with a  high dose, see Management of Acute Asthma table,  p. 173. Patients whose asthma has deteriorated rapidly  usually respond quickly to corticosteroids. The dose can  usually be stopped abruptly; tapering is not needed  provided that the patient receives an inhaled cortico-  steroid in an adequate dose (apart from those on main-  tenance oral corticosteroid treatment or where oral  corticosteroids are required for 3 or more weeks); see  also Withdrawal of Corticosteroids, section 6.3.2. In  patients who have needed several courses of oral corti-  costeroids and in whom the possibility of a period on  maintenance corticosteroids is being considered, it may  be useful to taper the corticosteroid dose gradually to  identify a threshold dose for asthma control. This should  only be done after other standard options for controlling  asthma have been tried (see the Management of  Chronic Asthma table, p. 172).    In chronic asthma, when the response to other drugs  has been inadequate, longer term administration of an  oral corticosteroid may be necessary; in such cases high  doses of an inhaled corticosteroid should be continued  to minimise oral corticosteroid requirements, see Man-  agement of Chronic Asthma table, p. 172. Patients tak-  ing long-term oral corticosteroids for asthma can often  be transferred to an inhaled corticosteroid but the  transfer must be slow, with gradual reduction in the  dose of the oral corticosteroid, and at a time when the  asthma is well controlled.    During an acute exacerbation of chronic obstructive  pulmonary disease, prednisolone 30 mg daily should  be given for 7-14 days; treatment can be stopped  abruptly. Prolonged treatment with oral prednisolone  is of no benefit and maintenance treatment is not  normally recommended.   An oral corticosteroid should normally be taken as a  single dose in the morning to reduce the disturbance to  circadian cortisol secretion. Dosage should always be  titrated to the lowest dose that controls symptoms.  Regular peak-flow measurements help to optimise the  dose.    Parenteral For the use of hydrocortisone injection in  the emergency treatment of acute severe asthma, see  Management of Acute Asthma table, p. 173.   • By inhalation of dry powder (important: for  Asmabec® and Becodisks®, see under preparations),  200-400 micrograms twice daily; adjusted as neces-  sary up to 800 micrograms twice daily; CHILD over 5  years 100-200 micrograms twice daily, adjusted as  necessary    Beclometasone (Non-proprietary) (Ml  Dry powder for inhalation, beclometasone  dipropionate 100 micrograms /metered inhalation, net  price 100-dose unit = £5.36; 200 micrograms/  metered inhalation, 100-dose unit = £9.89, 200-dose  unit = £14.93; 400 micrograms /metered inhalation,  100-dose unit = £19.61. Label: 8, counselling, admin-  istration; also 10 and steroid card with high doses   Inhalation powder, hard capsule (for use with  Cyclohaler® device), beclometasone dipropionate  100 micrograms, net price 120-cap pack = £15.99;  200 micrograms, 120-cap pack = £25.00; 400 micr-  ograms, 120-cap pack = £32.25. Label: 8, counselling,  administration; also 10 and steroid card with high  doses    Asmabec Clickhaler® (UCB Pharma) (Ml  Dry powder for inhalation, beclometasone  dipropionate 50 micrograms /metered inhalation, net  price 200-dose unit = £6.42; 100 micrograms/  metered inhalation, 200-dose unit = £9.43; 250 micr-  ograms/metered inhalation, 100-dose unit = £11.83.  Label: 8, counselling, administration; also 10 and  steroid card with high doses  Dose by inhalation of powder, prophylaxis of asthma, 100-  400 micrograms twice daily, adjusted as necessary; max. 1 mg  twice daily; CHILD 6-12 years 50-200 micrograms twice daily,  adjusted as necessary   Dry powder for inhalation, disks containing 8 blisters  of beclometasone dipropionate 100 micrograms/blis-  ter, net price 15 disks with Diskhaler® device =  £11.30, 1 5-disk refill = £10.76; 200 micrograms/  blister, 15 disks with Diskhaler® device = £21.54, 15-  disk refill = £20.99; 400 micrograms /blister, 15 disks  with Diskhaler® device = £42.52, 15-disk refill =  £41.98. Label: 8, counselling, administration; also 10  and steroid card with high doses  Dose by inhalation of powder, prophylaxis of asthma, 400 micr-  ograms twice daily, adjusted as necessary to 800 micrograms  twice daily; CHILD 5-12 years 100-200 micrograms twice daily,  adjusted as necessary    Clenil Modulite® (Chiesi) (Ml  Aerosol inhalation, beclometasone dipropionate  50 micrograms /metered inhalation, net price 200-  dose unit = £3.70; 100 micrograms/metered inhala-  tion = £7.42; 200 micrograms/metered inhalation =  £16.17; 250 micrograms /metered inhalation = £16.29.   Dose by aerosol inhalation, 200-400 micrograms twice daily,  adjusted as necessary up to 1 mg twice daily; CHILD under 12  years 100-200 micrograms twice daily   Note Clenil Modulite ® is not interchangeable with other CFC-free  beclometasone dipropionate inhalers; the MHRA has advised  (July 2008) that CFC-free beclometasone dipropionate inhalers  should be prescribed by brand name, see p. 185  Dental prescribing on NHS Clenil Modulite ® 50 micrograms/  metered inhalation may be prescribed   Aerosol inhalation, beclometasone dipropionate  50 micrograms/metered inhalation, net price 200-  dose unit = £7.87; 100 micrograms /metered inhala-  tion, 200-dose unit = £17.21. Label: 8, counselling,  administration; also 10 and steroid card with high  doses   Autohaler® (breath-actuated aerosol inhalation),  beclometasone dipropionate 50 micrograms/metered  inhalation, net price 200-dose unit = £7.87; 100 micr-  ograms/metered inhalation, 200-dose unit = £17.21.  Label: 8, counselling, administration; also 10 and  steroid card with high doses  Easi-Breathe® (breath-actuated aerosol inhalation),  beclometasone dipropionate 50 micrograms /metered  inhalation, net price 200-dose = £7.74; 100 micr-  ograms/metered inhalation, 200-dose = £16.95.  Label: 8, counselling, administration; also 10 and  steroid card with high doses   Dose by aerosol inhalation, prophylaxis of asthma, ADULT and  CHILD over 12 years, 50-200 micrograms twice daily, increased if  necessary to max. 400 micrograms twice daily  Important When switching a patient with well-controlled asthma  from another corticosteroid inhaler, initially a 100-microgram  metered dose of Qvar® should be prescribed for:   When switching a patient with poorly controlled asthma from  another corticosteroid inhaler, initially a 100-microgram metered  dose of Qvar® should be prescribed for 100 micrograms of  beclometasone dipropionate, budesonide, or fluticasone  propionate; the dose of Qvar® should be adjusted according to  response   Note Qvar® is not interchangeable with other CFC-free  beclometasone dipropionate inhalers; the MHRA has advised  (July 2008) that beclometasone dipropionate CFC-free inhalers  should be prescribed by brand name, p. 185.   Aerosol inhalation, beclometasone dipropionate  100 micrograms, formoterol fumarate 6 micrograms/  metered inhalation, net price 120-dose unit = £29.32.  Label: 8, counselling, administration, 10, steroid card  with high doses   Dose by aerosol inhalation, asthma, ADULT over 18 years, 1-2  puffs twice daily; max. 4 puffs daily   When switching patients from other beclometasone dipropionate  and formoterol fumarate inhalers, Fostair ® 100/6 can be  prescribed for patients already using beclometasone dipropionate  250 micrograms in another CFC-free inhaler; the dose of Fostair ®  should be adjusted according to response  Note The MHRA has advised (July 2008) that beclometasone  dipropionate CFC-free inhalers should be prescribed by brand  name, see p. 185   Pregnancy see p. 170  Breast-feeding see p. 170  Side-effects see notes above   Dry powder for inhalation, budesonide 100 micr-  ograms/metered inhalation, net price 200-dose unit =  £8.86; 200 micrograms/metered inhalation, 200-dose  unit = £17.71; 400 micrograms /metered inhalation,  100-dose unit = £17.71. Label: 8, counselling, admin-  istration; also 10 and steroid card with high doses    Inhalation powder, hard capsule (for use with  Cyclohaler® device), budesonide 200 micrograms,  net price 100-cap pack = £15.48; 400 micrograms, 50-  cap pack = £15.48. Label: 8, counselling, administra-  tion; also 10 and steroid card with high doses  Brands include Budesonide Cyclocaps ®   Dose by inhalation of powder, ADULT and CHILD over 12 years,  100-800 micrograms twice daily, adjusted as necessary; alterna-  tively, in mild to moderate asthma, for patients previously stabi-  lised on a twice daily dose, 200-400 micrograms (max. 800 micr-  ograms) as a single dose in the evening; CHILD 6-12 years 100-  400 micrograms twice daily, adjusted as necessary; alternatively,  in mild to moderate asthma, for patients previously stabilised on a  twice daily dose, 200-400 micrograms as a single dose in the  evening   Dry powder for inhalation, budesonide 200 micr-  ograms, net price refillable inhaler device and 100-  dose cartridge = £14.86; 100-dose refill cartridge =  £9.59. Label: 8, counselling, administration; also 10  and steroid card with high doses  Dose by inhalation of powder, ADULT and CHILD over 12 years,  200-800 micrograms twice daily, adjusted as necessary; alterna-  tively, in mild to moderate asthma, for patients previously stabi-  lised on a twice daily dose, 200-400 micrograms (max. 800 micr-  ograms) as a single dose in the evening; CHILD 6-12 years 200-  400 micrograms twice daily, adjusted as necessary; alternatively,  in mild to moderate asthma, for patients previously stabilised on a  twice daily dose, 200-400 micrograms as a single dose in the  evening   Pulmicort® (AstraZeneca) (Ml  Aerosol inhalationT, budesonide 100 micrograms/  metered inhalation, net price 120-dose unit = £9.60;  200 micrograms/metered inhalation, 120-dose unit =  £13.20. Label: 8, counselling, administration; also 10  and steroid card with high doses  Dose by aerosol inhalation, ADULT and CHILD over 12 years,  100-400 micrograms twice daily, adjusted as necessary; max.   800 micrograms twice daily; CHILD 2-12 years, 100-400 micr-  ograms twice daily adjusted as necessary   Turbohaler® (= dry powder inhaler), budesonide  100 micrograms/metered inhalation, net price 200-  dose unit = £11.84; 200 micrograms /metered inhala-  tion, 100-dose unit = £11.84; 400 micrograms/  metered inhalation, 50-dose unit = £13.86. Label: 8,  counselling, administration; also 10 and steroid card  with high doses   Dose by inhalation of powder, ADULT and CHILD over 12 years,  100-800 micrograms twice daily, adjusted as necessary; alterna-  tively, in mild to moderate asthma, for patients previously stabi-  lised on a twice daily dose, 200-400 micrograms (max. 800 micr-  ograms) as a single dose in the evening; CHILD 5-12 years 100-  400 micrograms twice daily, adjusted as necessary; alternatively,  in mild to moderate asthma, for patients previously stabilised on a  twice daily dose, 200-400 micrograms as a single dose in the  evening    (500-microgram) unit = £20.02; 500 micrograms/mL,  20 x 2-mL (1-mg) unit = £30.30. May be diluted with  sterile sodium chloride 0.9%. Label: 8, counselling,  administration, 10, steroid card  Dose prophylaxis of asthma, by inhalation of nebulised sus-  pension, ADULT and CHILD over 12 years, 1-2 mg twice daily,  reduced to 0.5-1 mg twice daily; CHILD 3 months-12 years, 0.5-  1 mg twice daily, reduced to 250-500 micrograms twice daily  Croup, by inhalation of nebulised suspension, 2 mg as a single  dose (or as two 1-mg doses separated by 30 minutes)    Symbicort® (AstraZeneca) (Ml  Symbicort 100/6 Turbohaler® (= dry powder  inhaler), budesonide 100 micrograms, formoterol  fumarate 6 micrograms /metered inhalation, net price  120-dose unit = £33.00. Label: 8, counselling,  administration   Dose by inhalation of powder, asthma maintenance therapy, 1-2  puffs twice daily increased if necessary to max. 4 puffs twice daily,  reduced to 1 puff once daily if control maintained; CHILD 6-12  years, 1-2 puffs twice daily reduced to 1 puff once daily if control  maintained; 12-17 years, 1-2 puffs twice daily reduced to 1 puff  once daily if control maintained   Asthma, maintenance and reliever therapy, (but see p. 185) 2 puffs  daily in 1-2 divided doses; for relief of symptoms, 1 puff as needed  up to max. 6 puffs at a time; max. 8 puffs daily; up to 12 puffs daily  can be used for a limited time but medical assessment should be  considered; CHILD 12-18 years, see BNF for Children    Symbicort 200/6 Turbohaler® (= dry powder  inhaler), budesonide 200 micrograms, formoterol  fumarate 6 micrograms /metered inhalation, net price  120-dose unit = £38.00. Label: 8, counselling,  administration; also 10 and steroid card with high  doses   Dose by inhalation of powder, asthma maintenance therapy, 1-2  puffs twice daily increased if necessary to max. 4 puffs twice daily,  reduced to 1 puff once daily if control maintained; CHILD 12-17  years 1-2 puffs twice daily reduced to 1 puff once daily if control  maintained    Asthma, maintenance and reliever therapy, (but see p. 185) 2 puffs  daily in 1-2 divided doses, increased if necessary to 2 puffs twice  daily; for relief of symptoms, 1 puff as needed up to max. 6 puffs at  a time; max. 8 puffs daily; up to 12 puffs daily can be used for a  limited time but medical assessment should be considered; CHILD  12-18 years, see BNF for Children   Chronic obstructive pulmonary disease with forced expiratory  volume in 1 second <50% of predicted, 2 puffs twice daily    Symbicort 400/12 Turbohaler® (= dry powder  inhaler), budesonide 400 micrograms, formoterol  fumarate 12 micrograms /metered inhalation, net  price 60-dose unit = £38.00. Label: 8, counselling,  administration; also 10 and steroid card with high  doses   Dose by inhalation of powder, asthma maintenance therapy, 1  puff twice daily increased if necessary to max. 2 puffs twice daily,  reduced to 1 puff once daily if control maintained; CHILD 12-17  years 1 puff twice daily reduced to 1 puff once daily if control  maintained    Chronic obstructive pulmonary disease with forced expiratory  volume in 1 second <50% of predicted, 1 puff twice daily   Pregnancy see p. 170  Breast-feeding see p. 170  Side-effects see notes above   • By aerosol inhalation, 160 micrograms daily as a  single dose reduced to 80 micrograms daily if control  maintained; dose may be increased to max.   320 micrograms twice daily if necessary in severe  asthma [unlicensed]; CHILD 12-18 years, 160 micr-  ograms daily as a single dose reduced to 80 micr-  ograms daily if control maintained   Alvesco® (Nycomed) (Ml  Aerosol inhalation, ciclesonide 80 micrograms/  metered inhalation, net price 120-dose unit = £32.83;  160 micrograms/metered inhalation, 60-dose unit =  £19.31, 120-dose unit = £38.62. Label: 8, counselling,  administration   Side-effects see notes above; also very rarely dys-  pepsia, hyperglycaemia, and arthralgia   Accuhaler® (dry powder for inhalation), disk con-  taining 60 blisters of fluticasone propionate 50 micr-  ograms/blister with Accuhaler ® device, net price =  £6.38; 100 micrograms/blister with Accuhaler ®  device = £8.93; 250 micrograms/blister with  Accuhaler -® device = £21.26; 500 micrograms/blister  with Accuhaler ® device = £36.14. Label: 8, counsel-  ling, administration; also label 10 and steroid card  with high doses   Note Flixotide Accuhaler * 250 micrograms and 500 micrograms  are not indicated for children   Dose by inhalation of powder, prophylaxis of asthma, ADULT and  CHILD over 16 years, 100-500 micrograms twice daily, increased  according to severity of asthma; max. 1 mg twice daily (doses  above 500 micrograms twice daily initiated by a specialist); CHILD  5-16 years, 50-100 micrograms twice daily adjusted as necessary;  max. 200 micrograms twice daily   Evohaler® aerosol inhalation, fluticasone propionate  50 micrograms /metered inhalation, net price 120-  dose unit = £5.44; 125 micrograms /metered inhala-  tion, 120-dose unit = £21.26; 250 micrograms/  metered inhalation, 120-dose unit = £36.14. Label: 8,  counselling, administration; also label 10 and steroid  card with high doses   Note Flixotide Evohaler® 125 micrograms and 250 micrograms  not indicated for children   Dose by aerosol inhalation, prophylaxis of asthma, ADULT and  CHILD over 16 years, 100-500 micrograms twice daily, increased  according to severity of asthma; max. 1 mg twice daily; (doses  above 500 micrograms twice daily initiated by a specialist); CHILD  4-16 years, 50-100 micrograms twice daily adjusted as necessary;  max. 200 micrograms twice daily   10 x 2-mL (2-mg) unit = £37.35. May be diluted with   asthma, ADULT and CHILD over 16 years, 0.5-2 mg twice daily;   Seretide 100 Accuhaler® (dry powder for inhala-  tion), disk containing 60 blisters of fluticasone  propionate 100 micrograms, salmeterol (as xinafoate)  50 micrograms/blister with Accuhaler ® device, net  price = £31.19. Label: 8, counselling, administration  Dose by inhalation of powder, prophylaxis of asthma, ADULT and  CHILD over 5 years, 1 blister twice daily, reduced to 1 blister once  daily if control maintained   Seretide 250 Accuhaler® (dry powder for inhala-  tion), disk containing 60 blisters of fluticasone  propionate 250 micrograms, salmeterol (as xinafoate)  50 micrograms /blister with Accuhaler® device, net  price = £35.00. Label: 8, counselling, administration,  10, steroid card   Dose by inhalation of powder, prophylaxis of asthma, ADULT and  CHILD over 12 years, 1 blister twice daily   Seretide 500 Accuhaler® (dry powder for inhala-  tion), disk containing 60 blisters of fluticasone  propionate 500 micrograms, salmeterol (as xinafoate)  50 micrograms /blister with Accuhaler® device, net  price = £40.92. Label: 8, counselling, administration,  10, steroid card   Dose by inhalation of powder, prophylaxis of asthma, ADULT and  CHILD over 12 years, 1 blister twice daily  Chronic obstructive pulmonary disease with forced expiratory  volume in 1 second <60% of predicted (but see notes, p. 171),  ADULT 1 blister twice daily   Note The Scottish Medicines Consortium has advised (December  2008) that Seretide 500 Accuhaler ® is not recommended for use  within NHS Scotland for chronic obstructive pulmonary disease in  patients with a forced expiratory volume in 1 second (FE Vj ) less  than 60% and greater than 50% of the predicted normal value,  with significant symptoms despite regular bronchodilator therapy,  and a history of repeated exacerbations   Seretide 50 Evohaler® (aerosol inhalation), flutica-  sone propionate 50 micrograms, salmeterol (as  xinafoate) 25 micrograms /metered inhalation, net  price 120-dose unit = £18.00. Label: 8, counselling,  administration   Dose by aerosol inhalation, prophylaxis of asthma, ADULT and  CHILD over 5 years, 2 puffs twice daily, reduced to 2 puffs once  daily if control maintained   Seretide 125 Evohaler® (aerosol inhalation), flu-  ticasone propionate 125 micrograms, salmeterol (as  xinafoate) 25 micrograms /metered inhalation, net  price 120-dose unit = £35.00. Label: 8, counselling,  administration, 10, steroid card  Dose by aerosol inhalation, prophylaxis of asthma, ADULT and  CHILD over 12 years, 2 puffs twice daily   Seretide 250 Evohaler® (aerosol inhalation), flu-  ticasone propionate 250 micrograms, salmeterol (as  xinafoate) 25 micrograms /metered inhalation, net  price 120-dose unit = £59.48. Label: 8, counselling,  administration, 10, steroid card  Dose by aerosol inhalation, prophylaxis of asthma, ADULT and  CHILD over 12 years, 2 puffs twice daily   • By inhalation of powder, 200-400 micrograms as a  single dose in the evening or in 2 divided doses; dose  increased to 400 micrograms twice daily if necessary;  CHILD not recommended   Asmanex® (Schering-Plough) T (Ml  Twisthaler (= dry powder inhaler), mometasone fur-  oate 200 micrograms /metered inhalation, net price  30-dose unit = £15.70, 60-dose unit = £23.54;   400 micrograms/metered inhalation, 30-dose unit =  £21.78, 60-dose unit = £36.05. Label: 8, counselling,  administration, 10, steroid card  Note The Scottish Medicines Consortium has advised  (November 2003) that Asmanex ® is restricted for use  following failure of first-line inhaled corticosteroids    Cromoglicate and related  therapy, leukotriene  receptor antagonists, and  phosphodiesterase type-  4 inhibitors   The mode of action of sodium cromoglicate and nedo-  cromil is not completely understood. They may be of  value in asthma with an allergic basis, but, in practice, it  is difficult to predict who will benefit; they could prob-  ably be given for 4 to 6 weeks to assess response. Dose  frequency is adjusted according to response but is  usually 3 to 4 times a day initially; this may subsequently  be reduced. Withdrawal of sodium cromoglicate or  nedocromil should be done gradually over a period of  one week — symptoms of asthma may recur.   In general, prophylaxis with sodium cromoglicate is less  effective than prophylaxis with corticosteroid inha-  lations (see Management of Chronic Asthma table,  p. 172). There is evidence of efficacy of nedocromil in  children aged 5-12 years. Sodium cromoglicate and  nedocromil are of no value in the treatment of acute  attacks of asthma.   Sodium cromoglicate can prevent exercise-induced  asthma. However, exercise-induced asthma may reflect  poor overall control and the patient should be re-  assessed.   Side-effects see notes above; also pharyngitis, head-  ache; less commonly palpitation    Paradoxical bronchospasm If paradoxical broncho-  spasm occurs, a short-acting beta 2 agonist such as sal-  butamol or terbutaline (section 3. 1.1.1) should be used  to control symptoms; treatment with sodium cromogli-  cate or nedocromil should be discontinued.   Side-effects Side-effects associated with inhalation of  sodium cromoglicate and nedocromil include throat  irritation, cough, bronchospasm (including paradoxical  bronchospasm — see above), and headache.   Indications prophylaxis of asthma (see also Manage-  ment of Chronic Asthma table, p. 172); food allergy  (section 1.5.4); allergic conjunctivitis (section 11.4.2);  allergic rhinitis (section 12.2.1)   • By aerosol inhalation, ADULT and CHILD over 5 years,  10 mg (2 puffs) 4 times daily, increased if necessary to  6-8 times daily; or additional dose may also be taken  before exercise; maintenance, 5 mg (1 puff) 4 times  daily   Intal® CFC-Free Inhaler (Sanofi-Aventis) LmD  Aerosol inhalation, sodium cromoglicate 5 mg/  metered inhalation, net price 112-dose unit = £14.84.  Label: 8, counselling, administration   Side-effects see notes above; also nausea, vomiting,  dyspepsia, abdominal pain, pharyngitis; rarely taste  disturbances   • By aerosol inhalation, ADULT and CHILD over 6 years  4 mg (2 puffs) 4 times daily, when control achieved  may be possible to reduce to twice daily  Counselling Regular use is necessary   Tilade® CFC-free Inhaler (Sanofi-Aventis) T iMl  Aerosol inhalation, mint-flavoured, nedocromil sod-  ium 2 mg/metered inhalation, net price 112-dose unit  = £39.94. Label: 8, counselling, administration   The leukotriene receptor antagonists, montelukast and  zafirlukast, block the effects of cysteinyl leukotrienes in  the airways. They are effective in asthma when used  alone or with an inhaled corticosteroid (see Manage-  ment of Chronic Asthma table p. 172).   Montelukast has not been shown to be more effective  than a standard dose of inhaled corticosteroid, but the  two drugs appear to have an additive effect. The leuko-  triene receptor antagonists may be of benefit in exer-  cise-induced asthma and in those with concomitant  rhinitis, but they are less effective in those with severe  asthma who are also receiving high doses of other drugs.   Churg-Strauss syndrome has occurred very rarely in  association with the use of leukotriene receptor antago-    nists; in many of the reported cases the reaction fol-  lowed the reduction or withdrawal of oral corticosteroid  therapy. Prescribes should be alert to the development  of eosinophilia, vasculitic rash, worsening pulmonary  symptoms, cardiac complications, or peripheral neuro-  pathy.   Pregnancy There is limited evidence for the safe use  of leukotriene receptor antagonists during pregnancy;  however, they can be taken as normal in women who  have shown a significant improvement in asthma not  achievable with other drugs before becoming pregnant,  see also p. 170.   Indications prophylaxis of asthma, see notes above  and Management of Chronic Asthma table, p. 172;  symptomatic relief of seasonal allergic rhinitis in  patients with asthma   Side-effects abdominal pain, thirst; hyperkinesia (in  young children), headache; very rarely Churg-Strauss  syndrome (see notes above); dry mouth, diarrhoea,  dyspepsia, nausea, vomiting, hepatic disorders, pal-  pitation, oedema, increased bleeding, epistaxis,  hypersensitivity reactions (including anaphylaxis,  angioedema, and skin reactions), respiratory infec-  tions, depression, suicidal thoughts and behaviour,  tremor, asthenia, dizziness, hallucinations, paraes-  thesia, hypoaesthesia, sleep disturbances, sleep-  walking, abnormal dreams, agitation, anxiety,  aggression, seizures, pyrexia, arthralgia, and myalgia,  also reported  Dose   • Prophylaxis of asthma, ADULT and CHILD over 15 years,  10 mg once daily in the evening; CHILD 6 months-6  years 4 mg once daily in the evening, 6-15 years 5 mg  once daily in the evening   • Seasonal allergic rhinitis, ADULT and CHILD over 15  years, 10 mg once daily in the evening   Chewable tablets, pink, cherry-flavoured, montelu-  kast (as sodium salt) 4 mg, net price 28-tab pack =  £25.69; 5 mg, 28-tab pack = £25.69. Label: 23, 24   Excipients include aspartame equivalent to phenylalanine 674micr-  ograms/4-mg tablet and 842 micrograms/ 5-mg tablet (section 9.4.1)   Granules, montelukast (as sodium salt) 4 mg, net  price 28-sachet pack = £25.69. Counselling, adminis-  tration   Counselling Granules may be swallowed or mixed with cold  food (but not fluid) and taken immediately   10 mg, net price 28-tab pack = £26.97  Note The Scottish Medicines Consortium has advised (June  2007) that Singulair ® chewable tablets and granules are  restricted for use as an alternative to low-dose inhaled  corticosteroids for children 2-14 years with mild persistent  asthma who have not recently had serious asthma attacks that  required oral corticosteroid use and who are not capable of  using inhaled corticosteroids; Singulair ® chewable tablets and  granules should be initiated by a specialist in paediatric asthma   Hepatic disorders Patients or their carers should be told  how to recognise development of liver disorder and advised  to seek medical attention if symptoms or signs such as  persistent nausea, vomiting, malaise, or jaundice develop  Hepatic impairment manufacturer advises avoid  Renal impairment manufacturer advises caution in  moderate to severe impairment  Pregnancy manufacturer advises use only if potential  benefit outweighs risk; see also notes above  Breast-feeding present in milk — manufacturer  advises avoid   Side-effects gastro-intestinal disturbances, respir-  atory infections, headache, insomnia, malaise; rarely  bleeding disorders, hypersensitivity reactions includ-  ing angioedema and skin reactions, arthralgia, myal-  gia, hepatitis, hyperbilirubinaemia, thrombocytope-  nia; very rarely Churg-Strauss syndrome (see notes  above), agranulocytosis  Dose   • ADULT and CHILD over 12 years, 20 mg twice daily   Accolate® (AstraZeneca) (Ml  Tablets, f/c, zafirlukast 20 mg, net price 56-tab pack =  £17.75. Label: 23   Roflumilast is a phosphodiesterase type-4 inhibitor  with anti-inflammatory properties; it is licensed as an  adjunct to bronchodilators for the maintenance treat-  ment of patients with severe chronic obstructive pulm-  onary disease associated with chronic bronchitis and a  history of frequent exacerbations.   Cautions monitor body-weight; latent infection (such  as tuberculosis, viral hepatitis, herpes infection);  moderate to severe cardiac failure; history of psy-  chiatric illness, or concomitant use of drugs likely to  cause psychiatric events; interactions: Appendix 1  (roflumilast)   Contra-indications severe immunological disease;  severe acute infectious disease; cancer (except basal  cell carcinoma); concomitant treatment with immu-  nosuppressive drugs (except short-term systemic  corticosteroids)   Hepatic impairment caution in mild impairment;  avoid in moderate to severe impairment   Pregnancy manufacturer advises avoid — toxicity in  animal studies; women of child-bearing age should  use effective contraception   Side-effects diarrhoea, nausea, abdominal pain,  weight loss, decreased appetite, headache, insomnia;  less commonly gastritis, vomiting, gastro-oesophageal    reflux, dyspepsia, palpitation, anxiety, tremor, vertigo,  dizziness, malaise, muscle spasm, myalgia, back pain,  rash; rarely taste disturbances, haematochezia, con-  stipation, respiratory tract infections, depression,  nervousness, suicidal ideation, gynaecomastia, raised  creatine kinase, urticaria  Dose   • ADULT over 18 years, 500 micrograms once daily  Daxas® (MSD) T ®   Tablets, yellow, f/c, roflumilast 500 micrograms, net  price 30-tab pack = £37.71, 90-tab pack = £113.14.  Counselling, patient card   Counselling Patients should be given a patient card before starting  treatment and advised to record body-weight at regular intervals   All antihistamines are of potential value in the treatment  of nasal allergies, particularly seasonal allergic rhinitis  (hay fever), and they may be of some value in vasomotor  rhinitis. They reduce rhinorrhoea and sneezing but are  usually less effective for nasal congestion. Antihist-  amines are used topically in the eye (section 11.4.2),  in the nose (section 12.2.1), and on the skin (section  13.3).   Oral antihistamines are also of some value in preventing  urticaria and are used to treat urticarial rashes, pruritus,  and insect bites and stings; they are also used in drug  allergies. Injections of chlorphenamine or promethazine  are used as an adjunct to adrenaline (epinephrine) in the  emergency treatment of anaphylaxis and angioedema  (section 3.4.3). For the use of antihistamines (including  cinnarizine, cyclizine, and promethazine teoclate) in  nausea and vomiting, see section 4.6. Buclizine is  included as an anti-emetic in a preparation for migraine  (section 4.7.4. 1). For reference to the use of antihist-  amines for occasional insomnia, see section 4.1.1.   All older antihistamines cause sedation but alimema-  zine and promethazine may be more sedating whereas  chlorphenamine and cyclizine (section 4.6) may be  less so. This sedating activity is sometimes used to  manage the pruritus associated with some allergies.  There is little evidence that any one of the older, ‘sedat-  ing’ antihistamines is superior to another and patients  vary widely in their response.   Non-sedating antihistamines such as acrivastine, cetir-  izine, desloratadine (an active metabolite of lorat-  adine), fexofenadine (an active metabolite of terfen-  adine), levocetirizine (an isomer of cetirizine),  loratadine, mizolastine, and rupatadine cause less  sedation and psychomotor impairment than the older    antihistamines because they penetrate the blood brain  barrier only to a slight extent.   Cautions and contra-indications Sedating antihist-  amines have significant antimuscarinic activity and they  should therefore be used with caution in prostatic hyper-  trophy, urinary retention, susceptibility to angle-closure  glaucoma, and pyloroduodenal obstruction. Caution  may be required in epilepsy. Children and the elderly  are more susceptible to side-effects. Many antihist-  amines should be avoided in acute porphyria but  some are thought to be safe, see section 9.8.2. Interac-  tions: Appendix 1 (antihistamines).   Hepatic impairment Sedating antihistamines should  be avoided in severe liver disease — increased risk of  coma.   Pregnancy Most manufacturers of antihistamines  advise avoiding their use during pregnancy; however,  there is no evidence of teratogenicity except for  hydroxyzine where toxicity has been reported with  high doses in animal studies. The use of sedating anti-  histamines in the latter part of the third trimester may  cause adverse effects in neonates such as irritability,  paradoxical excitability, and tremor.   Breast-feeding Most antihistamines are present in  breast milk in varying amounts; although not known to  be harmful, most manufacturers advise avoiding their  use in mothers who are breast-feeding.    Side-effects Drowsiness is a significant side-effect  with most of the older antihistamines although para-  doxical stimulation may occur rarely, especially with  high doses or in children and the elderly. Drowsiness  may diminish after a few days of treatment and is  considerably less of a problem with the newer antihist-  amines (see also notes above). Side-effects that are  more common with the older antihistamines include  headache, psychomotor impairment, and anti-  muscarinic effects such as urinary retention, dry  mouth, blurred vision, and gastro-intestinal distur-  bances.   Other rare side-effects of antihistamines include hypo-  tension, palpitation, arrhythmias, extrapyramidal  effects, dizziness, confusion, depression, sleep distur-  bances, tremor, convulsions, hypersensitivity reactions  (including bronchospasm, angioedema, and anaphy-  laxis, rashes, and photosensitivity reactions), blood dis-  orders, liver dysfunction, and angle-closure glaucoma.   Driving Although drowsiness is rare, nevertheless  patients should be advised that it can occur and may  affect performance of skilled tasks (e.g. driving); excess  alcohol should be avoided.   • ADULT and CHILD over 12 years, 8 mg 3 times daily   Capsules, acrivastine 8 mg, net price 12-cap pack =  £2.59, 24-cap pack = £4.49. Counselling, driving  Brands include Benadryl ® Allergy Relief   Indications symptomatic relief of allergy such as hay  fever, chronic idiopathic urticaria  Cautions see notes above  Contra-indications see notes above  Renal impairment use half normal dose if eGFR 30-  50 mL/minute/ 1.73 m 2 ; use half normal dose and  reduce dose frequency to alternate days if eGFR 10-  30 mL/minute/ 1.73 m 2 ; avoid if eGFR less than  10 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • ADULT and CHILD over 12 years, 10 mg once daily; CHILD  1-2 years see BNF for Children, 2-6 years 2.5 mg  twice daily, 6-12 years 5 mg twice daily   Tablets, cetirizine hydrochloride 10 mg, net price 30-  tab pack = 95p. Counselling, driving  Dental prescribing on NHS Cetirizine 10 mg tablets may be  prescribed   Oral solution, cetirizine hydrochloride 5mg/5mL,  net price 200 mL = £2.03. Counselling, driving  Note Sugar-free versions are available and can be ordered by  specifying sugar-free on the prescription  Excipients may include propylene glycol (see Excipients, p. 2)   • 5 mg once daily; CHILD 1-6 years 1.25 mg once daily,  6-12 years 2.5 mg once daily   Neoclarityn® (Schering-Plough) (SMI  Tablets, blue, f/c, desloratadine 5 mg, net price 30-tab  pack = £6.77. Counselling, driving  Oral solution, desloratadine 2.5 mg/5 mL, net price  100 mL (bubblegum-flavour) = £6.77, 150 mL =  £10.15. Counselling, driving   Note Fexofenadine is a metabolite of terfenadine  Indications see under Dose  Cautions see notes above   • Seasonal allergic rhinitis, 120 mg once daily; CHILD 6-  12 years, 30 mg twice daily   • Chronic idiopathic urticaria, ADULT and CHILD over 12  years, 180 mg once daily   Fexofenadine (Non-proprietary) (Ml  Tablets, f/c, fexofenadine hydrochloride 120 mg, net  price 30-tab pack = £2.95; 180 mg, 30-tab pack =  £3.68. Label: 5, counselling, driving   Telfast® (Sanofi-Aventis) (Ml  Tablets, f/c, peach, fexofenadine hydrochloride  30 mg, net price 60-tab pack = £5.46; 120 mg, 30-tab  pack = £5.99; 180 mg, 30-tab pack = £7.58. Label: 5,  counselling, driving   Contra-indications see notes above; also susceptibil-  ity to QT-interval prolongation (including cardiac  disease and hypokalaemia)   • ADULT and CHILD over 12 years, 10 mg once daily   Mizollen® (Sanofi-Aventis) (Ml  Tablets, m/r, f/c, scored, mizolastine 10 mg, net price  30-tab pack = £5.77. Label: 25, counselling, driving    Indications symptomatic relief of allergy such as hay  fever, urticaria  Cautions see notes above  Contra-indications see notes above  Renal impairment 5 mg on alternate days if eGFR 30-  50mL/minute/1.73m 2 ; 5 mg every 3 days if eGFR  10-30 mL/minute/1.73 m 2 ; avoid if eGFR less than  10 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; very rarely weight gain  Dose   • ADULT and CHILD over 6 years, 5 mg once daily; CHILD  2-6 years 1.25 mg twice daily   Xyzal® (UCB Pharma) (M  Tablets, f/c, levocetirizine hydrochloride 5 mg, net  price 30-tab pack = £4.39. Counselling, driving  Oral solution, sugar-free, levocetirizine hydrochloride  2.5 mg/5 mL, net price 200 mL = £6.00. Counselling,  driving   Cautions see notes above; also susceptibility to QT-  interval prolongation (including cardiac disease and  hypokalaemia); elderly   Side-effects see notes above; also asthenia; less  commonly pyrexia, irritability, increased appetite,  arthralgia, and myalgia    • ADULT and CHILD over 12 years, 10 mg once daily   Tablets, pink, rupatadine (as fumarate) 10 mg, net  price 30-tab pack = £5.00. Counselling, driving   Contra-indications see notes above  Hepatic impairment reduce dose frequency to alter-  nate days in severe impairment  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • ADULT and CHILD over 12 years 10 mg once daily; CHILD  2-12 years, body-weight under 30 kg, 5 mg once daily;  body-weight over 30 kg, 10 mg once daily   Tablets, loratadine 10 mg, net price 30-tab pack =  £1.20. Counselling, driving   Syrup, loratadine 5mg/5mL, net price 100 mL =  £2.65. Counselling, driving   Driving Drowsiness may affect performance of skilled  tasks (e.g. driving); sedating effects enhanced by  alcohol.   Indications urticaria and pruritus, premedication  Cautions see notes above; see also section 4.2.1  Contra-indications see notes above; see also section  4.2.1   • Urticaria and pruritus, 10 mg 2-3 times daily, in severe  cases up to max. 100 mg daily has been used; ELDERLY  10 mg 1-2 times daily; CHILD under 2 years, see    BNF for Children, 2-5 years 2.5 mg 3-4 times daily,  5-12 years 5 mg 3-4 times daily  • Premedication, CHILD 2-7 years up to 2 mg/kg 1-2  hours before operation   Alimemazine (Non-proprietary) (Ml  Tablets, alimemazine tartrate 10 mg, net price 28-tab  pack = £4.28. Label: 2   Syrup, alimemazine tartrate 7.5mg/5mL, net price  100 mL = £6.83; 30 mg/5 mL, 100 mL = £7.55.    Indications symptomatic relief of allergy such as hay  fever, urticaria; emergency treatment of anaphylactic  reactions (section 3.4.3)   Contra-indications see notes above  Hepatic impairment see notes above  Pregnancy see notes above   Breast-feeding see notes above  Side-effects see notes above; also exfoliative  dermatitis and tinnitus reported; injections may cause  transient hypotension or CNS stimulation and may be  irritant   • By mouth, 4 mg every 4-6 hours, max. 24 mg daily  (ELDERLY max. 12 mg daily); CHILD under 1 year see  BNF for Children, 1-2 years 1 mg twice daily; 2-6  years 1 mg every 4-6 hours, max. 6 mg daily; 6-12  years 2 mg every 4-6 hours, max. 12 mg daily   • By intramuscular injection or by intravenous injection  over 1 minute, 10 mg, repeated if required up to max.  4 doses in 24 hours; CHILD under 6 months 250 micr-  ograms/kg (max. 2.5 mg); 6 months-6 years 2.5 mg;  6-12 years 5 mg; these doses may be repeated if  required up to max. 4 doses in 24 hours   Tablets, yellow, scored, chlorphenamine maleate  4 mg, net price 28 = £1.62. Label: 2  Syrup, chlorphenamine maleate 2 mg/ 5 mL, net price  150mL = £2.39. Label: 2   Contra-indications see notes above  Hepatic impairment see notes above  Pregnancy see notes above   • 1 mg twice daily, increased up to 6 mg daily if  required; INFANT under 1 year not recommended,  CHILD 1-3 years 250-500 micrograms twice daily; 3-6  years 500 micrograms twice daily; 6-12 years 0.5-  1 mg twice daily   Contra-indications see notes above  Hepatic impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • Allergy, usual dose 4 mg 3-4 times daily; usual range  4-20 mg daily, max. 32 mg daily; INFANT under 2 years  not recommended, CHILD 2-6 years 2 mg 2-3 times  daily, max. 12 mg daily; 7-14 years 4 mg 2-3 times  daily, max. 16 mg daily   Tablets, scored, cyproheptadine hydrochloride 4 mg,  net price 30-tab pack = 86p. Label: 2   Hepatic impairment reduce daily dose by one-third;  see also notes above   Pregnancy toxicity in animal studies with high doses;  see also notes above   • Pruritus, initially 25 mg at night increased if necessary  to 25 mg 3-4 times daily; CHILD 1-6 years initially 5-  15 mg at night increased if necessary to 50 mg daily in  3-4 divided doses; 6-12 years initially 15-25 mg at  night increased if necessary to 50-100 mg daily in 3-4  divided doses; CHILD under 1 year see BNF for Chil-  dren   Tablets, both f/c, hydroxyzine hydrochloride 10 mg  (orange), net price 84-tab pack = £2.18; 25 mg (green),  28-tab pack = £1.17. Label: 2   Ucerax® (UCB Pharma) (Ml  Tablets!^ f/c, scored, hydroxyzine hydrochloride  25 mg, net price 25-tab pack = £1.22. Label: 2  Syrup, hydroxyzine hydrochloride 10mg/5mL, net  price 200-mL pack = £1.78. Label: 2   Side-effects see notes above; also excitation, irrit-  ability, nervousness; less commonly cystitis; rarely  weight gain; very rarely Stevens-Johnson syndrome   • 1 mg twice daily with food increased if necessary to  2 mg twice daily; initial treatment in readily sedated  patients 0.5-1 mg at night; CHILD 3 years and over,   1 mg, net price 60-tab pack = £7.53. Label: 2, 21  Elixir, ketotifen (as hydrogen fumarate), 1 mg/5mL,  net price 300 mL (strawberry-flavoured) = £8.91.  Label: 2, 21   Immunotherapy using allergen vaccines containing  house dust mite, animal dander (cat or dog), or extracts  of grass and tree pollen can reduce symptoms of asthma  and allergic rhinoconjunctivitis. A vaccine containing  extracts of wasp and bee venom is used to reduce the  risk of severe anaphylaxis and systemic reactions in  individuals with hypersensitivity to wasp and bee stings.  An oral preparation of grass pollen extract ( Grazax ®) is  also licensed for grass pollen-induced rhinitis and  conjuctivitis. Those requiring immunotherapy must be  referred to a hospital specialist for accurate diagnosis,  assessment, and treatment.   In view of concerns about the safety of desensitising  vaccines, it is recommended that they are used by  specialists and only for the following indications:   • seasonal allergic hay fever (caused by pollen)  that has not responded to anti-allergic drugs;   • hypersensitivity to wasp and bee venoms.  Desensitising vaccines should generally be avoided  or used with particular care in patients with asthma.   Indications symptomatic relief of allergy such as hay  fever and urticaria; emergency treatment of anaphy-  lactic reactions; sedation (section 4.1.1); nausea and  vomiting (section 4.6)   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment use with caution  Pregnancy see notes above   Breast-feeding see notes above  Side-effects see notes above; also restlessness; intra-  muscular injection may be painful   • By mouth, 10-20 mg 2-3 times daily; CHILD 2-5 years  5-15 mg daily in 1-2 divided doses, 5-10 years 10-  25 mg daily in 1-2 divided doses   • By slow intravenous injection in emergencies, 25-  50 mg as a solution containing 2.5 mg/mL in water for  injections; max. 100 mg   Promethazine (Non-proprietary) [Ml  1 Injection, promethazine hydrochloride 25 mg/mL,  net price 1-mL amp = 68p, 2-mL amp = £1.20  1. (5°M] restriction does not apply where administration is for  saving life in emergency   Tablets, both blue, f/c, promethazine hydrochloride  10 mg, net price 56-tab pack = £2.85; 25 mg, 56-tab  pack = £4.34. Label: 2   Dental prescribing on NHS May be prescribed as Promethazine  Hydrochloride Tablets 10 mg or 25 mg   Elixir, golden, promethazine hydrochloride 5 mg/  5mL, net price 100 mL = £2.67. Label: 2  Dental prescribing on NHS May be prescribed as Promethazine  Hydrochloride Oral Solution 5mg/5mL   Injection (Ml 1 , promethazine hydrochloride 25 mg/  mL, net price 1-mL amp = 67p  1. (Ml restriction does not apply where administration is for  saving life in emergency    Desensitising vaccines should be avoided in pregnant  women, in children under five years old, and in those  taking beta-blockers (adrenaline may be ineffective in  case of a hypersensitivity reaction), or ACE inhibitors  (risk of severe anaphylactoid reactions).  Hypersensitivity reactions to immunotherapy (espe-  cially to wasp and bee venom extracts) can be life-  threatening; bronchospasm usually develops within 1  hour and anaphylaxis within 30 minutes of injection.  Therefore, cardiopulmonary resuscitation must be  immediately available and patients need to be moni-  tored for at least 1 hour after injection. If symptoms or  signs of hypersensitivity develop (e.g. rash, urticaria,  bronchospasm, faintness), even when mild, the patient  should be observed until these have resolved comple-  tely.   The first dose of oral grass pollen extract (Grazax®)  should be taken under medical supervision and the  patient should be monitored for 20-30 minutes.    Each set of allergen extracts usually contains vials for  the administration of graded amounts of allergen to  patients undergoing hyposensitisation. Maintenance  sets containing vials at the highest strength are also  available. Product literature must be consulted for  details of allergens, vial strengths, and administration.    Pharmalgen® (ALK-Abello) (Ml  Bee venom extract (Apis mellifera) or wasp venom  extract ( Vespula spp.), net price initial treatment set =  £54.81 (bee), £67.20 (wasp); maintenance treatment  set = £63.76 (bee), £82.03 (wasp)    accepted for restricted use within NHS Scotland as add-  on therapy to improve asthma control in children (6 to  12 years), adolescents, and adults with severe persistent  allergic asthma. Omalizumab is restricted to patients  who are prescribed chronic systemic corticosteroids  and in whom all other treatments have failed. The  response should be assessed at 16 weeks and omalizu-  mab treatment discontinued in patients who have not  shown a marked improvement in overall asthma con-  trol.    Indications treatment of seasonal allergic hay fever  due to grass or tree pollen in patients who have failed  to respond to anti-allergy drugs (see notes above)   Grasses and rye or tree pollen extract, net price initial  treatment set (3 vials) and extension course treatment  (1 vial) = £450.00    M Grass pollen extract  Grazax® (ALK-Abello) ▼ (M  Oral lyophilisates (= freeze-dried tablets), grass  pollen extract 75 000 units, net price 30-tab pack =  £66.56. Counselling, administration  Dose ADULT and CHILD over 5 years, 1 tablet daily; start treat-  ment at least 4 months before start of pollen season and continue  for up to 3 years   Counselling Tablets should be placed under the tongue and  allowed to disperse. Advise patient not to swallow for 1 minute,  or eat or drink for 5 minutes after taking the tablet   Omalizumab is a monoclonal antibody that binds to  immunoglobulin E (IgE). It is used as additional therapy  in individuals with proven IgE-mediated sensitivity to  inhaled allergens, whose severe persistent allergic  asthma cannot be controlled adequately with high-  dose inhaled corticosteroid together with a long-acting  beta 2 agonist. Omalizumab should be initiated by phy-  sicians in specialist centres experienced in the treatment  of severe persistent asthma.   Omalizumab is recommended as additional therapy  for the prophylaxis of severe persistent allergic  asthma in adults and children over 12 years, who  cannot be controlled adequately with high-dose  inhaled corticosteroids and long-acting beta 2 ago-  nists in addition to leukotriene receptor antagonists,  theophylline, oral corticosteroids, oral beta 2 ago-  nists, and smoking cessation where clinically appro-  priate. The following conditions apply:   • confirmation of IgE-mediated allergy to a per-  ennial allergen by clinical history and allergy  skin testing;   • either 2 or more severe exacerbations of asthma  requiring hospital admission within the previous  year, or 3 or more severe exacerbations of  asthma within the previous year, at least one  of which required hospital admission, and a  further 2 which required treatment or monitor-  ing in excess of the patient’s usual regimen, in an  accident and emergency unit.   Omalizumab should be initiated and monitored by a  physician experienced in both allergy and respir-  atory medicine in a specialist centre, and discontin-  ued at 16 weeks in patients who have not shown an  adequate response to therapy.   Omalizumab for the treatment of severe  persistent allergic asthma in children aged 6  to 11 years (October 2010)   Omalizumab is not recommended for the treatment  of severe persistent allergic asthma in children aged  6 to 1 1 years.    Churg-Strauss syndrome has occurred rarely in patients  given omalizumab; the reaction is usually associated  with the reduction of oral corticosteroid therapy.  Churg-Strauss syndrome can present as eosinophilia,  vasculitic rash, cardiac complications, worsening pulm-  onary symptoms, or peripheral neuropathy. Hypersensi-  tivity reactions can also occur immediately following  treatment with omalizumab or sometimes more than 24  hours after the first injection.   The Scottish Medicines Consortium p. 4 has advised  (September 2007 and March 2010) that omalizumab is    Side-effects headache; injection-site reactions; less  commonly nausea, diarrhoea, dyspepsia, flushing,  fatigue, dizziness, drowsiness, paraesthesia, influenza-  like symptoms, photosensitivity, hypersensitivity  reactions (including hypotension, bronchospasm, lar-  yngoedema, rash, pruritus, serum sickness, and  anaphylaxis); Churg-Strauss syndrome (see notes  above), thrombocytopenia, arthralgia, myalgia, and  alopecia also reported  Dose   • By subcutaneous injection, ADULT and CHILD over 6  years, according to immunoglobulin E concentration  and body-weight, consult product literature    Adrenaline (epinephrine) provides physiological rever-  sal of the immediate symptoms associated with hyper-  sensitivity reactions such as anaphylaxis and angio-  edema.   Anaphylaxis is a severe, life-threatening, generalised or  systemic hypersensitivity reaction. It is characterised by  the rapid onset of respiratory and/or circulatory pro-  blems and is usually associated with skin and mucosal  changes; prompt treatment is required. Patients with  pre-existing asthma, especially poorly controlled  asthma, are at particular risk of life-threatening reac-  tions. Insect stings are a recognised risk (in particular  wasp and bee stings). Latex and certain foods, including  eggs, fish, cow’s milk protein, peanuts, sesame, shellfish,  soy, and tree nuts may also precipitate anaphylaxis.  Medicinal products particularly associated with anaphy-  laxis include blood products, vaccines, hyposensitising  (allergen) preparations, antibacterials, aspirin and other  NSAIDs, and neuromuscular blocking drugs. In the case  of drugs, anaphylaxis is more likely after parenteral  administration; resuscitation facilities must always be  available for injections associated with special risk.  Anaphylactic reactions may also be associated with  additives and excipients in foods and medicines.  Refined arachis (peanut) oil, which may be present in  some medicinal products, is unlikely to cause an allergic  reaction — nevertheless it is wise to check the full for-  mula of preparations which may contain allergenic fats  or oils.   First-line treatment of anaphylaxis includes securing  the airway, restoration of blood pressure (laying the  patient flat and raising the legs, or in the recovery  position if unconscious or nauseated and at risk of  vomiting) and administration of adrenaline (epinephr-  ine) injection. Adrenaline is given intramuscularly in a  dose of 500 micrograms (0.5 mL adrenaline injection 1  in 1000); a dose of 300 micrograms (0.3 mL adrenaline  injection 1 in 1000) may be appropriate for immediate  self-administration. The dose is repeated if necessary at  5-minute intervals according to blood pressure, pulse,    and respiratory function (important: possible need for  intravenous route using dilute solution, see below).  Patients receiving beta-blockers require special consid-  eration (see under Adrenaline, p. 198). High-flow oxy-  gen administration (section 3.6) and intravenous fluids  (section 9.2.2) are also of primary importance. An anti-  histamine (e.g. chlorphenamine, given by slow intra-  venous injection or intramuscular injection in a dose of  10 mg, see p. 194) is a useful adjunctive treatment, given  after adrenaline. An intravenous corticosteroid e.g.  hydrocortisone (as sodium succinate) in a dose of  200 mg (section 6.3.2) is of secondary value in the initial  management of anaphylaxis because the onset of action  is delayed for several hours, but should be given to  prevent further deterioration in severely affected  patients.   Continuing respiratory deterioration requires further  treatment with bronchodilators including inhaled or  intravenous salbutamol (see p. 177), inhaled ipra-  tropium (see p. 180), intravenous aminophylline (see  p. 181), or intravenous magnesium sulphate [unlicensed  indication] (see Acute Severe Asthma, p. 171); in addi-  tion to oxygen, assisted respiration and possibly emer-  gency tracheotomy may be necessary.   When a patient is so ill that there is doubt about the  adequacy of the circulation, the initial injection of adr-  enaline may need to be given as a dilute solution by the  intravenous route, for details of cautions, dose, and Jfl  strength, see under Intravenous Adrenaline (Epinephr- E  ine), p. 198.   For advice on the management of medical emergencies ^  in dental practice, see p. 26.   On discharge, patients should be considered for further  treatment with an oral antihistamine (section 3.4.1) and  an oral corticosteroid (section 6.3.2) for up to 3 days to  reduce the risk of further reaction. Patients should be  instructed to return to hospital if symptoms recur and to  contact their general practitioner for follow-up.   Patients who are suspected of having had an anaphy-  lactic reaction should be referred to a specialist for  specific allergy diagnosis. Avoidance of the allergen is  the principal treatment; if appropriate, an adrenaline  auto-injector should be given or a replacement supplied  (see Self-administration of Adrenaline).   The intramuscular route is the first choice route for the  administration of adrenaline (epinephrine) in the man-  agement of anaphylaxis. Adrenaline is best given as an  intramuscular injection into the anterolateral aspect of  the middle third of the thigh; it has a rapid onset of  action after intramuscular administration and in the  shocked patient its absorption from the intramuscular  site is faster and more reliable than from the subcuta-  neous site (the intravenous route should be reserved for  extreme emergency when there is doubt about the  adequacy of the circulation, see Intravenous Adrenaline  (Epinephrine), below).   Patients with severe allergy should be instructed in the  self-administration of adrenaline by intramuscular injec-    tion (for details see under Self-administration of Adr-  enaline (Epinephrine), below).   Prompt injection of adrenaline is of paramount impor-  tance. The following adrenaline doses are based on the  revised recommendations of the Working Group of the  Resuscitation Council (UK).   Child under 6 years 150 micrograms 0.15 ml * 1  Child 6-12 years 300 micrograms 0.3 mL   These doses may be repeated several times if necessary at  5-minute intervals according to blood pressure, pulse,  and respiratory function.   Intravenous adrenaline should be given only by those  experienced in its use, in a setting where patients can be  carefully monitored. When the patient is severely ill and  there is real doubt about the adequacy of the circulation  and absorption after intramuscular injection, adrenaline  (epinephrine) can be given by slow intravenous injec-  tion in a dose of 50 micrograms (0.5 mL of the dilute 1 in  10 000 adrenaline injection) repeated according to  response; if multiple doses are required, adrenaline  should be given as a slow intravenous infusion stopping  when a response has been obtained, children may  respond to as little as 1 microgram/kg (O.OlmL/kg of  the dilute 1 in 10 000 adrenaline injection) by slow  intravenous injection.   Great vigilance is needed to ensure that the correct  strength of adrenaline injection is used; anaphylactic  shock kits need to make a very clear distinction between  the 1 in 10 000 strength and the 1 in 1000 strength. It is  also important that, where intramuscular injection  might still succeed, time should not be wasted seeking  intravenous access.   For reference to the use of the intravenous route for  cardiac resuscitation, see section 2.7.3.   Individuals at considerable risk of anaphylaxis need to  carry adrenaline (epinephrine) at all times and need to  be instructed in advance when and how to inject it;  injection technique is device specific. In addition, the  packs need to be labelled so that in the case of rapid  collapse someone else is able to administer the adrena-  line. It is important to ensure that an adequate supply is  provided to treat symptoms until medical assistance is  available.   Adrenaline for administration by intramuscular injection  is available in ‘auto-injectors’ (e.g. AnaPen® and  EpiPen®), pre-assembled syringes fitted with a needle  suitable for very rapid administration (if necessary by a  bystander or a healthcare provider if it is the only  preparation available).   Indications emergency treatment of acute anaphy-  laxis; angioedema; cardiopulmonary resuscitation  (section 2.7.3); priapism [unlicensed] (section 7.4.5)  Cautions for cautions in non-life-threatening situa-  tions, see section 2.7.3   Interactions Severe anaphylaxis in patients taking beta-  blockers may not respond to adrenaline, calling for bronch-  odilator therapy, see intravenous salbutamol (p. 177); adr-  enaline can cause severe hypertension and bradycardia in  those taking non-cardioselective beta-blockers. Other  interactions, see Appendix 1 (sympathomimetics).   Renal impairment section 2.7.3  Pregnancy section 2.7.3  Breast-feeding section 2.7.3  Side-effects section 2.7.3  Dose   • Acute anaphylaxis, by intramuscular injection (pre-  ferably midpoint in anterolateral thigh) of 1 in 1000  (1 mg/mL) solution, see notes and table above   • Acute anaphylaxis when there is doubt as to the  adequacy of the circulation, by slow intravenous  injection of 1 in 10 000 (100 micrograms /mL) solution  (extreme caution — specialist use only), see notes  above   Injection, adrenaline (as acid tartrate) 1 mg/mL, net  price 0.5-mL amp = 52p; 1-mL amp = 57p   1 Minijet® Adrenaline 1 in 1000 (UCB Pharma) (m\  Injection, adrenaline (as hydrochloride) 1 in 1000  (1 mg/mL), net price 1 mL (with 25 gauge x 0.25 inch  needle for subcutaneous injection) = £10.79, 1 mL  (with 21 gauge x 1.5 inch needle for intramuscular  injection) = £6.36 (both disposable syringes)   Injection, adrenaline (as acid tartrate) lOOmicr-  ograms/mL, 10-mL amp, 1-mL and 10-mL prefilled  syringe   Minijet® Adrenaline 1 in 10 000 (UCB Pharma) ®  Injection, adrenaline (as hydrochloride) 1 in 10 000  (lOOmicrograms/mL), net price 3-mL prefilled  syringe = £6.27; 10-mL prefilled syringe = £6.15   ^Intramuscular injection for self-administration  Anapen® (Lincoln Medical) (Ml  Anapen® 500 (delivering a single dose of adrenaline  500 micrograms), adrenaline 1.7 mg/mL, net price  1.05-mL auto-injector device = £30.67   Note 0.75 mL of the solution remains in the auto-injector device  after use   Dose by intramuscular injection, ADULT and CHILD body-weight  over 60 kg or those at risk of severe anaphylaxis, 500 micrograms  repeated after 10-15 minutes as necessary    1 Anapen® 300 (delivering a single dose of adrenaline  300 micrograms), adrenaline 1 mg/mL (1 in 1000), net  price 1.05-mL auto-injector device = £30.67   Note 0.75 mL of the solution remains in the auto-injector device  after use   Dose by intramuscular injection, ADULT and CHILD body-weight  over 30 kg, 300 micrograms repeated after 10-15 minutes as  necessary   Anapen® 150 (delivering a single dose of adrenaline  150 micrograms), adrenaline 500 micrograms/mL (1  in 2000), net price 1.05-mL auto-injector device =  £30.67   Note 0.75 mL of the solution remains in the auto-injector device  after use   Dose by intramuscular injection, CHILD body-weight 15-30 kg,  150 micrograms repeated after 10-15 minutes as necessary;  CHILD body-weight under 15 kg, [unlicensed] 150 micrograms  repeated after 10-15 minutes as necessary   1 EpiPen® Auto-injector 0.3 mg (delivering a single  dose of adrenaline 300 micrograms), adrenaline  1 mg/mL (1 in 1000), net price 2-mL auto-injector  device = £28.77   Note 1.7 mL of the solution remains in the auto-injector device  after use   Dose by intramuscular injection, ADULT and CHILD body-weight  over 30 kg, 300 micrograms repeated after 5-15 minutes as  necessary   Epipen® Jr Auto-injector 0.15 mg (delivering a single  dose of adrenaline 150 micrograms), adrenaline  500 micrograms/mL (1 in 2000), net price 2-mL auto-  injector device = £28.77   Note 1.7 mL of the solution remains in the auto-injector device  after use   Dose by intramuscular injection, CHILD body-weight 15-30 kg,  150 micrograms (but on the basis of a dose of 10 micrograms /kg,  300 micrograms may be more appropriate for some children)  repeated after 5-15 minutes as necessary; CHILD body-weight  under 15 kg, [unlicensed] 150 micrograms repeated after 5-15  minutes as necessary   Angioedema is dangerous if laryngeal oedema is pre-  sent. In this circumstance adrenaline (epinephrine)  injection and oxygen should be given as described  under Anaphylaxis (see p. 197); antihistamines and cor-  ticosteroids should also be given. Tracheal intubation  may be necessary.   Hereditary angioedema The administration of Cl-  esterase inhibitor, an endogenous complement blocker  derived from human plasma, (in fresh frozen plasma or  in partially purified form) can terminate acute attacks of  hereditary angioedema, but is not practical for long-  term prophylaxis; it can also be used for short-term  prophylaxis before surgery or dental procedures [unli-  censed indication], Icatibant is licensed for the treat-  ment of acute attacks of hereditary angioedema in  adults with Cl -esterase inhibitor deficiency.   Tranexamic acid (section 2.11) and danazol (section  6.7.2) [unlicensed indication] are used for short-term  and long-term prophylaxis of hereditary angioedema.  Short-term prophylaxis with tranexamic acid or danazol    is started several days before planned procedures (e.g.  dental work) and continued for 2-5 days afterwards.  Danazol should be avoided in children because of its  androgenic effects.   Cautions vaccination against hepatitis A, p. 754 and  hepatitis B, p. 755 may be required   Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — no information  available   • By slow intravenous injection or intravenous infusion,  ADULT and CHILD 20 units/kg   Indications acute attacks of hereditary angioedema in  patients with Cl-esterase inhibitor deficiency  Cautions ischaemic heart disease, stroke   Pregnancy manufacturer advises use only if potential  benefit outweighs risk — toxicity in animal studies  Breast-feeding manufacturer advises avoid for 12  hours after administration   30 mg as a single dose, repeated after 6 hours if  necessary; a third dose may be given after a further 6  hours (max. 3 doses in 24 hours)   Injection, icatibant (as acetate) 10 mg/mL, net price  3-mL prefilled syringe = £1395.00   Respiratory stimulants (analeptic drugs) have a limited  place in the treatment of ventilatory failure in patients  with chronic obstructive pulmonary disease. They are  effective only when given by intravenous injection or  infusion and have a short duration of action. Their use  has largely been replaced by ventilatory support includ-    ing nasal intermittent positive pressure ventilation.  However, occasionally when ventilatory support is con-  tra-indicated and in patients with hypercapnic respir-  atory failure who are becoming drowsy or comatose,  respiratory stimulants in the short term may arouse  patients sufficiently to co-operate and clear their secre-  tions.   Respiratory stimulants can also be harmful in respir-  atory failure since they stimulate non-respiratory as well  as respiratory muscles. They should only be given under  expert supervision in hospital and must be combined  with active physiotherapy. There is at present no oral  respiratory stimulant available for long-term use in  chronic respiratory failure.   Doxapram is given by continuous intravenous infusion.  Frequent arterial blood gas and pH measurements are  necessary during treatment to ensure correct dosage.   Pulmonary surfactants are used in the management of  respiratory distress syndrome (hyaline membrane dis-  ease) in neonates and preterm neonates. They may also  be given prophylactically to those considered at risk of  developing the syndrome.   Cautions Continuous monitoring is required to avoid  hyperoxaemia caused by rapid improvement in arterial  oxygen concentration.   Side-effects Pulmonary haemorrhage and brady-  cardia have been rarely associated with pulmonary  surfactants; obstruction of the endotracheal tube by  mucous secretions and intracranial haemorrhage have  also been reported.   For the use of caffeine in the management of neonatal  apnoea, see BNF for Children.   Cautions give with oxygen in severe irreversible air-  ways obstruction or severely decreased lung compli-  ance (because of increased work load of breathing);  give with beta 2 agonist in bronchoconstriction;  hypertension (avoid if severe), impaired cardiac  reserve; phaeochromocytoma; interactions: Appen-  dix 1 (doxapram)   Contra-indications severe hypertension; status asth-  maticus; coronary artery disease; hyperthyroidism;  epilepsy and other convulsive disorders; physical  obstruction of respiratory tract; cerebral oedema,  cerebrovascular accident  Hepatic impairment use with caution  Pregnancy no evidence of harm, but manufacturer  advises avoid unless benefit outweighs risk  Side-effects nausea, vomiting; hypertension, tachy-  cardia, bradycardia, extrasystoles, arrhythmias, chest  pain, flushing; dyspnoea, cough, bronchospasm, lar-  yngospasm; pyrexia, headache, dizziness, hyperactiv-  ity, confusion, hallucination, convulsions; urinary  retention, incontinence, perineal warmth; muscle  spasms   • Postoperative respiratory depression, by intravenous  injection over at least 30 seconds, 1-1.5 mg/kg  repeated if necessary after intervals of 1 hour or  alternatively by intravenous infusion, 2-3 mg/minute  adjusted according to response; CHILD not recom-  mended   • Acute respiratory failure, by intravenous infusion,  1.5-4 mg/minute adjusted according to response  (given concurrently with oxygen and whenever pos-  sible monitor with frequent measurement of blood gas  tensions); CHILD not recommended   Injection, doxapram hydrochloride 20mg/mL. Net  price 5-mL amp = £3.00  Intravenous infusion, doxapram hydrochloride  2mg/mL in glucose 5%. Net price 500-mL bottle =  £21.33   Indications treatment of respiratory distress  syndrome in preterm neonates over 700 g; prophy-  laxis of respiratory distress syndrome in preterm  neonates less than 32 weeks post-menstrual age   • By endotracheal tube, phospholipid 100 mg/kg  equivalent to a volume of 4 mL/kg, preferably within 8  hours of birth (preferably within 15 minutes of birth  for prophylaxis); dose may be repeated within 48  hours at intervals of at least 6 hours for up to 4 doses   Suspension, beractant (bovine lung extract) provid-  ing phospholipid 25 mg/mL, with lipids and proteins,  net price 8-mL vial = £306.43   Indications treatment of respiratory distress  syndrome or hyaline membrane disease in neonates  over 700 g; prophylaxis of respiratory distress  syndrome in preterm neonates 24-32 weeks post-  menstrual age   • By endotracheal tube, treatment, 100-200 mg/kg;  further doses of 100 mg/kg may be repeated at  intervals of 12 hours; max. total dose 300-400 mg/kg;  prophylaxis, 100-200 mg/kg soon after birth (prefer-  ably within 15 minutes); further doses of 100 mg/kg  may be repeated 6-12 hours later and after a further  12 hours if still intubated; max. total dose 300-  400 mg/kg   Suspension, poractant alfa (porcine lung phospholi-  pid fraction) 80 mg/mL, net price 1.5-mL vial =  £281.64; 3-mL vial = £547.40    risk of fire. Smoking cessation therapy (section 4.10.2)  should be tried before home oxygen prescription.   Air travel Some patients with arterial hypoxaemia  require supplementary oxygen for air travel. The  patient’s requirement should be discussed with the air-  line before travel.   Oxygen should be regarded as a drug. It is prescribed for  hypoxaemic patients to increase alveolar oxygen ten-  sion and decrease the work of breathing. The concen-  tration of oxygen required depends on the condition  being treated; the administration of an inappropriate  concentration of oxygen can have serious or even  fatal consequences.   Oxygen is probably the most common drug used in  medical emergencies. It should be prescribed initially to  achieve a normal or near-normal oxygen saturation; in  most acutely ill patients with a normal or low arterial  carbon dioxide (P a C0 2 ), oxygen saturation should be  94-98% oxygen saturation. However, in some clinical  situations such as cardiac arrest and carbon monoxide  poisoning (see also Emergency Treatment of Poisoning,  p. 40) it is more appropriate to aim for the highest  possible oxygen saturation until the patient is stable. A  lower target of 88-92% oxygen saturation is indicated  for patients at risk of hypercapnic respiratory failure, see  below.   High concentration oxygen therapy is safe in uncom-  plicated cases of conditions such as pneumonia, pulm-  onary thromboembolism, pulmonary fibrosis, shock,  severe trauma, sepsis, or anaphylaxis. In such condi-  tions low arterial oxygen (P a 0 2 ) is usually associated  with low or normal arterial carbon dioxide (-P a C0 2 ), and  therefore there is little risk of hypoventilation and car-  bon dioxide retention.   In acute severe asthma, the arterial carbon dioxide  (P a C0 2 ) is usually subnormal but as asthma deteriorates  it may rise steeply (particularly in children). These  patients usually require high concentrations of oxygen  and if the arterial carbon dioxide (P a C0 2 ) remains high  despite other treatment, intermittent positive-pressure  ventilation needs to be considered urgently.   Low concentration oxygen therapy (controlled oxygen  therapy) is reserved for patients at risk of hypercapnic  respiratory failure, which is more likely in those with:   • an overdose of opioids, benzodiazepines, or other  drugs causing respiratory depression.   Until blood gases can be measured, initial oxygen  should be given using a controlled concentration of  28% or less, titrated towards a target oxygen saturation  of 88-92%. The aim is to provide the patient with  enough oxygen to achieve an acceptable arterial oxygen  tension without worsening carbon dioxide retention and  respiratory acidosis. Patients may carry an oxygen alert  card, see section 3.1.    Domiciliary oxygen Oxygen should only be pre-  scribed for use in the home after careful evaluation in  hospital by respiratory experts.   Patients should be advised of the risks of continuing to  smoke when receiving oxygen therapy, including the   Long-term administration of oxygen (usually at least 15  hours daily) prolongs survival in some patients with  chronic obstructive pulmonary disease.   Assessment for long-term oxygen therapy requires mea-  surement of arterial blood gas tensions. Measurements  should be taken on 2 occasions at least 3 weeks apart to  demonstrate clinical stability, and not sooner than 4  weeks after an acute exacerbation of the disease.  Long-term oxygen therapy should be considered for  patients with:   • chronic obstructive pulmonary disease with  P & 0 2 < 7.3 kPa when breathing air during a period  of clinical stability;   7.3-8 kPa in the presence of secondary polycythae-  mia, nocturnal hypoxaemia, peripheral oedema, or  evidence of pulmonary hypertension; Jfl   • interstitial lung disease with P a 0 2 < 8 kPa and in $  patients with P a 0 2 > 8 kPa with disabling dyspnoea; "2   • cystic fibrosis when P a 0 2 < 7.3 kPa or if P a 0 2 7.3- g-  8 kPa in the presence of secondary polycythaemia, ^  nocturnal hypoxaemia, pulmonary hypertension, or  peripheral oedema;   • pulmonary hypertension, without parenchymal  lung involvement when P a 0 2 < 8 kPa;   • obstructive sleep apnoea despite continuous posi-  tive airways pressure therapy, after specialist  assessment;   • heart failure with daytime P a 0 2 <7.3kPa when  breathing air or with nocturnal hypoxaemia;   Increased respiratory depression is seldom a problem in  patients with stable respiratory failure treated with low  concentrations of oxygen although it may occur during  exacerbations; patients and relatives should be warned  to call for medical help if drowsiness or confusion occur.   Oxygen is occasionally prescribed for short-burst (inter-  mittent) use for episodes of breathlessness not relieved  by other treatment in patients with severe chronic  obstructive pulmonary disease, interstitial lung disease,  heart failure, and in palliative care. It is important,  however, that the patient does not rely on oxygen  instead of obtaining medical help or taking more spe-  cific treatment. Short-burst oxygen therapy can be used    to improve exercise capacity and recovery; it should  only be continued if there is proven improvement in  breathlessness or exercise tolerance.   Ambulatory oxygen is prescribed for patients on long-  term oxygen therapy who need to be away from home  on a regular basis. Patients who are not on long-term  oxygen therapy can be considered for ambulatory oxy-  gen therapy if there is evidence of exercise-induced  oxygen desaturation and of improvement in blood oxy-  gen saturation and exercise capacity with oxygen.  Ambulatory oxygen therapy is not recommended for  patients with heart failure or those who smoke.    Under the NHS oxygen may be supplied as oxygen  cylinders. Oxygen flow can be adjusted as the cylinders  are equipped with an oxygen flow meter with ‘medium’  (2 litres/minute) and ‘high’ (4 litres /minute) settings.   Oxygen concentrators are more economical for  patients who require oxygen for long periods, and in  England and Wales can be ordered on the NHS on a  regional tendering basis (see below). A concentrator is  recommended for a patient who requires oxygen for  more than 8 hours a day (or 21 cylinders per month).  Exceptionally, if a higher concentration of oxygen is  required the output of 2 oxygen concentrators can be  combined using a ‘Y’ connection.    A nasal cannula is usually preferred for long-term oxy-  gen therapy from an oxygen concentrator. It can, how-  ever, produce dermatitis and mucosal drying in sensi-  tive individuals.    Giving oxygen by nasal cannula allows the patient to  talk, eat, and drink, but the concentration of oxygen is  not controlled; this may not be appropriate for acute  respiratory failure. When oxygen is given through a  nasal cannula at a rate of 1-2 litres/minute the inspira-  tory oxygen concentration is usually low, but it varies  with ventilation and can be high if the patient is under-  ventilating.   The type of oxygen service (or combination of services)  should be ordered on a Home Oxygen Order Form  (HOOF); the amount of oxygen required (hours per  day) and flow rate should be specified. The supplier  will determine the appropriate equipment to be pro-  vided. Special needs or preferences should be specified  on the HOOF.   The clinician should obtain the patient’s consent to pass  on the patient’s details to the supplier and the fire  brigade. The supplier will contact the patient to make  arrangements for delivery, installation, and maintenance    of the equipment. The supplier will also train the patient  to use the equipment.   The clinician should send order forms to the supplier by  facsimile (see below); a copy of the HOOF should be  sent to the Primary Care Trust or Local Health Board.  The supplier will continue to provide the service until a  revised order is received, or until notified that the  patient no longer requires the home oxygen service.    In Scotland refer the patient for assessment by a resp-  iratory consultant. If the need for a concentrator is  confirmed the consultant will arrange for the provision  of a concentrator through the Common Services  Agency. In Northern Ireland oxygen concentrators  and cylinders should be prescribed on form HS21; oxy-  gen concentrators are supplied by a local contractor. In  Scotland and Northern Ireland prescriptions for oxy-  gen cylinders and accessories can be dispensed by  pharmacists contracted to provide domiciliary oxygen  services.   Mucolytics are prescribed to facilitate expectoration by  reducing sputum viscosity. In some patients with  chronic obstructive pulmonary disease and a chronic  productive cough, mucolytics can reduce exacerbations;  mucolytic therapy should be stopped if there is no  benefit after a 4-week trial. Steam inhalation with pos-  tural drainage is effective in bronchiectasis and in some  cases of chronic bronchitis.   Mucolytics should be used with caution in those with a  history of peptic ulceration because they may disrupt  the gastric mucosal barrier.    Side-effects rarely gastrointestinal bleeding; hyper-  sensitivity reactions (including rash and anaphylaxis)  also reported   • Initially 2.25 g daily in divided doses, then 1.5 g daily  in divided doses as condition improves; CHILD 2-5  years 62.5-125 mg 4 times daily, 5-12 years 250 mg 3  times daily   Carbocisteine (Sanofi-Aventis) (Ml  Capsules, carbocisteine 375 mg, net price 120-cap  pack = £16.03  Brands include Mucodyne ®   Oral liquid, carbocisteine 125 mg/ 5 mL, net price  300 mL = £4.39; 250 mg/5 mL, 300 mL = £5.61  Brands include Mucodyne ® Paediatric 125 mg/ 5 mL (cherry- and  raspberry-flavoured) and Mucodyne ® 250 mg/5 mL (cinnamon-  and rum-flavoured)   300 mg daily in mild to moderate impairment; avoid in  severe impairment   Side-effects very rarely nausea, vomiting, diarrhoea,  abdominal pain, taste disturbance, headache, rash,  and urticaria   • ADULT over 18 years, 300 mg twice daily for up to 10  days   Capsules, yellow/green, erdosteine 300 mg, net price  20-cap pack = £5.75   Note The Scottish Medicines Consortium (October 2007)  has advised that erdosteine ( Erdotin ®) is not recommended  for the symptomatic treatment of acute exacerbations of  chronic bronchitis   • 200 mg 4 times daily for 2 days, then 200 mg 3 times  daily for 6 weeks, then 200 mg twice daily; CHILD 5-12  years 100 mg 3 times daily   Tablets, yellow, s/c, e/c, mecysteine hydrochloride  100 mg, net price 100 = £17.65. Label: 5, 22, 25   Domase alfa is a genetically engineered version of a  naturally occurring human enzyme which cleaves extra-  cellular deoxyribonucleic acid (DNA). It is used in cystic  fibrosis and is administered by inhalation using a jet  nebuliser (section 3.1.5).    Indications management of cystic fibrosis patients  with a forced vital capacity (FVC) of greater than 40%  of predicted to improve pulmonary function  Pregnancy no evidence of teratogenicity; manufac-  turer advises use only if potential benefit outweighs  risk   Breast-feeding amount probably too small to be  harmful — manufacturer advises caution  Side-effects rarely dyspepsia, chest pain, dysphonia,  dyspnoea, pharyngitis, laryngitis, pyrexia, con-  junctivitis, rhinitis, rash, urticaria  Dose    • ADULT and CHILD over 5 years, by inhalation of neb-  ulised solution (by jet nebuliser), 2500 units (2.5 mg)  once daily (patients over 2 1 years may benefit from  twice daily dosage)   Pulmozyme® (Roche) (Ml  Nebuliser solution, dornase alfa 1000 units (lmg)/  mL. Net price 2.5-mL (2500 units) vial = £16.55  Note For use undiluted with jet nebulisers only; ultrasonic nebu-  lisers are unsuitable   Nebulised hypertonic sodium chloride solution (3-7%)  is used to mobilise lower respiratory tract secretions in  mucous consolidation (e.g. cystic fibrosis). Temporary  irritation, such as coughing, hoarseness, or reversible  bronchoconstriction may occur; an inhaled bronchodi-  lator can be used before treatment with hypertonic  sodium chloride to reduce the risk of these adverse  effects.   Nebuliser solution, sodium chloride 7%, net price 60  x 4 mL =£27.00   Dose by inhalation of nebulised solution, 4 mL up to twice daily    Inhalations containing volatile substances such as  eucalyptus oil are traditionally used and although the  vapour may contain little of the additive it encourages  deliberate inspiration of warm moist air which is often  comforting in bronchitis; boiling water should not be    used owing to the risk of scalding. Inhalations are also  used for the relief of nasal obstruction in acute rhinitis or  sinusitis. Menthol and eucalyptus inhalation is used to  relieve sinusitis affecting the maxillary antrum (section  12 . 2 . 2 )   Children The use of strong aromatic decongestants  (applied as rubs or to pillows) is not advised for infants  under the age of 3 months. Carers of young infants in  whom nasal obstruction with mucus is a problem can  readily be taught appropriate techniques of suction  aspiration but sodium chloride 0.9% given as nasal  drops is preferred.   Tincture, balsamic acids approx. 4.5%. Label: 15  Dose add one teaspoonful to a pint of hot, not boiling, water and  inhale the vapour   Inhalation, racementhol or levomenthol 2g,  eucalyptus oil 10 mL, light magnesium carbonate 7 g,  water to 100 mL   Dose add one teaspoonful to a pint of hot, not boiling, water and  inhale the vapour   Cough may be a symptom of an underlying disorder,  such as asthma (section 3.1.1), gastro-oesophageal  reflux disease (section 1.1), or rhinitis (section 12.2.1),  which should be addressed before prescribing cough  suppressants. Cough may be a side-effect of another  drug, such as an ACE inhibitor (section 2.5.5. 1), or it can  be associated with smoking or environmental pollutants.  Cough can also have a significant habit component.  When there is no identifiable cause, cough suppressants  may be useful, for example if sleep is disturbed. They  may cause sputum retention and this may be harmful in  patients with chronic bronchitis and bronchiectasis.   Codeine may be effective but it is constipating and can  cause dependence; dextromethorphan and phol-  codine have fewer side-effects.   Sedating antihistamines are used as the cough sup-  pressant component of many compound cough prepara-  tions on sale to the public; all tend to cause drowsiness  which may reflect their main mode of action.   Children The use of over-the-counter cough suppres-  sants containing codeine should be avoided in children  under 18 years. Cough suppressants containing similar  opioid analgesics such as dextromethorphan and phol-  codine are not generally recommended in children and  should be avoided in children under 6 years.   MHRA/CHM advice (March 2008 and February  2009) Over-the-counter cough and cold med-  icines for children   Children under 6 years should not be given over-the-  counter cough and cold medicines containing the  following ingredients:   • brompheniramine, chlorphenamine, diphen-  hydramine, doxylamine, promethazine, or tri-  prolidine (antihistamines);   Over-the-counter cough and cold medicines can be  considered for children aged 6-12 years after basic  principles of best care have been tried, but treatment  should be restricted to 5 days or less. Children  should not be given more than 1 cough or cold  preparation at a time because different brands may  contain the same active ingredient; care should be  taken to give the correct dose.    MHRA/CHM advice (October 2010) Over-the-  counter codeine-containing liquid medicines  for children   Children under 18 years should not use codeine-  containing over-the-counter liquid medicines for  cough suppression   Indications dry or painful cough; diarrhoea (section  1.4.2); pain (section 4.7.2)   Contra-indications section 4.7.2  Hepatic impairment section 4.7.2  Renal impairment section 4.7.2  Pregnancy section 4.7.2  Breast-feeding section 4.7.2  Side-effects section 4.7.2  Dose   Dose 5-10 mL 3-4 times daily; CHILD (but not generally recom-  mended, see MHRA advice above) 5-12 years, 2.5-5 mL  Note BP directs that when Diabetic Codeine Linctus is prescribed,  Codeine Linctus formulated with a vehicle appropriate for  administration to diabetics, whether or not labelled ‘Diabetic  Codeine Linctus’, shall be dispensed or supplied   Dose CHILD (but not generally recommended, see MHRA advice  above) 2-5 years 5 mL 3-4 times daily   Note BP directs that Paediatric Codeine Linctus may be prepared  extemporaneously by diluting Codeine Linctus with a suitable  vehicle in accordance with the manufacturer’s instructions   Cautions asthma; chronic, persistent, or productive  cough; interactions: Appendix 1 (pholcodine)   Contra-indications chronic bronchitis, chronic  obstructive pulmonary disease, bronchiectasis,  patients at risk of respiratory failure  Hepatic impairment avoid   Side-effects nausea, vomiting, constipation, sputum  retention, drowsiness, dizziness, excitation, confusion,  rash   Linctus (= oral solution), pholcodine 5mg/5mL in a  suitable flavoured vehicle, containing citric acid  monohydrate 1%. Net price 100 mL = 31p  Brands include Pavacol-D® (sugar-free), Galenphol ® (sugar-free)  Dose 5-10 mL 3-4 times daily; CHILD (but not generally recom-  mended, see notes above) 6-12 years 2.5-5 mL   Linctus (= oral solution), pholcodine 10 mg/5 mL in a  suitable flavoured vehicle, containing citric acid  monohydrate 2%. Net price 100 mL = 44p  Dose ADULT and CHILD over 12 years, 5mL 3-4 times daily  Brands include Galenphol ®   Paediatric linctus (= oral solution), orange, sugar-  free, pholcodine 2 mg/ 5 mL. Net price 90-mL pack =  £ 1.20   Dose CHILD (but not generally recommended, see notes above)  6-12 years 10 mL 3 times daily   Diamorphine and methadone have been used to control  distressing cough in terminal lung cancer although mor-  phine is now preferred (see p. 22). In other circum-  stances they are contra-indicated because they induce  sputum retention and ventilatory failure as well as  causing opioid dependence. Methadone linctus should  be avoided because it has a long duration of action and  tends to accumulate.   Contra-indications section 4.7.2  Hepatic impairment section 4.7.2  Renal impairment section 4.7.2  Pregnancy section 4.7.2   Linctus (= oral solution), methadone hydrochloride  2 mg/ 5 mL in a suitable vehicle with a tolu flavour.  Label: 2   Dose 2.5-5 mL every 4-6 hours, reduced to twice daily on  prolonged use   Contra-indications section 4.7.2  Hepatic impairment section 4.7.2  Renal impairment section 4.7.2  Pregnancy section 4.7.2  Breast-feeding section 4.7.2  Side-effects section 4.7.2  Dose   Demulcent cough preparations contain soothing sub-  stances such as syrup or glycerol and some patients  believe that such preparations relieve a dry irritating  cough. Preparations such as simple linctus have the  advantage of being harmless and inexpensive; paed-  iatric simple linctus is particularly useful in children.  Expectorants are claimed to promote expulsion of  bronchial secretions, but there is no evidence that any  drug can specifically facilitate expectoration.  Compound preparations are on sale to the public for  the treatment of cough and colds but should not be used  in children under 6 years; the rationale for some is  dubious. Care should be taken to give the correct dose  and to not use more than one preparation at a time, see  MHRA/CHM advice, p. 204.   Dose ADULT and CHILD over 12 years 5mL 3-4 times daily  A sugar-free version is also available   Dose CHILD 1 month-12 years 5-10 mL 3-4 times daily  A sugar-free version is also available   Nasal decongestants for administration by mouth may  not be as effective as preparations for local application  (section 12.2.2) but they do not give rise to rebound  nasal congestion on withdrawal. Pseudoephedrine is   Systemic decongestants should be used with caution in  diabetes, hypertension, hyperthyroidism, susceptibility  to angle-closure glaucoma, prostatic hypertrophy,  ischaemic heart disease, and should be avoided in  patients taking monoamine oxidase inhibitors; interac-  tions: Appendix 1 (sympathomimetics).   Renal impairment manufacturer advises caution in  moderate to severe impairment  Pregnancy defective closure of the abdominal wall  (gastroschisis) reported very rarely in newborns after  first trimester exposure   Breast-feeding amount too small to be harmful  Side-effects tachycardia, anxiety, restlessness,  insomnia; rarely hallucinations, rash; very rarely  angle-closure glaucoma; urinary retention also  reported  Dose   • 60 mg 3-4 times daily; CHILD 6-12 years 30 mg 3-4  times daily   Tablets, pseudoephedrine hydrochloride 60 mg, net  price 24-tab pack = £2.00   Linctus, orange, sugar-free, pseudoephedrine hydro-  chloride 30 mg/5 mL, net price 100 mL = 70p   Tablets, red, f/c, pseudoephedrine hydrochloride  60 mg, net price 24 = £2.12  Elixir, red, pseudoephedrine hydrochloride 30 mg/  5mL, net price 100 mL = £1.05    1. Can be sold to the public provided no more than 720 mg of  pseudoephedrine salts are supplied, and ephedrine base (or  salts) are not supplied at the same time; for details see  Medicines, Ethics and Practice, No. 34, London, Pharma-  ceutical Press, 2010 (and subsequent editions as available)   Most anxiolytics (‘sedatives’) will induce sleep when  given at night and most hypnotics will sedate when  given during the day. Prescribing of these drugs is  widespread but dependence (both physical and psycho-  logical) and tolerance occur. This may lead to difficulty  in withdrawing the drug after the patient has been taking  it regularly for more than a few weeks (see Dependence  and Withdrawal, below). Hypnotics and anxiolytics  should therefore be reserved for short courses to alle-  viate acute conditions after causal factors have been  established.   Benzodiazepines are the most commonly used anxio-  lytics and hypnotics; they act at benzodiazepine recep-  tors which are associated with gamma-aminobutyric  acid (GABA) receptors. Older drugs such as mepro-  bamate and barbiturates are not recommended — they  have more side-effects and interactions than benzodiaz-  epines and are much more dangerous in overdosage.   Paradoxical effects A paradoxical increase in hosti-  lity and aggression may be reported by patients taking  benzodiazepines. The effects range from talkativeness  and excitement to aggressive and antisocial acts.  Adjustment of the dose (up or down) sometimes attenu-  ates the impulses. Increased anxiety and perceptual  disorders are other paradoxical effects. Increased hosti-  lity and aggression after barbiturates and alcohol usually  indicates intoxication.   Driving Hypnotics and anxiolytics may impair judge-  ment and increase reaction time, and so affect ability to  drive or operate machinery; they increase the effects of  alcohol. Moreover the hangover effects of a night dose  may impair driving on the following day. See also Drugs  and Driving under General Guidance, p. 3.   Dependence and withdrawal Withdrawal of a ben-  zodiazepine should be gradual because abrupt with-  drawal may produce confusion, toxic psychosis, con-  vulsions, or a condition resembling delirium tremens.  Abrupt withdrawal of a barbiturate is even more likely to  have serious effects.    The benzodiazepine withdrawal syndrome may develop  at any time up to 3 weeks after stopping a long-acting  benzodiazepine, but may occur within a day in the case  of a short-acting one. It is characterised by insomnia,  anxiety, loss of appetite and of body-weight, tremor,  perspiration, tinnitus, and perceptual disturbances.  Some symptoms may be similar to the original com-  plaint and encourage further prescribing; some symp-  toms may continue for weeks or months after stopping  benzodiazepines.   A benzodiazepine can be withdrawn in steps of about  one-eighth (range one-tenth to one-quarter) of the daily  dose every fortnight. A suggested withdrawal protocol  for patients who have difficulty is as follows:   2. Reduce diazepam dose every 2-3 weeks in steps of  2 or 2.5 mg; if withdrawal symptoms occur, main-  tain this dose until symptoms improve   3. Reduce dose further, if necessary in smaller steps; 2  it is better to reduce too slowly rather than too  quickly   4. Stop completely; period needed for withdrawal can  vary from about 4 weeks to a year or more   Counselling may help; beta-blockers should only be  tried if other measures fail; antidepressants should be  used only where depression or panic disorder co-exist  or emerge; avoid antipsychotics (which may aggravate  withdrawal symptoms).   1. Benzodiazepines are indicated for the short-  term relief (two to four weeks only) of anxiety  that is severe, disabling, or causing the patient  unacceptable distress, occurring alone or in  association with insomnia or short-term psycho-  somatic, organic, or psychotic illness.   3. Benzodiazepines should be used to treat insom-  nia only when it is severe, disabling, or causing  the patient extreme distress.   Before a hypnotic is prescribed the cause of the insom-  nia should be established and, where possible, under-  lying factors should be treated. However, it should be  noted that some patients have unrealistic sleep expecta-  tions, and others understate their alcohol consumption  which is often the cause of the insomnia. Short-acting  hypnotics are preferable in patients with sleep onset  insomnia, when sedation the following day is undesir-  able, or when prescribing for elderly patients (but see  below). Long-acting hypnotics are indicated in patients  with poor sleep maintenance (e.g. early morning wak-  ing) that causes daytime effects, when an anxiolytic   1. Approximate equivalent doses, diazepam 5 mg  = chlordiazepoxide 15 mg   = loprazolam 0.5-1 mg  = lorazepam 0.5-1 mg  = lormetazepam 0.5-1 mg  = nitrazepam 5 mg  = oxazepam 15 mg  = temazepam 10 mg   2. Steps may be adjusted according to initial dose and  duration of treatment and can range from diazepam  500 micrograms (one-quarter of a 2-mg tablet) to 2.5 mg   Transient insomnia may occur in those who normally  sleep well and may be due to extraneous factors such as  noise, shift work, and jet lag. If a hypnotic is indicated  one that is rapidly eliminated should be chosen, and  only one or two doses should be given.   Short-term insomnia is usually related to an emotional  problem or serious medical illness. It may last for a few  weeks and may recur; a hypnotic can be useful but  should not be given for more than three weeks (pre-  ferably only one week). Intermittent use is desirable  with omission of some doses. A short-acting drug is  usually appropriate.   Chronic insomnia is rarely benefited by hypnotics and is  sometimes due to mild dependence caused by injudi-  cious prescribing of hypnotics. Psychiatric disorders  such as anxiety, depression, and abuse of drugs and  alcohol are common causes. Sleep disturbance is very  common in depressive illness and early wakening is  often a useful pointer. The underlying psychiatric com-  plaint should be treated, adapting the drug regimen to  alleviate insomnia. For example, clomipramine or mir-  tazapine prescribed for depression will also help to  promote sleep if taken at night. Other causes of insom-  nia include daytime cat-napping and physical causes  such as pain, pruritus, and dyspnoea.   Hypnotics should not be prescribed indiscriminately  and routine prescribing is undesirable. They should be  reserved for short courses in the acutely distressed.  Tolerance to their effects develops within 3 to 14 days  of continuous use and long-term efficacy cannot be  assured. A major drawback of long-term use is that  withdrawal can cause rebound insomnia and a with-  drawal syndrome (section 4.1).   Where prolonged administration is unavoidable hypno-  tics should be discontinued as soon as feasible and the  patient warned that sleep may be disturbed for a few  days before normal rhythm is re-established; broken  sleep with vivid dreams may persist for several weeks.   Children The prescribing of hypnotics to children,  except for occasional use such as for night terrors and  somnambulism (sleep-walking), is not justified.   Elderly Hypnotics should be avoided in the elderly,  because the elderly are at greater risk of becoming  ataxic and confused, leading to falls and injury.   Dental procedures Some anxious patients may ben-  efit from the use of a hypnotic the night before the dental  appointment. Hypnotics do not relieve pain, and if pain  interferes with sleep an appropriate analgesic should be  given. Diazepam (section 4.1.2), nitrazepam or tem-  azepam are used at night for dental patients. Temaze-  pam is preferred when it is important to minimise any  residual effect the following day. For information on  anxiolytics for dental procedures, see section 15.1.4.1.   Benzodiazepines used as hypnotics include nitrazepam  and flurazepam which have a prolonged action and  may give rise to residual effects on the following day;  repeated doses tend to be cumulative.   Loprazolam, lormetazepam, and temazepam act for a  shorter time and they have little or no hangover effect.   If insomnia is associated with daytime anxiety then the  use of a long-acting benzodiazepine anxiolytic such as  diazepam given as a single dose at night may effectively  treat both symptoms.   For general guidelines on benzodiazepine prescribing  see section 4.1.2 and for benzodiazepine withdrawal see  section 4.1.   Hepatic impairment Benzodiazepines can precipitate  coma if used in hepatic impairment. If treatment is  necessary, benzodiazepines with shorter half lives are  safer, such as temazepam or oxazepam. Start with  smaller initial doses or reduce dose; avoid in severe  impairment.   Renal impairment Patients with renal impairment  have increased cerebral sensitivity to benzodiazepines;  start with small doses in severe impairment.   Pregnancy There is a risk of neonatal withdrawal  symptoms when benzodiazepines are used during  pregnancy. Avoid regular use and use only if there is a  clear indication such as seizure control. High doses  administered during late pregnancy or labour may  cause neonatal hypothermia, hypotonia, and respiratory  depression.   Breast-feeding Benzodiazepines are present in milk,  and should be avoided if possible during breast-feeding.   Indications insomnia (short-term use; see p. 208)  Cautions respiratory disease, muscle weakness and  myasthenia gravis, history of drug or alcohol abuse,  marked personality disorder; reduce dose in elderly  and debilitated; avoid prolonged use (and abrupt  withdrawal thereafter); acute porphyria (section  9.8.2); interactions: Appendix 1 (anxiolytics and  hypnotics)   Driving Drowsiness may persist the next day and affect  performance of skilled tasks (e.g. driving); effects of alcohol  enhanced   Contra-indications respiratory depression; marked  neuromuscular respiratory weakness including  unstable myasthenia gravis; acute pulmonary insuffi-  ciency; sleep apnoea syndrome; not for use alone to  treat depression (or anxiety associated with depres-  sion) or chronic psychosis  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects drowsiness and lightheadedness the next  day; confusion and ataxia (especially in the elderly);  amnesia may occur; dependence; see also under  Diazepam (section 4.1.2); overdosage: see Emer-  gency Treatment of Poisoning, p. 37  Dose   • 5-10 mg at bedtime; ELDERLY (or debilitated) 2.5-5 mg;  CHILD 1 month-2 years (infantile spasms) see BNF for  Children   Nitrazepam (Non-proprietary) (Ml  Tablets, nitrazepam 5 mg, net price 28 = 98p.   Indications insomnia (short-term use; see p. 208)  Cautions see under Nitrazepam  Contra-indications see under Nitrazepam  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see under Nitrazepam  Dose   CHILD not recommended  Dalmane® (Meda) (Ml M  Capsules, flurazepam (as hydrochloride), 15 mg  (grey /yellow), net price 30-cap pack = £6.73; 30 mg  (black/ grey), 30-cap pack = £8.63. Label: 19   • 1 mg at bedtime, increased to 1.5 or 2 mg if required;  ELDERLY (or debilitated) 0.5 or 1 mg; CHILD not recom-  mended   Loprazolam (Non-proprietary) (Ml  Tablets, loprazolam 1 mg (as mesilate). Net price 28-  tab pack = £18.00. Label: 19   500 micrograms; CHILD not recommended  Lormetazepam (Non-proprietary) (Ml  Tablets, lormetazepam 500 micrograms, net price 30-  tab pack = £56.25; 1 mg, 30-tab pack = £54.60.   Contra-indications see under Nitrazepam  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above   • 10-20 mg at bedtime, exceptional circumstances 30-  40 mg; ELDERLY (or debilitated) 10 mg at bedtime,  exceptional circumstances 20 mg; CHILD not recom-  mended   Temazepam (Non-proprietary) (Ml  Tablets, temazepam 10 mg, net price 28-tab pack =  £3.42; 20 mg, 28-tab pack = £2.24. Label: 19  Dental prescribing on NHS Temazepam Tablets may be pre-  scribed   Oral solution, temazepam 10 mg/5 mL, net price  300 mL = £33.44. Label: 19   Zaleplon, zolpidem and zopiclone are non-benzodia-  zepine hypnotics, but they act at the benzodiazepine  receptor. They are not licensed for long-term use; dep-  endence has been reported in a small number of  patients. Zolpidem and zopiclone have a short duration  of action; zaleplon is very short acting.   Indications insomnia (short-term use — up to 2 weeks)  Cautions respiratory insufficiency (avoid if severe);  muscle weakness and myasthenia gravis, history of  drug or alcohol abuse; depression (risk of suicidal  ideation); avoid prolonged use (risk of tolerance and  withdrawal symptoms); interactions: Appendix 1  (anxiolytics and hypnotics)   Contra-indications sleep apnoea syndrome, marked  neuromuscular respiratory weakness including  unstable myasthenia gravis  Hepatic impairment can precipitate coma; reduce  dose to 5 mg (avoid if severe impairment)  Pregnancy use only if necessary and restrict to occa-  sional short-term use; risk of withdrawal symptoms in  neonate if used in late pregnancy  Breast-feeding present in milk but amount probably  too small to be harmful   Side-effects amnesia, paraesthesia, drowsiness; dys-  menorrhea; less commonly nausea, anorexia, asthe-  nia, incoordination, confusion, impaired concentra-  tion, depression, depersonalisation, dizziness,  hallucinations, disturbances of smell, hearing, speech,  and vision; photosensitivity; paradoxical effects (see  p. 207) and sleep-walking also reported  Dose   • ADULT over 18 years, 10 mg at bedtime or after going to  bed if difficulty falling asleep; ELDERLY 5 mg  Note Patients should be advised not to take a second dose  during a single night   Capsules, zaleplon 5 mg (white/light brown), net  price 14-cap pack = £3.12; 10 mg (white), 14-cap pack  = £3.76. Label: 2   Indications insomnia (short-term use — up to 4 weeks)  Cautions depression, muscle weakness and myas-  thenia gravis, history of drug or alcohol abuse; elderly;  avoid prolonged use (and abrupt withdrawal there-  after); interactions: Appendix 1 (anxiolytics and  hypnotics)   Driving Drowsiness may persist the next day and affect  performance of skilled taste (e.g. driving); effects of alcohol  enhanced   Contra-indications obstructive sleep apnoea, acute or  severe respiratory depression, marked neuromuscular  respiratory weakness including unstable myasthenia  gravis, psychotic illness   Hepatic impairment can precipitate coma; reduce  dose to 5 mg (avoid if severe impairment)   Renal impairment use with caution  Pregnancy avoid regular use (risk of neonatal with-  drawal symptoms); high doses during late pregnancy  or labour may cause neonatal hypothermia, hypoto-  nia, and respiratory depression  Breast-feeding small amounts present in milk — avoid  Side-effects diarrhoea, nausea, vomiting, dizziness,  headache, drowsiness, hallucination, agitation, asthe-  nia, amnesia; dependence, memory disturbances,  nightmares, depression, confusion, perceptual distur-  bances or diplopia, tremor, ataxia, falls, skin reactions,  changes in libido; paradoxical effects (see p. 207),  muscular weakness, and sleep-walking also reported  Dose   • ADULT over 18 years, 10 mg at bedtime; ELDERLY (or  debilitated) 5 mg   Zolpidem (Non-proprietary) (Ml  Tablets, zolpidem tartrate 5 mg, net price 28-tab pack  = £1.41; 10 mg, 28-tab pack = £1.46. Label: 19   Stilnoct® (Sanofi-Aventis) (Ml  Tablets, both f/c, zolpidem tartrate 5 mg, net price 28-  tab pack = £2.96; 10 mg, 28-tab pack = £4.31.   Indications insomnia (short-term use — up to 4 weeks)  Cautions elderly; muscle weakness and myasthenia  gravis, history of drug abuse, psychiatric illness; avoid  prolonged use (risk of tolerance and withdrawal  symptoms); interactions: Appendix 1 (anxiolytics and  hypnotics)   Driving Drowsiness may persist the next day and affect  performance of skilled taste (e.g. driving); effects of alcohol  enhanced   Contra-indications marked neuromuscular respir-  atory weakness including unstable myasthenia gravis,  respiratory failure, severe sleep apnoea syndrome  Hepatic impairment can precipitate coma; reduce  dose (avoid if severe impairment)   Renal impairment start with small doses in severe  impairment; increased cerebral sensitivity  Pregnancy avoid regular use (risk of neonatal with-  drawal symptoms); high doses during late pregnancy  or labour may cause neonatal hypothermia, hypoto-  nia, and respiratory depression  Breast-feeding present in milk — avoid  Side-effects taste disturbance; less commonly nausea,  vomiting; dizziness, drowsiness, dry mouth, headache;    rarely amnesia, confusion, depression, hallucinations,  nightmares; very rarely light headedness, incoordi-  nation; paradoxical effects (see p. 207) and sleep-  walking also reported   • ADULT over 18 years, 7.5 mg at bedtime; ELDERLY initi-  ally 3.75 mg at bedtime increased if necessary   Zopiclone (Non-proprietary) (Ml  Tablets, zopiclone 3.75 mg, net price 28-tab pack =  £1.34; 7.5 mg, 28-tab pack = £1.35. Label: 19   Zimovane® (Sanofi-Aventis) (S  Tablets, f/c, zopiclone 3.75 mg {Zimovane® LS), net  price 28-tab pack = £2.24; 7.5 mg (scored), 28-tab  pack = £3.26. Label: 19   Chloral hydrate and derivatives were formerly popular  hypnotics for children (but the use of hypnotics in  children is not usually justified). There is no convincing  evidence that they are particularly useful in the elderly  and their role as hypnotics is now very limited.   Cautions reduce dose in elderly and debilitated; avoid  prolonged use (and abrupt withdrawal thereafter);  avoid contact with skin and mucous membranes;  interactions: Appendix 1 (anxiolytics and hypnotics)  Driving Drowsiness may persist the next day and affect  performance of skilled tasks (e.g. driving); effects of alcohol  enhanced   Hepatic impairment can precipitate coma; reduce  dose in mild to moderate impairment; avoid in severe  impairment   Breast-feeding risk of sedation in infant — avoid  Side-effects gastric irritation (nausea and vomiting  reported), abdominal distention, flatulence, headache,  tolerance, dependence, excitement, delirium (espe-  cially on abrupt withdrawal), ketonuria, and rash  Dose   Mixture, chloral hydrate 500 mg/5 mL in a suitable  vehicle. Label: 19, 27   Elixir, chloral hydrate 200 mg/5 mL (4%) in a suitable  vehicle with a black currant flavour. Label: 1, 27  Dose CHILD 1 month-1 year 30-50 mg/kg, taken well diluted  with water at bedtime    diCloral betaine  Welldorm® (Alphashow) (Ml (3  Tablets, blue-purple, f/c, cloral betaine 707 mg  (= chloral hydrate 414 mg), net price 30-tab pack =  £12.10. Label: 19, 27   Dose ADULT and CHILD over 12 years, 1-2 tablets with water or  milk at bedtime, max. 5 tablets (chloral hydrate 2 g) daily   Elixir, red, chloral hydrate 143.3 mg/5 mL, net price  150-mL pack = £8.70. Label: 19, 27  Dose 15-45 mL (chloral hydrate 0.4-1. 3 g) with water or milk, at  bedtime, max. 70 mL (chloral hydrate 2 g) daily; CHILD 2-12 years,  1-1.75 mL/kg (chloral hydrate 30-50 mg/kg), max. 35 mL  (chloral hydrate 1 g) daily   Clomethiazole may be a useful hypnotic for elderly  patients because of its freedom from hangover but, as  with all hypnotics, routine administration is undesirable  and dependence occurs. It is also licensed for use in  acute alcohol withdrawal, but see section 4.10.1.   Cautions cardiac and respiratory disease (confusional  state may indicate hypoxia), chronic pulmonary  insufficiency, sleep apnoea syndrome; history of drug  abuse; avoid prolonged use (and abrupt withdrawal  thereafter); marked personality disorder; elderly;  excessive sedation may occur (particularly with  higher doses); interactions: Appendix 1 (anxiolytics  and hypnotics)   Driving Drowsiness may persist the next day and affect  performance of skilled tasks (e.g. driving); effects of alcohol  enhanced   alcohol-dependent patients who continue to drink  Hepatic impairment can precipitate coma; reduce  dose   Side-effects nasal congestion and irritation  (increased nasopharyngeal and bronchial secretions),  conjunctival irritation, headache; rarely gastrointes-  tinal disturbances, paradoxical excitement, confusion,  dependence, rash, urticaria, bullous eruption,  anaphylaxis, alterations in liver enzymes  Dose   • Severe insomnia in the elderly (short-term use), 1-2  capsules at bedtime; CHILD not recommended   • Restlessness and agitation in the elderly, 1 capsule 3  times daily   • Alcohol withdrawal (but see section 4.10.1), initially  2-4 capsules, if necessary repeated after some hours;  day 1 (first 24 hours), 9-12 capsules in 3-4 divided  doses; day 2, 6-8 capsules in 3-4 divided doses; day 3,  4-6 capsules in 3-4 divided doses; then gradually  reduced over days 4-6; total treatment for not more  than 9 days    Heminevrin® (AstraZeneca) (Ml  Capsules, grey-brown, clomethiazole base 192 mg in  an oily basis. Net price 60-cap pack = £4.78. Label: 19   Some antihistamines (section 3.4.1) such as prometh-  azine are on sale to the public for occasional insomnia;  their prolonged duration of action can often cause  drowsiness the following day. The sedative effect of  antihistamines may diminish after a few days of con-  tinued treatment; antihistamines are associated with  headache, psychomotor impairment and antimuscarinic  effects.   Promethazine is also popular for use in children, but the  use of hypnotics in children is not usually justified.   Indications sedation (short-term use); allergy and  urticaria (section 3.4.1); nausea and vomiting (section  4.6)   Contra-indications see notes in section 3.4.1  Hepatic impairment see notes in section 3.4.1  Renal impairment see Promethazine Hydrochloride,  section 3.4.1   Pregnancy see notes in section 3.4.1  Breast-feeding see notes in section 3.4.1  Side-effects see Promethazine Hydrochloride, section   • By mouth, 25-50 mg; CHILD 2-5 years 15-20 mg, 5-10  years 20-25 mg    Side-effects nausea, vomiting, diarrhoea, abdominal  pain, anorexia; hypertension, peripheral oedema;  dyspnoea; sleep disorders, confusion, disorientation,  paraesthesia, hypoaesthesia, impaired attention,  depression, drowsiness, anxiety, dizziness, headache,  tremor, asthenia, fatigue; urinary incontinence,  nocturnal enuresis; arthralgia, muscle cramps; blurred  vision; sweating; less commonly faecal incontinence,  myoclonus, psychosis, paranoia, hallucination, agita-  tion, amnesia, and rash; respiratory depression, dep-  endence, seizures, suicidal ideation, and urticaria also  reported   • ADULT over 18 years, initially 2.25 g on retiring and  repeated 2.5-4 hours later, increased according to  response in steps of 1.5 g daily in 2 divided doses at  intervals of 1-2 weeks; max. 9 g daily in two divided  doses   Note Dose titration should be repeated if restarting after  interval of more than 14 days   Counselling Dilute each dose with 60 mL water; prepare  both doses before retiring. Observe the same time interval  (2-3 hours) each night between the last meal and the first  dose   Oral solution, sugar-free, sodium oxybate 500 mg/  mL, net price 180 mL (with graduated syringe) =  £360.00. Label: 13, 19, counselling, administration   Melatonin is a pineal hormone; it is licensed for the  short-term treatment of insomnia in adults over 55  years. For information on the use of melatonin in  children and adolescents, see BNF for Children.   Alcohol is a poor hypnotic because the diuretic action  interferes with sleep during the latter part of the night.  Alcohol also disturbs sleep patterns, and so can worsen  sleep disorders; interactions: Appendix 1 (alcohol).   Sodium oxybate is a central nervous system depressant  that is licensed for the treatment of narcolepsy with  cataplexy.   Cautions history of drug abuse or depression; epi-  lepsy; elderly; respiratory disorders; heart failure and  hypertension (high sodium content); risk of disconti-  nuation effects including rebound cataplexy and  withdrawal symptoms; acute porphyria (section  9.8.2); interactions: Appendix 1 (sodium oxybate)  Hepatic impairment halve initial dose  Renal impairment caution — contains 3.96 mmol  Na + /mL   Pregnancy no information available — avoid  Breast-feeding present in milk — avoid  Side-effects less commonly abdominal pain, dys-  pepsia, dry mouth, mouth ulceration, weight gain,  hypertension, chest pain, malaise, dizziness, restless-  ness, nervousness, irritability, anxiety, migraine, pro-  teinuria, glycosuria, pruritus, rash, dry skin; rarely  thirst, flatulence, halitosis, salivation, vomiting, gas-  tritis, hypertriglyceridaemia, angina, palpitation, syn-  cope, hot flushes, aggression, impaired memory,  restless legs syndrome, paraesthesia, mood changes,  priapism, increased libido, prostatitis, polyuria, hae-  maturia, leucopenia, thrombocytopenia, electrolyte  disturbances, muscle spasm, arthritis, lacrimation,  visual disturbances, nail disorder  Dose   • ADULT over 55 years, 2 mg once daily 1-2 hours before  bedtime for up to 13 weeks; CHILD 1 month-18 years  see BNF for Children   Tablets, m/r, melatonin 2 mg, net price 21-tab pack =  £10.77. Label: 2, 21, 25    Benzodiazepine anxiolytics can be effective in alleviat-  ing anxiety states. Although these drugs are sometimes  prescribed for stress-related symptoms, unhappiness, or  minor physical disease, their use in such conditions is  inappropriate. Benzodiazepine anxiolytics should not be  used as sole treatment for chronic anxiety, and they are  not appropriate for treating depression or chronic psy-  chosis. In bereavement, psychological adjustment may  be inhibited by benzodiazepines. In children, anxiolytic  treatment should be used only to relieve acute anxiety  (and related insomnia) caused by fear (e.g. before sur-  gery)-    Anxiolytic benzodiazepine treatment should be limited  to the lowest possible dose for the shortest possible time  (see p. 208). Dependence is particularly likely in patients  with a history of alcohol or drug abuse and in patients  with marked personality disorders.    Some antidepressants (section 4.3) are licensed for use  in anxiety and related disorders; see section 4.3 for a  comment on their role in chronic anxiety. Some anti-  psychotics, in low doses, are also sometimes used in  severe anxiety for their sedative action, but long-term  use should be avoided because of the risk of adverse  effects (section 4.2.1). The use of antihistamines (e.g.  hydroxyzine) for their sedative effect in anxiety is not  appropriate.    Beta-blockers (section 2.4) do not affect psychological  symptoms of anxiety, such as worry, tension, and fear,  but they do reduce autonomic symptoms, such as  palpitation and tremor; they do not reduce non-auto-  nomic symptoms, such as muscle tension. Beta-blockers  are therefore indicated for patients with predominantly  somatic symptoms; this, in turn, may prevent the onset  of worry and fear.   Benzodiazepines are indicated for the short-term relief  of severe anxiety, long-term use should be avoided (see  p. 208). Diazepam, alprazolam, chlordiazepoxide, and  clobazam have a sustained action. Shorter-acting com-  pounds such as lorazepam and oxazepam may be  preferred in patients with hepatic impairment but they  carry a greater risk of withdrawal symptoms.   In panic disorders (with or without agoraphobia) resis-  tant to antidepressant therapy (section 4.3), a benzodia-  zepine (lorazepam 3-5 mg daily or clonazepam 1-2 mg  daily (section 4.8.1) [both unlicensed]) may be used;  alternatively, a benzodiazepine may be used as short-  term adjunctive therapy at the start of antidepressant  treatment to prevent the initial worsening of symptoms.  Diazepam or lorazepam are very occasionally adminis-  tered intravenously for the control of panic attacks. This  route is the most rapid but the procedure is not without  risk (section 4.8.2) and should be used only when  alternative measures have failed. The intramuscular  route has no advantage over the oral route.   Hepatic impairment Benzodiazepines can precipitate  coma if used in hepatic impairment. If treatment is  necessary, benzodiazepines with shorter half lives are    safer, such as temazepam or oxazepam. Start with  smaller initial doses or reduce dose; avoid in severe  impairment.   Renal impairment Patients with renal impairment  have increased cerebral sensitivity to benzodiazepines;  start with small doses in severe impairment.   Pregnancy There is a risk of neonatal withdrawal  symptoms when benzodiazepines are used during  pregnancy. Avoid regular use and use only if there is a  clear indication such as seizure control. High doses  administered during late pregnancy or labour may  cause neonatal hypothermia, hypotonia, and respiratory  depression.   Breast-feeding Benzodiazepines are present in milk,  and should be avoided if possible during breast-feeding.    Indications short-term use in anxiety or insomnia (see  p. 208); adjunct in acute alcohol withdrawal; status  epilepticus (section 4.8.2); febrile convulsions (section  4.8.3); muscle spasm (section 10.2.2); peri-operative  use (section 15.1.4.1)   Cautions respiratory disease, muscle weakness and  myasthenia gravis, history of drug or alcohol abuse,  marked personality disorder; reduce dose in elderly  and debilitated; avoid prolonged use (and abrupt  withdrawal thereafter); special precautions for intra-  venous injection (section 4.8.2); acute porphyria  (section 9.8.2); when given parenterally, close obser-  vation required until full recovery from sedation;  interactions: Appendix 1 (anxiolytics and hypnotics)  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced  Contra-indications respiratory depression; marked  neuromuscular respiratory weakness including  unstable myasthenia gravis; acute pulmonary insuffi-  ciency; sleep apnoea syndrome; not for chronic psy-  chosis; should not be used alone in depression or in  anxiety with depression; avoid injections containing  benzyl alcohol in neonates (see under preparations  below)   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   Breast-feeding see notes above  Side-effects drowsiness and lightheadedness the next  day; confusion and ataxia (especially in the elderly);  amnesia; dependence; paradoxical increase in  aggression (see also section 4.1); muscle weakness;  occasionally: headache, vertigo, hypotension, saliva-  tion changes, gastro-intestinal disturbances, visual  disturbances, dysarthria, tremor, changes in libido,  incontinence, urinary retention; blood disorders and  jaundice reported; skin reactions; on intravenous  injection, pain, thrombophlebitis, and rarely apnoea;  overdosage: see Emergency Treatment of Poisoning,  p. 37  Dose   • By mouth, anxiety, 2 mg 3 times daily increased if  necessary to 15-30 mg daily in divided doses; ELDERLY  (or debilitated) half adult dose   • By intramuscular injection or slow intravenous  injection (into a large vein, at a rate of not more than    5 mg/minute), for severe acute anxiety, control of  acute panic attacks, and acute alcohol withdrawal,   10 mg, repeated if necessary after not less than 4  hours   Note Only use intramuscular route when oral and intra-  venous routes not possible; emulsion formulation preferred  for intravenous injection; special precautions for intravenous  injection section 4.8.2   • By rectum as rectal solution, acute anxiety and agi-  tation, 500 micrograms /kg repeated after 12 hours as  required; ELDERLY 250 micrograms /kg; CHILD not  recommended   As suppositories, anxiety when oral route not appro-  priate, 10-30 mg (higher dose divided); dose form not  appropriate for less than 10 mg    Diazepam (Non-proprietary) [Ml  Tablets, diazepam 2 mg, net price 28-tab pack = 89p;  5 mg, 28-tab pack = 90p; 10 mg, 28-tab pack = 92p.  Label: 2 or 19   Dental prescribing on NHS Diazepam Oral Solution 2 mg/  5 mL may be prescribed   Excipients may include benzyl alcohol (avoid in neonates, see Excipi-  ents, p. 2), ethanol, propylene glycol   Note Do not dilute (except for intravenous infusion, see  Appendix 6)    Rectal tubes (= rectal solution), diazepam 2 mg/mL,  net price 1.25-mL (2.5-mg) tube = 90p, 2.5-mL (5-mg)  tube = £1.41; 4 mg/mL, 2.5-mL (10-mg) tube =£1.88.  Label: 2 or 19   Contra-indications see under Diazepam  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see under Diazepam  Dose   • 250-500 micrograms 3 times daily (ELDERLY or debili-  tated 250 micrograms 2-3 times daily), increased if  necessary to a total of 3 mg daily; CHILD not recom-  mended   Alprazolam (Non-proprietary) (Ml (Ml  Tablets, alprazolam 250 micrograms, net price 60-tab  pack = £2.97; 500 micrograms, 60-tab pack = £5.69.  Label: 2   Contra-indications see under Diazepam  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see under Diazepam  Dose   • Anxiety, 10 mg 3 times daily increased if necessary to  60-100 mg daily in divided doses; ELDERLY (or debili-  tated) half adult dose; CHILD not recommended   • Treatment of alcohol withdrawal in primary care, 10-  50 mg 4 times daily, gradually reduced over 5-10 days   Chlordiazepoxide (Non-proprietary) Ml  Capsules, chlordiazepoxide hydrochloride 5 mg, net  price 100-cap pack = £6.21; 10 mg, 100-cap pack =  £13.13. Label: 2   Tablets, chlordiazepoxide hydrochloride 5 mg, net  price 100 = £4.24; 10 mg, 100 = £11.34. Label: 2   Indications short-term use in anxiety or insomnia (see  p. 208); status epilepticus (section 4.8.2); peri-opera-  tive (section 15.1.4.1)   Cautions see under Diazepam; short acting; when  given parenterally, facilities for managing respiratory  depression with mechanical ventilation must be  available   • By mouth, anxiety, 1-4 mg daily in divided doses;  ELDERLY (or debilitated) half adult dose   Insomnia associated with anxiety, 1-2 mg at bedtime;  CHILD not recommended   • By intramuscular or slow intravenous injection (into a  large vein), acute panic attacks, 25-30 micrograms/kg  (usual range 1.5-2. 5 mg), repeated every 6 hours if  necessary; CHILD not recommended   Lorazepam (Non-proprietary) (M  Tablets, lorazepam 1 mg, net price 28-tab pack =  £5.42; 2.5 mg, 28-tab pack = £7.11. Label: 2 or 19  Injection, lorazepam 4 mg/mL, net price 1-mL amp =  35p   Note For intramuscular injection it should be diluted with an equal  volume of water for injections or physiological saline (but only use  when oral and intravenous routes not possible)   Contra-indications see under Diazepam  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see under Diazepam  Dose   • Anxiety, 15-30 mg (elderly or debilitated 10-20 mg)  3-4 times daily; CHILD not recommended   • Insomnia associated with anxiety, 15-25 mg (max.  50 mg) at bedtime; CHILD not recommended   Tablets, oxazepam 10 mg, net price 28-tab pack =  £4.85; 15 mg, 28-tab pack = £5.16. Label: 2   Buspirone is thought to act at specific serotonin  (5HT ia ) receptors. Response to treatment may take up  to 2 weeks. It does not alleviate the symptoms of  benzodiazepine withdrawal. Therefore a patient taking  a benzodiazepine still needs to have the benzodiazepine  withdrawn gradually; it is advisable to do this before  starting buspirone. The dependence and abuse potential  of buspirone is low; it is, however, licensed for short-  term use only (but specialists occasionally use it for  several months).   Cautions does not alleviate benzodiazepine with-  drawal (see notes above); interactions: Appendix 1  (anxiolytics and hypnotics)   Driving May affect performance of skilled tasks (e.g. driv-  ing); effects of alcohol may be enhanced  Contra-indications epilepsy; acute porphyria (section  9.8.2)   Hepatic impairment reduce dose in mild to moderate  disease; avoid in severe disease  Renal impairment reduce dose; avoid if eGFR less  than 20 mL/minute/ 1.73 m 2  Pregnancy avoid  Breast-feeding avoid   Side-effects nausea; dizziness, headache, nervous-  ness, excitement; rarely dry mouth, tachycardia, pal-  pitation, chest pain, drowsiness, confusion, seizures,  fatigue, and sweating   • ADULT over 18 years, 5 mg 2-3 times daily, increased as  necessary every 2-3 days; usual range 15-30 mg daily  in divided doses; max. 45 mg daily  Buspirone Hydrochloride (Non-proprietary) ®  Tablets, buspirone hydrochloride 5 mg, net price 30-  tab pack = £13.01; 10 mg, 30-tab pack = £15.34.  Counselling, driving   Meprobamate is less effective than the benzodiaz-  epines, more hazardous in overdosage, and can also  induce dependence. It is not recommended.  Important: MHRA/CHM have advised that treatment  with meprobamate should not be initiated.   Cautions respiratory disease, muscle weakness, epi-  lepsy (may induce seizures), history of drug or alcohol  abuse, marked personality disorder; elderly and  debilitated; avoid prolonged use, abrupt withdrawal  (may precipitate convulsions); interactions: Appen-  dix 1 (anxiolytics and hypnotics)   Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced  Contra-indications acute pulmonary insufficiency;   respiratory depression; acute porphyria (section 9.8.2)  Hepatic impairment can precipitate coma  Renal impairment start with small doses in severe  impairment; increased cerebral sensitivity  Pregnancy avoid if possible  Breast-feeding avoid; concentration in milk may  exceed maternal plasma concentrations fourfold and  may cause drowsiness in infant  Side-effects see under Diazepam, but incidence  greater and drowsiness most common side-effect;  also gastro-intestinal disturbances, hypotension,  paraesthesia, weakness, CNS effects including head-  ache, paradoxical excitement, disturbances of vision;  rarely agranulocytosis and rashes  Dose   • 400 mg 3-4 times daily; ELDERLY half adult dose or less;  CHILD not recommended   Note Meprobamate treatment should not be initiated in new  patients, see notes above   Meprobamate (Non-proprietary) (SOL I  Tablets, scored, meprobamate 400 mg, net price 84-  tab pack = £19.95. Label: 2   The intermediate-acting barbiturates have a place only  in the treatment of severe intractable insomnia in  patients already taking barbiturates; they should be  avoided in the elderly. Intermediate-acting barbiturate  preparations containing amobarbital sodium, butobar-  bital, and secobarbital sodium are available on a named-  patient basis.   The long-acting barbiturate phenobarbital is still some-  times of value in epilepsy (section 4.8.1) but its use as a  sedative is unjustified.   The very short-acting barbiturate thiopental is used in  anaesthesia (section 15.1.1).   Advice of Royal College of Psychiatrists on doses of  antipsychotic drugs above BNF upper limit. Unless  otherwise stated, doses in the BNF are licensed doses —    any higher dose is therefore unlicensed (for an explana-  tion of the significance of this, see p. 2).    1. Consider alternative approaches including adjuvant  therapy and newer or atypical neuroleptics such as  clozapine.   2. Bear in mind risk factors, including obesity — parti-  cular caution is indicated in older patients espe-  cially those over 70.   4. Carry out ECG to exclude untoward abnormalities  such as prolonged QT interval; repeat ECG periodi-  cally and reduce dose if prolonged QT interval or  other adverse abnormality develops.   5. Increase dose slowly and not more often than once  weekly.   6. Carry out regular pulse, blood pressure, and tem-  perature checks; ensure that patient maintains ade-  quate fluid intake.   7. Consider high-dose therapy to be for limited period  and review regularly; abandon if no improvement  after 3 months (return to standard dosage).  Important When prescribing an antipsychotic for administra-  tion on an emergency basis, the intramuscular dose should be  lower than the corresponding oral dose (owing to absence of  first-pass effect), particularly if the patient is very active  (increased blood flow to muscle considerably increases the rate  of absorption). The prescription should specify the dose for  each route and should not imply that the same dose can be  given by mouth or by intramuscular injection. The dose of  antipsychotic for emergency use should be reviewed at least  daily.    Antipsychotic drugs are also known as ‘neuroleptics’  and (misleadingly) as ‘major tranquillisers’. Antipsy-  chotic drugs generally tranquillise without impairing  consciousness and without causing paradoxical excite-  ment but they should not be regarded merely as tran-  quillisers. For conditions such as schizophrenia the  tranquillising effect is of secondary importance.    In the short term they are used to calm disturbed  patients whatever the underlying psychopathology,  which may be schizophrenia, brain damage, mania,  toxic delirium, or agitated depression. Antipsychotic  drugs are used to alleviate severe anxiety but this too  should be a short-term measure.    Schizophrenia Antipsychotic drugs relieve psychotic  symptoms such as thought disorder, hallucinations, and  delusions, and prevent relapse. Although they are usual-  ly less effective in apathetic withdrawn patients, they  sometimes appear to have an activating influence.  Patients with acute schizophrenia generally respond  better than those with chronic symptoms. Patients  should receive antipsychotic drugs for 4-6 weeks before  the drug is deemed ineffective.   Long-term treatment of a patient with a definite diag-  nosis of schizophrenia may be necessary even after the  first episode of illness in order to prevent the illness  from becoming chronic. Withdrawal of drug treatment  requires careful surveillance because the patient who  appears well on medication may suffer a disastrous  relapse if treatment is withdrawn inappropriately. In  addition the need for continuation of treatment may  not become immediately evident because relapse is   Antipsychotic drugs are considered to act by interfering  with dopaminergic transmission in the brain by blocking  dopamine D 2 receptors, which may give rise to the  extrapyramidal effects described below, and also to  hyperprolactinaemia. Antipsychotic drugs may also  affect cholinergic, alpha-adrenergic, histaminergic, and  serotonergic receptors.   Cautions Antipsychotic drugs should be used with  caution in patients with cardiovascular disease; an ECG  may be required (see individual drug monographs),  particularly if physical examination identifies cardiovas-  cular risk factors, if there is a personal history of  cardiovascular disease, or if the patient is being  admitted as an inpatient. Antipsychotic drugs should  also be used with caution in Parkinson’s disease (may be  exacerbated by antipsychotics), epilepsy (and condi-  tions predisposing to epilepsy), depression, myasthenia  gravis, prostatic hypertrophy, or a susceptibility to  angle-closure glaucoma. Caution is also required in  severe respiratory disease and in patients with a history  of jaundice or who have blood dyscrasias (perform  blood counts if unexplained infection or fever develops).  As photosensitisation may occur with higher dosages,  patients should avoid direct sunlight. Patients with  schizophrenia should have physical health monitoring  (including cardiovascular disease risk assessment) at  least once per year. Interactions: Appendix 1 (antipsy-  chotics).   Contra-indications Antipsychotic drugs maybe con-  tra-indicated in comatose states, CNS depression, and  phaeochromocytoma.   Prescribing for the elderly  The balance of risks and benefit should be consid-  ered before prescribing antipsychotic drugs for  elderly patients. In elderly patients with dementia,  antipsychotic drugs are associated with a small  increased risk of mortality and an increased risk of  stroke or transient ischaemic attack. Furthermore,  elderly patients are particularly susceptible to pos-  tural hypotension and to hyper- and hypothermia in  hot or cold weather.   • Antipsychotic drugs should not be used in  elderly patients to treat mild to moderate psy-  chotic symptoms.   • Initial doses of antipsychotic drugs in elderly  patients should be reduced (to half the adult  dose or less), taking into account factors such  as the patient’s weight, co-morbidity, and con-  comitant medication.    Driving Drowsiness may affect performance of skilled  tasks (e.g. driving or operating machinery), especially at  start of treatment; effects of alcohol are enhanced.   Withdrawal There is a high risk of relapse if medica-  tion is stopped after 1-2 years. Withdrawal of antipsy-  chotic drugs after long-term therapy should always be  gradual and closely monitored to avoid the risk of acute  withdrawal syndromes or rapid relapse. Patients should  be monitored for 2 years after withdrawal of antipsy-  chotic medication for signs and symptoms of relapse.    Hepatic impairment All antipsychotics can precipi-  tate coma if used in hepatic impairment; phenothiazines  are hepatotoxic. The manufacturer of zuclopenthixol  ( Clopixol ®) advises that the dose should be halved in  hepatic impairment, and serum-level monitoring should  be considered.   Renal impairment Start with small doses of antipsy-  chotic drugs in severe renal impairment because of  increased cerebral sensitivity. Pericyazine should be  avoided in renal impairment. The dose of  zuclopenthixol should be halved in patients with renal  failure.   Pregnancy Extrapyramidal effects have been reported  occasionally in the neonate when antipsychotic drugs  are taken during the third trimester of pregnancy.   Breast-feeding There is limited information available  on the short- and long-term effects of antipsychotics on  the breast-fed infant. Animal studies indicate possible  adverse effects of antipsychotic medicines on the devel-  oping nervous system. Chronic treatment with antipsy-  chotics whilst breast-feeding should be avoided unless  absolutely necessary.   Side-effects Extrapyramidal symptoms are the most  troublesome. They occur most frequently with the  piperazine phenothiazines (fluphenazine, perphenazine,  prochlorperazine, and trifluoperazine), the butyro-  phenones (benperidol and haloperidol), and the depot  preparations. They are easy to recognise but cannot be  predicted accurately because they depend on the dose,  the type of drug, and on individual susceptibility.  Extrapyramidal symptoms consist of:   • parkinsonian symptoms (including tremor), which  may occur more commonly in adults or the elderly  and may appear gradually;   • dystonia (abnormal face and body movements) and  dyskinesia, which occur more commonly in chil-  dren or young adults and appear after only a few  doses;   • akathisia (restlessness), which characteristically  occurs after large initial doses and may resemble  an exacerbation of the condition being treated; and   • tardive dyskinesia (rhythmic, involuntary move-  ments of tongue, face, and jaw), which usually  develops on long-term therapy or with high dosage,  but it may develop on short-term treatment with  low doses — short-lived tardive dyskinesia may  occur after withdrawal of the drug.   Parkinsonian symptoms remit if the drug is withdrawn  and may be suppressed by the administration of anti-  muscarinic drugs (section 4.9.2). However, routine  administration of such drugs is not justified because  not all patients are affected and because they may  unmask or worsen tardive dyskinesia.   Tardive dyskinesia is of particular concern because it  may be irreversible on withdrawing therapy and treat-  ment is usually ineffective. However, some manufac-  turers suggest that drug withdrawal at the earliest signs  of tardive dyskinesia (fine vermicular movements of the  tongue) may halt its full development. Tardive dys-  kinesia occurs fairly frequently, especially in the elderly,  and treatment must be carefully and regularly reviewed.  Hypotension and interference with temperature regula-  tion are dose-related side-effects and are liable to cause  dangerous falls and hypothermia or hyperthermia in the  elderly.    Neuroleptic malignant syndrome (hyperthermia, fluc-  tuating level of consciousness, muscle rigidity, and  autonomic dysfunction with pallor, tachycardia, labile  blood pressure, sweating, and urinary incontinence) is a  rare but potentially fatal side-effect of some drugs.  Discontinuation of the antipsychotic is essential because  there is no proven effective treatment, but cooling,  bromocriptine, and dantrolene have been used. The  syndrome, which usually lasts for 5-7 days after drug  discontinuation, may be unduly prolonged if depot pre-  parations have been used.   Other side-effects include: drowsiness; apathy; agitation,  excitement and insomnia; convulsions; dizziness; head-  ache; confusion; gastro-intestinal disturbances; nasal  congestion; antimuscarinic symptoms (such as dry  mouth, constipation, difficulty with micturition, and  blurred vision; very rarely, precipitation of angle-closure  glaucoma); cardiovascular symptoms (such as hypo-  tension, tachycardia, and arrhythmias); ECG changes  (cases of sudden death have occurred); venous throm-  boembolism; endocrine effects such as menstrual dis-  turbances, galactorrhoea, gynaecomastia, impotence,  and weight gain; blood dyscrasias (such as agranulo-  cytosis and leucopenia), photosensitisation, contact  sensitisation and rashes, and jaundice (including chole-  static); comeal and lens opacities, and purplish pigmen-  tation of the skin, cornea, conjunctiva, and retina.    Drugs of other chemical groups resemble the phenothi-  azines of group 3 in their clinical properties. They  include the butyrophenones (benperidol and halo-  peridol); diphenylbutylpiperidines (pimozide); thio-  xanthenes (flupentixol and zuclopenthixol); and the  substituted benzamides (sulpiride).   For details of the newer antipsychotic drugs amisul-  pride, aripiprazole, clozapine, olanzapine, paliperidone,  quetiapine, and risperidone see under Atypical Antipsy-  chotic Drugs, p. 222.   Choice As indicated above, the various drugs differ  somewhat in predominant actions and side-effects.  Selection is influenced by the degree of sedation  required and the patient’s susceptibility to extrapyra-  midal side-effects. However, the differences between  antipsychotic drugs are less important than the great  variability in patient response; moreover, tolerance to  secondary effects such as sedation usually develops.  The atypical antipsychotics may be appropriate if extra-  pyramidal side-effects are a particular concern (see    Overdosage: for poisoning with phenothiazines and  related compounds, see Emergency Treatment of Pois-  oning, p. 38.   Classification of antipsychotics The phenothia-  zine derivatives can be divided into 3 main groups.  Group 1 : chlorpromazine, levomepromazine, and  promazine, generally characterised by pronounced  sedative effects and moderate antimuscarinic and  extrapyramidal side-effects.   Group 2\ pericyazine and pipotiazine, generally  characterised by moderate sedative effects, marked  antimuscarinic effects, but fewer extrapyramidal  side-effects than groups 1 or 3.   Group 3: fluphenazine, perphenazine, prochlorper-  azine, and trifluoperazine, generally characterised  by fewer sedative effects, fewer antimuscarinic  effects, but more pronounced extrapyramidal side-  effects than groups 1 and 2.    under Atypical Antipsychotic Drugs, below). Clozapine  is used for schizophrenia when other antipsychotics are  ineffective or not tolerated.   Prescribing of more than one antipsychotic drug at the  same time is not recommended; it may constitute a  hazard and there is no significant evidence that side-  effects are minimised.    Chlorpromazine is still widely used despite the wide  range of adverse effects associated with it. It has a  marked sedating effect and is useful for treating violent  patients without causing stupor. Agitated states in the  elderly can be controlled without confusion, a dose of 10  to 25 mg once or twice daily usually being adequate.  Flupentixol and pimozide (see ECG monitoring,  p. 220) are less sedating than chlorpromazine.   Sulpiride in high doses controls florid positive symp-  toms, but in lower doses it can have an alerting effect on  apathetic withdrawn schizophrenics.   also of value but their use is limited by the high inci-  dence of extrapyramidal symptoms. Haloperidol may be  preferred for the rapid control of hyperactive psychotic  states; it causes less hypotension than chlorpromazine  and is therefore also popular for agitation and restless-  ness in the elderly, despite the high incidence of extra-  pyramidal side-effects.   Promazine is not sufficiently active by mouth to be  used as an antipsychotic drug; it has been used to treat  agitation and restlessness in the elderly (see Other uses,  below).   After an initial period of stabilisation, in most  patients, the total daily oral dose can be given as a  single dose. For the advice of The Royal College of  Psychiatrists on doses above the BNF upper limit,  see p. 215.   Cautions see notes above; also manufacturer advises  regular blood counts and liver function tests during  long-term treatment; risk factors for stroke  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • 0.25-1.5 mg daily in divided doses, adjusted accord-  ing to response; ELDERLY (or debilitated) initially half  adult dose; CHILD not recommended   Tablets, scored, benperidol 250 micrograms, net price  112-tab pack = £97.76. Label: 2  Note The proprietary name Benquil ® has been used for  benperidol tablets    Other uses Nausea and vomiting (section 4.6), chor-  eas, motor tics (section 4.9.3), and intractable hiccup  (see under Chlorpromazine Hydrochloride and under  Haloperidol). Benperidol is used in deviant antisocial  sexual behaviour but its value is not established; see also  section 6.4.2 for the role of cyproterone acetate.   Psychomotor agitation should be investigated for an  underlying cause; it can be managed with low doses  of chlorpromazine or haloperidol used for short periods.  Antipsychotic drugs can be used with caution for the  short-term treatment of severe agitation and restless-  ness in the elderly (but see p. 216).    These equivalences are intended only as an approxi-  mate guide; individual dosage instructions should also  be checked; patients should be carefully monitored  after any change in medication   Important These equivalences must not be extrapolated  beyond the maximum dose for the drug. Higher doses   Warning Owing to the risk of contact sensitisation, pharma-  cists, nurses, and other health workers should avoid direct  contact with chlorpromazine; tablets should not be crushed  and solutions should be handled with care   Cautions see notes above; also diabetes; patients  should remain supine, with blood pressure monitoring  for 30 minutes after intramuscular injection; dose  adjustment may be necessary if smoking started or  stopped during treatment   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   • By mouth, schizophrenia and other psychoses, mania,  short-term adjunctive management of severe anxiety,  psychomotor agitation, excitement, and violent or  dangerously impulsive behaviour, initially 25 mg 3  times daily (or 75 mg at night), adjusted according to  response, to usual maintenance dose of 75-300 mg  daily (but up to 1 g daily may be required in psych-  oses); ELDERLY (or debilitated) third to half adult dose;  CHILD (childhood schizophrenia and autism) 1-6 years  500 micrograms/kg every 4-6 hours (max. 40 mg  daily); 6-12 years 10 mg 3 times daily (max. 75 mg  daily)    • By deep intramuscular injection, (for relief of acute  symptoms but see also Cautions and Side-effects),  25-50 mg every 6-8 hours; CHILD 1-6 years   500 micrograms/kg every 6-8 hours (max. 40 mg  daily); 6-12 years 500 micrograms/kg every 6-8  hours (max. 75 mg daily)   • By rectum in suppositories as chlorpromazine base  100 mg every 6-8 hours [unlicensed]   Note For equivalent therapeutic effect 100 mg chlorprom-  azine base given rectally as a suppository = 20-25 mg  chlorpromazine hydrochloride by intramuscular injection =  40-50 mg of chlorpromazine base or hydrochloride by  mouth   Chlorpromazine (Non-proprietary) (Ml  Tablets, coated, chlorpromazine hydrochloride  25 mg, net price 28-tab pack = £1.77; 50 mg, 28-tab  pack = £2.37; 100 mg, 28-tab pack = £2.31. Label: 2,  11   Oral solution, chlorpromazine hydrochloride 25 mg/  5mL, net price 150 mL = £1.79, 100 mg/5 mL,   150 mL = £4.28. Label: 2, 11  Injection, chlorpromazine hydrochloride 25mg/mL,  net price 1-mL amp = 60p; 2-mL amp = 63p  Suppositories, chlorpromazine 25 mg and 100 mg.  Label: 2, 11   Largactil® (Sanofi-Aventis) (Ml  Injection, chlorpromazine hydrochloride 25mg/mL,  net price 2-mL amp = 60p   Indications schizophrenia and other psychoses, par-  ticularly with apathy and withdrawal but not mania or  psychomotor hyperactivity; depression (section 4.3.4)  Cautions see notes above; diabetes; avoid in acute  porphyria (section 9.8.2)   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   • Psychosis, initially 3-9 mg twice daily adjusted  according to the response; max. 18 mg daily; ELDERLY  (or debilitated) initially quarter to half adult dose;  CHILD not recommended    thyrotoxicosis; arteriosclerosis; dose adjustment may  be necessary if smoking started or stopped during  treatment    Contra-indications see notes above; QT-interval  prolongation (avoid concomitant administration of  drugs that prolong QT interval); bradycardia  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above, but less sedating and  fewer antimuscarinic or hypotensive symptoms; pig-  mentation and photosensitivity reactions rare;  depression; weight loss; less commonly dyspnoea,  oedema; rarely bronchospasm, hypoglycaemia, and  inappropriate antidiuretic hormone secretion; hyper-  tension, sweating, Stevens- Johnson syndrome, and  toxic epidermal necrolysis also reported   • Schizophrenia and other psychoses, mania, short-  term adjunctive management of psychomotor agita-  tion, excitement, and violent or dangerously impulsive  behaviour, ADULT and CHILD over 12 years, by mouth,  initially 0.5-3 mg 2-3 times daily or 3-5 mg 2-3 times  daily in severely affected or resistant patients; in  resistant schizophrenia up to 30 mg daily may be  needed; adjusted according to response to lowest  effective maintenance dose (as low as 5-10 mg daily);  ELDERLY (or debilitated) initially half adult dose   By intramuscular or by intravenous injection, ADULT  over 18 years, initially 2-10 mg, then every 4-8 hours  according to response to total max. 18 mg daily;  severely disturbed patients may require initial dose of  up to 18 mg; ELDERLY (or debilitated) initially half adult  dose   • Agitation and restlessness in the elderly, by mouth,  initially 0.5- 1.5 mg once or twice daily   • Short-term adjunctive management of severe anxiety,  by mouth, ADULT over 18 years, 500 micrograms twice  daily   • Motor tics, adjunctive treatment in choreas and  Tourette syndrome, by mouth, 0.5-1. 5 mg 3 times  daily adjusted according to response; 10 mg daily or  more may occasionally be necessary in Tourette  syndrome; CHILD 5-12 years, Tourette syndrome,  12.5-25 microgram/kg twice daily, adjusted accord-  ing to response up to max. 10 mg daily   • Nausea and vomiting, see Prescribing in Palliative  Care, p. 22   Tablets, yellow, s/c, flupentixol 3 mg (as dihy-  drochloride), net price 100 = £6.23. Label: 2   Cautions see notes above; also subarachnoid  haemorrhage; metabolic disturbances such as hypo-  kalaemia, hypocalcaemia, or hypomagnesaemia;    Haloperidol (Non-proprietary) (Ml  Tablets, haloperidol 500 micrograms, net price 28-tab  pack = 91p; 1.5 mg, 28-tab pack = £1.39; 5 mg, 28-tab  pack = £2.15; 10 mg, 28-tab pack = £5.53; 20 mg, 28-  tab pack = £14.07. Label: 2   Haldol® Qanssen-Cilag) (Ml  Tablets, both scored, haloperidol 5 mg (blue), net  price 100 = £7.21; 10 mg (yellow), 100 = £14.08.  Label: 2    Oral liquid, sugar-free, haloperidol 2mg/mL, net  price 100-mL pack (with pipette) = £4.45. Label: 2  Injection, haloperidol 5mg/mL, net price 1-mL amp  = 37p   £1.74; 5 mg (pink), 30-tab pack = £3.95; 10 mg (pale   Cautions see notes above; diabetes; patients receiving  large initial doses should remain supine  Elderly Risk of postural hypotension; not recommended for  ambulant patients over 50 years unless risk of hypotensive  reaction assessed   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   • Schizophrenia, by mouth initially 25-50 mg daily in  divided doses increased as necessary; bedpatients  initially 100-200 mg daily usually in 3 divided doses,  increased if necessary to 1 g daily; ELDERLY, see Cau-  tions   • Restlessness and confusion in palliative care, see  p. 23; CHILD 1-18 years, see BNF for Children   • Nausea and vomiting in palliative care, by mouth, see  p. 22, or by subcutaneous infusion, see p. 23; CHILD 1  month-18 years, see BNF for Children   Nozinan® (Sanofi-Aventis) IMl  Tablets, scored, levomepromazine maleate 25 mg, net  price 84-tab pack = £20.26. Label: 2  Injection, levomepromazine hydrochloride 25 mg/  mL, net price 1-mL amp = £2.01   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   • Schizophrenia and other psychoses, initially 75 mg  daily in divided doses increased at weekly intervals by   300 mg daily (elderly initially 15-30 mg daily); CHILD  and INFANT over 1 year (schizophrenia or behavioural  disorders only), initially, 500 micrograms daily for 10-  kg child, increased by 1 mg for each additional 5 kg  body-weight to max. total daily dose of 10 mg; dose  may be gradually increased according to response but  maintenance should not exceed twice initial dose   • Short-term adjunctive management of severe anxiety,  psychomotor agitation, and violent or dangerously  impulsive behaviour, initially 15-30 mg (elderly 5-  10 mg) daily divided into 2 doses, taking the larger  dose at bedtime, adjusted according to response;  CHILD not recommended   Pericyazine (Non-proprietary) (Ml  Tablets, yellow, scored, pericyazine 2.5 mg, net price  84-tab pack = £9.23; 10 mg, 84-tab pack = £24.95.  Label: 2   Indications see under Dose; antiemetic (section 4.6)  Cautions see notes above; hypothyroidism  Contra-indications see notes above; also agitation  and restlessness in the elderly   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   Breast-feeding see notes above  Side-effects see notes above; less sedating; extra-  pyramidal symptoms, especially dystonia, more fre-  quent, particularly at high dosage; rarely systemic  lupus erythematosus  Dose   • Schizophrenia and other psychoses, mania, short-  term adjunctive management of anxiety, severe psy-  chomotor agitation, excitement, and violent or dan-  gerously impulsive behaviour, initially 4 mg 3 times  daily adjusted according to the response; max. 24 mg  daily; ELDERLY quarter to half adult dose (but see  Cautions); CHILD under 14 years not recommended   Tablets, s/c, perphenazine 2 mg, net price 100 =  £22.38; 4 mg, 100 = £26.34. Label: 2   Indications see under Dose  Cautions see notes above  ECG monitoring Following reports of sudden unexplained  death, an ECG is recommended before treatment. It is also  recommended that patients taking pimozide should have an  annual ECG (if the QT interval is prolonged, treatment  should be reviewed and either withdrawn or dose reduced  under close supervision) and that pimozide should not be  given with other antipsychotic drugs (including depot pre-  parations), tricyclic antidepressants or other drugs which  prolong the QT interval, such as certain antimalarials, anti-  arrhythmic drugs and certain antihistamines and should not  be given with drugs which cause electrolyte disturbances  (especially diuretics)   Contra-indications see notes above; history of  arrhythmias or congenital QT prolongation   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above    Side-effects see notes above; less sedating; serious  arrhythmias reported; glycosuria and, rarely, hypo-  natraemia reported   • Schizophrenia, ADULT and CHILD over 12 years, initially  2 mg daily, increased according to response in steps of  2-4 mg at intervals of not less than 1 week; usual dose  range 2-20 mg daily; ELDERLY half usual starting dose   • Monosymptomatic hypochondriacal psychosis, para-  noid psychosis, ADULT and CHILD over 12 years, initially  4 mg daily, increased according to response in steps of  2-4 mg at intervals of not less than 1 week; max.   Indications see under Dose; antiemetic (section 4.6)  Cautions see notes above; also hypotension more  likely after intramuscular injection  Contra-indications see notes above; children, but see  section 4.6 for use as antiemetic  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; less sedating; extra-  pyramidal symptoms, particularly dystonias, more  frequent; respiratory depression may occur in sus-  ceptible patients  Dose   • By mouth, schizophrenia and other psychoses, mania,  prochlorperazine maleate or mesilate, 12.5 mg twice  daily for 7 days adjusted at intervals of 4-7 days to  usual dose of 75-100 mg daily according to response;  CHILD not recommended   Short-term adjunctive management of severe anxiety,  15-20 mg daily in divided doses; max. 40 mg daily;  CHILD not recommended   • By deep intramuscular injection, psychoses, mania,  prochlorperazine mesilate 12.5-25 mg 2-3 times  daily; CHILD not recommended   • Short-term adjunctive management of psychomotor  agitation, 100-200 mg 4 times daily; CHILD not  recommended   • Agitation and restlessness in elderly, 25-50 mg 4  times daily    Promazine (Non-proprietary) [Ml  Tablets, coated, promazine hydrochloride 25 mg, net  price 100 = £12.38; 50 mg, 100 = £22.00. Label: 2  Oral solution, promazine hydrochloride 25 mg/5 mL,  net price 150 mL = £4.65; 50 mg/5 mL, 150 mL =  £4.80. Label: 2   Cautions see notes above; also excited, agitated, or  aggressive patients (even low doses may aggravate  symptoms)   • ADULT and CHILD over 14 years, 200-400 mg twice  daily; max. 800 mg daily in predominantly negative  symptoms, and 2.4 g daily in mainly positive symp-  toms; ELDERLY, lower initial dose, increased gradually  according to response    Sulpiride (Non-proprietary) (Ml  Tablets, sulpiride 200 mg, net price 30-tab pack =  £8.09, 56-tab pack = £6.46; 400 mg, 30-tab pack =  £18.57. Label: 2  Dolmatil® (Sanofi-Aventis) (Ml  Tablets, both scored, sulpiride 200 mg, net price 100-  tab pack = £13.31; 400 mg (f/c), 100-tab pack =  £34.87. Label: 2   Oral solution, sugar-free, lemon- and aniseed-fla-  voured, sulpiride 200 mg/5 mL, net price 150 mL =  £25.38. Label: 2   Side-effects see notes above; extrapyramidal symp-  toms more frequent, especially at doses exceeding  6 mg daily; anorexia; muscle weakness   • Schizophrenia and other psychoses, short-term  adjunctive management of psychomotor agitation,  excitement, and violent or dangerously impulsive  behaviour, ADULT and CHILD over 12 years, initially   5 mg twice daily, increased by 5 mg daily after 1 week,  then at intervals of 3 days, according to the response;  ELDERLY reduce initial dose by at least half   • Short-term adjunctive management of severe anxiety,  ADULT and CHILD over 12 years, 2-4 mg daily in divided  doses, increased if necessary to 6 mg daily; CHILD 3-5  years up to 1 mg daily, 6-12 years up to 4 mg daily;  ELDERLY reduce initial dose by at least half   Trifluoperazine (Non-proprietary) (Ml  Tablets, coated, trifluoperazine (as hydrochloride)  lmg, net price 112-tab pack = £6.57; 5 mg, 112-tab  pack = £4.89. Label: 2    Oral solution, trifluoperazine (as hydrochloride)  5mg/5mL, net price 150-mL = £10.84. Label: 2  Stelazine® (Goldshield) (Ml  Tablets, both blue, f/c, trifluoperazine (as hydro-  chloride) 1 mg, net price 112 = £3.43; 5 mg, 112 =  £4.89. Label: 2   Syrup, sugar-free, yellow, trifluoperazine (as hydro-  chloride) 1 mg/ 5 mL, net price 200-mL pack = £2.95.  Label: 2   Indications short-term management of acute psy-  chosis, mania, or exacerbations of chronic psychosis  Cautions see notes above; avoid in acute porphyria  (section 9.8.2)   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • By deep intramuscular injection into the gluteal  muscle or lateral thigh, 50-150 mg (ELDERLY 50-  100 mg), if necessary repeated after 2-3 days (1  additional dose may be needed 1-2 days after the first  injection); max. cumulative dose 400 mg per course  and max. 4 injections; max. duration of treatment 2  weeks — if maintenance treatment necessary change  to an oral antipsychotic 2-3 days after last injection,  or to a longer acting antipsychotic depot injection  given concomitantly with last injection of  zuclopenthixol acetate; CHILD not recommended    Clopixol Acuphase® (Lundbeck) (Ml  Injection (oily), zuclopenthixol acetate 50mg/mL,  net price 1-mL amp = £2.17; 2-mL amp = £2.94   Side-effects see notes above; urinary frequency or  incontinence; weight loss (less common than weight  gain)   • By mouth, initially 20-30 mg daily in divided doses,  increasing to a max. of 150 mg daily if necessary;  usual maintenance dose 20-50 mg daily; max. single  dose 40 mg; ELDERLY (or debilitated) initially quarter to  half adult dose; CHILD not recommended   Tablets, f/c, zuclopenthixol (as dihydrochloride) 2 mg  (red), net price 100 = £3.14; 10 mg (light red-brown),  100 = £5.64; 25 mg (red-brown), 100 = £7.22. Label: 2   The ‘atypical’ antipsychotic drugs amisulpride, aripi-  prazole, clozapine, olanzapine, paliperidone, quetia-  pine, and risperidone may be better tolerated than  other antipsychotic drugs; extrapyramidal symptoms  may be less frequent than with older antipsychotic  drugs.   Aripiprazole, clozapine, olanzapine, and quetiapine  cause little or no elevation of prolactin concentration;  when changing from other antipsychotic drugs, a reduc-  tion in prolactin may increase fertility.   Clozapine is licensed for the treatment of schizophrenia  only in patients unresponsive to, or intolerant of, con-  ventional antipsychotic drugs. It can cause agranulo-  cytosis and its use is restricted to patients registered  with a clozapine patient monitoring service (see under  Clozapine).   The Scottish Medicines Consortium (p. 4) has advised  (April 2009) that quetiapine ( Seroquel ®) is not recom-  mended for use within NHS Scotland for the treatment  of major depressive episodes associated with bipolar  disorder.   • the atypical antipsychotics (amisulpride, olanza-  pine, quetiapine, risperidone, and zotepine)  should be considered when choosing first-line  treatment of newly diagnosed schizophrenia',   • an atypical antipsychotic is considered the treat-  ment option of choice for managing an acute  schizophrenic episode when discussion with the  individual is not possible;   • an atypical antipsychotic should be considered  for an individual who is suffering unacceptable  side-effects from a conventional antipsychotic;   • an atypical antipsychotic should be considered  for an individual in relapse whose symptoms  were previously inadequately controlled;   • changing to an atypical antipsychotic is not  necessary if a conventional antipsychotic con-  trols symptoms adequately and the individual  does not suffer unacceptable side-effects;   • clozapine should be introduced if schizophrenia  is inadequately controlled despite the sequential  use of two or more antipsychotics (one of which  should be an atypical antipsychotic) each for at  least 6-8 weeks.   • If symptoms do not respond adequately to an  optimised dose of clozapine, measure clozapine  plasma levels before adding a second antipsy-  chotic to augment clozapine. If a second anti-  psychotic is added, there should be 8-10 weeks  treatment duration to assess for response.    Cautions and contra-indications While atypical  antipsychotic drugs have not generally been associated  with clinically significant prolongation of the QT inter-  val, they should be used with care if prescribed with  other drugs that increase the QT interval. Atypical anti-  psychotic drugs should be used with caution in patients  with cardiovascular disease, or a history of epilepsy;  they should be used with great caution in the elderly  (see p. 216); interactions: Appendix 1 (antipsychotics).    Driving Atypical antipsychotic drugs may affect per-  formance of skilled tasks (e.g. driving); effects of alcohol  are enhanced.   Withdrawal Withdrawal of antipsychotic drugs after  long-term therapy should always be gradual and closely  monitored to avoid the risk of acute withdrawal syn-  dromes or rapid relapse.   Side-effects Side-effects of the atypical antipsychotic  drugs include weight gain, dizziness, postural hypo-  tension (especially during initial dose titration) which  may be associated with syncope or reflex tachycardia in  some patients, extrapyramidal symptoms (usually mild  and transient and which respond to dose reduction or to  an antimuscarinic drug), and occasionally tardive dys-  kinesia on long-term administration (discontinue drug  on appearance of early signs); venous thromboembo-  lism has been reported. Hyperglycaemia and sometimes  diabetes can occur, particularly with clozapine, olanza-  pine, and risperidone; monitoring weight and plasma-  glucose concentration may identify the development of  hyperglycaemia. Neuroleptic malignant syndrome has  been reported rarely. Hypersalivation associated with  clozapine therapy can be treated with hyoscine hydro-  bromide [unlicensed indication] (p. 256), provided that  the patient is not at particular risk from the additive  antimuscarinic side-effects of hyoscine and clozapine.   Renal impairment halve dose if eGFR 30-60 mL/  minute/ 1.73 m 2 ; use one-third dose if eGFR 10-  30 mL/minute/ 1.73 m 2 ; no information available if  eGFR less than 10 mL/minute/ 1.73 m 2  Pregnancy avoid   Side-effects see notes above; also insomnia, anxiety,  agitation, drowsiness, gastro-intestinal disorders such  as constipation, nausea, vomiting, and dry mouth;  hyperprolactinaemia; occasionally bradycardia;  rarely seizures   • Acute psychotic episode, 400-800 mg daily in 2  divided doses, adjusted according to response; max.  1.2 g daily; CHILD under 15 years not recommended   Tablets, amisulpride 50 mg, net price 60-tab pack =  £7.18; 100 mg, 60-tab pack = £31.74; 200 mg, 60-tab  pack = £16.47; 400 mg, 60-tab pack = £105.68.   Side-effects see notes above; gastro-intestinal distur-  bances; tachycardia; fatigue, insomnia, akathisia,  drowsiness, restlessness, tremor, headache, asthenia;  blurred vision; less commonly depression; very rarely  anorexia, dysphagia, oropharyngeal spasm, laryn-  gospasm, hepatitis, jaundice, hypersalivation, pan-  creatitis, oedema, thromboembolism, arrhythmias,  bradycardia, hypertension, chest pain, agitation,  anxiety, speech disorder, suicidal ideation, seizures,  hyponatraemia, stiffness, myalgia, rhabdomyolysis,  priapism, urinary retention and incontinence, blood  disorders, sweating, alopecia, photosensitivity reac-  tions, rash, weight loss, and impaired temperature  regulation; with injection, dry mouth  Dose    • Schizophrenia, by mouth, ADULT over 18 years 10-  15 mg once daily, usual maintenance 15 mg once  daily; max. 30 mg once daily; CHILD 15-18 years,  initially 2 mg once daily for 2 days, then 5 mg once  daily for 2 days, then 10 mg daily; thereafter increased  if necessary in steps of 5 mg to max. 30 mg daily   • Treatment and prevention of mania, by mouth, ADULT  over 18 years, 15 mg once daily, increased if neces-  sary; max. 30 mg once daily   • Control of agitation and disturbed behaviour in  schizophrenia, by intramuscular injection, ADULT over  18 years, initially 5.25-15 mg (usual dose 9.75 mg) as  a single dose followed by 5.25-15 mg after 2 hours if  necessary; max. 3 injections daily; max. daily com-  bined oral and parenteral dose 30 mg   Abilify® (Bristol-Myers Squibb) (Ml  Tablets, aripiprazole 5 mg (blue), net price 28-tab  pack = £95.74; 10 mg (pink), 28-tab pack = £95.74;   15 mg (yellow), 28-tab pack = £95.74; 30 mg (pink),  28-tab pack = £191.47. Label: 2  Orodispersible tablets, aripiprazole 10 mg (pink), net  price 28-tab pack = £95.74; 15 mg (yellow), 28-tab  pack = £95.74. Label: 2, counselling, administration   Counselling Tablets should be placed on the tongue and  allowed to dissolve, or be dispersed in water and swallowed   Oral solution, aripiprazole 1 mg/mL, net price  150 mL with measuring cup = £102.57. Label: 2  Injection T, aripiprazole 7.5 mg/mL, net price 1.3-mL  (9.75-mg) vial = £3.42    Solian® (Sanofi-Aventis) 2°M1  Tablets, scored, amisulpride 50 mg, net price 60-tab  pack = £22.76; 100 mg, 60-tab pack = £35.29; 200 mg,  60-tab pack = £58.99; 400 mg, 60-tab pack = £1 17.97.  Label: 2    Indications schizophrenia (including psychosis in  Parkinson’s disease) in patients unresponsive to, or  intolerant of, conventional antipsychotic drugs  Cautions see notes above; elderly; monitor leucocyte  and differential blood counts (see Agranulocytosis,  below); prostatic hypertrophy, susceptibility to angle-  closure glaucoma; taper off other antipsychotics    before starting; close medical supervision during  initiation (risk of collapse because of hypotension);  dose adjustment may be necessary if smoking started  or stopped during treatment   Withdrawal On planned withdrawal reduce dose over 1-2  weeks to avoid risk of rebound psychosis. If abrupt with-  drawal necessary observe patient carefully  Agranulocytosis Neutropenia and potentially fatal  agranulocytosis reported. Leucocyte and differential blood  counts must be normal before starting; monitor counts every  week for 18 weeks then at least every 2 weeks and if cloz-  apine continued and blood count stable after 1 year at least  every 4 weeks (and 4 weeks after discontinuation); if leuco-  cyte count below 3000/mm 3 or if absolute neutrophil count  below 1500/mm 3 discontinue permanently and refer to  haematologist. Patients who have a low white blood cell  count because of benign ethnic neutropenia may be started  on clozapine with the agreement of a haematologist. Avoid  drugs which depress leucopoiesis; patients should report  immediately symptoms of infection, especially influenza-like  illness   Myocarditis and cardiomyopathy Fatal myocarditis (most  commonly in first 2 months) and cardiomyopathy reported.   • Perform physical examination and take full medical  history before starting   • Specialist examination required if cardiac abnormalities  or history of heart disease found — clozapine initiated  only in absence of severe heart disease and if benefit  outweighs risk   • Persistent tachycardia especially in first 2 months  should prompt observation for other indicators for myo-  carditis or cardiomyopathy   • If myocarditis or cardiomyopathy suspected clozapine  should be stopped and patient evaluated urgently by  cardiologist   Gastro-intestinal obstruction Reactions resembling gas-  trointestinal obstruction reported. Clozapine should be used  cautiously with drugs which cause constipation (e.g. anti-  muscarinic drugs) or in history of colonic disease or bowel  surgery. Monitor for constipation and prescribe laxative if  required    Contra-indications severe cardiac disorders (e.g.  myocarditis; see Cautions); history of neutropenia or  agranulocytosis (see Cautions); bone-marrow disor-  ders; paralytic ileus (see Cautions); alcoholic and toxic  psychoses; history of circulatory collapse; drug  intoxication; coma or severe CNS depression;  uncontrolled epilepsy    Side-effects see notes above; also constipation (see  Cautions), hypersalivation, dry mouth, nausea, vomi-  ting, anorexia; tachycardia, ECG changes, hyper-  tension; drowsiness, dizziness, headache, tremor, sei-  zures, fatigue, impaired temperature regulation;  urinary incontinence and retention; leucopenia,  eosinophilia, leucocytosis; blurred vision; sweating;  less commonly agranulocytosis (important: see  Cautions); rarely dysphagia, hepatitis, cholestatic  jaundice, pancreatitis, circulatory collapse, arrhyth-  mia, myocarditis (important: see Cautions), peri-  carditis, thromboembolism, agitation, confusion,  delirium, anaemia; very rarely parotid gland enlarge-  ment, intestinal obstruction (see Cautions), cardio-  myopathy, myocardial infarction, respiratory depres-  sion, priapism, interstitial nephritis,  thrombocytopenia, thrombocythaemia, hypertrigly-    ceridaemia, hypercholesterolaemia, hyperlipidaemia,  angle-closure glaucoma, fulminant hepatic necrosis,  and skin reactions   • Schizophrenia, ADULT over 16 years, 12.5 mg once or  twice (ELDERLY 12.5 mg once) on first day then 25-  50 mg (ELDERLY 25-37.5 mg) on second day then  increased gradually (if well tolerated) in steps of 25-  50 mg daily (ELDERLY max. increment 25 mg daily) over  14-21 days up to 300 mg daily in divided doses (larger  dose at night, up to 200 mg daily may be taken as a  single dose at bedtime); if necessary may be further  increased in steps of 50-100 mg once (preferably) or  twice weekly; usual dose 200-450 mg daily (max.   Note Restarting after interval of more than 2 days, 12.5 mg  once or twice on first day (but may be feasible to increase  more quickly than on initiation) — extreme caution if previous  respiratory or cardiac arrest with initial dosing   • Psychosis in Parkinson’s disease, ADULT over 16 years,  12.5 mg at bedtime then increased according to  response in steps of 12.5 mg up to twice weekly; usual  dose range 25-37.5 mg at bedtime, usual max. 50 mg  daily; exceptionally, dose may be increased further in  steps of 12.5 mg weekly to max. 100 mg daily in 1-2  divided doses   Tablets, yellow, clozapine 25 mg (scored), net price  28-tab pack = £5.40, 84-tab pack (hosp. only) =  £16.18, 100-tab pack (hosp. only) = £19.26; 100 mg,  28-tab pack = £21.56, 84-tab pack (hosp. only) =  £64.68, 100-tab pack (hosp. only) = £77.00. Label: 2,  10, patient information leaflet   Tablets, yellow, scored, clozapine 25 mg, net price 28-  tab pack = £6.17, 84-tab pack = £16.64, 100-tab pack  = £19.80; 50 mg, 50-tab pack = £19.80; 100 mg, 28-tab  pack = £24.64, 84-tab pack = £66.53, 100-tab pack =  £79.20; 200 mg, 50-tab pack = £79.20. Label: 2, 10,  patient information leaflet   Counselling Shake well for 90 seconds when dispensing or if  visibly settled; otherwise shake well for 10 seconds before use  Note May be diluted with water   Tablets, yellow, scored, clozapine 25 mg, net price 84-  tab pack = £8.28; 100 mg, 84-tab pack = £33.88.  Label: 2, 10, patient information leaflet  Note Patient, prescriber, and supplying pharmacist must be regis-  tered with the Zaponex Treatment Access System — takes several  days to do this   Cautions see notes above; also prostatic hypertrophy,  susceptibility to angle-closure glaucoma, paralytic  ileus, diabetes mellitus (risk of exacerbation or keto-  acidosis), low leucocyte or neutrophil count, bone-    marrow depression, hypereosinophilic disorders,  myeloproliferative disease, Parkinson’s disease; dose  adjustment may be necessary if smoking started or  stopped during treatment   CNS and respiratory depression Blood pressure, pulse  and respiratory rate should be monitored for at least 4 hours  after intramuscular injection, particularly in those also  receiving another antipsychotic or benzodiazepine   Contra-indications for injection, acute myocardial  infarction, unstable angina, severe hypotension or  bradycardia, sick sinus syndrome, recent heart sur-  gery   Renal impairment consider initial dose of 5 mg daily  Pregnancy use only if potential benefit outweighs risk;  neonatal lethargy, tremor, and hypertonia reported  when used in third trimester  Breast-feeding avoid — present in milk  Side-effects see notes above; also mild, transient  antimuscarinic effects (very rarely precipitation of  angle-closure glaucoma); drowsiness, speech diffi-  culty, exacerbation of Parkinson’s disease, abnormal  gait, hallucinations, akathisia, asthenia, fatigue,  increased appetite, increased body temperature,  raised triglyceride concentration, oedema, hyperpro-  lactinaemia (but clinical manifestations uncommon);  eosinophilia; less commonly hypotension, brady-  cardia, QT-interval prolongation, urinary incont-  inence, and photosensitivity; rarely seizures, leuco-  penia, and rash; very rarely hepatitis, pancreatitis,  thromboembolism, hypercholesterolaemia, hypo-  thermia, urinary retention, priapism, thrombocytope-  nia, neutropenia, rhabdomyolysis, and alopecia; with  injection, sinus pause and hypoventilation  Dose   • Schizophrenia, combination therapy for mania, pre-  venting recurrence in bipolar disorder, by mouth,  ADULT over 18 years, 10 mg daily adjusted to usual  range of 5-20 mg daily; doses greater than 10 mg daily  only after reassessment; max. 20 mg daily; CHILD 12-  18 years, see BNF for Children   • Monotherapy for mania, by mouth, ADULT over 18  years, 15 mg daily adjusted to usual range of 5-20 mg  daily; doses greater than 15 mg only after reassess-  ment; max. 20 mg daily; CHILD 12-18 years, see BNF  for Children   • Control of agitation and disturbed behaviour in  schizophrenia or mania, by intramuscular injection,  ADULT over 18 years, initially 5-10 mg (usual dose  10 mg) as a single dose followed by 5-10 mg after 2  hours if necessary; ELDERLY initially 2.5-5 mg as a  single dose followed by 2.5-5 mg after 2 hours if  necessary; max. 3 injections daily for 3 days; max.  daily combined oral and parenteral dose 20 mg   Note When one or more factors present that might result in  slower metabolism (e.g. female gender, elderly, non-smoker)  consider lower initial dose and more gradual dose increase   Tablets, f/c, olanzapine 2.5 mg, net price 28-tab pack  = £21.85; 5 mg, 28-tab pack = £43.70; 7.5 mg, 56-tab  pack = £131.10; lOmg, 28-tab pack = £87.40, 15mg  (blue), 28-tab pack = £119.18; 20 mg (pink), 28-tab  pack = £158.90. Label: 2   Orodispersible tablet ( Velotab ®), yellow, olanzapine  5 mg, net price 28-tab pack = £48.07; 10 mg, 28-tab  pack = £87.40; 15mg, 28-tab pack = £131.10; 20 mg,   Counselling Velotab ® may be placed on the tongue and allowed  to dissolve, or dispersed in water, orange juice, apple juice, milk,  or coffee   Injection T, powder for reconstitution, olanzapine  5mg/mL, net price 10-mg vial = £3.48   Cautions see notes above; predisposition to gastro-  intestinal obstruction; elderly patients with dementia  and risk factors for stroke; Parkinson’s disease   Renal impairment initially 3 mg once daily if eGFR  50-80 mL/minute/ 1.73 m 2 (max. 6 mg once daily);  initially 1.5 mg once daily if eGFR 10-50 mL/minute/  1.73 m 2 (max. 3 mg once daily); avoid if eGFR less  than 10mL/minute/1.73m 2  Pregnancy use only if potential benefit outweighs  risk — toxicity in animal studies; if discontinuation  during pregnancy is necessary, withdraw gradually  Breast-feeding avoid — present in milk  Side-effects see notes above; also abdominal pain,  dry mouth, hypersalivation, vomiting; tachycardia,  bradycardia, first-degree AV block, bundle branch  block; drowsiness, agitation, headache, asthenia; less  commonly palpitation, arrhythmias, ischaemia,  oedema, seizures, nightmare, syncope, menstrual  disturbances, erectile dysfunction, galactorrhoea,  gynaecomastia, and rash; cerebrovascular accident  also reported  Dose   • ADULT over 18 years, 6 mg once daily in the morning,  adjusted if necessary in increments of 3 mg over at  least 5 days; usual range 3-12 mg daily  Counselling Always take with breakfast or always take on an  empty stomach   Tablets, m/r, paliperidone 3 mg (white), net price 28-  tab pack = £97.28; 6 mg (beige), 28-tab pack = £97.28;  9 mg (pink), 28-tab pack = £145.92. Label: 2, 25,  counselling, administration   Indications schizophrenia; mania, either alone or with  mood stabilisers; depression in bipolar disorder;  adjunctive treatment in major depressive disorder  Cautions see notes above; also cerebrovascular dis-  ease; patients at risk of aspiration pneumonia; treat-  ment of depression in patients under 25 years  (increased risk of suicide)   Hepatic impairment for immediate-release tablets,  initially 25 mg daily, increased daily in steps of 25-  50 mg; for modified-release tablets, initially 50 mg  daily, increased daily in steps of 50 mg  Pregnancy use only if potential benefit outweighs risk  Breast-feeding avoid — no information available  Side-effects see notes above; also dry mouth, con-  stipation, dyspepsia; tachycardia, hypertension, ele-  vated plasma-triglyceride and -cholesterol concen-  trations, peripheral oedema; drowsiness, headache,    irritability, dysarthria, asthenia; hyperprolactinaemia;  leucopenia, neutropenia; blurred vision; rhinitis; less  commonly dysphagia, seizures, restless legs  syndrome, and eosinophilia; rarely jaundice and  priapism; very rarely hepatitis, angioedema, and Ste-  vens- Johnson syndrome; suicidal behaviour (particu-  larly on initiation) also reported  Dose   • Schizophrenia, ADULT over 18 years, 25 mg twice daily  on day 1, 50 mg twice daily on day 2, 100 mg twice  daily on day 3, 150 mg twice daily on day 4, then  adjusted according to response, usual range 300-  450 mg daily in 2 divided doses; max. 750 mg daily;  ELDERLY initially 25 mg daily as a single dose, increased  in steps of 25-50 mg daily in 2 divided doses; CHILD  12-18 years, see BNF for Children   • Treatment of mania in bipolar disorder, ADULT over 18  years, 50 mg twice daily on day 1, 100 mg twice daily  on day 2, 150 mg twice daily on day 3, 200 mg twice  daily on day 4, then adjusted according to response in  steps of up to 200 mg daily to max. 800 mg daily; usual  range 400-800 mg daily in 2 divided doses; ELDERLY  initially 25 mg daily as a single dose, increased in steps  of 25-50 mg daily in 2 divided doses   • Treatment of depression in bipolar disorder, ADULT  over 18 years, 50 mg once daily (at bedtime) on day 1,  100 mg once daily on day 2, 200 mg once daily on day  3, 300 mg once daily on day 4; adjust according to  response, usual dose 300 mg once daily, max. 600 mg  daily   • Prevention of mania and depression in bipolar dis-  order, ADULT over 18 years, continue at the dose  effective for treatment of bipolar disorder and adjust  to lowest effective dose; usual range 300-800 mg in 2  divided doses    Seroquel® (AstraZeneca) tMl  Tablets, f/c, quetiapine (as fumarate) 25 mg (peach),  net price 60-tab pack = £33.83; 100 mg (yellow), 60-  tab pack = £113.10; 150 mg (pale yellow), 60-tab pack  = £113.10; 200 mg (white), 60-tab pack = £113.10;  300 mg (white), 60-tab pack = £170.00. Label: 2   Seroquel® XL (AstraZeneca) ▼ CMC  Tablets, m/r, quetiapine (as fumarate) 50 mg (peach),  net price 60-tab pack = £67.66; 150 mg (white) 60-tab  pack = £113.10; 200 mg (yellow), 60-tab pack =  £113.10; 300 mg (pale yellow), 60-tab pack = £170.00;  400 mg (white), 60-tab pack = £226.20. Label: 2, 23,  25   Dose schizophrenia, ADULT over 18 years, 300 mg once daily on  day 1, then 600 mg once daily on day 2; adjust according to  response, usual dose 600 mg once daily; max. 800 mg under  specialist supervision; ELDERLY initially 50 mg once daily adjusted  according to response in steps of 50 mg daily  Treatment of mania in bipolar disorder, ADULT over 18 years,   300 mg once daily on day 1, then 600 mg once daily on day 2, then  adjusted according to response; dose range 400-800 mg once  daily; ELDERLY initially 50 mg once daily adjusted according to  response in steps of 50 mg daily   Treatment of depression in bipolar disorder, ADULT over 18 years,  50 mg once daily (at bedtime) on day 1, 100 mg once daily on day  2, 200 mg once daily on day 3, 300 mg once daily on day 4; adjust  according to response, usual dose 300 mg once daily, max. 600 mg  daily   Prevention of mania and depression in bipolar disorder, ADULT  over 18 years, continue at the dose effective for treatment of  bipolar disorder and adjust to lowest effective dose; usual range  300-800 mg once daily   Adjunctive treatment of major depression, ADULT over 18 years,  50 mg once daily at bedtime for 2 days, then 1 50 mg once daily for    2 days, then adjusted according to response, usual range 150-  300 mg once daily; ELDERLY, initially 50 mg once daily for 3 days,  then increase if necessary to 100 mg once daily for 4 days;  thereafter adjusted in steps of 50 mg according to response, usual  range 50-300 mg once daily (dose of 300 mg should not be  reached before day 22 of treatment)   Indications acute and chronic psychoses, mania;  short-term treatment (up to 6 weeks) of persistent  aggression in patients with moderate to severe Alz-  heimer’s dementia unresponsive to non-pharmacol-  ogical interventions and when there is a risk of harm  to self or others; short-term treatment (up to 6 weeks)  of persistent aggression in conduct disorder (under  specialist supervision)   Pregnancy use only if potential benefit outweighs risk;  extrapyramidal effects reported in neonates when  taken in third trimester   Breast-feeding use only if potential benefit outweighs  risk — small amount present in milk   Side-effects see notes above; also gastro-intestinal  disturbances (including diarrhoea, constipation,  nausea and vomiting, dyspepsia, abdominal pain), dry  mouth; dyspnoea; drowsiness, asthenia, tremor, sleep  disturbances, agitation, anxiety, headache; urinary  incontinence; arthralgia, myalgia; abnormal vision;  epistaxis; rash; less commonly anorexia, ECG  changes, hypoaesthesia, impaired concentration,  hyperprolactinaemia (with galactorrhoea, menstrual  disturbances, gynaecomastia), sexual dysfunction,  blood disorders, tinnitus, angioedema; rarely intes-  tinal obstruction, pancreatitis, jaundice, seizures,  hyponatraemia, abnormal temperature regulation;  oedema and priapism also reported   • Psychoses, 2 mg in 1-2 divided doses on first day then   4 mg in 1-2 divided doses on second day (slower  titration appropriate in some patients); usual dose  range 4-6 mg daily; doses above 10 mg daily only if  benefit considered to outweigh risk (max. 16 mg  daily); ELDERLY initially 500 micrograms twice daily  increased in steps of 500 micrograms twice daily to 1-  2 mg twice daily; CHILD 12-18 years see BNF for  Children   • Mania, initially 2 mg once daily, increased if necessary  in steps of 1 mg daily; usual dose range 1-6 mg daily;  ELDERLY initially 500 micrograms twice daily increased  in steps of 500 micrograms twice daily to 1-2 mg  twice daily   • Persistent aggression in Alzheimer’s dementia, initi-  ally 250 micrograms twice daily, increased according  to response in steps of 250 micrograms twice daily on  alternate days; usual dose 500 micrograms twice daily  (up to 1 mg twice daily has been required)   5 years, body-weight under 50 kg, initially 250 micr-  ograms once daily, increased according to response in  steps of 250 micrograms on alternate days; usual dose  500 micrograms daily (up to 750 micrograms once  daily has been required); CHILD over 5 years, body-    weight over 50 kg, initially 500 micrograms once daily,  increased according to response in steps of  500 micrograms on alternate days; usual dose 1 mg  daily (up to 1.5 mg once daily has been required)   Risperidone (Non-proprietary) ▼ (Ml  Tablets, risperidone 500 micrograms, net price 20-tab  pack = 97p; 1 mg, 20-tab pack = £1.18, 60-tab pack =  £1.70; 2 mg, 60-tab pack = £2.13; 3 mg, 60-tab pack =  £2.71; 4 mg, 60-tab pack = £31.52; 6 mg, 28-tab pack =  £24.12. Label: 2   Orodispersible tablets, risperidone 0.5 mg, net price  28-tab pack = £16.88; 1 mg, 28-tab pack = £20.51;   2 mg, 28-tab pack = £37.72; 3 mg, 28-tab pack =  £14.39; 4 mg, 28-tab pack = £15.20. Label: 2, coun-  selling, administration   Counselling Tablets should be placed on the tongue,  allowed to dissolve and swallowed   Liquid, risperidone 1 mg/mL, net price 100-mL pack  = £57.40. Label: 2, counselling, use of dose syringe  Note Liquid may be diluted with any non-alcoholic drink,  except tea   Risperdal® Oanssen-Cilag) T (Ml  Tablets, f/c, scored, risperidone 500 micrograms  (brown-red), net price 20-tab pack = £5.08; 1 mg  (white), 20-tab pack = £8.36, 60-tab pack = £25.08;   2 mg (orange), 60-tab pack = £49.46; 3 mg (yellow),  60-tab pack = £72.73; 4 mg (green), 60-tab pack =  £96.00; 6 mg (yellow), 28-tab pack = £67.88. Label: 2  Orodispersible tablets ( Quicklet ®), pink, risperidone  500 micrograms, net price 28-tab pack = £8.23; 1 mg,  28-tab pack = £17.32; 2 mg, 28-tab pack = £32.65;   3 mg, 28-tab pack = £36.24; 4 mg, 28-tab pack =  £46.68. Label: 2, counselling, administration   Counselling Tablets should be placed on the tongue, allowed to  dissolve and swallowed   Liquid, risperidone 1 mg/mL, net price 100 mL =  £52.87. Label: 2, counselling, use of dose syringe  Note Liquid may be diluted with any non-alcoholic drink, except  tea    alleviate side-effects, it is important to recognise that  the plasma-drug concentration may not fall for some  time after reducing the dose, therefore it may be a  month or longer before side-effects subside.   Dosage Individual responses to neuroleptic drugs  are very variable and to achieve optimum effect,  dosage and dosage interval must be titrated accord-  ing to the patient’s response. For the advice of The  Royal College of Psychiatrists on doses above the  BNF upper limit, see p. 215.    These equivalences are intended only as an approxi-  mate guide; individual dosage instructions should also  be checked; patients should be carefully monitored  after any change in medication   Important These equivalences must not be extrapolated  beyond the maximum dose for the drug    Choice There is no clear-cut division in the use of the  conventional antipsychotics, but zuclopenthixol may  be suitable for the treatment of agitated or aggressive  patients whereas flupentixol can cause over-excite-  ment in such patients. The incidence of extrapyramidal  reactions is similar for the conventional antipsychotics.   Cautions See section 4.2.1. Treatment requires careful  monitoring for optimum effect. When transferring from  oral to depot therapy, the dose by mouth should be  reduced gradually.   Long-acting depot injections are used for maintenance  therapy especially when compliance with oral treatment  is unreliable. However, depot injections of conventional  antipsychotics may give rise to a higher incidence of  extrapyramidal reactions than oral preparations; extra-  pyramidal reactions occur less frequently with atypical  antipsychotic depot preparations, such as risperidone  and olanzapine embonate.   Administration Depot antipsychotics are adminis-  tered by deep intramuscular injection at intervals of 1  to 4 weeks. When initiating therapy with sustained-  release preparations of conventional antipsychotics,  patients should first be given a small test-dose as  undesirable side-effects are prolonged. In general not  more than 2-3 mL of oily injection should be adminis-  tered at any one site; correct injection technique (includ-  ing the use of z-track technique) and rotation of injection  sites are essential. If the dose needs to be reduced to    Side-effects See section 4.2.1. Pain may occur at  injection site and occasionally erythema, swelling, and  nodules. For side-effects of specific antipsychotics see  under the relevant drug.   Cautions see Flupentixol (section 4.2.1) and notes  above; an alternative antipsychotic may be necessary  if symptoms such as aggression or agitation appear  Contra-indications see Flupentixol (section 4.2.1) and  notes above   Hepatic impairment see section 4.2.1  Renal impairment see section 4.2.1  Pregnancy see section 4.2.1  Breast-feeding see section 4.2.1  Side-effects see Flupentixol (section 4.2.1) and notes  above, but may have a mood elevating effect   • By deep intramuscular injection into the upper outer  buttock or lateral thigh, test dose 20 mg, then after at  least 7 days 20-40 mg repeated at intervals of 2-4  weeks, adjusted according to response; max. 400 mg  weekly; usual maintenance dose 50 mg every 4 weeks  to 300 mg every 2 weeks; ELDERLY initially quarter to  half adult dose; CHILD not recommended   Injection (oily), flupentixol decanoate 20mg/mL, net  price 1-mL amp = £1.28; 2-mL amp = £2.49   Depixol Cone.® (Lundbeck) (Ml  Injection (oily), flupentixol decanoate lOOmg/mL,  net price 0.5-mL amp = £1.53; 1-mL amp = £1.84   Depixol Low Volume® (Lundbeck) (Ml  Injection (oily), flupentixol decanoate 200mg/mL,  net price 1-mL amp = £3.01   Cautions see section 4.2.1 and notes above; dose  adjustment may be necessary if smoking started or  stopped during treatment; QT-interval prolongation  (avoid concomitant drugs that prolong QT interval)   Side-effects see section 4.2.1 and notes above; less  sedating and fewer antimuscarinic or hypotensive  symptoms, but extrapyramidal symptoms, particu-  larly dystonic reactions and akathisia, more frequent;  systemic lupus erythematosus, inappropriate anti-  diuretic hormone secretion, and oedema also  reported; extrapyramidal symptoms usually appear a  few hours after injection and continue for about 2  days but may be delayed   • By deep intramuscular injection into the gluteal  muscle, test dose 12.5 mg (6.25 mg in elderly), then  after 4-7 days 12.5-100 mg repeated at intervals of  14-35 days, adjusted according to response; CHILD not  recommended   Fluphenazine decanoate (Non-proprietary) (Ml  Injection (oily), fluphenazine decanoate 25mg/mL,  net price 1-mL amp = £2.35; 100 mg/mL, 0.5-mL amp  = £4.50, 1-mL amp = £8.79   Modecate® (Sanofi-Aventis) (Ml  Injection (oily), fluphenazine decanoate 25 mg/mL,  net price 0.5-mL amp = £1.30, 1-mL amp = £2.26, 2-  mL amp = £4.44   Modecate Concentrate® (Sanofi-Aventis) (Ml  Injection (oily), fluphenazine decanoate lOOmg/mL,  net price 0.5-mL amp = £4.47, 1-mL amp = £8.75   Hepatic impairment see section 4.2.1  Renalimpairment see section 4.2.1  Pregnancy see section 4.2.1  Breast-feeding see section 4.2.1  Side-effects see Haloperidol (section 4.2.1) and notes  above  Dose   • By deep intramuscular injection into the gluteal  muscle, initially 50 mg every 4 weeks, if necessary  increasing by 50-mg increments to 300 mg every 4  weeks; higher doses may be needed in some patients;  ELDERLY, initially 12.5-25 mg every 4 weeks; CHILD not  recommended   Haldol Decanoate® (Janssen-Cilag) iMl  Injection (oily), haloperidol (as decanoate) 50 mg/  mL, net price 1-mL amp = £3.82; lOOmg/mL, 1-mL  amp = £5.06   Indications maintenance in schizophrenia in patients  tolerant to olanzapine by mouth  Cautions see under Olanzapine (section 4.2.1) and  notes above; observe patient for at least 3 hours after  injection   increase with caution in moderate impairment  Renal impairment initially 150 mg every 4 weeks  Pregnancy see under Olanzapine (section 4.2.1)  Breast-feeding see under Olanzapine (section 4.2.1)  Side-effects see under Olanzapine (section 4.2.1) and  notes above; post-injection reactions have been  reported leading to signs and symptoms of overdose  Dose   • By deep intramuscular injection into the gluteal  muscle, ADULT 18-75 years, patients taking oral  olanzapine 10 mg daily, initially 210 mg every 2  weeks or 405 mg every 4 weeks, then maintenance  dose after 2 months treatment, 150 mg every 2 weeks  or 300 mg every 4 weeks; patients taking oral olan-  zapine 15 mg daily, initially 300 mg every 2 weeks,  then maintenance dose after 2 months treatment,   210 mg every 2 weeks or 405 mg every 4 weeks;  patients taking oral olanzapine 20 mg daily, initially  300 mg every 2 weeks, then maintenance dose after 2  months treatment 300 mg every 2 weeks; dose  adjusted according to response; max. 300 mg every 2  weeks   Injection, powder for reconstitution, olanzapine  embonate 210-mg vial, net price = £142.76, 300-mg  vial = £222.64, 405-mg vial = £285.52 (all with diluent)   Cautions see section 4.2.1 and notes above; also  thyrotoxicosis; hypothyroidism  Contra-indications see section 4.2.1 and notes above   • By deep intramuscular injection into the gluteal  muscle, test dose 25 mg, then a further 25-50 mg after   4- 7 days, then adjusted according to response at  intervals of 4 weeks; usual maintenance range 50-  100 mg (max. 200 mg) every 4 weeks; ELDERLY initially   Piportil Depot® (Sanofi-Aventis) 2°M1  Injection (oily), pipotiazine palmitate 50mg/mL, net  price 1-mL amp = £16.29; 2-mL amp = £26.65   Hepatic impairment if an oral dose of at least 2 mg  daily tolerated, 25 mg as a depot injection can be  given every 2 weeks   Renal impairment see Risperidone (section 4.2.1)  Pregnancy see Risperidone (section 4.2.1)  Breast-feeding see Risperidone (section 4.2.1)  Side-effects see Risperidone (section 4.2.1); also  hypertension; depression, paraesthesia; less com-  monly apathy, weight loss, injection-site reactions,  and pruritus  Dose   • By deep intramuscular injection into the deltoid or  gluteal muscle, patients taking oral risperidone up to  4 mg daily, initially 25 mg every 2 weeks; patients  taking oral risperidone over 4 mg daily, initially  37.5 mg every 2 weeks; dose adjusted at intervals of at  least 4 weeks in steps of 12.5 mg to max. 50 mg every  2 weeks; CHILD under 18 years not recommended  Note During initiation risperidone by mouth may need to be  continued for 4-6 weeks; risperidone by mouth may also be  used during dose adjustment of depot injection   Risperdal Consta® Oanssen-Cilag) ▼ (Ml  Injection, powder for reconstitution, risperidone 25-  mg vial, net price = £79.69; 37.5-mg vial = £111.32;  50-mg vial = £142.76 (all with diluent)   Cautions see section 4.2.1 and notes above; QT-  interval prolongation (avoid concomitant use of drugs  that prolong QT interval); avoid in acute porphyria  (section 9.8.2)   • By deep intramuscular injection into the upper outer  buttock or lateral thigh, test dose 100 mg, followed  after at least 7 days by 200-500 mg or more, repeated  at intervals of 1-4 weeks, adjusted according to  response; max. 600 mg weekly; ELDERLY quarter to half  usual starting dose; CHILD not recommended   Clopixol® (Lundbeck) (Ml  Injection (oily), zuclopenthixol decanoate 200 mg/  mL, net price 1-mL amp = £1.99   Injection (oily), zuclopenthixol decanoate 500 mg/  mL, net price 1-mL amp = £3.65   Antimanic drugs are used to control acute attacks and  to prevent recurrence of episodes of mania or hypoma-  nia. Long-term treatment of bipolar disorder should  continue for at least two years from the last manic  episode and up to five years if the patient has risk  factors for relapse.    An antidepressant drug (section 4.3) may also be  required for the treatment of co-existing depression,  but should be avoided in patients with rapid-cycling  bipolar disorder, a recent history of hypomania, or  with rapid mood fluctuations.   Use of benzodiazepines (such as lorazepam) (section  4.1) may be helpful in the initial stages of treatment for  behavioural disturbance or agitation; they should not be  used for long periods because of the risk of dependence.   Antipsychotic drugs (normally olanzapine, quetiapine,  or risperidone) (section 4.2.1) are useful in acute epi-  sodes of mania and hypomania; if the response to anti-  psychotic drugs is inadequate, lithium or valproate may  be added. An antipsychotic drug may be used conco-  mitantly with lithium or valproate in the initial treatment  of severe acute mania.   Olanzapine can be used for the long-term management  of bipolar disorder [unlicensed use] either as monother-  apy, or in combination with lithium or valproate if the  patient has frequent relapses or continuing functional  impairment.    When discontinuing antipsychotics, the dose should be  reduced gradually over at least 4 weeks if the patient is  continuing with other antimanic drugs; if the patient is  not continuing with other antimanic drugs or if there is a  history of manic relapse, a withdrawal period of up to 3  months should be considered.   High doses of haloperidol or flupentixol may be hazar-  dous when used with lithium; irreversible toxic  encephalopathy has been reported.    Depakote® (Sanofi-Aventis) (Ml  Tablets, e/c, valproic acid (as semisodium valproate)  250 mg, net price 90-tab pack = £12.17; 500 mg, 90-  tab pack = £24.29. Label: 21, 25  Note Semisodium valproate comprises equimolar amounts of  sodium valproate and valproic acid   Carbamazepine (section 4.8.1) may be used under spe-  cialist supervision for the prophylaxis of bipolar disorder  (manic-depressive disorder) in patients unresponsive to  a combination of other prophylactic drugs; it is used in  patients with rapid-cycling manic-depressive illness (4  or more affective episodes per year). The dose of carba-  mazepine should not normally be increased if an acute  episode of mania occurs.   When stopping treatment with carbamazepine, reduce  the dose gradually over a period of at least 4 weeks.   Valproic acid (as the semisodium salt) is licensed for the  treatment of manic episodes associated with bipolar  disorder. Sodium valproate (section 4.8.1) is unlicensed  for the treatment of bipolar disorder.   Valproate is also used for the prophylaxis of bipolar  disorder [unlicensed use]; however, it should not nor-  mally be prescribed for women of child-bearing poten-  tial. In patients with frequent relapse or continuing  functional impairment, consider switching therapy to  lithium or olanzapine, or adding lithium or olanzapine to  valproate. If a patient taking valproate experiences an  acute episode of mania that is not ameliorated by  increasing the valproate dose, consider concomitant  therapy with olanzapine, quetiapine, or risperidone.   If treatment with valproate is stopped, reduce the dose  gradually over at least 4 weeks.   Indications treatment of manic episodes associated  with bipolar disorder; migraine prophylaxis (section  4.7.4.2)   Cautions see Sodium Valproate, section 4.8.1; monitor  closely if dose greater than 45 mg/kg daily   • Mania, initially 750 mg daily in 2-3 divided doses,  increased according to response, usual dose 1-2 g  daily; CHILD under 18 years not recommended   • Migraine prophylaxis [unlicensed], initially 250 mg  twice daily, increased if necessary to 1 g daily in  divided doses    Lithium salts are used in the prophylaxis and treatment  of mania, in the prophylaxis of bipolar disorder (manic-  depressive disorder), as concomitant therapy with anti-  depressant medication in patients who have had an  incomplete response to treatment for acute depression  in bipolar disorder, and in the prophylaxis of recurrent  depression (unipolar illness or unipolar depression).  Lithium is also used as an augmenting agent in patients  with treatment-resistant depression (section 4.3).   In acute mania, lithium should only be used in patients  who have responded to lithium before and whose  symptoms are not severe.   The decision to give prophylactic lithium usually  requires specialist advice, and must be based on careful  consideration of the likelihood of recurrence in the  individual patient, and the benefit of treatment weighed  against the risks. The full prophylactic effect of lithium  may not occur for six to twelve months after the initia-  tion of therapy. Olanzapine or valproate (given alone or  as adjunctive therapy with lithium) are alternative pro-  phylactic treatments in patients who experience fre-  quent relapses or continued functional impairment.  Long-term use of lithium has been associated with thy-  roid disorders and mild cognitive and memory impair-  ment. Long-term treatment should therefore be under-  taken only with careful assessment of risk and benefit,  and with monitoring of thyroid function every 6 months  (more often if there is evidence of deterioration). Renal  function should be monitored at baseline and every 6  months thereafter (more often if there is evidence of  deterioration or if the patient has other risk factors, such  as starting ACE inhibitors, NSAIDs, or diuretics). The  need for continued therapy should be assessed regularly  and patients should be maintained on lithium after 3-5  years only if benefit persists.   Serum concentrations Lithium salts have a narrow  therapeutic/toxic ratio and should therefore not be  prescribed unless facilities for monitoring serum-lithium  concentrations are available. Samples should be taken  12 hours after the dose to achieve a serum-lithium  concentration of 0.4-1 mmol/litre (lower end of the  range for maintenance therapy and elderly patients). A  target serum-lithium concentration of 0.8-1 mmol/litre  is recommended for acute episodes of mania, and for  patients who have previously relapsed or have sub-  syndromal symptoms. It is important to determine the  optimum range for each individual patient. Routine  serum-lithium monitoring should be performed weekly  after initiation and after each dose change until levels  are stable, then every 3 months thereafter. Additional  serum-lithium measurements should be made if a  patient develops significant intercurrent disease or if  there is a significant change in a patient’s sodium or fluid  intake.   Overdosage, usually with serum-lithium concentration  of over 1.5 mmol/litre, may be fatal and toxic effects    include tremor, ataxia, dysarthria, nystagmus, renal  impairment, and convulsions. If these potentially hazar-  dous signs occur, treatment should be stopped, serum-  lithium concentrations redetermined, and steps taken to  reverse lithium toxicity. In mild cases withdrawal of  lithium and administration of sodium salts and fluid  will reverse the toxicity. A serum-lithium concentration  in excess of 2 mmol/litre requires urgent treatment as  described under Emergency Treatment of Poisoning,  p. 38.   Interactions Lithium toxicity is made worse by sod-  ium depletion, therefore concurrent use of diuretics  (particularly thiazides) is hazardous and should be  avoided. For other interactions with lithium, see  Appendix 1 (lithium).   Withdrawal While there is no clear evidence of with-  drawal or rebound psychosis, abrupt discontinuation of  lithium increases the risk of relapse. If lithium is to be  discontinued, the dose should be reduced gradually over  a period of at least 4 weeks (preferably over a period of  up to 3 months). Patients should be warned of the risk of  relapse if lithium is discontinued abruptly. If lithium is  stopped or is to be discontinued abruptly, consider  changing therapy to an atypical antipsychotic or val-  proate.   Lithium treatment packs  A lithium treatment pack may be given to patients  on initiation of treatment with lithium. The pack  consists of a patient information booklet, lithium  alert card, and a record book for tracking serum-  lithium concentration.   Indications treatment and prophylaxis of mania,  bipolar disorder, and recurrent depression (see also  notes above); aggressive or self-mutilating behaviour  Cautions see notes above; also measure serum-lithium  concentration regularly (every 3 months on stabilised  regimens), measure renal function and thyroid func-  tion every 6 months on stabilised regimens and advise  patient to seek attention if symptoms of hypo-  thyroidism develop (women at greater risk) e.g.  lethargy, feeling cold; maintain adequate sodium and  fluid intake; test renal function before initiating and if  evidence of toxicity; cardiac disease; QT-interval  prolongation; conditions with sodium imbalance such  as Addison’s disease; reduce dose or discontinue in  diarrhoea, vomiting, and intercurrent infection  (especially if sweating profusely); psoriasis (risk of  exacerbation); elderly (reduce dose); diuretic treat-  ment; myasthenia gravis; surgery (section 15.1); avoid  abrupt withdrawal (see notes above); interactions:  Appendix 1 (lithium)   Counselling Patients should maintain adequate fluid intake  and avoid dietary changes which reduce or increase sodium  intake; lithium treatment packs are available (see above)  Renal impairment avoid if possible or reduce dose  and monitor serum-lithium concentration carefully  Pregnancy avoid if possible in the first trimester (risk  of teratogenicity, including cardiac abnormalities);  dose requirements increased during the second and  third trimesters (but on delivery return abruptly to    normal); close monitoring of serum-lithium concen-  tration advised (risk of toxicity in neonate)   Side-effects gastro-intestinal disturbances, fine tre-  mor, renal impairment (particularly impaired urinary  concentration and polyuria), polydipsia, leucocytosis;  also weight gain and oedema (may respond to dose  reduction); hyperparathyroidism, hyperthyroidism,  hyperglycaemia, hypermagnesaemia, and hypercal-  caemia reported; signs of intoxication are blurred  vision, increasing gastro-intestinal disturbances (ano-  rexia, vomiting, diarrhoea), muscle weakness,  increased CNS disturbances (mild drowsiness and  sluggishness increasing to giddiness with ataxia,  coarse tremor, lack of co-ordination, dysarthria), and  require withdrawal of treatment; with severe over-  dosage (serum-lithium concentration above 2 mmol/  litre) hyperreflexia and hyperextension of limbs,  convulsions, toxic psychoses, syncope, renal failure,  circulatory failure, coma, and occasionally, death;  goitre, raised antidiuretic hormone concentration,  hypothyroidism, hypokalaemia, ECG changes, and  kidney changes may also occur; see also Emergency  Treatment of Poisoning, p. 38    • See under preparations below, adjusted to achieve a  serum-lithium concentration of 0.4-1 mmol/litre 12  hours after a dose on days 4-7 of treatment, then  every week until dosage has remained constant for 4  weeks and every 3 months thereafter; doses are  initially divided throughout the day, but once daily  administration is preferred when serum-lithium con-  centration stabilised   Note Preparations vary widely in bioavailability; chan-  ging the preparation requires the same precautions as  initiation of treatment   Camcolit 250® tablets, f/c, scored, lithium carb-  onate 250 mg (Li + 6.8 mmol), net price 100-tab pack =  £3.09. Label: 10, lithium card, counselling, see above  Camcolit 400® tablets, m/r, f/c, scored, lithium  carbonate 400 mg (Li + 10.8 mmol), net price 100-tab  pack = £4.13. Label: 10, lithium card, 25, counselling,  see above   ADULT and CHILD over 12 years, treatment, initially 1-1.5 g daily;   Tablets, m/r, f/c, scored, lithium carbonate 450 mg  (Li + 12.2 mmol), net price 60-tab pack = £2.88.   ADULT and CHILD over 12 years, treatment, initially 450-675 mg  twice daily (elderly initially 225 mg twice daily); prophylaxis,  initially 450 mg twice daily (elderly 225 mg twice daily)   Priadel® (Sanofi-Aventis) (Ml  Tablets, m/r, both scored, lithium carbonate 200 mg  (Li + 5.4 mmol), net price 100-tab pack= £2.30; 400 mg  (Li + 10.8 mmol), 100-tab pack = £3.35. Label: 10,  lithium card, 25, counselling, see above  Dose (see Dose above for advice on bioavailability and serum  monitoring):   Treatment and prophylaxis, initially 0.4-1. 2 g daily as a single  dose or in 2 divided doses (elderly or patients less than 50 kg,  400 mg daily); CHILD not recommended   Counselling Patients should maintain an adequate fluid  intake and should avoid dietary changes which might  reduce or increase sodium intake; lithium treatment cards  are available from pharmacies (see above)   Renal impairment see Lithium Carbonate  Pregnancy see Lithium Carbonate  Breast-feeding see Lithium Carbonate  Side-effects see under Lithium Carbonate and notes  above  Dose   • See under preparations below, adjusted to achieve  serum-lithium concentration of 0.4-1 mmol/litre as  described under Lithium Carbonate  Note Preparations vary widely in bioavailability; chan-  ging the preparation requires the same precautions as  initiation of treatment   5.4 mmol/5 mL), yellow, net price 150-mL pack =  £5.79; 1.018 g/5mL (Li + 10.8 mmol/ 5 mL), orange,  150-mL pack = £11.58. Label: 10, lithium card,  counselling, see above   Treatment and prophylaxis, initially 1.018-3.054 g daily in 2  divided doses (elderly or patients less than 50 kg, initially 509 mg  twice daily); CHILD not recommended   Note 5-mL dose of 509 mg/5 mL oral solution is equivalent to  200 mg lithium carbonate   Tablets, see under Lithium Carbonate  Liquid, sugar-free, lithium citrate 520 mg/5 mL  (approx. Li + 5.4 mmol/5 mL), net price 150-mL pack  = £5.61. Label: 10, lithium card, counselling, see  above   Treatment and prophylaxis, initially 1.04-3.12 g daily in 2 divided  doses (elderly or patients less than 50 kg, 520 mg twice daily);  CHILD not recommended   Antidepressant drugs are effective for treating moderate  to severe depression associated with psychomotor and  physiological changes such as loss of appetite and sleep  disturbance; improvement in sleep is usually the first  benefit of therapy. Ideally, patients with moderate to  severe depression should be treated with psychological  therapy in addition to drug therapy. Antidepressant  drugs are also effective for dysthymia (lower grade   Antidepressant drugs should not be used routinely in  mild depression, and psychological therapy should be  considered initially; however, a trial of antidepressant  therapy may be considered in cases refractory to psy-  chological treatments or those associated with psycho-  social or medical problems. Drug treatment of mild  depression may also be considered in patients with a  history of moderate or severe depression.   Choice The major classes of antidepressant drugs  include the tricyclic and related antidepressants (section  4.3.1), the selective serotonin re-uptake inhibitors  (SSRIs) (section 4.3.3), and the monoamine oxidase  inhibitors (MAOIs) (section 4.3.2). A number of anti-  depressant drugs cannot be accommodated easily into  this classification; these are included in section 4.3.4.   There is little to choose between the different classes of  antidepressant drugs in terms of efficacy, so choice  should be based on the individual patient’s require-  ments, including the presence of concomitant disease,  existing therapy, suicide risk, and previous response to  antidepressant therapy. Since there may be an interval  of 2 weeks before the antidepressant action takes place,  electroconvulsive treatment may be required in severe  depression when delay is hazardous or intolerable. Dur-  ing the first few weeks of treatment, there is an  increased potential for agitation, anxiety, and suicidal  ideation (see p. 233).   SSRIs are better tolerated and are safer in overdose than  other classes of antidepressants and should be consid-  ered first-line for treating depression. In patients with  unstable angina or who have had a recent myocardial  infarction, sertraline has been shown to be safe.   Tricyclic antidepressants have similar efficacy to SSRIs  but are more likely to be discontinued because of side-  effects; toxicity in overdosage is also a problem. See  section 4.3.1 for more details.   MAOIs have dangerous interactions with some foods  and drugs, and should be reserved for use by specialists.   Although anxiety is often present in depressive illness  (and may be the presenting symptom), the use of an  antipsychotic or an anxiolytic may mask the true diag-  nosis. Anxiolytics (section 4.1.2) or antipsychotic drugs  (section 4.2.1) should therefore be used with caution in  depression but they are useful adjuncts in agitated  patients. Augmenting antidepressants with antipsy-  chotics under specialist supervision may also be neces-  sary in patients who have depression with psychotic  symptoms.   See section 4.2.3 for notes on the management of  bipolar disorder.   St John’s wort {Hypericum perforatum ) is a popular  herbal remedy on sale to the public for treating mild  depression. It should not be prescribed or recom-  mended for depression because St John’s wort can  induce drug metabolising enzymes and a number of  important interactions with conventional drugs, includ-  ing conventional antidepressants, have been identified  (see Appendix 1, St John’s wort). Furthermore, the  amount of active ingredient varies between different  preparations of St John’s wort and switching from one  to another can change the degree of enzyme induction.  If a patient stops taking St John’s wort, concentrations of  interacting drugs may increase, leading to toxicity.    Hyponatraemia and antidepressant therapy  Hyponatraemia (usually in the elderly and possibly  due to inappropriate secretion of antidiuretic horm-  one) has been associated with all types of anti-  depressants; however, it has been reported more  frequently with SSRIs than with other antidepres-  sants. Hyponatraemia should be considered in all  patients who develop drowsiness, confusion, or con-  vulsions while taking an antidepressant.   The use of antidepressants has been linked with  suicidal thoughts and behaviour; children, young  adults, and patients with a history of suicidal beha-  viour are particularly at risk. Where necessary  patients should be monitored for suicidal behaviour,  self-harm, or hostility, particularly at the beginning  of treatment or if the dose is changed.    Management Patients should be reviewed every 1-2  weeks at the start of antidepressant treatment. Treat-  ment should be continued for at least 4 weeks (6 weeks  in the elderly) before considering whether to switch  antidepressant due to lack of efficacy. In cases of partial  response, continue for a further 2-4 weeks (elderly  patients may take longer to respond).   Following remission, antidepressant treatment should  be continued at the same dose for at least 6 months  (about 12 months in the elderly). Patients with a history  of recurrent depression should receive maintenance  treatment for at least 2 years.    Failure to respond Failure to respond to initial treat-  ment with an SSRI may require an increase in the dose,  or switching to a different SSRI or mirtazapine. Other  second-line choices include lofepramine, moclobemide,  and reboxetine. Other tricyclic antidepressants and  venlafaxine should be considered for more severe  forms of depression; irreversible MAOIs should only  be prescribed by specialists. Failure to respond to a  second antidepressant may require the addition of  another antidepressant of a different class, or use of  an augmenting agent (such as lithium (section 4.2.3),  aripiprazole [unlicensed], olanzapine [unlicensed], que-  tiapine, or risperidone [unlicensed] (section 4.2.1)), but  such adjunctive treatment should be initiated only by  doctors with special experience of these combinations.  Electroconvulsive therapy may be initiated in severe  refractory depression.    Withdrawal Withdrawal effects may occur within 5  days of stopping treatment with antidepressant drugs;  they are usually mild and self-limiting, but in some cases  may be severe. Drugs with a shorter half-life, such as  paroxetine (p. 241) and venlafaxine (p. 244), are asso-  ciated with a higher risk of withdrawal symptoms. The  risk of withdrawal symptoms is also increased if the  antidepressant is stopped suddenly after regular admin-  istration for 8 weeks or more. The dose should prefer-  ably be reduced gradually over about 4 weeks, or longer  if withdrawal symptoms emerge (6 months in patients  who have been on long-term maintenance treatment).  See also section 4.3.1, section 4.3.2, and section 4.3.3.    Anxiety disorders and obsessive-compulsive  disorder Management of acute anxiety generally  involves the use of a benzodiazepine or buspirone (sec-  tion 4.1.2). For chronic anxiety (of longer than 4 weeks’  duration) it may be appropriate to use an antidepres-  sant. Combined therapy with a benzodiazepine may be  required until the antidepressant takes effect. General-  ised anxiety disorder, a form of chronic anxiety, is  treated with an SSRI such as escitalopram or paroxetine;  pregabalin and venlafaxine are also licensed for the  treatment of generalised anxiety disorder.   Panic disorder, obsessive-compulsive disorder, post-  traumatic stress disorder, and phobic states such as  social anxiety disorder are treated with SSRIs. Clomi-  pramine or imipramine can be used second-line in panic  disorder [unlicensed]; clomipramine can also be used  second-line for obsessive-compulsive disorder. Moclo-  bemide is licensed for the treatment of social anxiety  disorder.   This section covers tricyclic antidepressants and also 1-,  2-, and 4-ring structured drugs with broadly similar  properties.   Some tricyclic antidepressants are used in the manage-  ment of panic and other anxiety disorders (section 4.3).  For reference to the role of some tricyclic antidepres-  sants in some forms of neuralgia, see section 4.7.3, and  in nocturnal enuresis in children, see section 7.4.2.   Cautions Tricyclic and related antidepressant drugs  should be used with caution in patients with cardiovas-  cular disease (see also Contra-indications, below);  because of the risk of arrhythmias, patients with con-  comitant conditions such as hyperthyroidism and  phaeochromocytoma should be treated with care.  Care is also needed in patients with epilepsy and dia-  betes.   Tricyclic antidepressant drugs have antimuscarinic  activity, and therefore caution is needed in patients  with prostatic hypertrophy, chronic constipation,  increased intra-ocular pressure, urinary retention, or  those with a susceptibility to angle-closure glaucoma.  Tricyclic and related antidepressant drugs should be  used with caution in patients with a significant risk of  suicide, or a history of psychosis or bipolar disorder,  because antidepressant therapy may aggravate these  conditions; treatment should be stopped if the patient  enters a manic phase.   Elderly patients are particularly susceptible to many of  the side-effects of tricyclic antidepressants; low initial  doses should be used, with close monitoring, particu-  larly for psychiatric and cardiac side-effects.   Overdosage Limited quantities of tricyclic antidepres-  sants should be prescribed at any one time because their  cardiovascular and epileptogenic effects are dangerous  in overdosage. In particular, overdosage with dosulepin  and amitriptyline is associated with a relatively high rate  of fatality. Lofepramine is associated with the lowest risk  of fatality in overdosage, in comparison with other tri-  cyclic antidepressant drugs. For advice on overdosage  see Emergency Treatment of Poisoning, p. 37.    Withdrawal Amitriptyline and imipramine are the  tricyclic antidepressants most commonly associated  with withdrawal symptoms. These symptoms include  influenza-like symptoms (chills, myalgia, sweating,  headache, nausea), insomnia, vivid dreams, and may  occasionally include movement disorders, mania, and  cardiac arrhythmia. If possible tricyclic and related anti-  depressants should be withdrawn slowly (see also sec-  tion 4.3).   Interactions A tricyclic or related antidepressant (or  an SSRI or related antidepressant) should not be started  until 2 weeks after stopping an MAOI (3 weeks if starting  clomipramine or imipramine). Conversely, an MAOI  should not be started until at least 7-14 days after a  tricyclic or related antidepressant (3 weeks in the case of  clomipramine or imipramine) has been stopped. For  guidance relating to the reversible monoamine oxidase  inhibitor, moclobemide, see p. 239. For other tricyclic  antidepressant interactions, see Appendix 1 (anti-  depressants, tricyclic and antidepressants, tricyclic  (related)).   Driving Drowsiness may affect the performance of  skilled tasks (e.g. driving); effects of alcohol enhanced.   Contra-indications Tricyclic and related antidepres-  sants are contra-indicated in the immediate recovery  period after myocardial infarction, in arrhythmias (par-  ticularly heart block), and in the manic phase of bipolar  disorder. Avoid treatment with tricyclic antidepressant  drugs in acute porphyria (section 9.8.2).   Hepatic impairment Tricyclic antidepressants are  preferable to MAOIs in hepatic impairment but sedative  effects are increased. They should be avoided in severe  liver disease.   Breast-feeding The amount of tricyclic antidepres-  sants (including related drugs such as mianserin and  trazodone) secreted into breast milk is too small to be  harmful (but see Doxepin, p. 236).   Side-effects Arrhythmias and heart block occasion-  ally follow the use of tricyclic antidepressants, particu-  larly amitriptyline, and may be a factor in the sudden  death of patients with cardiac disease; other cardiovas-  cular side-effects include postural hypotension, tachy-  cardia, and ECG changes. The tricyclic-related anti-  depressant drugs may be associated with a lower risk  of cardiotoxicity in overdosage.   Central nervous system side-effects are common, parti-  cularly in the elderly, and include anxiety, dizziness,  agitation, confusion, sleep disturbances, irritability, and  paraesthesia; drowsiness is associated with some of the  tricyclic antidepressants (see under Choice, below).  Convulsions, hallucinations, delusions, mania, and  hypomania may occur (see also under Cautions,  above), and, rarely, extrapyramidal symptoms including  tremor and dysarthria.   Antimuscarinic side-effects include dry mouth, blurred  vision (very rarely precipitation of angle-closure glauc-  oma), constipation (rarely leading to paralytic ileus,  particularly in the elderly), and urinary retention. Tri-  cyclic-related antidepressant drugs have a lower inci-  dence of antimuscarinic side-effects than older tricyc-  lics.   Endocrine effects include breast enlargement, galacto-  rrhoea, and gynaecomastia. Sexual dysfunction may  occur. Changes in blood sugar, increased appetite, and    weight gain can accompany treatment with tricyclic  antidepressant drugs, but anorexia and weight loss are  also seen. Hepatic and haematological reactions may  occur and have been particularly associated with mian-  serin. Another side-effect to which the elderly are parti-  cularly susceptible is hyponatraemia (see Hyponatr-  aemia and Antidepressant Therapy, p. 233). Other  class side-effects include nausea, vomiting, taste distur-  bance, tinnitus, rash, urticaria, pruritus, photosensitivity,  alopecia, and sweating.   The patient should be encouraged to persist with treat-  ment as some tolerance to these side-effects seems to  develop. They are reduced if low doses are given  initially and then gradually increased, but this must be  balanced against the need to obtain a full therapeutic  effect as soon as possible.   Neuroleptic malignant syndrome (section 4.2.1) may,  very rarely, occur in the course of antidepressant drug  treatment.   Dosage About 10 to 20% of patients fail to respond to  tricyclic and related antidepressant drugs and inade-  quate dosage may account for some of these failures. It  is important to use doses that are sufficiently high for  effective treatment but not so high as to cause toxic  effects. Low doses should be used for initial treatment in  the elderly (see under Side-effects, below).   In most patients the long half-life of tricyclic antidepres-  sant drugs allows once-daily administration, usually at  night; the use of modified-release preparations is there-  fore unnecessary.   Choice Tricyclic and related antidepressants block the  re-uptake of both serotonin and noradrenaline, although  to different extents. For example, clomipramine is more  selective for serotonergic transmission, and imipramine  is more selective for noradrenergic transmission. Tri-  cyclic and related antidepressant drugs can be roughly  divided into those with additional sedative properties  and those that are less sedating. Agitated and anxious  patients tend to respond best to the sedative com-  pounds, whereas withdrawn and apathetic patients will  often obtain most benefit from the less sedating ones.  Those with sedative properties include amitriptyline,  clomipramine, dosulepin, doxepin, mianserin,  trazodone, and trimipramine. Those with less sedative  properties include imipramine, lofepramine, and nor-  triptyline.   Tricyclic and related antidepressants also have varying  degrees of antimuscarinic side-effects and cardiotoxi-  city in overdosage, which may be important in indivi-  dual patients. Lofepramine has a lower incidence of  side-effects and is less dangerous in overdosage but is  infrequently associated with hepatic toxicity. Imipra-  mine is also well established, but has more marked  antimuscarinic side-effects than other tricyclic and  related antidepressants. Amitriptyline and dosulepin  are effective but they are particularly dangerous in  overdosage (see Overdosage, above) and are not recom-  mended for the treatment of depression; dosulepin  should only be prescribed by specialists.   Children and adolescents Studies have shown that  tricyclic antidepressants are not effective for treating  depression in children; see also Depressive Illness in  Children and Adolescents, p. 239.   Indications depressive illness (but not recommended,  see notes above); nocturnal enuresis in children  (section 7.4.2); neuropathic pain [unlicensed] (section  4.7.3); migraine prophylaxis [unlicensed] (section  4.7.4.2)   Side-effects see notes above; also abdominal pain,  stomatitis, palpitation, oedema, hypertension, rest-  lessness, fatigue, mydriasis, and increased intra-ocular  pressure; high rate of fatality in overdose — see notes  above   • Depression (but not recommended, see notes above),  ADULT and CHILD over 16 years, initially 75 mg (elderly  and adolescents 30-75 mg) daily in divided doses or  as a single dose at bedtime increased gradually as  necessary to 150-200 mg   • Nocturnal enuresis, CHILD 7-11 years 10-20 mg at  night, 11-16 years 25-50 mg at night; max. period of  treatment (including gradual withdrawal) 3 months —  full physical examination, including ECG, before  further course   10 mg daily at night, gradually increased if necessary  to 75 mg daily; higher doses under specialist super-  vision   • Migraine prophylaxis [unlicensed indication], initially  10 mg at night, increased if necessary to maintenance  of 50-75 mg at night; max. 150 mg at night   Amitriptyline (Non-proprietary) (Ml  Tablets, coated, amitriptyline hydrochloride 10 mg,  net price 28-tab pack = 90p; 25 mg, 28-tab pack =  90p; 50 mg, 28-tab pack = £1.00. Label: 2  Oral solution, amitriptyline hydrochloride 25 mg/  5mL, net price 150 mL = £15.47; 50 mg/5 mL,   Tablets, pink, s/c, amitriptyline hydrochloride 25 mg,  perphenazine 2 mg, net price 100-tab pack = £25.49.  Label: 2   Dose depression with anxiety, ADULT and CHILD over 14 years, 1  tablet 3 times daily; an additional tablet may be taken at bedtime  when required   Indications depressive illness, phobic and obsessional  states; adjunctive treatment of cataplexy associated  with narcolepsy  Cautions see notes above   Breast-feeding see notes above  Side-effects see notes above; also abdominal pain,  diarrhoea, hypertension, flushing, restlessness, fati-    gue, aggression, impaired memory, muscle weakness,  muscle hypertonia, myoclonus, mydriasis, and yawn-  ing; very rarely allergic alveolitis   • Depressive illness, ADULT over 18 years, initially 10 mg  daily, increased gradually as necessary to 30-150 mg  daily in divided doses or as a single dose at bedtime;  max. 250 mg daily; ELDERLY initially 10 mg daily  increased carefully over approx. 10 days to 30-75 mg  daily   • Phobic and obsessional states, ADULT over 18 years,  initially 25 mg daily (ELDERLY 10 mg daily) increased  over 2 weeks to 100-150 mg daily; max. 250 mg daily   • Adjunctive treatment of cataplexy associated with  narcolepsy, ADULT over 18 years, initially 10 mg daily,  gradually increased until satisfactory response (range  10-75 mg daily)   Clomipramine (Non-proprietary) (Ml  Capsules, clomipramine hydrochloride 10 mg, net  price 28-cap pack = £1.71; 25 mg, 28-cap pack =  £2.01; 50 mg, 28-cap pack = £2.75. Label: 2   Anafranil® (Novartis) (Ml  Capsules, clomipramine hydrochloride 10 mg (yel-  low/caramel), net price 84-cap pack = £3.23; 25 mg  (orange/caramel), 84-cap pack = £6.35; 50 mg (grey/  caramel), 56-cap pack = £8.06. Label: 2   Tablets, m/r, grey-red, f/c, clomipramine hydro-  chloride 75 mg, net price 28-tab pack = £8.83.  Label: 2, 25   • Initially 75 mg (ELDERLY 50-75 mg) daily in divided  doses or as a single dose at bedtime, increased  gradually as necessary to 1 50 mg daily (ELDERLY 75 mg  may be sufficient); up to 225 mg daily in some cir-  cumstances (e.g. hospital use); CHILD not recom-  mended   Dosulepin (Non-proprietary) [Ml  Capsules, dosulepin hydrochloride 25 mg, net price  28-cap pack = £1.11. Label: 2  Tablets, dosulepin hydrochloride 75 mg, net price 28-  tab pack = £1.34. Label: 2   Capsules, red/red-brown, dosulepin hydrochloride  25 mg, net price 28-cap pack = £1.70. Label: 2  Tablets, red, s/c, dosulepin hydrochloride 75 mg, net  price 28-tab pack = £2.97. Label: 2   Breast-feeding see notes above; accumulation of  metabolite may cause sedation and respiratory  depression in neonate   Side-effects see notes above; also abdominal pain,  stomatitis, diarrhoea, flushing, and oedema   • ADULT and CHILD over 12 years, initially 75 mg daily in  divided doses or as a single dose at bedtime, adjusted  according to response; usual maintenance 30-300 mg  daily (doses above 100 mg given in 3 divided doses);  ELDERLY initially 10-50 mg daily adjusted according to  response (usual maintenance 30-50 mg daily)   Sinepin® (Marlborough) [Ml  Capsules, doxepin (as hydrochloride) 25 mg, net price  28-cap pack = £3.77; 50 mg, 28-cap pack = £5.71.  Label: 2   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment use with caution in severe impair-  ment   Pregnancy colic, tachycardia, dyspnoea, irritability,  and muscle spasms reported in neonates when used  in the third trimester  Breast-feeding see notes above  Side-effects see notes above; also palpitation, flush-  ing, restlessness, headache, fatigue; very rarely  abdominal pain, stomatitis, hypertension, oedema,  cardiac decompensation, allergic alveolitis, aggres-  sion, myoclonus, peripheral vasospasm, and mydriasis  Dose   • Depression, initially up to 75 mg daily in divided doses  increased gradually to 150-200 mg (up to 300 mg in  hospital patients); up to 150 mg may be given as a  single dose at bedtime; ELDERLY initially 10 mg daily,  increased gradually to 30-50 mg daily; CHILD not  recommended for depression   • Nocturnal enuresis, CHILD 7-8 years 25 mg, 8-1 1 years  25-50 mg, over 11 years 50-75 mg at bedtime; max.  period of treatment (including gradual withdrawal) 3  months — full physical examination before further  course   • 140-210 mg daily in divided doses; ELDERLY may  respond to lower doses; CHILD under 18 years not  recommended   Lofepramine (Non-proprietary) (Ml  Tablets, lofepramine 70 mg (as hydrochloride), net  price 56-tab pack = £5.69. Label: 2   Oral suspension, lofepramine 70 mg/5 mL (as  hydrochloride), net price 150 mL = £22.22. Label: 2  Brands include Lomont® (sugar-free)   Indications depressive illness; nocturnal enuresis in  children (section 7.4.2); neuropathic pain [unlicensed]  (section 4.7.3)   Cautions see notes above; manufacturer advises  plasma-nortriptyline concentration monitoring if dose  above 100 mg daily, but evidence of practical value  uncertain   Breast-feeding see notes above  Side-effects see notes above; also abdominal pain,  stomatitis, diarrhoea, hypertension, oedema, flushing,  restlessness, fatigue, and mydriasis   • Depression, low dose initially increased as necessary  to 75-100 mg daily in divided doses or as a single  dose (max. 150 mg daily); ADOLESCENT and ELDERLY 30-  50 mg daily in divided doses; CHILD not recommended  for depression   • Nocturnal enuresis, CHILD 7 years 10 mg, 8-11 years  10-20 mg, over 1 1 years 25-35 mg, 30 minutes before  bedtime; max period of treatment (including gradual  withdrawal) 3 months — full physical examination and  ECG before further course   • Neuropathic pain [unlicensed], initially 10 mg daily at  night, gradually increased if necessary to 75 mg daily;  higher doses under specialist supervision   Tablets, nortriptyline (as hydrochloride) 10 mg, net  price 100-tab pack = £12.06; 25 mg (orange, scored),  100-tab pack = £24.02. Label: 2   • Initially 50-75 mg daily in divided doses or as a single  dose at bedtime, increased as necessary to 150—   300 mg daily; ELDERLY initially 10-25 mg 3 times daily,  maintenance half adult dose may be sufficient; CHILD  not recommended   Surmontil® (Sanofi-Aventis) (Ml  Capsules, green/white, trimipramine 50 mg (as mal-  eate), net price 28-cap pack = £7.60. Label: 2  Tablets, trimipramine (as maleate) 10 mg, net price  28-tab pack = £3.43, 84-tab pack = £10.27; 25 mg, 28-  tab pack = £4.53, 84-tab pack = £13.55. Label: 2    time; may be increased to 300 mg daily; hospital  patients up to max. 600 mg daily in divided doses;  CHILD not recommended   • Anxiety, 75 mg daily, increasing if necessary to  300 mg daily; CHILD not recommended   Trazodone (Non-proprietary) [Ml  Capsules, trazodone hydrochloride 50 mg, net price  84-cap pack = £4.72; 100 mg, 56-cap pack = £4.85.  Label: 2, 21   Tablets, trazodone hydrochloride 150 mg, net price  28-tab pack = £4.57. Label: 2, 21   Molipaxin® (Sanofi-Aventis) (5°M1  Capsules, trazodone hydrochloride 50 mg (violet/  green), net price 84-cap pack = £23.92; 100 mg (vio-  let/fawn), 56-cap pack = £28.14. Label: 2, 21  Tablets, pink, f/c, trazodone hydrochloride 150 mg,  net price 28-tab pack = £16.08. Label: 2, 21  Liquid, sugar-free, trazodone hydrochloride 50 mg/  5mL, net price 120 mL = £13.37. Label: 2, 21   Indications depressive illness, particularly where  sedation is required  Cautions see notes above  Blood counts A full blood count is recommended every 4  weeks during the first 3 months of treatment; clinical mon-  itoring should continue subsequently and treatment should  be stopped and a full blood count obtained if fever, sore  throat, stomatitis, or other signs of infection develop  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment caution in renal impairment  Pregnancy avoid  Breast-feeding see notes above  Side-effects see notes above; also jaundice, oedema,  blood dyscrasias, arthritis, and arthralgia  Dose   • ADULT over 18 years, initially 30-40 mg (elderly 30 mg)  daily in divided doses or as a single dose at bedtime,  increased gradually as necessary; usual dose range  30-90 mg   Mianserin (Non-proprietary) [MI  Tablets, mianserin hydrochloride 10 mg, net price 28-  tab pack = £8.05; 30 mg, 28-tab pack = £14.05.   • Depression, initially 150 mg (elderly 100 mg) daily in  divided doses after food or as a single dose at bed-   Monoamine-oxidase inhibitors are used much less fre-  quently than tricyclic and related antidepressants, or  SSRIs and related antidepressants because of the dan-  gers of dietary and drug interactions and the fact that it  is easier to prescribe MAOIs when tricyclic antidepres-  sants have been unsuccessful than vice versa. Tranyl-  cypromine is the most hazardous of the MAOIs  because of its stimulant action. The drugs of choice  are phenelzine or isocarboxazid which are less stimu-  lant and therefore safer.   Phobic patients and depressed patients with atypical,  hypochondriacal, or hysterical features are said to  respond best to MAOIs. However, MAOIs should be  tried in any patients who are refractory to treatment  with other antidepressants as there is occasionally a  dramatic response. Response to treatment may be  delayed for 3 weeks or more and may take an additional  1 or 2 weeks to become maximal.   Withdrawal MAOIs are associated with withdrawal  symptoms on cessation of therapy. Symptoms include  agitation, irritability, ataxia, movement disorders,  insomnia, drowsiness, vivid dreams, cognitive impair-  ment, and slowed speech. Withdrawal symptoms occa-  sionally experienced when discontinuing MAOIs  include hallucinations and paranoid delusions. If possi-  ble MAOIs should be withdrawn slowly (see also section  4.3).   Hepatic impairment MAOIs may cause idiosyncratic  hepatotoxicity if used in patients with hepatic impair-  ment. See also individual monographs.   Pregnancy There is an increased risk of neonatal  malformations when phenelzine, isocarboxazid, or  tranylcypromine is used during pregnancy. The safety  of moclobemide in pregnancy has not been established.  Manufacturers advise avoid use unless there are com-  pelling reasons.    Interactions MAOIs inhibit monoamine oxidase,  thereby causing an accumulation of amine neurotrans-  mitters. The metabolism of some amine drugs such as  indirect-acting sympathomimetics (present in many  cough and decongestant preparations, section 3.10) is  also inhibited and their pressor action may be poten-  tiated; the pressor effect of tyramine (in some foods,  such as mature cheese, pickled herring, broad bean  pods, and Bovril®, Oxo®, Marmite® or any similar  meat or yeast extract or fermented soya bean extract)  may also be dangerously potentiated. These interac-  tions may cause a dangerous rise in blood pressure. An  early warning symptom may be a throbbing headache.  Patients should be advised to eat only fresh foods and  avoid food that is suspected of being stale or ‘going off.  This is especially important with meat, fish, poultry or  offal; game should be avoided. The danger of interaction  persists for up to 2 weeks after treatment with MAOIs is  discontinued. Patients should also avoid alcoholic drinks  or de-alcoholised (low alcohol) drinks.   Other antidepressants should not be started for 2 weeks  after treatment with MAOIs has been stopped (3 weeks  if starting clomipramine or imipramine). Some psychia-  trists use selected tricyclics in conjunction with MAOIs  but this is hazardous, indeed potentially lethal, except in  experienced hands and there is no evidence that the  combination is more effective than when either consti-  tuent is used alone. The combination of tranyl-  cypromine with clomipramine is particularly danger-  ous.   Conversely, an MAOI should not be started until at least  7-14 days after a tricyclic or related antidepressant (3  weeks in the case of clomipramine or imipramine) has  been stopped.    In addition, an MAOI should not be started for at least 2  weeks after a previous MAOI has been stopped (then  started at a reduced dose).    For other interactions with MAOIs including those with  opioid analgesics (notably pethidine), see Appendix 1  (MAOIs). For guidance on interactions relating to the  reversible monoamine oxidase inhibitor, moclobemide,  see p. 239; for guidance on interactions relating to  SSRIs, see p. 240.   Indications depressive illness  Cautions diabetes mellitus, cardiovascular disease,  epilepsy, blood disorders, concurrent electroconvul-  sive therapy; elderly (great caution); monitor blood  pressure (risk of postural hypotension and hyperten-  sive responses — discontinue if palpitations or fre-  quent headaches); if possible avoid abrupt withdrawal;  severe hypertensive reactions to certain drugs and  foods; avoid in agitated patients; acute porphyria  (section 9.8.2); surgery (section 15.1); interactions:  Appendix 1 (MAOIs)    effects include drowsiness, insomnia, headache,  weakness and fatigue, dry mouth, constipation and  other gastro-intestinal disturbances, oedema, myo-  clonic movement, hyperreflexia, elevated liver  enzymes; agitation and tremors, nervousness,  euphoria, arrhythmias, blurred vision, nystagmus,  difficulty in micturition, sweating, convulsions, rashes,  purpura, leucopenia, sexual disturbances, and weight  gain with inappropriate appetite may also occur;  psychotic episodes with hypomanic behaviour, con-  fusion, and hallucinations may be induced in suscep-  tible persons; suicidal behaviour (see p. 233); jaundice  has been reported and, on rare occasions, fatal pro-  gressive hepatocellular necrosis; paraesthesia, per-  ipheral neuritis, peripheral neuropathy may be due to  pyridoxine deficiency; hyponatraemia (see Hypo-  natraemia and Antidepressant Therapy, p. 233)   • 15 mg 3 times daily, increased if necessary to 4 times  daily after 2 weeks (hospital patients, max. 30 mg 3  times daily), then reduced gradually to lowest possible  maintenance dose (15 mg on alternate days may be  adequate); CHILD not recommended   Tablets, orange, f/c, phenelzine (as sulphate) 15 mg,  net price 100-tab pack = £18.75. Label: 3, 10, patient  information leaflet   Indications depressive illness  Cautions see under Phenelzine  Contra-indications see under Phenelzine  Hepatic impairment avoid in hepatic impairment; see  also notes above   • Initially 30 mg daily in single or divided doses until  improvement occurs (increased after 4 weeks if  necessary to max. 60 mg daily for 4-6 weeks under  close supervision), then reduced to usual mainte-  nance dose 10-20 mg daily (but up to 40 mg daily may  be required); ELDERLY 5-10 mg daily; CHILD not  recommended   Indications depressive illness  Cautions see under Phenelzine  Contra-indications see under Phenelzine; hyper-  thyroidism   Hepatic impairment see notes above  Pregnancy see notes above  Breast-feeding present in milk in animal studies  Side-effects see under Phenelzine; insomnia; hyper-  tensive crises with throbbing headache requiring dis-  continuation of treatment more frequent than with  other MAOIs; liver damage less frequent than with  phenelzine; blood dyscrasias also reported   • Initially 10 mg twice daily not later than 3 p.m.,  increasing the second daily dose to 20 mg after 1 week  if necessary; doses above 30 mg daily under close  supervision only; usual maintenance dose 10 mg  daily; CHILD not recommended   Tranylcypromine (Non-proprietary) (Ml  Tablets, tranylcypromine (as sulphate) 10 mg, net  price 28-tab pack = £46.24. Label: 3, 10, patient  information leaflet    doses, continued for 8-12 weeks to assess efficacy;  CHILD not recommended   Moclobemide (Non-proprietary) [Ml  Tablets, moclobemide 150 mg, net price 30-tab pack  = £3.76; 300 mg, 30-tab pack = £5.86. Label: 10,  patient information leaflet, 21   Tablets, yellow, f/c, scored, moclobemide 150 mg, net  price 30-tab pack = £9.33; 300 mg, 30-tab pack =  £13.99. Label: 10, patient information leaflet, 21   Moclobemide is indicated for major depression and  social anxiety disorder; it is reported to act by reversible  inhibition of monoamine oxidase type A (it is therefore  termed a RIMA). It should be reserved as a second-line  treatment.   Interactions Moclobemide is claimed to cause less  potentiation of the pressor effect of tyramine than the  traditional (irreversible) MAOIs, but patients should  avoid consuming large amounts of tyramine-rich food  (such as mature cheese, yeast extracts and fermented  soya bean products).   The risk of drug interactions is also claimed to be less  but patients still need to avoid sympathomimetics such  as ephedrine and pseudoephedrine. In addition, moclo-  bemide should not be given with another antidepres-  sant. Owing to its short duration of action no treatment-  free period is required after it has been stopped but it  should not be started until at least a week after a tri-  cyclic or related antidepressant or an SSRI or related  antidepressant has been stopped (2 weeks in the case of  sertraline, and at least 5 weeks in the case of fluoxetine),  or for at least a week after an MAOI has been stopped.  For other interactions, see Appendix 1 (moclobemide).   Indications depressive illness; social anxiety disorder  Cautions avoid in agitated or excited patients (or give  with sedative for up to 2-3 weeks), thyrotoxicosis,  may provoke manic episodes in bipolar disorders;  interactions: see notes above and Appendix 1  (moclobemide)   Hepatic impairment reduce dose in severe disease  Pregnancy see notes above, p. 237  Breast-feeding amount too small to be harmful, but  patient information leaflet advises avoid  Side-effects sleep disturbances, dizziness, gastro-  intestinal disorders, headache, restlessness, agitation;  paraesthesia, dry mouth, visual disturbances, oedema,  skin reactions, confusional states reported; rarely  raised liver enzymes, galactorrhoea; hyponatraemia  (see Hyponatraemia and Antidepressant Therapy,  p. 233)   • Depression, initially 300 mg daily usually in divided  doses after food, adjusted according to response;  usual range 150-600 mg daily; CHILD not recom-  mended   • Social anxiety disorder, initially 300 mg daily  increased on fourth day to 600 mg daily in 2 divided   Citalopram, escitalopram, fluoxetine, fluvoxamine,  paroxetine, and sertraline selectively inhibit the re-  uptake of serotonin (5-hydroxytryptamine, 5-HT); they  are termed selective serotonin re-uptake inhibitors  (SSRIs). For a general comment on the management  of depression and on the comparison between tricyclic  and related antidepressants and the SSRIs and related  antidepressants, see section 4.3.   Depressive illness in children and adolescents  The balance of risks and benefits for the treatment of  depressive illness in individuals under 18 years is  considered unfavourable for the SSRIs citalopram,  escitalopram, paroxetine, and sertraline, and for  mirtazapine and venlafaxine. Clinical trials have  failed to show efficacy and have shown an increase  in harmful outcomes. However, it is recognised that  specialists may sometimes decide to use these drugs  in response to individual clinical need; children and  adolescents should be monitored carefully for suici-  dal behaviour, self-harm or hostility, particularly at  the beginning of treatment.   Only fluoxetine has been shown in clinical trials to  be effective for treating depressive illness in children  and adolescents. However, it is possible that, in  common with the other SSRIs, it is associated with  a small risk of self-harm and suicidal thoughts. Over-  all, the balance of risks and benefits for fluoxetine in  the treatment of depressive illness in individuals  under 18 years is considered favourable, but children  and adolescents must be carefully monitored as  above.   Cautions SSRIs should be used with caution in patients  with epilepsy (avoid if poorly controlled, discontinue if  convulsions develop), cardiac disease, diabetes mellitus,  susceptibility to angle-closure glaucoma, a history of  mania or bleeding disorders (especially gastro-intestinal  bleeding), and if used with other drugs that increase the  risk of bleeding. They should also be used with caution  in those receiving concurrent electroconvulsive therapy  (prolonged seizures reported with fluoxetine). SSRIs  may also impair performance of skilled tasks (e.g. driv-  ing). Interactions: see below and Appendix 1 (anti-  depressants, SSRI).   Withdrawal The risk of withdrawal reactions is higher  with paroxetine (see also Withdrawal, section 4.3). Gas-  tro-intestinal disturbances, headache, anxiety, dizziness,  paraesthesia, electric shock sensation in the head, neck,  and spine, tinnitus, sleep disturbances, fatigue, influ-  enza-like symptoms, and sweating are the most com-    mon features of abrupt withdrawal of an SSRI or marked  reduction of the dose; palpitation and visual distur-  bances can occur less commonly. The dose should be  tapered over a few weeks to avoid these effects. For  some patients, it may be necessary to withdraw treat-  ment over a longer period; consider obtaining specialist  advice if symptoms persist.   Interactions An SSRI or related antidepressant should  not be started until 2 weeks after stopping an MAOI.  Conversely, an MAOI should not be started until at least  a week after an SSRI or related antidepressant has been  stopped (2 weeks in the case of sertraline, at least 5  weeks in the case of fluoxetine). For guidance relating to  the reversible monoamine oxidase inhibitor, moclobe-  mide, see above. For other SSRI antidepressant interac-  tions, see Appendix 1 (antidepressants, SSRI).   Contra-indications SSRIs should not be used if the  patient enters a manic phase.   Pregnancy Manufacturers advise that SSRIs should  not be used during pregnancy unless the potential  benefit outweighs the risk. There is a small increased  risk of congenital heart defects when SSRIs are taken  during early pregnancy. If SSRIs are used during the  third trimester there is a risk of neonatal withdrawal  symptoms, and persistent pulmonary hypertension in  the newborn has been reported; see also individual  monographs.   Side-effects SSRIs are less sedating and have fewer  antimuscarinic and cardiotoxic effects than tricyclic  antidepressants (section 4.3.1). Side-effects of the  SSRIs include gastro-intestinal effects (dose-related  and fairly common — include nausea, vomiting, dys-  pepsia, abdominal pain, diarrhoea, constipation), ano-  rexia with weight loss (increased appetite and weight  gain also reported) and hypersensitivity reactions  including rash (consider discontinuation — may be sign  of impending serious systemic reaction, possibly asso-  ciated with vasculitis), urticaria, angioedema, anaphy-  laxis, arthralgia, myalgia and photosensitivity; other  side-effects include dry mouth, nervousness, anxiety,  headache, insomnia, tremor, dizziness, asthenia, hallu-  cinations, drowsiness, convulsions (see Cautions above),  galactorrhoea, sexual dysfunction, urinary retention,  sweating, hypomania or mania (see Cautions above),  movement disorders and dyskinesias, visual distur-  bances, hyponatraemia (see Hyponatraemia and Anti-  depressant Therapy, p. 233), and bleeding disorders  including ecchymoses and purpura. Suicidal behaviour  has been linked with antidepressants (see p. 233). Stu-  dies have shown an increased risk of bone fractures in  patients receiving SSRIs. Angle-closure glaucoma may  very rarely be precipitated by treatment with SSRIs.   Indications depressive illness, panic disorder  Cautions see notes above  Contra-indications see notes above  Hepatic impairment use doses at lower end of range  Renal impairment no information available for eGFR  less than 20 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding present in milk — avoid    Side-effects see notes above; also hepatitis, palpita-  tion, tachycardia, oedema, bradycardia, postural  hypotension, coughing, yawning, confusion, impaired  concentration, aggression, malaise, amnesia,  migraine, paraesthesia, abnormal dreams, mydriasis,  taste disturbance, increased salivation, rhinitis, tinni-  tus, polyuria, micturition disorders, euphoria, pruritus;  paradoxical increased anxiety during initial treatment  of panic disorder (reduce dose)   • By mouth as tablets, depressive illness, 20 mg once  daily increased if necessary in steps of 20 mg daily at  intervals of 3-4 weeks; max. 60 mg daily (ELDERLY over  65 years, max. 40 mg daily); CHILD under 18 years see  BNF for Children and Depressive Illness in Children  and Adolescents, p. 239   Panic disorder, ADULT over 18 years, initially 10 mg  daily increased gradually if necessary in steps of  10 mg daily, usual dose 20-30 mg daily; max. 60 mg  daily (ELDERLY over 65 years, max. 40 mg daily)   • By mouth as oral drops, depressive illness, 16 mg  daily as a single dose increased if necessary in steps of  16 mg daily at intervals of 3-4 weeks; max. 48 mg  daily (ELDERLY over 65 years, max. 32 mg daily); CHILD  under 18 years see BNF for Children and Depressive  Illness in Children and Adolescents, p. 239   Panic disorder, ADULT over 18 years, initially 8 mg daily  as a single dose increased gradually if necessary in  steps of 8 mg, usual dose 16-24 mg daily; max. 48 mg  daily (ELDERLY over 65 years, max. 32 mg daily)   Citalopram (Non-proprietary) (Ml  Tablets, citalopram (as hydrobromide) 10 mg, net  price 28-tab pack = £1.03; 20 mg, 28-tab pack = £1.30;  40 mg, 28-tab pack = £1.37. Counselling, driving  Oral drops, citalopram (as hydrochloride) 40mg/mL,  net price 15 mL = £17.92. Counselling, driving,  administration   Note 4 drops (8 mg) is equivalent in therapeutic effect to 10-  mg tablet   Mix with water, orange juice, or apple juice before taking  Cipramil® (Lundbeck) ®   Tablets, f/c, citalopram (as hydrobromide) 10 mg, net  price 28-tab pack = £5.38; 20 mg (scored), 28-tab pack  = £8.95; 40 mg, 28-tab pack = £15.12. Counselling,  driving   Oral drops, sugar-free, citalopram (as hydrochloride)  40mg/mL, net price 15 mL = £10.08. Counselling,  driving, administration   Note 4 drops (8 mg) is equivalent in therapeutic effect to 10-mg  tablet   Indications see under Dose  Cautions see notes above  Contra-indications see notes above  Hepatic impairment initial dose 5 mg daily for 2  weeks, thereafter increased to 10 mg daily according  to response; particular caution in severe impairment  Renal impairment caution if eGFR less than 30 mL/  minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding present in milk; avoid    Side-effects see notes above; also sinusitis, yawning;  fatigue, restlessness, abnormal dreams, paraesthesia;  pyrexia; less commonly taste disturbance, bruxism,  syncope, tachycardia, oedema, confusion, menstrual  disturbances, epistaxis, mydriasis, tinnitus, pruritus,  and alopecia; rarely bradycardia, aggression, and  depersonalisation; hepatitis, postural hypotension, QT  interval prolongation, and thrombocytopenia also  reported; paradoxical increased anxiety during initial  treatment of panic disorder (reduce dose)   • ADULT over 18 years, depressive illness, generalised  anxiety disorder, and obsessive-compulsive disorder,  10 mg once daily increased if necessary to max. 20 mg  daily; ELDERLY initially half adult dose, lower mainte-  nance dose may be sufficient; CHILD not recom-  mended (see Depressive Illness in Children and  Adolescents, p. 239)   • ADULT over 18 years, panic disorder, initially 5 mg once  daily increased to 10 mg daily after 7 days; max.   20 mg daily; ELDERLY initially half adult dose, lower  maintenance dose may be sufficient   • ADULT over 18 years, social anxiety disorder, initially  10 mg once daily adjusted after 2-4 weeks; usual dose  5-20 mg daily   Tablets, f/c, escitalopram (as oxalate) 5 mg, net price  28-tab pack = £8.97; 10 mg (scored), 28-tab pack =  £14.91; 20 mg (scored), 28-tab pack = £25.20. Coun-  selling, driving   Oral drops, sugar-free, escitalopram (as oxalate)  lOmg/mL, net price 28 mL = £18.82; 20mg/mL,  15mL = £20.16. Counselling, driving, administration  Note Can be mixed with water, orange juice, or apple juice  before taking   Side-effects see notes above; also vasodilatation,  postural hypotension, pharyngitis, dyspnoea, chills,  taste disturbance, sleep disturbances, euphoria, con-  fusion, yawning, impaired concentration, changes in  blood sugar, alopecia, urinary frequency; rarely  pulmonary inflammation and fibrosis; very rarely  hepatitis, toxic epidermal necrolysis, and neuroleptic  malignant syndrome-like event   • Major depression, 20 mg once daily increased after 3-  4 weeks if necessary, and at appropriate intervals  thereafter; max. 60 mg once daily (ELDERLY usual max.  40 mg once daily but 60 mg can be used); CHILD 8-18  years, 10 mg once daily increased after 1-2 weeks if  necessary, max. 20 mg once daily (but see also  Depressive Illness in Children and Adolescents,   • Bulimia nervosa, ADULT over 18 years, 60 mg once  daily   • Obsessive-compulsive disorder, ADULT over 18 years,  20 mg once daily; increased gradually if necessary to  max. 60 mg once daily (ELDERLY usual max. 40 mg    once daily but 60 mg can be used); review treatment if  inadequate response after 10 weeks  Long duration of action Consider the long half-life of fluox-  etine when adjusting dosage (or in overdosage)   Fluoxetine (Non-proprietary) [Ml  Capsules, fluoxetine (as hydrochloride) 20 mg, net  price 30-cap pack = £1.90; 60 mg, 30-cap pack =  £54.43. Counselling, driving  Brands include Oxactin ®   Liquid, fluoxetine (as hydrochloride) 20 mg/5 mL, net  price 70 mL = £11.12. Counselling, driving   Cautions see notes above  Contra-indications see notes above  Hepatic impairment start with low dose  Renal impairment start with low dose  Pregnancy see notes above  Breast-feeding present in milk — avoid  Side-effects see notes above; palpitation, tachycardia,  malaise; less commonly postural hypotension, confu-  sion, ataxia; rarely abnormal liver function, usually  symptomatic (discontinue treatment); also reported  paraesthesia, taste disturbance, neuroleptic malignant  syndrome-like event  Dose   • Depression, ADULT over 18 years, initially 50-100 mg  daily in the evening, increased gradually if necessary  to max. 300 mg daily (over 150 mg in divided doses);  usual maintenance dose 100 mg daily   • Obsessive-compulsive disorder, initially 50 mg in the  evening increased gradually if necessary after some  weeks to max. 300 mg daily (over 150 mg in divided  doses); usual maintenance dose 100-300 mg daily;  CHILD over 8 years initially 25 mg daily increased if  necessary in steps of 25 mg every 4-7 days to max.  200 mg daily (over 50 mg in 2 divided doses)   Note If no improvement in obsessive-compulsive disorder  within 10 weeks, treatment should be reconsidered   Tablets, fluvoxamine maleate 50 mg, net price 60-tab  pack = £10.81; 100 mg, 30-tab pack = £11.67. Coun-  selling, driving   Faverin® (Abbott Healthcare) [Ml  Tablets, f/c, scored, fluvoxamine maleate 50 mg, net  price 60-tab pack = £17.10; 100 mg, 30-tab pack =  £17.10. Counselling, driving   Indications major depression, obsessive-compulsive  disorder, panic disorder; social anxiety disorder; post-  traumatic stress disorder; generalised anxiety disorder  Cautions see notes above; also achlorhydria or high  gastric pH (reduced absorption of oral suspension)  Contra-indications see notes above  Hepatic impairment reduce dose    Renal impairment reduce dose if eGFR less than  30 mL/minute/ 1.73 m 2   Pregnancy increased risk of congenital malforma-  tions, especially if used in the first trimester; see also  notes above   Breast-feeding present in milk but amount too small  to be harmful   Side-effects see notes above; also yawning; abnormal  dreams; raised cholesterol; less commonly arrhyth-  mias, confusion, urinary incontinence; rarely panic  attacks and paradoxical increased anxiety during  initial treatment of panic disorder (reduce dose),  depersonalisation, and neuroleptic malignant  syndrome-like event; rarely restless legs syndrome;  very rarely peripheral oedema, acute glaucoma,  hepatic disorders (e.g. hepatitis), and priapism; also  reported tinnitus, extrapyramidal reactions (including  orofacial dystonias) and withdrawal reactions (see  notes above)   • Major depression, social anxiety disorder, post-trau-  matic stress disorder, generalised anxiety disorder,  ADULT over 18 years, recommended dose 20 mg each  morning (no evidence of greater efficacy at higher  doses); max. 50 mg daily (ELDERLY 40 mg daily); CHILD  under 18 years not recommended (see Depressive  Illness in Children and Adolescents, p. 239)   • Obsessive-compulsive disorder, ADULT over 18 years,  initially 20 mg each morning, increased gradually in  steps of 10 mg to recommended dose of 40 mg daily  (no evidence of greater efficacy at higher doses); max.  60 mg daily (ELDERLY 40 mg daily)   • Panic disorder, ADULT over 18 years, initially 10 mg  each morning, increased gradually in steps of 10 mg  to recommended dose of 40 mg daily (no evidence of  greater efficacy at higher doses); max. 60 mg daily  (ELDERLY 40 mg daily)    Paroxetine (Non-proprietary) tMl  Tablets, paroxetine (as hydrochloride) 20 mg, net  price 30-tab pack = £2.29; 30 mg, 30-tab pack = £3.17.  Label: 21, counselling, driving   10 mg, net price 28-tab pack = £11.84; 20 mg, 30-tab  pack = £12.69; 30 mg (blue), 30-tab pack = £22.28.  Label: 21, counselling, driving  Oral suspension, orange, sugar-free, paroxetine (as  hydrochloride) 10 mg/5 mL, net price 150-mL pack =  £9.12. Label: 5, 21, counselling, driving   Indications see under Dose  Cautions see notes above  Contra-indications see notes above  Hepatic impairment reduce dose or increase dose  interval in mild or moderate impairment; avoid in  severe impairment   Renal impairment use with caution  Pregnancy see notes above  Breast-feeding not known to be harmful but consider  discontinuing breast-feeding  Side-effects see notes above; pancreatitis, hepatitis,  jaundice, liver failure, stomatitis, palpitation, hyper-  tension, hypercholesterolaemia, tachycardia, postural  hypotension, bronchospasm, amnesia, paraesthesia,    aggression, hypoglycaemia, hypothyroidism, hyper-  prolactinaemia, urinary incontinence, menstrual irre-  gularities, leucopenia, and tinnitus also reported   • Depressive illness, initially 50 mg daily, increased if  necessary by increments of 50 mg at intervals of at  least 1 week to max. 200 mg daily; usual maintenance  dose 50 mg daily; CHILD under 18 years, see BNF for  Children and Depressive Illness in Children and  Adolescents, p. 239   • Obsessive-compulsive disorder, ADULT and CHILD over  12 years initially 50 mg daily, increased if necessary in  steps of 50 mg at intervals of at least 1 week; max.  200 mg daily; CHILD 6-12 years initially 25 mg daily,  increased to 50 mg daily after 1 week, further  increased if necessary in steps of 50 mg at intervals of  at least 1 week; max. 200 mg daily   • Panic disorder, post-traumatic stress disorder, or  social anxiety disorder, ADULT over 18 years, initially  25 mg daily, increased after 1 week to 50 mg daily; if  response is partial and if drug tolerated, dose  increased in steps of 50 mg at intervals of at least 1  week to max. 200 mg daily   Sertraline (Non-proprietary) (Ml  Tablets, sertraline (as hydrochloride) 50 mg, net price  28-tab pack = £1.15; 100 mg, 28-tab pack = £1.53.  Counselling, driving   Tablets, f/c, sertraline (as hydrochloride) 50 mg  (scored), net price 28-tab pack = £17.82; 100 mg, 28-  tab pack = £29.16. Counselling, driving   Agomelatine is a melatonin receptor agonist and a  selective serotonin-receptor antagonist; it does not  affect the uptake of serotonin, noradrenaline, or  dopamine.   Duloxetine inhibits the re-uptake of both serotonin and  noradrenaline and is licensed to treat major depressive  disorder.   The thioxanthene flupentixol ( Fluanxol ®) has anti-  depressant properties when given by mouth in low  doses. Flupentixol is also used for the treatment of  psychoses (section 4.2.1 and section 4.2.2)  Mirtazapine, a presynaptic alpha 2 -adrenoreceptor  antagonist, increases central noradrenergic and seroto-  nergic neurotransmission. It has few antimuscarinic  effects, but causes sedation during initial treatment.   Reboxetine, a selective inhibitor of noradrenaline re-  uptake, has been introduced for the treatment of depres-  sive illness.   Tryptophan is licensed as adjunctive therapy for  depression resistant to standard antidepressants; it has  been associated with eosinophilia-myalgia syndrome.  Tryptophan should be initiated under specialist super-  vision.   Venlafaxine is a serotonin and noradrenaline re-uptake  inhibitor; it lacks the sedative and antimuscarinic effects  of the tricyclic antidepressants. Treatment with venla-  faxine is associated with a higher risk of withdrawal  effects compared with other antidepressants.   Cautions cardiovascular disease (including cardiac  disorders and cerebral arteriosclerosis), QT-interval  prolongation (avoid concomitant administration of  drugs that prolong QT interval); diabetes; senile  confusional states, parkinsonism; elderly; acute por-  phyria (section 9.8.2); see also section 4.2.1; interac-  tions: Appendix 1 (antipsychotics)   Renal impairment increased cerebral sensitivity in  severe impairment; manufacturer advises caution in  renal failure   Side-effects section 4.2.1; also hypersalivation, dys-  pnoea, asthenia, hyperglycaemia, myalgia; torsade de  pointes and sudden death also reported   • ADULT over 18 years, initially 1 mg (ELDERLY 500 micr-  ograms) in the morning, increased after 1 week to  2 mg (ELDERLY 1 mg) if necessary; max. 3 mg (ELDERLY  1.5 mg) daily, doses above 2 mg (ELDERLY 1 mg) in  divided doses, last dose before 4 pm; discontinue if no  response after 1 week at max. dosage  Counselling Although drowsiness may occur, can also have  an alerting effect so should not be taken in the evening   Tablets, yellow, s/c, flupentixol (as dihydrochloride)  500 micrograms, net price 60-tab pack = £2.63; 1 mg,  60-tab pack = £2.72. Label: 2, counselling, adminis-  tration   Indications major depression  Cautions elderly, cardiac disorders, hypotension, his-  tory of urinary retention, susceptibility to angle-clo-  sure glaucoma, diabetes mellitus, psychoses (may  aggravate psychotic symptoms), history of seizures or  bipolar depression; interactions: Appendix 1 (mirta-  zapine)   Blood disorders Patients should be advised to report any  fever, sore throat, stomatitis or other signs of infection during  treatment. Blood count should be performed and the drug  stopped immediately if blood dyscrasia suspected  Withdrawal Nausea, vomiting, dizziness, agitation, anxiety,  and headache are most common features of withdrawal if  treatment stopped abruptly or if dose reduced markedly;  dose should be reduced over several weeks   Indications major depression  Cautions elderly; mania or hypomania; concomitant  use of drugs associated with hepatic injury; excessive  alcohol consumption; monitor liver function before  treatment and after 6, 12 and 24 weeks of treatment,  then as appropriate (discontinue if serum transami-  nases exceed 3 times the upper limit of reference  range); interactions: Appendix 1 (agomelatine)  Contra-indications dementia  Hepatic impairment avoid  Renal impairment caution in moderate to severe  impairment  Pregnancy caution   Side-effects nausea, diarrhoea, constipation, abdo-  minal pain, increased serum transaminases (see  Cautions); headache, dizziness, drowsiness, insomnia,  fatigue, anxiety; back pain; sweating; less commonly  paraesthesia, blurred vision, and eczema; rarely  hepatitis and rash; suicidal behaviour (see Suicidal  Behaviour and Antidepressant Therapy, p. 233) also  reported  Dose   • ADULT over 18 years, 25 mg at bedtime, increased if  necessary after 2 weeks to 50 mg at bedtime   Tablets, orange-yellow, f/c, agomelatine 25 mg, net  price 28-tab pack = £43.77   Indications major depressive disorder; generalised  anxiety disorder; diabetic neuropathy (section 6.1.5);  stress urinary incontinence (section 7.4.2)   Contra-indications section 7.4.2  Hepatic impairment section 7.4.2  Renal impairment section 7.4.2  Pregnancy toxicity in animal studies — use only if  potential benefit outweighs risk; risk of neonatal  withdrawal symptoms if used near term  Breast-feeding section 7.4.2  Side-effects section 7.4.2  Dose   • Major depression, ADULT over 18 years, 60 mg once  daily   • Generalised anxiety disorder, ADULT over 18 years,  initially 30 mg daily, increased if necessary to 60 mg  once daily; max. 120 mg daily   • Diabetic neuropathy, ADULT over 18 years, 60 mg once  daily; max. 120 mg daily in divided doses   Note In diabetic neuropathy, discontinue if inadequate  response after 2 months; review treatment at least every 3  months   Capsules, duloxetine (as hydrochloride) 30 mg  (white/blue), net price 28-cap pack = £22.40; 60 mg  (green/blue), 28-cap pack = £27.72. Label: 2  Note The Scottish Medicines Consortium has advised (Sep-  tember 2006) that duloxetine ( Cymbalta ®) should be  restricted for use by specialists when other treatments for  diabetic peripheral neuropathic pain are unsuitable or  inadequate    Hepatic impairment use with caution  Renal impairment clearance reduced by 30% if eGFR  less than 40 mL/minute/ 1.73 m 2 ; clearance reduced  by 50% if eGFR less than 10 mL/minute/ 1.73 m 2  Pregnancy use with caution — limited experience;   Side-effects increased appetite, weight gain, dry  mouth; postural hypotension, peripheral oedema;    drowsiness, fatigue, tremor, dizziness, abnormal  dreams, confusion, anxiety, insomnia; arthralgia,  myalgia; less commonly syncope, hypotension, mania,  hallucinations, movement disorders; rarely myoclo-  nus; very rarely blood disorders (see Cautions), con-  vulsions, hyponatraemia (see Hyponatraemia and  Antidepressant Therapy, p. 233), suicidal behaviour  (see p. 233), and angle-closure glaucoma  Dose   • Initially 15-30 mg daily at bedtime increased within  2-4 weeks according to response; max. 45 mg daily as  a single dose at bedtime or in 2 divided doses; CHILD  under 18 years not recommended (see Depressive  Illness in Children and Adolescents, p. 239)   Tablets, mirtazapine 15 mg, net price 28-tab pack =  £3.36; 30 mg, 28-tab pack = £2.04; 45 mg, 28-tab pack  = £3.71. Label: 2, 25   Orodispersible tablets, mirtazapine 15 mg, net price  30-tab pack = £2.59; 30 mg, 30-tab pack = £2.94;   Zispin SolTab® (Organon) (Ml  Orodispersible tablets, mirtazapine 15 mg, net price  6-tab pack = £3.84, 30-tab pack = £15.06; 30 mg, 30-  tab pack = £15.06; 45 mg, 30-tab pack = £15.06.  Label: 2, counselling, administration   Counselling Zispin SolTab ® should be placed on the tongue,  allowed to disperse and swallowed   Indications major depression  Cautions history of cardiovascular disease and epi-  lepsy; bipolar disorder; urinary retention; prostatic  hypertrophy; susceptibility to angle-closure glauc-  oma; avoid abrupt withdrawal; interactions: Appen-  dix 1 (reboxetine)   Hepatic impairment initial dose 2 mg twice daily,  increased according to tolerance  Renal impairment initial dose 2 mg twice daily,  increased according to tolerance  Pregnancy use only if potential benefit outweighs  risk — limited information available  Breast-feeding small amount present in milk — use  only if potential benefit outweighs risk  Side-effects nausea, dry mouth, constipation, ano-  rexia; tachycardia, palpitation, vasodilation, postural  hypotension; headache, insomnia, dizziness; chills;  impotence; urinary retention; impaired visual  accommodation; sweating; lowering of plasma-  potassium concentration on prolonged administration  in the elderly; very rarely angle-closure glaucoma;  also reported vomiting, hypertension, paraesthesia,  agitation, anxiety, irritability, hallucinations, aggres-  sion, hyponatraemia, testicular pain, cold extremities,  and rash; suicidal behaviour (see p. 233)   • 4 mg twice daily increased if necessary after 3-4  weeks to 10 mg daily in divided doses, max. 12 mg  daily; CHILD under 18 years and ELDERLY not recom-  mended    Edronax® (Pharmacia) (Ml  Tablets, scored, reboxetine (as mesilate) 4 mg, net  price 60-tab pack = £18.91. Counselling, driving   Indications see notes above  Cautions eosinophilia-myalgia syndrome has been  reported (withhold treatment if increased eosinophil  count, myalgia, arthralgia, fever, dyspnoea, neuro-  pathy, oedema or skin lesions develop until possibility  of eosinophilia-myalgia syndrome excluded); inter-  actions: Appendix 1 (tryptophan)  Contra-indications history of eosinophilia-myalgia  syndrome following use of tryptophan  Pregnancy no information available  Breast-feeding no information available  Side-effects drowsiness, nausea, headache, light-  headedness, suicidal behaviour (see p. 233); eosino-  philia-myalgia syndrome, see Cautions  Dose   • 1 g 3 times daily; max. 6 g daily; ELDERLY lower dose  may be appropriate especially in renal or hepatic  impairment; CHILD not recommended  Optimax® (Merck Serono) (Ml  Tablets, scored, tryptophan 500 mg, net price 84-tab  pack = £23.47. Label: 3   Cautions heart disease (monitor blood pressure); dia-  betes; history of epilepsy; history or family history of  mania; susceptibility to angle-closure glaucoma;  concomitant use of drugs that increase risk of bleed-  ing, history of bleeding disorders; interactions:  Appendix 1 (venlafaxine)   Driving May affect performance of skilled tasks (e.g. driving)  Withdrawal Gastro-intestinal disturbances, headache,  anxiety, dizziness, paraesthesia, tremor, sleep disturbances,  and sweating are most common features of withdrawal if  treatment stopped abruptly or if dose reduced markedly;  dose should be reduced over several weeks  Contra-indications conditions associated with high  risk of cardiac arrhythmia, uncontrolled hypertension  Hepatic impairment consider reducing dose by 50%  in mild or moderate impairment; use with caution and  reduce dose by at least 50% in severe impairment  Renal impairment use with caution; use half normal  dose (immediate-release tablets may be given once  daily) if eGFR less than 30 mL/minute/ 1.73 m 2  Pregnancy avoid unless potential benefit outweighs  risk — toxicity in animal studies; risk of withdrawal  effects in neonate   Breast-feeding present in milk — avoid  Side-effects constipation, nausea, anorexia, weight  changes, vomiting; hypertension, palpitation, vasodi-  latation, changes in serum cholesterol; chills, yawn-  ing; dizziness, dry mouth, insomnia, nervousness,  drowsiness, asthenia, headache, abnormal dreams,  anxiety, confusion, hypertonia, sensory disturbances,  tremor; difficulty with micturition, sexual dysfunction,  menstrual disturbances; visual disturbances, mydria-  sis (very rarely angle-closure glaucoma); sweating;  less commonly bruxism, diarrhoea, taste disturbance,  postural hypotension, arrhythmias, agitation, apathy,  incoordination, hallucinations, myoclonus, urinary    retention, bleeding disorders (including ecchymosis  and gastro-intestinal haemorrhage), tinnitus, alopecia,  photosensitivity, and rash; rarely mania, hypomania,  seizures, and extrapyramidal symptoms including  akathisia; also reported hepatitis, pancreatitis, hypo-  tension, QT-interval prolongation, aggression, neuro-  leptic malignant syndrome, delirium, syndrome of  inappropriate anti-diuretic hormone secretion (see  Hyponatraemia and Antidepressant Therapy, p. 233),  hyperprolactinaemia, blood dyscrasias, rhabdomyo-  lysis, pruritus, urticaria, Stevens-Johnson syndrome;  suicidal behaviour (see p. 233)   • Depression, ADULT over 18 years, initially 75 mg daily  in 2 divided doses increased if necessary at intervals  of at least 2 weeks; max. 375 mg daily; CHILD under 18  years not recommended (see Depressive Illness in  Children and Adolescents, p. 239)   Venlafaxine (Non-proprietary) (Ml  Tablets, venlafaxine (as hydrochloride) 37.5 mg, net  price 56-tab pack = £3.60; 75 mg, 56-tab pack = £4.71.  Label: 3, counselling, driving   Capsules, m/r, venlafaxine (as hydrochloride) 75 mg;  150 mg. Label: 3, 25, counselling, driving   Brands include Bonilux XL 9 , Depefex 9 XL, Foraven XL ® , Politid  XL 9 , Ranfaxine XL 9 , Tifaxin XL 9 , VenaxxXL 9 , VensirXL 9 ,  Winfex 9 XL   Dose depression, ADULT over 18 years, 75 mg once daily,  increased if necessary at intervals of at least 2 weeks; max. 375 mg  once daily; CHILD under 18 years not recommended (see  Depressive Illness in Children and Adolescents, p. 239)   Note Faster dose titration may be necessary in some patients  Generalised anxiety disorder, ADULT over 18 years, 75 mg once  daily, increased if necessary at intervals of at least 2 weeks; max.  225 mg once daily   Social anxiety disorder, ADULT over 18 years, recommended dose  75 mg once daily (no evidence of greater efficacy at higher doses);  dose may be increased at intervals of at least 2 weeks; max.   Tablets, m/r, venlafaxine (as hydrochloride) 75 mg;  150 mg; 225 mg. Label: 3, 25, counselling, driving  Brands include Venlalic 9 XL   Dose depression, ADULT over 18 years, 75 mg once daily,  increased if necessary at intervals of at least 2 weeks; max. 375 mg  once daily; CHILD under 18 years not recommended (see  Depressive Illness in Children and Adolescents, p. 239)   Capsules, m/r, venlafaxine (as hydrochloride) 75 mg  (peach), net price 28-cap pack = £22.50; 150 mg  (orange), 28-cap pack = £37.51. Label: 3, 25, coun-  selling, driving   Dose depression, ADULT over 18 years, 75 mg once daily,  increased if necessary at intervals of at least 2 weeks; max. 375 mg  once daily; CHILD under 18 years not recommended (see  Depressive Illness in Children and Adolescents, p. 239)   Note Faster dose titration may be necessary in some patients  Generalised anxiety disorder, ADULT over 18 years, 75 mg once  daily, increased if necessary at intervals of at least 2 weeks; max.  225 mg once daily   Social anxiety disorder, ADULT over 18 years, recommended dose  75 mg once daily (no evidence of greater efficacy at higher doses);  dose may be increased at intervals of at least 2 weeks; max.    H CNS stimulants and drugs  used for attention deficit  hyperactivity disorder   Central nervous system stimulants include the amfeta-  mines (notably dexamfetamine) and related drugs (e.g.  methylphenidate). They have very few indications and  in particular, should not be used to treat depression,  obesity, senility, debility, or for relief of fatigue.   CNS stimulants should be prescribed for children with  severe and persistent symptoms of attention deficit  hyperactivity disorder (ADHD), when the diagnosis  has been confirmed by a specialist; children with mod-  erate symptoms of ADHD can be treated with CNS  stimulants when psychological interventions have  been unsuccessful or are unavailable. Prescribing of  CNS stimulants may be continued by general practi-  tioners, under a shared-care arrangement. Treatment of  ADHD often needs to be continued into adolescence,  and may need to be continued into adulthood. Initiating  treatment in adulthood is unlicensed.   Drug treatment of ADHD should be part of a compre-  hensive treatment programme. The choice of medica-  tion should take into consideration co-morbid condi-  tions (such as tic disorders, Tourette syndrome, and  epilepsy), the adverse effect profile, potential for drug  misuse, and preferences of the patient and carers,  Methylphenidate and atomoxetine are used for the  management of ADHD; dexamfetamine is an alterna-  tive in children who do not respond to these drugs.  Before initiation of drug therapy, and every 6 months  thereafter, pulse, blood pressure, weight, and height  should be measured.   The need to continue drug treatment for ADHD should  be reviewed at least annually. This may involve sus-  pending treatment.   Modafinil is used for the treatment of daytime sleepi-  ness associated with narcolepsy or obstructive sleep  apnoea syndrome; dependence with long-term use can-  not be excluded and it should therefore be used with  caution.   Dexamfetamine and methylphenidate [unlicensed indi-  cation] are also used to treat narcolepsy.   Indications attention deficit hyperactivity disorder  (initiated by a specialist physician experienced in  managing the condition)   Cautions see notes above; also cardiovascular disease  including hypertension and tachycardia; structural  cardiac abnormalities; QT-interval prolongation  (avoid concomitant administration of drugs that pro-  long QT interval); psychosis or mania; history of  seizures; aggressive behaviour, hostility, or emotional  lability; susceptibility to angle-closure glaucoma;  interactions: Appendix 1 (atomoxetine)   Hepatic disorders Following rare reports of hepatic dis-  orders, patients and carers should be advised of the risk and  be told how to recognise symptoms; prompt medical atten-  tion should be sought in case of abdominal pain, unexplained  nausea, malaise, darkening of the urine, or jaundice  Suicidal ideation Following reports of suicidal thoughts  and behaviour, patients and their carers should be informed  about the risk and told to report clinical worsening, suicidal  thoughts or behaviour, irritability, agitation, or depression   Side-effects anorexia, dry mouth, nausea, vomiting,  abdominal pain, constipation, dyspepsia, flatulence;  palpitation, tachycardia, increased blood pressure,  postural hypotension, hot flushes; sleep disturbance,  dizziness, headache, fatigue, lethargy, depression,  psychotic or manic symptoms, aggression, hostility,  emotional lability, drowsiness, anxiety, irritability,  tremor, rigors; urinary retention, enuresis, prostatitis,  sexual dysfunction, menstrual disturbances; mydria-  sis, conjunctivitis; dermatitis, pruritus, rash, sweating,  weight changes; less commonly suicidal ideation (see  Suicidal Ideation, above), cold extremities; very rarely  hepatic disorders (see Hepatic Disorders, above),  seizures, angle-closure glaucoma, and Raynaud’s  phenomenon  Dose   • ADULT over 18 years, body-weight over 70 kg, initially  40 mg daily for 7 days, increased according to  response; usual maintenance 80-100 mg daily, but  may be increased to max. 120 mg daily [unlicensed]  under the direction of a specialist; CHILD 6-18 years,  body-weight over 70 kg, initially 40 mg daily for 7  days, increased according to response; usual main-  tenance 80 mg daily, but may be increased to max.  120 mg daily [unlicensed] under the direction of a  specialist; ADULT and CHILD over 6 years, body-weight  under 70 kg, initially 500 micrograms /kg daily for 7  days, increased according to response; usual main-  tenance 1.2 mg/kg daily, but may be increased to  1.8 mg/kg daily (max. 120 mg daily) [unlicensed]  under the direction of a specialist  Note Total daily dose may be given either as a single dose in  the morning or in 2 divided doses with last dose no later than  early evening   Capsules, atomoxetine (as hydrochloride) 10 mg  (white), net price 7-cap pack = £15.62, 28-cap pack =  £62.46; 18 mg (gold/white), 7-cap pack = £15.62, 28-  cap pack = £62.46; 25 mg (blue/white), 7-cap pack =  £15.62, 28-cap pack = £62.46; 40 mg (blue), 7-cap  pack = £15.62, 28-cap pack = £62.46; 60 mg (blue/  gold), 28-cap pack = £62.46; 80 mg (brown/white),  28-cap pack = £83.28. Label: 3   Indications narcolepsy; refractory attention deficit  hyperactivity disorder (under specialist supervision)  Cautions see notes above; also anorexia; mild hyper-  tension (contra-indicated if moderate or severe);  psychosis or bipolar disorder; monitor for aggressive  behaviour or hostility during initial treatment; history  of epilepsy (discontinue if convulsions occur); tics and  Tourette syndrome (use with caution) — discontinue if  tics occur; monitor growth in children (see also  below); susceptibility to angle-closure glaucoma;  avoid abrupt withdrawal; data on safety and efficacy  of long-term use not complete; acute porphyria (sec-   Special cautions in children Monitor height and weight as  growth restriction may occur during prolonged therapy  (drug-free periods may allow catch-up in growth but with-  draw slowly to avoid inducing depression or renewed  hyperactivity)   Driving May affect performance of skilled tasks (e.g. driv-  ing); effects of alcohol unpredictable  Contra-indications cardiovascular disease including  moderate to severe hypertension, structural cardiac  abnormalities, advanced arteriosclerosis, hyperexcit-  ability or agitated states, hyperthyroidism, history of  drug or alcohol abuse  Renal impairment use with caution  Pregnancy avoid (retrospective evidence of uncertain  significance suggesting possible embryotoxicity)  Breast-feeding significant amount in milk — avoid  Side-effects insomnia, restlessness, irritability and  excitability, night terrors, euphoria, tremor, dizziness,  aggression, paranoia, anxiety, confusion, depression,  fatigue, headache; seizures (see also Cautions); dep-  endence and tolerance, psychosis; anorexia, gastro-  intestinal symptoms, growth restriction in children  (see also under Cautions); dry mouth, sweating,  tachycardia (and anginal pain), palpitation, myo-  cardial infarction, hypertension, hypotension; impo-  tence; visual disturbances; alopecia, rash; cardio-  myopathy reported with chronic use; cardiovascular  collapse; cerebral vasculitis; central stimulants have  provoked choreoathetoid movements and dyskinesia,  tics and Tourette syndrome in predisposed individuals  (see also Cautions); very rarely angle-closure glauc-  oma; overdosage: see Emergency Treatment of  Poisoning, p. 38  Dose   • Narcolepsy, initially 10 mg (ELDERLY 5 mg) daily in  divided doses increased at weekly intervals by 10 mg  (ELDERLY 5 mg) daily to a max. of 60 mg daily   • Refractory attention deficit hyperactivity disorder,  ADULT over 18 years [unlicensed use], initially 5 mg  twice daily, increased at weekly intervals according to  response; max. 60 mg daily; CHILD 6-18 years, initially  5-10 mg daily, increased if necessary at weekly  intervals by 5 mg daily, usual max. 1 mg/kg (up to  20 mg) daily (40 mg daily has been required in some  children)   Dexamfetamine (Non-proprietary) d 3  Tablets, scored, dexamfetamine sulphate 5 mg, net  price 28-tab pack = £15.60. Counselling, driving   Indications attention deficit hyperactivity disorder  (under specialist supervision); narcolepsy [unlicensed  indication]   Cautions see notes above; also monitor for psychiatric  disorders; anxiety or agitation; tics or a family history  of Tourette syndrome; epilepsy (discontinue if  increased seizure frequency); susceptibility to angle-  closure glaucoma; avoid abrupt withdrawal; interac-  tions: Appendix 1 (sympathomimetics)  Contra-indications severe depression, suicidal idea-  tion; anorexia nervosa; drug or alcohol dependence;  psychosis; uncontrolled bipolar disorder; hyper-  thyroidism; cardiovascular disease (including heart    failure, cardiomyopathy, severe hypertension, and  arrhythmias), structural cardiac abnormalities;  phaeochromocytoma; vasculitis; cerebrovascular dis-  orders   Side-effects abdominal pain, nausea, vomiting, diarr-  hoea, dyspepsia, dry mouth, anorexia, reduced weight  gain; tachycardia, palpitation, arrhythmias, changes in  blood pressure; cough, nasopharyngitis; tics ( very  rarely Tourette syndrome), insomnia, nervousness,  asthenia, depression, irritability, aggression, head-  ache, drowsiness, dizziness, movement disorders;  fever; arthralgia; rash, pruritus, alopecia; growth  restriction; less commonly constipation, dyspnoea,  abnormal dreams, confusion, suicidal ideation,  urinary frequency, haematuria, muscle cramps, epis-  taxis; rarely angina, sweating, and visual disturbances;  very rarely hepatic dysfunction, myocardial infarction,  cerebral arteritis, psychosis, neuroleptic malignant  syndrome, tolerance and dependence, blood disor-  ders including leucopenia and thrombocytopenia,  angle-closure glaucoma, exfoliative dermatitis, and  erythema multiforme; supraventricular tachycardia,  bradycardia, and convulsions also reported  Dose   • Attention deficit hyperactivity disorder, ADULT over 18  years [unlicensed use], 5 mg 2-3 times daily increased  if necessary at weekly intervals according to response,  max. 100 mg daily in 2-3 divided doses; CHILD 6-18  years, initially 5 mg 1-2 times daily, increased if  necessary at weekly intervals by 5-10 mg daily; usual  max. 60 mg daily in 2-3 divided doses but may be  increased to 2.1 mg/kg daily in 2-3 divided doses  (max. 90 mg daily) under the direction of a specialist;  discontinue if no response after 1 month; CHILD 4-6  years see BNF for Children   Evening dose If effect wears off in evening (with rebound  hyperactivity) a dose at bedtime may be appropriate  (establish need with trial bedtime dose)   • Narcolepsy [unlicensed indication], 10-60 mg (usually  20-30 mg) daily in divided doses before meals   Tablets, methylphenidate hydrochloride 5 mg, net  price 30-tab pack = £2.67; 10 mg, 30-tab pack = £6.74;  20 mg, 30-tab pack = £9.59   Tablets, scored, methylphenidate hydrochloride  10 mg, net price 30-tab pack = £5.57   Concerta® XL (Janssen-Cilag) LZEI  Tablets, m/r, methylphenidate hydrochloride 18 mg  (yellow), net price 30-tab pack = £31.19; 27 mg (grey),  30-tab pack = £36.81; 36 mg (white), 30-tab pack =  £42.45. Label: 25   Note Concerta ® XL tablets consist of an immediate-release  component (22% of the dose) and a modified-release component  (78% of the dose)   Cautions dose form not appropriate for use in dysphagia or if  gastro-intestinal lumen restricted   Dose attention deficit hyperactivity disorder, ADULT over 18  years [unlicensed use], initially 18 mg once daily in the morning,    adjusted at weekly intervals according to response, max. 108 mg  daily; CHILD 6-18 years, initially 18 mg once daily (in the morn-  ing), increased if necessary at weekly intervals by 18 mg according  to response, usual max. 54 mg once daily, but may be increased to  2.1 mg/kg daily (max. 108 mg daily) [unlicensed] under the  direction of a specialist; discontinue if no response after 1 month  Note Total daily dose of 15 mg of standard-release formulation is  equivalent to Concerta ® XL 18 mg once daily   Capsules, m/r, methylphenidate hydrochloride 10 mg  (white/green), net price 30-cap pack = £25.00; 20 mg  (white/blue), 30-cap pack = £30.00; 30 mg (white/  brown), 30-cap pack = £35.00. Label: 25  Note Equasym XL ® capsules consist of an immediate-release  component (30% of the dose) and a modified-release component  (70% of the dose)   Dose attention deficit hyperactivity disorder, ADULT over 18  years [unlicensed use], initially 10 mg once daily in the morning  before breakfast, increased gradually at weekly intervals if  necessary, max. 100 mg daily; CHILD 6-18 years, initially 10 mg  once daily in the morning before breakfast, increased gradually at  weekly intervals if necessary, usual max. 60 mg daily but may be  increased to 2.1 mg/kg daily (max. 90 mg daily) [unlicensed]  under the direction of a specialist; discontinue if no response after  1 month   Note Contents of capsule can be sprinkled on a tablespoon of  apple sauce (then swallowed immediately without chewing)    Medikinet XL® (Flynn) dD  Capsules, m/r, methylphenidate hydrochloride 10 mg  (lilac/white), net price 28-cap pack = £20.18; 20 mg  (lilac), 28-cap pack = £26.91; 30 mg (purple/light  grey), 28-cap pack = £31.39; 40 mg (purple/grey), 28-  cap pack = £43.20. Label: 25   Note Medikinet XL ® capsules consist of an immediate-release  component (50% of the dose) and a modified-release component  (50% of the dose)   Dose attention deficit hyperactivity disorder, ADULT over 18  years [unlicensed use], initially 10 mg once daily in the morning  with breakfast, adjusted at weekly intervals according to response,  max. 100 mg daily; CHILD 6-18 years, initially 10 mg once daily in  the morning with breakfast, adjusted at weekly intervals according  to response, usual max. 60 mg daily but may be increased to  2.1 mg/kg daily (max. 90 mg daily) [unlicensed] under the direc-  tion of a specialist; discontinue if no response after 1 month  Note Contents of capsule can be sprinkled on a tablespoon of  apple sauce (then swallowed immediately without chewing)   Indications daytime sleepiness associated with  narcolepsy, obstructive sleep apnoea syndrome, and  chronic shift work   Cautions monitor blood pressure and heart rate in  hypertensive patients (but see Contra-indications);  history of psychosis, depression, mania, alcohol or  drug abuse; discontinue treatment if psychiatric  symptoms develop; possibility of dependence; dis-  continue treatment if rash develops; interactions:  Appendix 1 (modafinil)   Contra-indications moderate to severe uncontrolled  hypertension, arrhythmia; history of left ventricular  hypertrophy, cor pulmonale, or of clinically significant  signs of CNS stimulant-induced mitral valve prolapse  (including ischaemic ECG changes, chest pain and  arrhythmias)   Side-effects dry mouth, appetite changes, gastro-  intestinal disturbances (including nausea, diarrhoea,  constipation, and dyspepsia), abdominal pain; tachy-  cardia, vasodilatation, chest pain, palpitation; head-    ache (uncommonly migraine), anxiety, sleep distur-  bances, dizziness, drowsiness, depression, confusion,  paraesthesia, asthenia; visual disturbances; less com-  monly flatulence, reflux, vomiting, mouth ulcers,  glossitis, dysphagia, taste disturbance, weight  changes, hypertension, hypotension, bradycardia,  arrhythmia, peripheral oedema, hypercholesterol-  aemia, rhinitis, dyspnoea, epistaxis, dyskinesia,  amnesia, emotional lability, tremor, decreased libido,  agitation, aggression, hyperglycaemia, thirst, urinary  frequency, menstrual disturbances, eosinophilia,  leucopenia, myasthenia, muscle cramps, hypertonia,  myalgia, arthralgia, dry eye, sinusitis, acne, sweating,  rash, and pruritus; also reported psychosis, mania,  delusions, hallucinations, suicidal ideation, Stevens-  Johnson syndrome, and toxic epidermal necrolysis  Dose   • Narcolepsy and obstructive sleep apnoea syndrome,  ADULT over 12 years, initially 200 mg daily, either in 2  divided doses morning and at noon or as a single dose  in the morning, dose adjusted according to response  to 200-400 mg daily in 2 divided doses or as a single  dose; ELDERLY initiate at 100 mg daily; CHILD 5-12  years, see BNF for Children   • Chronic shift work sleep disorder, 200 mg taken 1  hour before the start of the work shift   Provigil® (Cephalon) ▼ iMl  Tablets, modafinil 100 mg, net price 30-tab pack =  £52.60; 200 mg (scored), 30 tab-pack = £105.20   Anti-obesity drugs acting on the  gastro-intestinal tract  Centrally acting appetite  suppressants   Obesity is associated with many health problems includ-  ing cardiovascular disease, diabetes mellitus, gallstones  and osteoarthritis. Factors that aggravate obesity may  include depression, other psychosocial problems, and  some drugs.   The main treatment of the obese individual is a suitable  diet, carefully explained to the individual, with appro-  priate support and encouragement; the individual  should also be advised to increase physical activity.  Smoking cessation (while maintaining body weight)  may be worthwhile before attempting supervised weight  loss since cigarette smoking may be more harmful than  obesity. Attendance at groups (e.g. ‘weight-watchers’)  helps some individuals.   Obesity should be managed in an appropriate setting by  staff who have been trained in the management of  obesity; the individual should receive advice on diet  and lifestyle modification and be monitored for changes  in weight as well as in blood pressure, blood lipids and  other associated conditions.   An anti-obesity drug should be considered only for  those with a body mass index (BMI, individual’s body-  weight divided by the square of the individual’s height)  of 30 kg/m 2 or greater in whom at least 3 months of   managed care involving supervised diet, exercise and  behaviour modification fails to achieve a realistic reduc-  tion in weight. In the presence of risk factors (such as  diabetes, coronary heart disease, hypertension, and  obstructive sleep apnoea), it may be appropriate to  prescribe a drug to individuals with a BMI of 27 kg/  m 2 or greater, provided that such use is permitted by the  drug’s marketing authorisation. Drugs should never be  used as the sole element of treatment. The individual  should be monitored on a regular basis; drug treatment  should be discontinued if the individual regains weight  at any time whilst receiving drug treatment.   Combination therapy involving more than one anti-  obesity drug is contra-indicated by the manufacturers;  there is no evidence-base to support such treatment.   Thyroid hormones have no place in the treatment of  obesity except in biochemically proven hypothyroid  patients. The use of diuretics, chorionic gonadotrophin,  or amfetamines is not appropriate for weight reduction.   Orlistat, a lipase inhibitor, reduces the absorption of  dietary fat. It is used in conjunction with a mildly  hypocaloric diet in individuals with a body mass index  (BMI) of 30 kg/m 2 or more or in individuals with a BMI  of 28 kg/m 2 in the presence of other risk factors such as  type 2 diabetes, hypertension, or hypercholesterol-  aemia.   Orlistat should be used in conjunction with other life-  style measures to manage obesity (section 4.5); treat-  ment should only be continued beyond 12 months after  discussing potential benefits and risks with the patient.  On stopping orlistat, there may be a gradual reversal of  weight loss.   Some of the weight loss in those taking orlistat probably  results from individuals reducing their fat intake to avoid  severe gastro-intestinal effects including steatorrhoea.  Vitamin supplementation (especially of vitamin D) may  be considered if there is concern about deficiency of fat-  soluble vitamins.   Methylcellulose is claimed to reduce food intake by  producing a feeling of satiety, but there is little evidence  to support its use in the management of obesity.   Indications adjunct in obesity (see notes above)  Cautions may impair absorption of fat-soluble vita-  mins; epilepsy; interactions: Appendix 1 (orlistat)  Multivitamins If a multivitamin supplement is required, it  should be taken at least 2 hours after orlistat dose or at  bedtime   Pregnancy use with caution  Breast-feeding avoid — no information available  Side-effects oily leakage from rectum, flatulence,  faecal urgency, liquid or oily stools, faecal incont-  inence, abdominal distension and pain (gastro-intes-  tinal effects minimised by reduced fat intake), tooth  and gingival disorders; respiratory infections; fatigue,  anxiety, headache; menstrual disturbances, urinary-    tract infection; hypoglycaemia; rarely rectal bleeding,  hypothyroidism; very rarely diverticulitis, cholelithia-  sis, hepatitis, and bullous eruptions; oxalate nephro-  pathy also reported   • ADULT over 18 years, 120 mg taken immediately  before, during, or up to 1 hour after each main meal  (up to max. 360 mg daily); continue treatment beyond  12 weeks only if weight loss since start of treatment  exceeds 5% (target for initial weight loss may be lower  in patients with type 2 diabetes); CHILD over 12 years,  initiated by specialist only [unlicensed use]   Note If a meal is missed or contains no fat, the dose of  orlistat should be omitted   Capsules, turquoise, orlistat 120 mg, net price 84-cap  pack = £31.63   1 . Orlistat can be sold to the public for the treatment of obesity  in adults over 18 years with a body mass index of 28 kg/m 2  or more, taken in conjunction with a mildly hypocaloric,  lower-fat diet (max. daily dose 180 mg)   Phentermine and diethylpropion are central  stimulants; they are not recommended for the treatment  of obesity. Phentermine has been associated with a risk  of pulmonary hypertension.   Sibutramine, dexfenfluramine, and fenfluramine have  been withdrawn from the market because the benefit  of treatment does not outweigh the risk of serious  adverse effects.   Antiemetics should be prescribed only when the cause  of vomiting is known because otherwise they may delay  diagnosis, particularly in children. Antiemetics are unne-  cessary and sometimes harmful when the cause can be  treated, such as in diabetic ketoacidosis, or in digoxin or  antiepileptic overdose.   If antiemetic drug treatment is indicated, the drug is  chosen according to the aetiology of vomiting.   Antihistamines are effective against nausea and vomi-  ting resulting from many underlying conditions. There is  no evidence that any one antihistamine is superior to  another but their duration of action and incidence of  adverse effects (drowsiness and antimuscarinic effects)  differ.   The phenothiazines are dopamine antagonists and act  centrally by blocking the chemoreceptor trigger zone.  They are of considerable value for the prophylaxis and  treatment of nausea and vomiting associated with  diffuse neoplastic disease, radiation sickness, and the  emesis caused by drugs such as opioids, general anaes-  thetics, and cytotoxics. Prochlorperazine, perphen-  azine, and trifluoperazine are less sedating than chlor-  promazine; severe dystonic reactions sometimes occur  with phenothiazines, especially in children. Some   phenothiazines are available as rectal suppositories,  which can be useful in patients with persistent vomiting  or with severe nausea; prochlorperazine can also be  administered as a buccal tablet which is placed between  the upper lip and the gum.   Droperidol is a butyrophenone, structurally related to  haloperidol, which blocks dopamine receptors in the  chemoreceptor trigger zone.   Other antipsychotic drugs including haloperidol and  levomepromazine are used for the relief of nausea and  vomiting in terminal illness (see Palliative Care, p. 22).    Metoclopramide is an effective antiemetic and its  activity closely resembles that of the phenothiazines.  Metoclopramide also acts directly on the gastrointes-  tinal tract and it may be superior to the phenothiazines  for emesis associated with gastroduodenal, hepatic, and  biliary disease. In postoperative nausea and vomiting,  metoclopramide in a dose of 10 mg has limited efficacy.  High-dose metoclopramide injection is now less com-  monly used for cytotoxic-induced nausea and vomiting.  As with the phenothiazines, metoclopramide can induce  acute dystonic reactions involving facial and skeletal  muscle spasms and oculogyric crises. These dystonic  effects are more common in the young (especially girls  and young women) and the very old; they usually occur  shortly after starting treatment with metoclopramide  and subside within 24 hours of stopping it. Injection of  an antiparkinsonian drug such as procyclidine (section  4.9.2) will abort dystonic attacks.   Domperidone acts at the chemoreceptor trigger zone; it  is used for the relief of nausea and vomiting, especially  when associated with cytotoxic therapy. It has the  advantage over metoclopramide and the phenothi-  azines of being less likely to cause central effects such  as sedation and dystonic reactions because it does not  readily cross the blood-brain barrier. In Parkinson’s  disease, it is used to prevent nausea and vomiting during  treatment with apomorphine and also to treat nausea  caused by other dopaminergic drugs (section 4.9.1).  Domperidone is also used to treat vomiting due to  emergency hormonal contraception (section 7.3.5).   Granisetron, ondansetron, and palonosetron are spe-  cific 5HT 3 -receptor antagonists which block 5HT 3  receptors in the gastro-intestinal tract and in the CNS.  Granisetron and ondansetron are of value in the man-  agement of nausea and vomiting in patients receiving  cytotoxics and in postoperative nausea and vomiting.  Palonosetron is licensed for prevention of nausea and  vomiting associated with moderately or highly emeto-  genic cytotoxic chemotherapy.   Dexamethasone (section 6.3.2) has antiemetic effects  and it is used in vomiting associated with cancer chemo-  therapy. It can be used alone or with metoclopramide,  prochlorperazine, lorazepam, or a 5HT 3 antagonist (sec-  tion 8.1).    Aprepitant and fosaprepitant are neurokinin 1 recep-  tor antagonists licensed for the prevention of acute and  delayed nausea and vomiting associated with cisplatin-  based cytotoxic chemotherapy; they are given with  dexamethasone and a 5HT 3 antagonist.   Nabilone is a synthetic cannabinoid with antiemetic  properties. It may be used for nausea and vomiting  caused by cytotoxic chemotherapy that is unresponsive  to conventional antiemetics. Side-effects such as drow-  siness and dizziness occur frequently with standard  doses.   Nausea in the first trimester of pregnancy is generally  mild and does not require drug therapy. On rare occa-  sions if vomiting is severe, short-term treatment with an  antihistamine, such as promethazine, may be required.  Prochlorperazine or metoclopramide may be consid-  ered as second-line treatments. If symptoms do not  settle in 24 to 48 hours then specialist opinion should  be sought. Hyperemesis gravidarum is a more serious  condition, which requires intravenous fluid and electro-  lyte replacement and sometimes nutritional support.  Supplementation with thiamine must be considered in  order to reduce the risk of Wernicke’s encephalopathy.   The incidence of postoperative nausea and vomiting  depends on many factors including the anaesthetic  used, and the type and duration of surgery. Other risk  factors include female sex, a history of postoperative  nausea and vomiting or motion sickness, and intra-  operative and postoperative use of opioids. Therapy to  prevent postoperative nausea and vomiting should be  based on the assessed risk of postoperative nausea and  vomiting in each patient. Drugs used include 5HT 3 -  receptor antagonists, droperidol, dexamethasone  (section 6.3.2), some phenothiazines (e.g. prochlorper-  azine), and antihistamines (e.g. cyclizine). A combina-  tion of two or more antiemetic drugs that have different  mechanisms of action is often indicated in those at high  risk of postoperative nausea and vomiting or where  postoperative vomiting presents a particular danger  (e.g. in some types of surgery). When a prophylactic  antiemetic drug has failed, postoperative nausea and  vomiting should be treated with one or more drugs from  a different class.   Antiemetics should be given to prevent motion sickness  rather than after nausea or vomiting develop. The most  effective drug for the prevention of motion sickness is  hyoscine. A transdermal hyoscine patch provides pro-  longed activity but it needs to be applied several hours  before travelling. The sedating antihistamines are  slightly less effective against motion sickness, but are  generally better tolerated than hyoscine. If a sedative  effect is desired promethazine is useful, but generally a  slightly less sedating antihistamine such as cyclizine or  cinnarizine is preferred. The 5HT 3 antagonists, dom-  peridone, metoclopramide, and the phenothiazines  (except the antihistamine phenothiazine promethazine)  are ineffective in motion sickness.   Management of vestibular diseases is aimed at treating  the underlying cause as well as treating symptoms of the  balance disturbance and associated nausea and vomi-  ting. Vertigo and nausea associated with Meniere’s dis-  ease and middle-ear surgery can be difficult to treat.   Betahistine is an analogue of histamine and is claimed  to reduce endolymphatic pressure by improving the  microcirculation. Betahistine is licensed for vertigo,   A diuretic alone or combined with salt restriction may  provide some benefit in vertigo associated with  Meniere’s disease; antihistamines (such as cinnarizine),  and phenothiazines (such as prochlorperazine) are also  used. Where possible, prochlorperazine should be  reserved for the treatment of acute symptoms.   For advice to avoid the inappropriate prescribing of  drugs (notably phenothiazines) for dizziness in the  elderly, see Prescribing for the Elderly, p. 24.   For the management of nausea and vomiting induced by  cytotoxic chemotherapy, see section 8.1.   For the management of nausea and vomiting in pallia-  tive care, see p. 22 and p. 23.   For the management of nausea and vomiting associated  with migraine, see p. 277.   Indications vestibular disorders, such as vertigo, tin-  nitus, nausea, and vomiting in Meniere’s disease;  motion sickness   Side-effects section 3.4.1; also rarely weight gain,  sweating, lichen planus, and lupus-like skin reactions   • Vestibular disorders, 30 mg 3 times daily; CHILD 5-12  years 15 mg 3 times daily   • Motion sickness, 30 mg 2 hours before travel then  15 mg every 8 hours during journey if necessary;  CHILD 5-12 years, 15 mg 2 hours before travel then  7.5 mg every 8 hours during journey if necessary   Tablets, scored, cinnarizine 15 mg, net price 15-tab  pack = £1.55, 100-tab pack = £4.18. Label: 2   Tablets, cinnarizine 20 mg, dimenhydrinate 40 mg,  net price 100-tab pack = £24.00. Label; 2  Dose ADULT over 18 years, 1 tablet 3 times daily   Indications nausea, vomiting, vertigo, motion sick-  ness, labyrinthine disorders  Cautions section 3.4.1; severe heart failure; may  counteract haemodynamic benefits of opioids; inter-  actions: Appendix 1 (antihistamines)  Contra-indications section 3.4.1  Hepatic impairment section 3.4.1  Pregnancy section 3.4.1  Breast-feeding no information available  Side-effects section 3.4.1; also hypertension, paraes-  thesia, and twitching  Dose   • By mouth, cyclizine hydrochloride 50 mg up to 3 times  daily; CHILD 6-12 years 25 mg up to 3 times daily  Note For motion sickness, take 1-2 hours before departure   • By intramuscular or intravenous injection, cyclizine  lactate 50 mg 3 times daily   Indications nausea, vomiting, vertigo, labyrinthine  disorders, motion sickness; allergy and urticaria  (section 3.4.1); sedation (section 4.1.1)   • By mouth, 20-25 mg at bedtime on night before travel,  repeat following morning if necessary; CHILD 2-5  years 5 mg at night, and following morning if neces-  sary, 5-10 years 10 mg at night, and following morn-  ing if necessary   Indications nausea, vertigo, labyrinthine disorders,  motion sickness (acts longer than the hydrochloride)  Cautions section 3.4.1; severe coronary artery dis-  ease; asthma, bronchitis, bronchiectasis; Reye’s  syndrome   Contra-indications section 3.4.1  Hepatic impairment section 3.4.1  Renal impairment use with caution  Pregnancy section 3.4.1  Breast-feeding section 3.4.1  Side-effects section 3.4.1   • 25-75 mg, max. 100 mg, daily; CHILD 5-10 years, 12.5-   • Motion sickness prevention, ADULT and CHILD over 10  years, 25 mg at bedtime on night before travel or   12.5 mg at bedtime on night before travel or 12.5 mg  1-2 hours before travel   • Motion sickness treatment, ADULT and CHILD over 10  years, 25 mg at onset, then 25 mg at bedtime for 2  days; CHILD 5-10 years, 12.5 mg at onset, then 12.5 mg  at bedtime for 2 days   100 mg daily (but see also Vomiting During  Pregnancy, p. 250)   Tablets, scored, promethazine teoclate 25 mg, net  price 10-tab pack = £1.13; 28-tab pack = £3.13.  Label: 2    Indications nausea and vomiting of terminal illness  (where other drugs have failed or are not available);  other indications (section 4.2.1)   Contra-indications see notes in section 4.2.1  Hepatic impairment see notes in section 4.2.1  Renal impairment see notes in section 4.2.1  Pregnancy see notes in section 4.2.1  Breast-feeding see notes in section 4.2.1  Side-effects see Chlorpromazine Hydrochloride, sec-  tion 4.2.1   500 micrograms/kg every 4-6 hours (1-5 years max.  40 mg daily, 6-12 years max. 75 mg daily)   • By deep intramuscular injection initially 25 mg then  25-50 mg every 3-4 hours until vomiting stops; CHILD  500 micrograms/kg every 6-8 hours (1-5 years max.  40 mg daily, 6-12 years max. 75 mg daily)   • By rectum in suppositories, chlorpromazine 100 mg  every 6-8 hours [unlicensed]   Indications prevention and treatment of postoper-  ative nausea and vomiting  Cautions section 4.2.1; also chronic obstructive  pulmonary disease or respiratory failure; electrolyte  disturbances; history of alcohol abuse; continuous  pulse oximetry required if risk of ventricular arrhyth-  mia — continue for 30 minutes following administra-  tion; interactions: Appendix 1 (droperidol)  Contra-indications section 4.2.1; QT-interval prolon-  gation (avoid concomitant administration of drugs    that prolong QT interval); hypokalaemia; hypo-  magnesaemia; bradycardia  Hepatic impairment in postoperative nausea and  vomiting, max. 625 micrograms repeated every 6  hours as required; for nausea and vomiting caused by  opioid analgesics in postoperative patient-controlled  analgesia, reduce dose   Renal impairment in postoperative nausea and  vomiting, max. 625 micrograms repeated every 6  hours as required; for nausea and vomiting caused by  opioid analgesics in postoperative patient-controlled  analgesia, reduce dose  Pregnancy section 4.2.1   • Prevention and treatment of postoperative nausea  and vomiting, ADULT over 18 years, by intravenous  injection, 0.625-1.25 mg (ELDERLY 625 micrograms) 30  minutes before end of surgery, repeated every 6 hours  as required; CHILD over 2 years (second-line use only)  20-50 micrograms/kg (max. 1.25 mg)   • Prevention of nausea and vomiting caused by opioid  analgesics in postoperative patient-controlled  analgesia (PCA), ADULT over 18 years, by intravenous   B injection, 15-50 micrograms of droperidol for every  1 mg of morphine in PCA (max. 5 mg droperidol  daily); ELDERLY reduce dose    Renal impairment see notes in section 4.2.1  Pregnancy see notes in section 4.2.1  Breast-feeding see notes in section 4.2.1  Side-effects see Prochlorperazine, section 4.2.1   Note Doses are expressed as prochlorperazine maleate or  mesilate; 1 mg prochlorperazine maleate = 1 mg prochlor-  perazine mesilate   • By mouth, nausea and vomiting, acute attack, 20 mg  initially then 10 mg after 2 hours; prevention 5-10 mg  2-3 times daily; CHILD (over 10 kg only) 250 micr-  ograms/kg 2-3 times daily   Labyrinthine disorders, 5 mg 3 times daily, gradually  increased if necessary to 30 mg daily in divided doses,  then reduced after several weeks to 5-10 mg daily;  CHILD not recommended   • By deep intramuscular injection, nausea and vomi-  ting, 12.5 mg when required followed if necessary  after 6 hours by an oral dose, as above; CHILD and  ADOLESCENT under 18 years, see BNF for Children   Prochlorperazine (Non-proprietary) (Ml  Tablets, prochlorperazine maleate 5 mg, net price 28-  tab pack = £1.25, 84-tab pack = £2.28. Label: 2  Injection, prochlorperazine mesilate 12.5 mg/mL, net  price 1-mL amp = 52p   Stemetil® (Sanofi-Aventis) (Ml  Tablets, prochlorperazine maleate 5 mg (off-white),  net price 28-tab pack = £1.98, 84-tab pack = £5.94.  Label: 2   Syrup, straw-coloured, prochlorperazine mesilate  5mg/5mL, net price 100-mL pack = £3.34. Label: 2  Injection, prochlorperazine mesilate 12.5 mg/mL, net  price 1-mL amp = 52p   Indications severe nausea, vomiting (see notes  above); other indications (section 4.2.1)   Cautions see notes in section 4.2.1  Contra-indications see Perphenazine, section 4.2.1  Hepatic impairment see notes in section 4.2.1  Renal impairment see notes in section 4.2.1  Pregnancy see notes in section 4.2.1  Breast-feeding see notes in section 4.2.1  Side-effects see Perphenazine, section 4.2.1  Dose   • 4 mg 3 times daily, adjusted according to response;  max. 24 mg daily (chemotherapy-induced); ELDERLY  quarter to half adult dose; CHILD under 14 years not  recommended   Cautions see Prochlorperazine, section 4.2.1; oral  route only for children (avoid if under 10 kg); elderly  (see notes above)   Tablets (buccal), pale yellow, prochlorperazine mal-  eate 3 mg, net price 5 x 10-tab pack = £5.89. Label: 2,  counselling, administration, see under Dose below  Dose ADULT and CHILD over 12 years, 1-2 tablets twice daily;  tablets are placed high between upper lip and gum and left to  dissolve   1 . Prochlorperazine maleate can be sold to the public for adults  over 18 years (provided packs do not contain more than  24 mg) for the treatment of nausea and vomiting in  previously diagnosed migraine only (max. daily dose 12 mg)   Indications severe nausea and vomiting (see notes  above); other indications (section 4.2.1)   Cautions see notes in section 4.2.1  Contra-indications see notes in section 4.2.1  Hepatic impairment see notes in section 4.2.1  Renal impairment see notes in section 4.2.1  Pregnancy see notes in section 4.2.1  Breast-feeding see notes in section 4.2.1  Side-effects see Trifluoperazine, section 4.2.1  Dose   • 2-4 mg daily in divided doses; max. 6 mg daily; CHILD  3-5 years up to 1 mg daily, 6-12 years up to 4 mg daily   Side-effects rarely gastro-intestinal disturbances  (including cramps) and hyperprolactinaemia; very  rarely ventricular arrhythmias, agitation, drowsiness,  nervousness, seizures, extrapyramidal effects, head-  ache, and rashes; also reported QT-interval prolon-  gation   • By mouth, ADULT and CHILD body-weight over 35 kg,  10-20 mg 3-4 times daily; max. 80 mg daily; CHILD  body-weight up to 35 kg (nausea and vomiting only),  250-500 micrograms/kg 3-4 times daily; max.   • By rectum, ADULT and CHILD body-weight over 35 kg,  60 mg twice daily; CHILD 15-35 kg (nausea and vomi-  ting only), 30 mg twice daily; CHILD body-weight under  15 kg, not recommended   domperidone (Non-proprietary) (Ml  Tablets, 10 mg (as maleate), net price 30-tab pack =  £1.12; 100-tab pack = £1.90  Suspension, domperidone 5mg/5mL, net price 200-  mL pack = £12.00   1. Domperidone can be sold to the public for adults over 16  years (provided packs do not contain more than 200 mg) for  the relief of postprandial symptoms of excessive fullness,  nausea, epigastric bloating and belching occasionally  accompanied by epigastric discomfort and heartburn, and  for the relief of nausea and vomiting of less than 48 hours’  duration (max. single dose 10 mg, max. daily dose 40 mg)   Motilium® (Sanofi-Aventis) [Ml  Tablets, f/c, domperidone 10 mg (as maleate), net  price 30-tab pack = £2.71; 100-tab pack = £9.04  Suppositories domperidone 30 mg, net price 10 =  £3.06   Indications adults, nausea and vomiting, particularly  in gastro-intestinal disorders (section 1.2) and treat-  ment with cytotoxics or radiotherapy; migraine (sec-  tion 4.7.4. 1)   Patients under 20 years Use restricted to severe intract-  able vomiting of known cause, vomiting of radiotherapy and  cytotoxics, aid to gastro-intestinal intubation, premedication;  dose should be determined on the basis of body-weight  Cautions elderly, young adults (15-19 years old), and  children; atopic allergy (including asthma); may mask  underlying disorders such as cerebral irritation; acute  porphyria (section 9.8.2); epilepsy; interactions:  Appendix 1 (metoclopramide)    Contra-indications gastro-intestinal obstruction, per-  foration or haemorrhage; 3-4 days after gastro-intes-  tinal surgery; phaeochromocytoma  Hepatic impairment reduce dose  Renal impairment avoid or use small dose in severe  impairment; increased risk of extrapyramidal reac-  tions   Pregnancy not known to be harmful  Breast-feeding small amount present in milk; avoid  Side-effects extrapyramidal effects (especially in  children and young adults (15-19 years old) — see  p. 249), hyperprolactinaemia, occasionally tardive  dyskinesia on prolonged administration; also  reported, anxiety, confusion, drowsiness, restlessness,  diarrhoea, depression, neuroleptic malignant  syndrome, rashes, pruritus, oedema; cardiac conduc-  tion abnormalities reported following intravenous  administration; rarely methaemoglobinaemia (more  severe in G6PD deficiency)   • By mouth or by intramuscular injection or by intra-  venous injection over 1-2 minutes, nausea and  vomiting, 10 mg (5 mg in young adults 15-19 years,  body-weight under 60 kg) 3 times daily; CHILD up to 1  year (body- weight up to 10 kg) 100 micrograms/kg  (max. lmg) twice daily, 1-3 years (body-weight 10-  14 kg) 1 mg 2-3 times daily, 3-5 years (body-weight  15-19 kg) 2 mg 2-3 times daily, 5-9 years (body-  weight 20-29 kg) 2.5 mg 3 times daily, 9-15 years  (body-weight 30 kg and over) 5 mg 3 times daily  Note Daily dose of metoclopramide should not normally  exceed 500 micrograms /kg, particularly for children and  young adults (restricted use, see above)   For diagnostic procedures, as a single dose 5-10  minutes before examination, 10-20 mg (10 mg in  young adults 15-19 years); CHILD under 3 years 1 mg,  3-5 years 2 mg, 5-9 years 2.5 mg, 9-14 years 5 mg    Metoclopramide (Non-proprietary) (Ml  Tablets, metoclopramide hydrochloride 10 mg, net  price 28-tab pack = £1.01   Oral solution, metoclopramide hydrochloride 5 mg/  5 mL, net price 150-mL pack = £6.51. Counselling, use  of pipette   Maxolon® (Amdipharm) (Ml  Tablets, scored, metoclopramide hydrochloride  10 mg, net price 84-tab pack = £5.24  Injection, metoclopramide hydrochloride 5mg/mL,  net price 2-mL amp = 27p   For dilution and use as an intravenous infusion in nausea and  vomiting associated with cytotoxic chemotherapy only  Dose by continuous intravenous infusion (preferred method),  initially (before starting chemotherapy), 2-4 mg/kg over 15-20  minutes, then 3-5 mg/kg over 8-12 hours; max. in 24 hours,   By intermittent intravenous infusion, initially (before starting  chemotherapy), up to 2 mg/kg over at least 15 minutes then up to  2 mg/kg over at least 15 minutes every 2 hours; max. in 24 hours,  10 mg/kg    4 Modified release  Maxolon SR® (Amdipharm) Ml  Capsules, m/r, dear, endosing white granules,  metoclopramide hydrochloride 15 mg, net price 56-  cap pack = £7.01. Label: 25  Dose patients over 20 years, 1 capsule twice daily    Breast-feeding avoid — no information available  Side-effects constipation, nausea, diarrhoea, vomi-  ting, abdominal pain; headache, drowsiness, asthenia;  fever; rarely hepatic dysfunction, chest pain,  arrhythmia; very rarely anorexia, dizziness, insomnia,  agitation, movement disorders, and rash   • Nausea and vomiting induced by cytotoxic chemo-  therapy or radiotherapy, by mouth, 1-2 mg within 1  hour before start of treatment, then 2 mg daily in 1-2  divided doses during treatment; when intravenous  infusion also used, max. combined total 9 mg in 24  hours; CHILD 20 micrograms/kg (max. lmg) within 1  hour before start of treatment, then 20 micrograms/  kg (max. 1 mg) twice daily for up to 5 days during  treatment    By intravenous injection (diluted in 15 mL sodium  chloride 0.9% and given over not less than 30 sec-  onds) or by intravenous infusion (over 5 minutes),  prevention, 3 mg before start of cytotoxic therapy (up  to 2 additional 3-mg doses may be given within 24  hours); treatment, as for prevention (the two addi-  tional doses must not be given less than 10 minutes  apart); max. 9 mg in 24 hours; CHILD, by intravenous  infusion, (over 5 minutes), prevention, 40 micr-  ograms/kg (max. 3 mg) before start of cytotoxic  therapy; treatment, as for prevention — one additional  dose of 40 micrograms/kg (max. 3 mg) may be given  within 24 hours (not less than 10 minutes after initial  dose)   • Postoperative nausea and vomiting, by intravenous  injection (diluted to 5 mL and given over 30 seconds),  prevention, 1 mg before induction of anaesthesia;  treatment, 1 mg, given as for prevention; max. 2 mg in  one day; CHILD not recommended    Granisetron (Non-proprietary) (Ml  Tablets, granisetron (as hydrochloride) 1 mg, net price  10-tab pack = £51.20   Injection, granisetron (as hydrochloride) lmg/mL,  for dilution before use, net price 1-mL amp = £1.20, 3-  mL amp = £4.80   Tablets, f/c, granisetron (as hydrochloride) 1 mg, net  price 10-tab pack = £52.39; 2 mg, 5-tab pack = £52.39  Injection, granisetron (as hydrochloride) lmg/mL,  for dilution before use, net price 1-mL amp = £6.88, 3-  mL amp = £20.63   Cautions QT-interval prolongation (avoid concomi-  tant use of drugs that prolong QT interval); subacute  intestinal obstruction; adenotonsillar surgery; inter-  actions: Appendix 1 (ondansetron)   Hepatic impairment max. 8 mg daily in moderate or  severe impairment   Side-effects constipation; headache; flushing; injec-  tion site-reactions; less commonly hiccups, hypo-  tension, bradycardia, chest pain, arrhythmias, move-  ment disorders, seizures; on intravenous  administration, rarely dizziness, transient visual dis-  turbances ( very rarely transient blindness); supposi-  tories may cause rectal irritation  Dose   • Moderately emetogenic chemotherapy or radiother-  apy, ADULT over 18 years, by mouth, 8 mg 1-2 hours  before treatment or by rectum, 16 mg 1-2 hours  before treatment or by intramuscular injection or slow  intravenous injection, 8 mg immediately before  treatment   then by mouth, 8 mg every 12 hours for up to 5 days  or by rectum, 16 mg daily for up to 5 days   • Severely emetogenic chemotherapy, ADULT over 18  years, by intramuscular injection or slow intravenous  injection, 8 mg immediately before treatment, where  necessary followed by 2 further doses of 8 mg at  intervals of 2-4 hours [or followed by 1 mg/hour by  continuous intravenous infusion for up to 24 hours)  then by mouth, 8 mg every 12 hours for up to 5 days  or by rectum, 16 mg daily for up to 5 days;  alternatively, by intravenous infusion over at least 15  minutes, 32 mg immediately before treatment or by  rectum, 16 mg 1-2 hours before treatment   then by mouth, 8 mg every 12 hours for up to 5 days  or by rectum, 16 mg daily for up to 5 days   • Chemotherapy-induced nausea and vomiting, CHILD 6  months-18 years, by intravenous infusion over at  least 15 minutes, 5 mg/m 2 (max. 8 mg) immediately  before chemotherapy, then for body-surface area less  than 0.6 m 2 2 mg by mouth every 12 hours for up to 5  days; for body-surface area 0.6 m 2 or greater 4 mg by  mouth every 12 hours for up to 5 days; max. total  daily dose 32 mg   alternatively, by intravenous infusion over at least 15  minutes, 150 micrograms/kg (max. 8 mg) immedi-  ately before chemotherapy repeated at intervals of 4  hours for 2 further doses, then for body-weight 10 kg  or less 2 mg by mouth every 12 hours for up to 5 days;  for body-weight over 10 kg 4 mg by mouth every 12  hours for up to 5 days; max. total daily dose 32 mg   • Prevention of postoperative nausea and vomiting, by  mouth, 16 mg 1 hour before anaesthesia or 8 mg 1  hour before anaesthesia followed by 8 mg at intervals  of 8 hours for 2 further doses   alternatively, by intramuscular or slow intravenous  injection, 4 mg at induction of anaesthesia; CHILD 1  month-18 years, by slow intravenous injection over at  least 30 seconds, 100 micrograms/kg (max. 4 mg)  before, during, or after induction of anaesthesia   • Treatment of postoperative nausea and vomiting, by  intramuscular or slow intravenous injection, 4 mg;    CHILD 1 month-18 years, by slow intravenous injec-  tion over at least 30 seconds, 100 micrograms /kg  (max. 4 mg)   Ondansetron (Non-proprietary) (Ml  Tablets, ondansetron (as hydrochloride) 4 mg, net  price 30-tab pack = £66.85; 8 mg, 10-tab pack =  £49.92   Injection, ondansetron (as hydrochloride) 2mg/mL,  net price 2-mL amp = £5.39, 4-mL amp = £10.79  Brands include Ondemet®   4 mg, net price 30-tab pack = £107.91; 8 mg, 10-tab  pack = £71.94   Oral lyophilisates [Zofran Melt®), ondansetron 4 mg,  net price 10-tab pack = £35.97; 8 mg, 10-tab pack =  £71.94. Counselling, administration   Counselling Tablets should be placed on the tongue, allowed to  disperse and swallowed   Oral solution, sugar-free, strawberry-flavoured,  ondansetron (as hydrochloride) 4mg/5mL, net price  50-mL pack = £35.97   Injection, ondansetron (as hydrochloride) 2mg/mL,  net price 2-mL amp = £5.99; 4-mL amp = £11.99  Suppositories, ondansetron 16mg, net price 1 =  £14.39   Indications prevention of nausea and vomiting  induced by moderately and severely emetogenic  chemotherapy   Cautions history of constipation; intestinal obstruc-  tion; concomitant use of drugs that prolong QT  interval   Driving Dizziness or drowsiness may affect performance of  skilled tasks (e.g. driving)   Side-effects diarrhoea, constipation; headache, dizzi-  ness; less commonly dyspepsia, abdominal pain, dry  mouth, flatulence, changes in blood pressure, tachy-  cardia, bradycardia, arrhythmia, myocardial ischae-  mia, hiccups, drowsiness, asthenia, insomnia, anxiety,  euphoria, paraesthesia, peripheral neuropathy, ano-  rexia, motion sickness, influenza-like symptoms,  urinary retention, glycosuria, hyperglycaemia,  electrolyte disturbance, arthralgia, eye irritation,  amblyopia, tinnitus, rash, pruritus   250 micrograms as a single dose 30 minutes before  treatment; CHILD and ADOLESCENT under 18 years not  recommended   Aloxi® (IS Pharmaceuticals) T (Ml  Injection, palonosetron (as hydrochloride) 50micr-  ograms/mL, net price 5-mL amp = £55.89    Indications adjunct to dexamethasone and a 5HT 3 -  receptor antagonist in preventing nausea and vomi-  ting associated with moderately and highly emeto-  genic chemotherapy   Cautions interactions: Appendix 1 (aprepitant)  Hepatic impairment caution in moderate to severe  impairment    Side-effects hiccups, dyspepsia, diarrhoea, constipa-  tion, anorexia; asthenia, headache, dizziness; less  commonly weight changes, dry mouth, colitis, flatu-  lence, stomatitis, abdominal pain, duodenal ulcer,  taste disturbance, oedema, bradycardia, palpitations,  cough, euphoria, anxiety, confusion, drowsiness,  thirst, abnormal dreams, chills, hyperglycaemia,  polyuria, anaemia, dysuria, haematuria, hyponatr-  aemia, neutropenia, myalgia, conjunctivitis, pharyng-  itis, sneezing, tinnitus, sweating, pruritus, rash, acne,  photosensitivity, and flushing; dyspnoea, insomnia,  visual disturbances, dysarthria, urticaria, and Stevens-  Johnson syndrome also reported   • ADULT over 18 years 125 mg 1 hour before chemo-  therapy, then 80 mg daily as a single dose for the next  2 days; consult product literature for dose of conco-  mitant corticosteroid and 5HT 3 antagonist   Capsules, aprepitant 80 mg (white), net price 2-cap  pack = £31.61; 125 mg (white/pink), 5-cap pack =  £79.03; 3-day pack of one 125-mg capsule and two 80-  mg capsules = £47.42   Indications adjunct to dexamethasone and a 5HT 3  antagonist in preventing nausea and vomiting asso-  ciated with moderately and highly emetogenic  chemotherapy   Cautions interactions: Appendix 1 (aprepitant)  Hepatic impairment see Aprepitant  Pregnancy see Aprepitant  Breast-feeding see Aprepitant  Side-effects see Aprepitant  Dose   • By intravenous infusion, over 15 minutes, ADULT over  18 years, 1 15 mg 30 minutes before chemotherapy on  day 1 of cycle (followed by aprepitant on days 2 and 3  of cycle); consult product literature for dose of con-  comitant corticosteroid and 5HT 3 antagonist   Injection, powder for reconstitution, fosaprepitant (as  dimeglumine), net price 115-mg vial = £20.55  The Scottish Medicines Consortium (p. 4) has advised (September  2008) that fosaprepitant {Ivemend®) is accepted for restricted use  for the prevention of acute and delayed nausea and vomiting  associated with highly emetogenic cisplatin-based chemotherapy   Indications nausea and vomiting caused by cytotoxic  chemotherapy, unresponsive to conventional anti-  emetics (under close observation, preferably in hos-  pital setting)   Cautions history of psychiatric disorder; elderly;  hypertension; heart disease; adverse effects on mental  state can persist for 48-72 hours after stopping;  interactions: Appendix 1 (nabilone)   Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced  Hepatic impairment avoid in severe impairment  Pregnancy avoid unless essential  Breast-feeding avoid — no information available  Side-effects drowsiness, vertigo, euphoria, dry  mouth, ataxia, visual disturbance, concentration dif-  ficulties, sleep disturbance, dysphoria, hypotension,  headache and nausea; also confusion, disorientation,  hallucinations, psychosis, depression, decreased  coordination, tremors, tachycardia, decreased appe-  tite, and abdominal pain   Behavioural effects Patients should be made aware of  possible changes of mood and other adverse behavioural  effects   • Initially 1 mg twice daily, increased if necessary to  2 mg twice daily, throughout each cycle of cytotoxic  therapy and, if necessary, for 48 hours after the last  dose of each cycle; max. 6 mg daily given in 3 divided  doses. The first dose should be taken the night before  initiation of cytotoxic treatment and the second dose  1-3 hours before the first dose of cytotoxic drug;  ADOLESCENT and CHILD under 18 years consult local  treatment protocol [unlicensed use]   Capsules, blue/white, nabilone 1 mg, net price 20-  cap pack = £125.84. Label: 2, counselling, behavioural  effects   Indications motion sickness; hypersalivation asso-  ciated with clozapine therapy; premedication (section  15.1.3); excessive respiratory secretions (see Pre-  scribing in Palliative Care, p. 21)   Cautions section 1.2; also epilepsy  Contra-indications section 1.2  Hepatic impairment section 15.1.3  Renal impairment section 15.1.3  Pregnancy section 15.1.3  Breast-feeding section 15.1.3  Side-effects section 1.2  Dose   • Motion sickness, by mouth, ADULT and CHILD over 10  years, 150-300 micrograms up to 30 minutes before  start of journey repeated every 6 hours if required;  max. 900 micrograms daily; CHILD 3-4 years 75 micr-  ograms up to 30 minutes before start of journey  repeated after 6 hours if required, max. 150 micr-    ograms daily; 4-10 years 75-150 micrograms up to 30  minutes before start of journey repeated every 6  hours if required; max. 450 micrograms daily   • Hypersalivation associated with clozapine therapy  [unlicensed indication], by mouth, 300 micrograms up  to 3 times daily; max. 900 micrograms daily; CHILD  under 18 years, see BNF for Children   Tablets, chewable, raspberry-flavoured, hyoscine  hydrobromide 150 micrograms, net price 12-tab pack  = £1.49. Label: 2, 24   Tablets, chewable, scored, hyoscine hydrobromide  150 micrograms ( Kwells ® Kids) (white), net price 12-  tab pack = £1.67; 300 micrograms (pink), 12-tab pack  = £1.67. Label: 2   Scopoderm TTS® (Novartis Consumer Health) CmD  Patch, self-adhesive, pink, releasing hyoscine approx.  1 mg/ 72 hours when in contact with skin, net price 2  = £4.30. Label: 19, counselling, see below  Dose motion sickness prevention, apply 1 patch to hairless area  of skin behind ear 5-6 hours before journey; replace if necessary  after 72 hours, siting replacement patch behind other ear; CHILD  under 10 years not recommended   Counselling Explain accompanying instructions to patient and in  particular emphasise advice to wash hands after handling and to  wash application site after removing, and to use one patch at a  time   Betahistine has been promoted as a specific treatment  for Meniere’s disease.   Indications vertigo, tinnitus and hearing loss asso-  ciated with Meniere’s disease   • Initially 16 mg 3 times daily, preferably with food;  maintenance 24-48 mg daily; CHILD not recom-  mended   Betahistine Dihydrochloride (Non-proprietary) (Ml  Tablets, betahistine dihydrochloride 8 mg, net price  84-tab pack = £2.15 120-tab pack = £1.76; 16 mg, 84-  tab pack = £2.24. Label: 21   Tablets, betahistine dihydrochloride 8 mg (Sere® -8),  net price 120-tab pack = £9.04; 16 mg (Sere® -16)  (scored), 84-tab pack = £12.65. Label: 21   The non-opioid drugs (section 4.7.1), paracetamol and  aspirin (and other NSAIDs), are particularly suitable for  pain in musculoskeletal conditions, whereas the opioid  analgesics (section 4.7.2) are more suitable for moder-  ate to severe pain, particularly of visceral origin.   Pain in palliative care For advice on pain relief in  palliative care, see p. 20.   Pain in sickle-cell disease The pain of mild sickle-  cell crises is managed with paracetamol, a NSAID (sec-  tion 10.1.1), codeine, or dihydrocodeine. Severe crises  may require the use of morphine or diamorphine; con-  comitant use of a NSAID may potentiate analgesia and  allow lower doses of the opioid to be used. Pethidine  should be avoided if possible because accumulation of a  neurotoxic metabolite can precipitate seizures; the rela-  tively short half-life of pethidine necessitates frequent  injections.    dose of each analgesic is used. Most combination  analgesic preparations have not been shown to provide  greater relief of pain than an adequate dose of the non-  opioid component given alone. Moreover, combination  preparations have the disadvantage of an increased  number of side-effects.   Any analgesic given before a dental procedure should  have a low risk of increasing postoperative bleeding. In  the case of pain after the dental procedure, taking an  analgesic before the effect of the local anaesthetic has  worn off can improve control. Postoperative analgesia  with ibuprofen or aspirin is usually continued for about  24 to 72 hours.   Temporomandibular dysfunction can be related to  anxiety in some patients who may clench or grind  their teeth (bruxism) during the day or night. The  muscle spasm (which appears to be the main source  of pain) may be treated empirically with an overlay  appliance which provides a free sliding occlusion and  may also interfere with grinding. In addition, diazepam  (section 4.1.2), which has muscle relaxant as well as  anxiolytic properties, may be helpful but it should only  be prescribed on a short-term basis during the acute  phase. Analgesics such as aspirin (section 4.7.1) or ibu-  profen (section 10.1.1) may also be required.   For the management of neuropathic pain, persistent  idiopathic facial pain, and trigeminal neuralgia, see  section 4.7.3.   Dental and orofacial pain Analgesics should be used  judiciously in dental care as a temporary measure until  the cause of the pain has been dealt with.   Dental pain of inflammatory origin, such as that asso-  ciated with pulpitis, apical infection, localised osteitis  (dry socket) or pericoronitis is usually best managed by  treating the infection, providing drainage, restorative  procedures, and other local measures. Analgesics  provide temporary relief of pain (usually for about 1 to  7 days) until the causative factors have been brought  under control. In the case of pulpitis, intra-osseous  infection or abscess, reliance on analgesics alone is  usually inappropriate.   Similarly the pain and discomfort associated with acute  problems of the oral mucosa (e.g. acute herpetic gingi-  vostomatitis, erythema multiforme) may be relieved by  benzydamine mouthwash or spray (p. 694) until the  cause of the mucosal disorder has been dealt with.  However, where a patient is febrile, the antipyretic  action of paracetamol (p. 259) or ibuprofen (p. 636)  is often helpful.   The choice of an analgesic for dental purposes should be  based on its suitability for the patient. Most dental pain  is relieved effectively by non-steroidal anti-inflamm-  atory drugs (NSAIDs). NSAIDs that are used for dental  pain include ibuprofen, diclofenac, and aspirin; for  further details see section 4.7.1 and section 10.1.1.  Paracetamol has analgesic and antipyretic effects but  no anti-inflammatory effect.   Opioid analgesics (section 4.7.2) such as dihydrocod-  eine act on the central nervous system and are tradi-  tionally used for moderate to severe pain. However,  opioid analgesics are relatively ineffective in dental  pain and their side-effects can be unpleasant. Paraceta-  mol, ibuprofen, or aspirin are adequate for most cases of  dental pain and an opioid is rarely required.   Combining a non-opioid with an opioid analgesic can  provide greater relief of pain than either analgesic given  alone. However, this applies only when an adequate    Dysmenorrhoea Use of an oral contraceptive pre-  vents the pain of dysmenorrhoea which is generally  associated with ovulatory cycles. If treatment is neces-  sary paracetamol or a NSAID (section 10.1.1) will gen-  erally provide adequate relief of pain. The vomiting and  severe pain associated with dysmenorrhoea in women  with endometriosis may call for an antiemetic (in addi-  tion to an analgesic). Antispasmodics (such as alverine  citrate, section 1.2) have been advocated for dysmenorr-  hoea but the antispasmodic action does not generally  provide significant relief.   Aspirin is indicated for headache, transient musculo-  skeletal pain, dysmenorrhoea and pyrexia. In inflamm-  atory conditions, most physicians prefer anti-inflamm-  atory treatment with another NSAID which may be  better tolerated and more convenient for the patient.  Aspirin is used increasingly for its antiplatelet properties  (section 2.9). Aspirin tablets or dispersible aspirin tablets  are adequate for most purposes as they act rapidly.  Gastric irritation may be a problem; it is minimised by  taking the dose after food. Enteric-coated preparations  are available, but have a slow onset of action and are  therefore unsuitable for single-dose analgesic use  (though their prolonged action may be useful for night  pain).   Aspirin interacts significantly with a number of other  drugs and its interaction with warfarin is a special  hazard, see interactions: Appendix 1 (aspirin).  Paracetamol is similar in efficacy to aspirin, but has no  demonstrable anti-inflammatory activity; it is less irri-  tant to the stomach and for that reason is now generally  preferred to aspirin, particularly in the elderly. Over-    dosage with paracetamol is particularly dangerous as it  may cause hepatic damage which is sometimes not  apparent for 4 to 6 days (see Emergency Treatment of  Poisoning, p. 34).   Nefopam may have a place in the relief of persistent  pain unresponsive to other non-opioid analgesics. It  causes little or no respiratory depression, but sympatho-  mimetic and antimuscarinic side-effects may be trou-  blesome.   (NSAIDs, section 10.1.1) are particularly useful for the  treatment of patients with chronic disease accompanied  by pain and inflammation. Some of them are also used  in the short-term treatment of mild to moderate pain  including transient musculoskeletal pain but paraceta-  mol is now often preferred, particularly in the elderly  (see also p. 25). They are also suitable for the relief of  pain in dysmenorrhoea and to treat pain caused by  secondary bone tumours, many of which produce lysis  of bone and release prostaglandins (see Prescribing in  Palliative Care, p. 20). Selective inhibitors of cyclo-oxy-  genase-2 may be used in preference to non-selective  NSAIDs for patients at high risk of developing serious  gastro-intestinal side-effects. NSAIDs including ketoro-  lac are also used for peri-operative analgesia (section  15.1.4.2).   A non-opioid analgesic administered by intrathecal infu-  sion (ziconotide (. Prialt ®), available from Eisai) is  licensed for the treatment of chronic severe pain;  ziconotide can be used by a hospital specialist as an  adjunct to opioid analgesics.   Dental and orofacial pain Most dental pain is  relieved effectively by NSAIDs (section 10.1.1). Aspirin  (below) is effective against mild to moderate dental  pain; dispersible tablets provide a rapidly absorbed  form of aspirin suitable for most purposes.   The analgesic effect of paracetamol in mild to moder-  ate dental pain is probably less than that of aspirin, but it  does not affect bleeding time or interact significantly  with warfarin. Moreover, it is less irritant to the stomach.  Paracetamol is a suitable analgesic for children; sugar-  free versions can be requested by specifying ‘sugar-free’  on the prescription.   For further information on the management of dental  and orofacial pain, see p. 257.   Compound analgesic preparations that contain a simple  analgesic (such as aspirin or paracetamol) with an  opioid component reduce the scope for effective titra-  tion of the individual components in the management of  pain of varying intensity.   Compound analgesic preparations containing paraceta-  mol or aspirin with a low dose of an opioid analgesic  (e.g. 8 mg of codeine phosphate per compound tablet)  are commonly used, but the advantages have not been  substantiated. The low dose of the opioid may be  enough to cause opioid side-effects (in particular, con-  stipation) and can complicate the treatment of over-  dosage (see p. 36) yet may not provide significant  additional relief of pain.   A full dose of the opioid component (e.g. 60 mg codeine  phosphate) in compound analgesic preparations effec-  tively augments the analgesic activity but is associated  with the full range of opioid side-effects (including  nausea, vomiting, severe constipation, drowsiness, resp-    iratory depression, and risk of dependence on long-term  administration). For details of the side-effects of opioid  analgesics, see p. 262 (important: the elderly are parti-  cularly susceptible to opioid side-effects and should  receive lower doses).   In general, when assessing pain, it is necessary to weigh  up carefully whether there is a need for a non-opioid and  an opioid analgesic to be taken simultaneously.   For information on the use of combination analgesic  preparations in dental and orofacial pain, see p. 257.  Caffeine is a weak stimulant that is often included, in  small doses, in analgesic preparations. It is claimed that  the addition of caffeine may enhance the analgesic  effect, but the alerting effect, mild habit-forming effect  and possible provocation of headache may not always  be desirable. Moreover, in excessive dosage or on with-  drawal caffeine may itself induce headache.  Co-proxamol tablets (dextropropoxyphene in combina-  tion with paracetamol) are no longer licensed because  of safety concerns, particularly toxicity in overdose. Co-  proxamol tablets [unlicensed] may still be prescribed for  patients who find it difficult to change, because alter-  natives are not effective or suitable.   Cautions asthma, allergic disease, dehydration; pre-  ferably avoid during fever or viral infection in children  (risk of Reye’s syndrome, see below); elderly; G6PD-  deficiency (section 9.1.5); concomitant use of drugs  that increase risk of bleeding; interactions: Appendix  1 (aspirin)   Contra-indications children under 16 years (Reye’s  syndrome, see below); previous or active peptic  ulceration, haemophilia; not for treatment of gout  Hypersensitivity Aspirin and other NSAIDs are contra-  indicated in patients with a history of hypersensitivity to  aspirin or any other NSAID — which includes those in whom  attacks of asthma, angioedema, urticaria or rhinitis have  been precipitated by aspirin or any other NSAID  Reye’s syndrome Owing to an association with Reye’s  syndrome, aspirin-containing preparations should not be  given to children under 16 years, unless specifically indi-  cated, e.g. for Kawasaki syndrome  Hepatic impairment avoid in severe impairment —  increased risk of gastro-intestinal bleeding  Renal impairment use with caution; avoid in severe  impairment; sodium and water retention; deteriora-  tion in renal function; increased risk of gastro-intes-  tinal bleeding   Pregnancy impaired platelet function with risk of  haemorrhage, and delayed onset and increased  duration of labour with increased blood loss, can  occur if used during delivery; avoid analgesic doses if  possible in last few weeks (low doses probably not  harmful); with high doses, closure of fetal ductus  arteriosus in utero and possibly persistent pulmonary  hypertension of newborn; kemicterus in jaundiced  neonates   Breast-feeding avoid — possible risk of Reye’s  syndrome; regular use of high doses could impair  platelet function and produce hypoprothrombinaemia  in infant if neonatal vitamin K stores low  Side-effects generally mild and infrequent but high  incidence of gastro-intestinal irritation with slight  asymptomatic blood loss, increased bleeding time,    bronchospasm and skin reactions in hypersensitive  patients. Prolonged administration, see section 10.1.1.  Overdosage: see Emergency Treatment of Poisoning,  p. 34   • By mouth, 300-900 mg every 4-6 hours when  necessary; max. 4g daily; CHILD under 16 years not  recommended (see Reye’s Syndrome, above)   Tablets (Ml 1 , e/c, aspirin 300 mg, net price 100-tab  pack = £5.29; 75 mg, see section 2.9. Label: 5, 25, 32  Dispersible tablets (Ml 1 , aspirin 300 mg, net price  100-tab pack = £2.88; 75 mg, see section 2.9.   Note BP directs that when no strength is stated the 300-mg  strength should be dispensed, and that when soluble aspirin  tablets are prescribed, dispersible aspirin tablets shall be dis-  pensed.   Dental prescribing on NHS Aspirin Dispersible Tablets 300 mg  may be prescribed   Suppositories (Ml, aspirin 150 mg, net price 10 =  £13.13; 300 mg, 12 = £59.28. Label: 32  Brands include Resprin ®   Tablets (Ml 1 , e/c, f/c, pink, aspirin 300 mg, net price  100-tab pack = £4.89; 75 mg, see section 2.9. Label: 5,  25, 32   Tablets (Ml 1 , e/c, aspirin 300 mg, net price 100-tab  pack = £4.15; 75 mg, see section 2.9. Label: 5, 25, 32   Dispersible tablets, co-codaprin 8/400 (codeine  phosphate 8 mg, aspirin 400 mg), net price 100-tab  pack = £35.22. Label: 13, 21, 32  Dose 1-2 tablets in water every 4-6 hours; max. 8 tablets daily  When co-codaprin tablets or dispersible tablets are prescribed  and no strength is stated, tablets or dispersible tablets, respec-  tively, containing codeine phosphate 8 mg and aspirin 400 mg  should be dispensed   Indications mild to moderate pain, pyrexia  Cautions alcohol dependence; max. daily infusion  dose 3 g in patients with hepatocellular insufficiency,  chronic alcoholism, chronic malnutrition, or dehy-  dration; interactions: Appendix 1 (paracetamol)  Hepatic impairment dose-related toxicity — avoid  large doses; see also Cautions  Renal impairment increase infusion dose interval to  every 6 hours if eGFR less than 30 mL/minute/  1.73m 2 ; note also sodium content of effervescent  tablets (see under relevant preparation entry)  Pregnancy not known to be harmful  Breast-feeding amount too small to be harmful  Side-effects side-effects rare, but rashes, blood dis-  orders (including thrombocytopenia, leucopenia,  neutropenia) reported; hypotension, flushing, and  tachycardia also reported on infusion; important:  liver damage (and less frequently renal damage) fol-  lowing overdosage, see Emergency Treatment of  Poisoning, p. 34   • By mouth, 0.5-1 g every 4-6 hours to a max. of 4g  daily; CHILD 2 months 60 mg for post-immunisation  pyrexia, repeated once after 6 hours if necessary;  otherwise under 3 months, see BNF for Children', 3  months-1 year 60-120 mg, 1-6 years 120-250 mg, 6-  12 years 250-500 mg; these doses may be repeated  every 4-6 hours when necessary (max. of 4 doses in  24 hours)   • By intravenous infusion over 15 minutes, ADULT and  CHILD over 50 kg, 1 g every 4-6 hours, max. 4g daily;  ADULT and CHILD 10-50 kg, 15 mg/kg every 4-6 hours,  max. 60 mg/kg daily; NEONATE and CHILD less than  10 kg, 7.5 mg/kg every 4-6 hours, max. 30 mg/kg  daily   • By rectum, ADULT and CHILD over 12 years 0.5-1 g  every 4-6 hours to a max. of 4 g daily; CHILD under 3  months, see BNF for Children, 3 months-1 year 60-  125 mg, 1-5 years 125-250 mg, 5-12 years 250-  500 mg; these doses may be repeated every 4-6 hours  as necessary (max. 4 doses in 24 hours)   Note For full Joint Committee on Vaccination and Immuni-  sation recommendation on post-immunisation pyrexia, see  section 14.1   onset of attack, repeated after 2 hours if necessary (max. 3 sachets   in 24 hours); YOUNG ADULT (under 20 years) and CHILD not   Important Metoclopramide can cause severe extrapyramidal  effects, particularly in children and young adults (for further  details, see p. 249)    1. Can be sold to the public provided packs contain no more  than 32 capsules or tablets; pharmacists can sell multiple  packs up to a total quantity of 100 capsules or tablets in  justifiable circumstances; for details see Medicines, Ethics  and Practice, No. 34, London, Pharmaceutical Press, 2010  (and subsequent editions as available)   Tablets (and caplets)(Ml 1 , paracetamol 500 mg, net  price 16-tab pack = 17p, 32-tab pack = £1.00, 100-tab  pack = £1.44. Label: 29, 30  Brands include Panadol ® ( P&\   Soluble tablets (= Dispersible tablets)(Ml 2 , para-  cetamol 500 mg, net price 60-tab pack = £4.39.   Brands include Panadol Soluble® U^\ (contains Na + 18.6 mmol/  tablet). Paracetamol Seltzer ® (contains Na + 16.9 mmol/tablet)  Dental prescribing on NHS Paracetamol Soluble Tablets  500 mg may be prescribed    2. Can be sold to the public in certain circumstances; for  exemptions see Medicines, Ethics and Practice, No. 34,  London, Pharmaceutical Press, 2010 (and subsequent  editions as available)   Brands include Disprol ® Soluble Paracetamol fSwSI  Oral suspension 120 mg/5 mL (= Paediatric Mix-  ture), paracetamol 120 mg/5 mL, net price 100 mL =  72p, 150 mL = 84p, 200 mL = £1.05, 500 mL = £1.94.  Label: 30   Note BP directs that when Paediatric Paracetamol Oral Suspen-  sion or Paediatric Paracetamol Mixture is prescribed Paracetamol  Oral Suspension 120 mg/ 5 mL should be dispensed; sugar-free  versions can be ordered by specifying ‘sugar-free’ on the pre-  scription   Brands include Calpol® Paediatric, Calpol ® Paediatric sugar-  free, Disprol ® Paediatric, Medinol ® Paediatric sugar-free,  Panadol ® sugar-free   Oral suspension 250 mg/5 mL (= Mixture), para-  cetamol 250 mg/5 mL, net price 100 mL = 82p,   Suppositories, paracetamol 60 mg, net price 10 =  £9.96; 125 mg, 10 = £11.50; 250 mg, 10 = £23.00;   Dose ADULT and CHILD over 12 years, 1 tablet up to 4 times daily,  not more often than every 4 hours    Perfalgan® (Bristol-Myers Squibb) ▼ (Ml  Intravenous infusion, paracetamol lOmg/mL, net  price 50-mL vial = £1.39, 100-mL vial = £1.52   When co-codamol tablets, dispersible (or efferves-  cent) tablets, or capsules are prescribed and no  strength is stated, tablets, dispersible (or efferves-  cent) tablets, or capsules, respectively, containing  codeine phosphate 8 mg and paracetamol 500 mg  should be dispensed.   Tablets, co-codamol 8/500 (codeine phosphate 8 mg,  paracetamol 500 mg), net price 30-tab pack = £1.25,  32-tab pack = 58p, 100-tab pack = £1.35. Label: 29, 30  Dose 1-2 tablets every 4-6 hours; max. 8 tablets daily; CHILD 6-  12 years Vz-1 tablet, max. 4 tablets daily   Effervescent or dispersible tablets, co-codamol 8/  500 (codeine phosphate 8 mg, paracetamol 500 mg),  net price 32-tab pack = £1.50, 100-tab pack = £4.32.  Label: 13, 29, 30  Brands include Paracodol ® <^\   Dose 1-2 tablets in water every 4-6 hours, max. 8 tablets daily;  CHILD 6-12 years V 2 -I tablet, max. 4 tablets daily    1. Can be sold to the public in certain circumstances; for  exemptions see Medicines, Ethics and Practice, No. 34,  London, Pharmaceutical Press, 2010 (and subsequent  editions as available)   When co-codamol tablets, dispersible (or efferves-  cent) tablets, or capsules are prescribed and no  strength is stated, tablets, dispersible (or efferves-  cent) tablets, or capsules, respectively, containing  codeine phosphate 8 mg and paracetamol 500 mg  should be dispensed (see preparations above).   Caplets (= tablets), co-codamol 15/500 (codeine  phosphate 15 mg, paracetamol 500 mg), net price  100-tab pack = £8.25. Label: 2, 29, 30  Dose 1-2 tablets every 4 hours; max. 8 tablets daily; CHILD under  12 years not recommended   Tablets, co-codamol 15/500 (codeine phosphate  15 mg, paracetamol 500 mg), net price 100-tab pack =  £8.25. Label: 2, 29, 30   Dose ADULT over 16 years 2 tablets every 4 hours; max. 8 tablets  daily; CHILD 12-16 years 1 tablet every 4 hours; max. 4 tablets  daily; CHILD under 12 years not recommended   When co-codamol tablets, dispersible (or efferves-  cent) tablets, or capsules are prescribed and no  strength is stated, tablets, dispersible (or efferves-  cent) tablets, or capsules, respectively, containing  codeine phosphate 8 mg and on paracetamol  500 mg should be dispensed (see preparations above).  See warnings and notes on p. 258 (important: special  care in elderly — reduce dose)    Co-codamol 30/500 (Non-proprietary) (Ml  Tablets (and caplets), co-codamol 30/500 (codeine  phosphate 30 mg, paracetamol 500 mg), net price  100-tab pack = £3.65. Label: 2, 29, 30  Dose 1-2 tablets every 4 hours; max. 8 tablets daily; CHILD under  12 years not recommended   Capsules, co-codamol 30/500 (codeine phosphate  30 mg, paracetamol 500 mg), net price 100-cap pack  = £5.55. Label: 2, 29, 30   Dose 1-2 capsules every 4 hours; max. 8 capsules daily; CHILD  under 12 years not recommended   Effervescent tablets, co-codamol 30/500 (codeine  phosphate 30 mg, paracetamol 500 mg), net price  100-tab pack = £7.67. Label: 2, 13, 29, 30  Brands include Medocodene ® Effervescent (contains Na +   Dose 1-2 tablets in water every 4 hours; max. 8 tablets daily;  CHILD under 12 years not recommended   Tablets, scored, co-codamol 30/500 (codeine phos-  phate 30 mg, paracetamol 500 mg), net price 30-tab  pack = £2.26 (hosp. only), 100-tab pack = £7.10.  Label: 2, 29, 30   Dose 1-2 tablets every 4 hours; max. 8 tablets daily; CHILD under  12 years not recommended   Capsules, co-codamol 30/500 (codeine phosphate  30 mg, paracetamol 500 mg), net price 100-cap pack  = £7.10. Label: 2, 29, 30   Dose 1-2 capsules every 4 hours; max. 8 capsules daily; CHILD  under 12 years not recommended    Solpadol® (Sanofi-Aventis) (Ml 6^1  Caplets (= tablets), co-codamol 30/500 (codeine  phosphate 30 mg, paracetamol 500 mg), net price  100-tab pack = £6.74. Label: 2, 29, 30  Dose 2 tablets every 4 hours; max. 8 tablets daily; CHILD under  12 years not recommended   Capsules, grey/purple, co-codamol 30/500 (codeine  phosphate 30 mg, paracetamol 500 mg), net price  100-cap pack = £6.74. Label: 2, 29, 30  Dose 2 capsules every 4 hours; max. 8 capsules daily; CHILD  under 12 years not recommended  Effervescent tablets, co-codamol 30/500 (codeine  phosphate 30 mg, paracetamol 500 mg), net price 32-  tab pack = £2.59, 100-tab pack = £8.09. Label: 2, 13,  29, 30   Dose 2 tablets in water every 4 hours; max. 8 tablets daily; CHILD  under 12 years not recommended   Capsules, co-codamol 30/500 (codeine phosphate  30 mg, paracetamol 500 mg), net price 100-cap pack  = £7.70. Label: 2, 29, 30   Dose 1-2 capsules every 4 hours; max. 8 capsules daily; CHILD  under 12 years not recommended  Effervescent tablets, co-codamol 30/500 (codeine  phosphate 30 mg, paracetamol 500 mg), net price  100-tab pack = £8.80. Label: 2, 13, 29, 30   Dose 1-2 tablets in water every 4 hours; max. 8 tablets daily;  CHILD under 12 years not recommended   A mixture of methionine and paracetamol; methion-  ine has no analgesic activity but may prevent para-  cetamol-induced liver toxicity if overdose taken   Tablets, f/c, co-methiamol 100/500 (DL-methionine  100 mg, paracetamol 500 mg), net price 24-tab pack =  £1.05, 96-tab pack = £2.77. Label: 29, 30  Dose 2 tablets every 4 hours; max. 8 tablets daily; CHILD under  12 years not recommended   When co-dydramol tablets are prescribed and no strength is  stated, tablets containing dihydrocodeine tartrate 10 mg and  paracetamol 500 mg should be dispensed   Co-dydramol (Non-proprietary) (Ml  Tablets, scored, co-dydramol 10/500 (dihydrocod-  eine tartrate 10 mg, paracetamol 500 mg), net price  30-tab pack = £1.21. Label: 29, 30  Dose 1-2 tablets every 4-6 hours; max. 8 tablets daily; CHILD  under 12 years not recommended   When co-dydramol tablets are prescribed and no strength is  stated, tablets containing dihydrocodeine tartrate 10 mg and  paracetamol 500 mg should be dispensed   Remedeine® (Napp) (M\Qd  Tablets, paracetamol 500 mg, dihydrocodeine tartrate  20 mg, net price 112-tab pack = £10.57. Label: 2, 29,  30   Dose 1-2 tablets every 4-6 hours; max. 8 tablets daily; CHILD  under 12 years not recommended  Forte tablets, paracetamol 500 mg, dihydrocodeine  tartrate 30 mg, net price 56-tab pack = £6.53. Label: 2,  29, 30   Dose 1-2 tablets every 4-6 hours; max. 8 tablets daily; CHILD  under 12 years not recommended    JiWith isometheptene mucate  Isometheptene mucate (in combination with para-  cetamol) is licensed for the treatment of acute attacks  of migraine; other more effective treatments are avail-  able.   Capsules, red, isometheptene mucate 65 mg, para-  cetamol 325 mg, net price 30-cap pack = £5.50.  Label: 30, counselling, dosage  Dose migraine, 2 capsules at onset of attack, followed by 1  capsule every hour if necessary; max. 5 capsules in 12 hours;  CHILD not recommended   1. A pack containing 15 capsules may be sold to the public   Tramacet® (Griinenthal) (Ml  Tablets, f/c, yellow, tramadol hydrochloride 37.5 mg,  paracetamol 325 mg, net price 60-tab pack = £9.68.  Label: 2, 25, 29, 30   Dose 2 tablets not more often than every 6 hours; max. 8 tablets  daily; CHILD under 12 years not recommended  Effervescent tablets, pink, tramadol hydrochloride  37.5 mg, paracetamol 325 mg, net price 60-tab pack =  £9.68. Label: 2, 13, 29, 30   Dose 2 tablets not more often than every 6 hours; max. 8 tablets  daily; CHILD under 12 years not recommended   Tablets, f/c, pink tablets, buclizine hydrochloride  6.25 mg, paracetamol 500 mg, codeine phosphate  8 mg; yellow tablets, paracetamol 500 mg, codeine  phosphate 8 mg, net price 48-tab Migraleve (Ml (32  pink + 16 yellow) = £4.81; 48 pink [Migraleve Pink) =  £5.24; 48 yellow [Migraleve Yellow) = £4.70. Label: 2,  [Migraleve Pink), 17, 30   Dose acute migraine, 2 pink tablets at onset of attack, followed  by 2 yellow tablets every 4 hours if necessary; max. 2 pink and 6  yellow in 24 hours; CHILD under 10 years, only under close  medical supervision; 10-14 years, half adult dose   Paramax® (Sanofi-Aventis) (Ml  Tablets, scored, paracetamol 500 mg, metoclo-  pramide hydrochloride 5 mg, net price 42-tab pack =  £9.64. Label: 17, 30   Sachets, effervescent powder, sugar-free, the con-  tents of 1 sachet = 1 tablet; to be dissolved in %  tumblerful of liquid before administration, net price  42-sachet pack = £12.52. Label: 13, 17, 30  Dose acute migraine, (tablets or sachets): 2 at onset of attack  then every 4 hours when necessary to max. of 6 in 24 hours;  YOUNG ADULT 12-19 years, 1 at onset of attack then 1 every 4  hours when necessary to max. of 3 in 24 hours (max. dose of  metoclopramide 500 micrograms/kg daily)   Important Metoclopramide can cause severe extrapyramidal  effects, particularly in children and young adults (for further  details, see p. 249)   Indications moderate pain  Cautions elderly, urinary retention; interactions:  Appendix 1 (nefopam)    Side-effects nausea, nervousness, urinary retention,  dry mouth, lightheadedness; less commonly vomiting,  blurred vision, drowsiness, sweating, insomnia,  tachycardia, headache; confusion and hallucinations  also reported, may colour urine (pink)   • By mouth, initially 60 mg (ELDERLY 30 mg) 3 times  daily, adjusted according to response; usual range 30-  90 mg 3 times daily; CHILD not recommended    sensitivity when patients with renal impairment are  treated with opioid analgesics; avoid use or reduce dose.   Pregnancy Respiratory depression and withdrawal  symptoms can occur in the neonate if opioid analgesics  are used during delivery; also gastric stasis and inhala-  tion pneumonia has been reported in the mother if  opioid analgesics are used during labour.   Tablets, f/c, nefopam hydrochloride 30 mg, net price  90-tab pack = £10.53. Label: 2, 14    Opioid analgesics are usually used to relieve moderate  to severe pain particularly of visceral origin. Repeated  administration may cause dependence and tolerance,  but this is no deterrent in the control of pain in terminal  illness, for guidelines see Prescribing in Palliative Care,  p. 20. Regular use of a potent opioid may be appropriate  for certain cases of chronic non-malignant pain; treat-  ment should be supervised by a specialist and the  patient should be assessed at regular intervals.   Cautions Opioids should be used with caution in  patients with impaired respiratory function (avoid in  chronic obstructive pulmonary disease) and asthma  (avoid during an acute attack), hypotension, shock,  myasthenia gravis, prostatic hypertrophy, obstructive  or inflammatory bowel disorders, diseases of the biliary  tract, and convulsive disorders. A reduced dose is  recommended in elderly or debilitated patients, in hypo-  thyroidism, and in adrenocortical insufficiency.  Repeated use of opioid analgesics is associated with  the development of psychological and physical depend-  ence; although this is rarely a problem with therapeutic  use, caution is advised if prescribing for patients with a  history of drug dependence. Avoid abrupt withdrawal  after long-term treatment. Transdermal preparations  (fentanyl or buprenorphine patches) are not suitable  for acute pain or in those patients whose analgesic  requirements are changing rapidly because the long  time to steady state prevents rapid titration of the  dose. Interactions: Appendix 1 (opioid analgesics;  important: special hazard with pethidine and possibly  other opioids and MAOIs).   Palliative care In the control of pain in terminal illness, the  cautions listed above should not necessarily be a deterrent to  the use of opioid analgesics.    Contra-indications Opioid analgesics should be  avoided in patients with acute respiratory depression  and when there is a risk of paralytic ileus. They are also  contra-indicated in conditions associated with raised  intracranial pressure and in head injury (opioid anal-  gesics interfere with pupillary responses vital for neu-  rological assessment). Comatose patients should not be  treated with opioid analgesics.    Hepatic impairment Opioid analgesics may precipi-  tate coma in patients with hepatic impairment; avoid  use or reduce dose.    Renal impairment The effects of opioid analgesia are  increased and prolonged and there is increased cerebral    Side-effects Opioid analgesics share many side-  effects, although qualitative and quantitative differences  exist. The most common side-effects include nausea  and vomiting (particularly in initial stages), constipation,  dry mouth, and biliary spasm; larger doses produce  muscle rigidity, hypotension, and respiratory depression  (for reversal of opioid-induced respiratory depression,  see section 15.1.7). Other common side-effects of opioid  analgesics include bradycardia, tachycardia, palpitation,  oedema, postural hypotension, hallucinations, vertigo,  euphoria, dysphoria, mood changes, dependence, dizzi-  ness, confusion, drowsiness, sleep disturbances, head-  ache, sexual dysfunction, difficulty with micturition,  urinary retention, ureteric spasm, miosis, visual distur-  bances, sweating, flushing, rash, urticaria, and pruritus.  Overdosage: see Emergency Treatment of Poisoning,  p. 36.   Long-term use of opioid analgesics can cause hypo-  gonadism and adrenal insufficiency in both men and  women. This can lead to amenorrhoea, reduced libido,  infertility, depression, and erectile dysfunction. Long-  term use of opioid analgesics has been associated with a  state of abnormal pain sensitivity (hyperalgesia). Pain  associated with hyperalgesia is usually qualitatively dis-  tinct from pain associated with disease progression or  breakthrough pain, and is often more diffuse and less  defined. Treatment of hyperalgesia involves reducing  the dose of opioid medication or switching therapy;  cases of suspected hyperalgesia should be referred to  a specialist pain team.    Driving Drowsiness may affect performance of skilled  tasks (e.g. driving); effects of alcohol enhanced. Driving  at the start of therapy with opioid analgesics, and  following dose changes, should be avoided.    Strong opioids Morphine remains the most valuable  opioid analgesic for severe pain although it frequently  causes nausea and vomiting. It is the standard against  which other opioid analgesics are compared. In addition  to relief of pain, morphine also confers a state of  euphoria and mental detachment.   Morphine is the opioid of choice for the oral treatment  of severe pain in palliative care. It is given regularly  every 4 hours (or every 12 or 24 hours as modified-  release preparations). For guidelines on dosage adjust-  ment in palliative care, see p. 20.   A modified-release epidural preparation of morphine is  available from Flynn Pharma Ltd ( Depodur JS> ).   Buprenorphine has both opioid agonist and antagonist  properties and may precipitate withdrawal symptoms,  including pain, in patients dependent on other opioids. It  has abuse potential and may itself cause dependence. It  has a much longer duration of action than morphine and  sublingually is an effective analgesic for 6 to 8 hours.  Unlike most opioid analgesics, the effects of bupren-  orphine are only partially reversed by naloxone.    Dipipanone used alone is less sedating than morphine  but the only preparation available contains an anti-  emetic and is therefore not suitable for regular regimens  in palliative care.   Diamorphine (heroin) is a powerful opioid analgesic. It  may cause less nausea and hypotension than morphine.  In palliative care the greater solubility of diamorphine  allows effective doses to be injected in smaller volumes  and this is important in the emaciated patient.  Alfentanil, fentanyl and remifentanil are used by  injection for intra-operative analgesia (section  15.1.4.3); fentanyl is available in a transdermal drug  delivery system as a self-adhesive patch which is chan-  ged every 72 hours.   Methadone is less sedating than morphine and acts for  longer periods. In prolonged use, methadone should not  be administered more often than twice daily to avoid the  risk of accumulation and opioid overdosage. Methadone  may be used instead of morphine in the occasional  patient who experiences excitation (or exacerbation of  pain) with morphine.   Oxycodone has an efficacy and side-effect profile simi-  lar to that of morphine. It is used primarily for control of  pain in palliative care.   Papaveretum is rarely used; morphine is easier to  prescribe and less prone to error with regard to the  strength and dose.   Pentazocine has both agonist and antagonist properties  and precipitates withdrawal symptoms, including pain  in patients dependent on other opioids. By injection it is  more potent than dihydrocodeine or codeine, but hallu-  cinations and thought disturbances may occur. It is not  recommended and, in particular, should be avoided  after myocardial infarction as it may increase pulm-  onary and aortic blood pressure as well as cardiac work.  Pethidine produces prompt but short-lasting analgesia;  it is less constipating than morphine, but even in high  doses is a less potent analgesic. It is not suitable for  severe continuing pain. It is used for analgesia in labour;  however, other opioids, such as morphine or diamor-  phine, are often preferred for obstetric pain.   Tramadol produces analgesia by two mechanisms: an  opioid effect and an enhancement of serotonergic and  adrenergic pathways. It has fewer of the typical opioid  side-effects (notably, less respiratory depression, less  constipation and less addiction potential); psychiatric  reactions have been reported.   Weak opioids Codeine is used for the relief of mild to  moderate pain but is too constipating for long-term use.  Dihydrocodeine has an analgesic efficacy similar to  that of codeine. The dose of dihydrocodeine by mouth  is usually 30 mg every 4 hours; doubling the dose to  60 mg may provide some additional pain relief but this  may be at the cost of more nausea and vomiting. A 40-  mg tablet is also available.   Meptazinol is claimed to have a low incidence of resp-  iratory depression. It has a reported length of action of 2  to 7 hours with onset within 15 minutes.   Dose The dose of opioids in the BNF may need to be  adjusted individually according to the degree of  analgesia and side-effects; patients’ response to opioids  varies widely.   Postoperative analgesia A combination of opioid  and non-opioid analgesics (section 4.7.1 and section    15.1.4.2) is used to treat postoperative pain. The use  of intra-operative opioids affects the prescribing of post-  operative analgesics. A postoperative opioid analgesic  should be given with care since it may potentiate any  residual respiratory depression (for the treatment of  opioid-induced respiratory depression, see section  15.1.7).   Morphine is used most widely. Tramadol is not as  effective in severe pain as other opioid analgesics.  Buprenorphine may antagonise the analgesic effect of  previously administered opioids and is generally not  recommended. Pethidine is generally not recom-  mended for postoperative pain because it is metabolised  to norpethidine which may accumulate, particularly in  renal impairment; norpethidine stimulates the central  nervous system and may cause convulsions.   Opioids are also given epidurally [unlicensed route] in  the postoperative period but are associated with side-  effects such as pruritus, urinary retention, nausea and  vomiting; respiratory depression can be delayed, parti-  cularly with morphine.   For details of patient-controlled analgesia (PCA) to  relieve postoperative pain, consult hospital protocols.  Formulations specifically designed for PCA are available  (Pharma-Ject® Morphine Sulphate ).    Dental and orofacial pain Opioid analgesics are  relatively ineffective in dental pain. Like other opioids,  dihydrocodeine often causes nausea and vomiting  which limits its value in dental pain; if taken for more  than a few doses it is also liable to cause constipation.  Dihydrocodeine is not very effective in postoperative  dental pain.   For the management of dental and orofacial pain, see  p. 257.   Although caution is necessary, patients who are depen-  dent on opioids or have a history of drug dependence  may be treated with opioid analgesics when there is a  clinical need. Treatment with opioid analgesics in this  patient group should normally be carried out with the  advice of specialists. However, doctors do not require a  special license to prescribe opioid analgesics to patients  with opioid dependence for relief of pain due to organic  disease or injury.   Cautions see notes above; also impaired conscious-  ness; effects only partially reversed by naloxone  Fever or external heat Monitor patients using patches for  increased side-effects if fever present (increased absorption  possible); avoid exposing application site to external heat  (may also increase absorption)   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above and section 4.10.3  Breast-feeding avoid unless essential — may inhibit  lactation; see also section 4.10.3  Side-effects see notes above; can induce mild with-  drawal symptoms in patients dependent on opioids;  also diarrhoea, abdominal pain, anorexia, dyspepsia;  vasodilatation; dyspnoea; paraesthesia, asthenia, fati-  gue, agitation, anxiety; less commonly flatulence,  taste disturbance, angina, hypertension, syncope,    hypoxia, wheezing, cough, restlessness, depersonali-  sation, dysarthria, impaired memory, hypoaesthesia,  tremor, influenza-like symptoms, pyrexia, rhinitis,  rigors, muscle cramp, myalgia, tinnitus, dry eye, and  dry skin; rarely paralytic ileus, dysphagia, impaired  concentration, and psychosis; very rarely retching,  hyperventilation, hiccups, and muscle fasciculation   • Moderate to severe pain, by sublingual administra-  tion, 200-400 micrograms every 6-8 hours; CHILD  over 6 years, 16-25 kg, 100 micrograms every 6-8  hours; 25-37.5 kg, 100-200 micrograms every 6-8  hours; 37.5-50 kg, 200-300 micrograms every 6-8  hours   By intramuscular or slow intravenous injection, 300-  600 micrograms every 6-8 hours; CHILD over 6  months 3-6 micrograms/kg every 6-8 hours (max.   Temgesic® (Reckitt Benckiser) £iLl  Tablets (sublingual), buprenorphine (as hydro-  chloride), 200 micrograms, net price 50-tab pack =  £5.13; 400 micrograms, 50-tab pack = £10.26. Label: 2,  26   Patches, self-adhesive, beige, buprenorphine, ‘5’  patch (releasing 5 micrograms/hour for 7 days), net  price 4 = £17.60; ‘10’ patch (releasing 10 micrograms/  hour for 7 days), 4 = £31.38; ‘20’ patch (releasing  20 micrograms/hour for 7 days), 4 = £57.16. Label: 2  Dose moderate, non-malignant pain unresponsive to non-opioid  analgesics, ADULT over 18 years, initially one ‘5 micrograms/hour’  patch; apply to dry, non-irritated, non-hairy skin on upper torso,  removing after 7 days and siting replacement patch on a different  area (avoid same area for at least 3 weeks)   Dose adjustment When starting, analgesic effect should not be  evaluated until the system has been worn for 72 hours (to allow  for gradual increase in plasma-buprenorphine concentration) — if  necessary, dose should be adjusted at 3-day intervals using a  patch of the next strength or 2 patches of the same strength  (applied at same time to avoid confusion). Max. 2 patches can be  used at any one time   Long duration of action In view of the long duration of action,  other opioids should not be administered within 24 hours of patch  removal   Patches, self-adhesive, skin-coloured, buprenorphine,  ‘35’ patch (releasing 35 micrograms/hour for 96  hours), net price 4 = £15.72; ‘52.5’ patch (releasing  52.5 micrograms/hour for 96 hours), 4 = £23.58; ‘70’  patch (releasing 70 micrograms /hour for 96 hours), 4  = £31.43. Label: 2   Dose moderate to severe chronic cancer pain and severe pain  unresponsive to non-opioid analgesics, ADULT over 18 years, apply  to dry, non-irritated, non-hairy skin on upper torso, removing after  no longer than 96 hours and siting replacement patch on a  different area (avoid same area for at least 6 days). Patients who  have not previously received strong opioid analgesic, initially, one  ‘35 micrograms /hour' patch replaced after no longer than 96  hours; patients who have received strong opioid analgesic, initial   Dose adjustment When starting, analgesic effect should not be  evaluated until the system has been worn for 24 hours (to allow  for gradual increase in plasma-buprenorphine concentration) — if  necessary, dose should be adjusted at intervals of no longer than  96 hours using a patch of the next strength or using 2 patches of  the same strength (applied at same time to avoid confusion). Max.  2 patches can be used at any one time. For breakthrough pain,  consider 200-400 micrograms buprenorphine sublingually.  Important: it may take approx. 30 hours for the plasma-bupren-  orphine concentration to decrease by 50% after patch is removed  Long duration of action In view of the long duration of action,  patients who have severe side-effects should be monitored for up  to 30 hours after removing patch   Indications mild to moderate pain; diarrhoea (section  1.4.2); cough suppression (section 3.9.1)   Variation in metabolism The capacity to metabolise cod-  eine can vary considerably and lead to either reduced  therapeutic effect or marked increase in side-effects   Breast-feeding amount usually too small to be  harmful; however mothers vary considerably in their  capacity to metabolise codeine — risk of morphine  overdose in infant   Side-effects see notes above; also abdominal pain,  anorexia, seizures, malaise, hypothermia, and muscle  fasciculation; pancreatitis also reported   • By mouth, 30-60 mg every 4 hours when necessary, to  a max. of 240 mg daily; CHILD 1-12 years, 3 mg/kg  daily in divided doses   • By intramuscular injection, 30-60 mg every 4 hours  when necessary   Tablets codeine phosphate 15 mg, net price 28-  tab pack = £1.14; 30 mg, 28-tab pack = £1.22; 60 mg,  28-tab pack = £1.84. Label: 2  Syrup codeine phosphate 25 mg/5 mL, net price  100 mL = 93p. Label: 2   Cautions see notes above; also severe diarrhoea; toxic  psychosis, CNS depression; severe cor pulmonale  Contra-indications see notes above; also delayed  gastric emptying; phaeochromocytoma  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding therapeutic doses unlikely to affect  infant; withdrawal symptoms in infants of dependent  mothers; breast-feeding not best method of treating  dependence in offspring    Side-effects see notes above; also anorexia, taste  disturbance; syncope; asthenia, raised intracranial  pressure; myocardial infarction also reported   • Acute pain, by subcutaneous or intramuscular injec-  tion, 5 mg repeated every 4 hours if necessary (up to  10 mg for heavier well-muscled patients); by slow  intravenous injection, quarter to half corresponding  intramuscular dose   • Myocardial infarction, by slow intravenous injection  (1-2 mg/minute), 5 mg followed by a further 2.5-5 mg  if necessary; elderly or frail patients, reduce dose by  half   • Acute pulmonary oedema, by slow intravenous  injection (1 mg/minute) 2.5-5 mg   • Chronic pain, by mouth or by subcutaneous or  intramuscular injection, 5-10 mg regularly every 4  hours; dose may be increased according to needs;  intramuscular dose should be approx, half corre-  sponding oral dose, and approx, one third corre-  sponding oral morphine dose — see also Prescribing in  Palliative Care, p. 20; by subcutaneous infusion  (using syringe driver), see Prescribing in Palliative  Care, p. 23   Diamorphine (Non-proprietary) (S*iL I  Tablets, diamorphine hydrochloride 10 mg, net price  100-tab pack = £16.42. Label: 2  Injection, powder for reconstitution, diamorphine  hydrochloride, net price 5-mg amp = £2.57, 10-mg  amp = £3.59, 30-mg amp = £3.82, 100-mg amp =  £9.34, 500-mg amp = £42.07   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   Side-effects see notes above; also paralytic ileus,  abdominal pain, and paraesthesia   • By mouth, 30 mg every 4-6 hours when necessary  (see also notes above); CHILD over 4 years 0.5-1 mg/  kg every 4-6 hours   • By deep subcutaneous or intramuscular injection, up  to 50 mg repeated every 4-6 hours if necessary; CHILD  over 4 years 0.5-1 mg/kg every 4-6 hours   Oral solution (^1, dihydrocodeine tartrate 10 mg/  5mL, net price 150 mL = £3.50. Label: 2  Injection fcpl, dihydrocodeine tartrate 50mg/mL, net  price 1-mL amp = £3.17   DF118 Forte® (Martindale) (Ml  Tablets, dihydrocodeine tartrate 40 mg, net price 100-  tab pack = £11.51. Label: 2   Dose ADULT and CHILD over 12 years, severe pain, 40-80 mg 3  times daily; max. 240 mg daily    4 Modified release  DHC Continus® (Napp) (Ml  Tablets, m/r, dihydrocodeine tartrate 60 mg, net price  56-tab pack = £5.18; 90 mg, 56-tab pack = £8.66;   Dose ADULT and CHILD over 12 years, chronic severe pain, 60-   Note Dihydrocodeine is an ingredient of some compound analge-  sic preparations, section 4.7. 1   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding no information available  Side-effects see notes above; also psychosis, rest-  lessness, raised intracranial pressure  Dose   Tablets, pink, scored, dipipanone hydrochloride  10 mg, cyclizine hydrochloride 30 mg, net price 50-tab  pack = £9.57. Label: 2   Dose acute pain, 1 tablet gradually increased to 3 tablets every 6  hours; CHILD not recommended   Caution Not recommended in palliative care, see Nausea and  Vomiting, p. 22   Cautions see notes above; also diabetes mellitus,  impaired consciousness, cerebral tumour; see also  Transdermal Fentanyl, p. 267  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding monitor infant for opioid-induced  side-effects   Side-effects see notes above; also abdominal pain,  anorexia, dyspepsia, dysphagia, mouth ulceration,  taste disturbance, stomatitis, dry mouth; vasodilata-  tion; apnoea; anxiety; myoclonus; less commonly  flatulence, diarrhoea, laryngospasm, dyspnoea,  hypoventilation, depersonalisation, dysarthria, amne-  sia, incoordination, paraesthesia, malaise, agitation,  tremor, thirst and muscle weakness; rarely hiccups  and arrhythmia; very rarely paralytic ileus, haemop-  tysis, psychosis, and seizures; shock, asystole, pyrexia,  ataxia, and muscle fasciculation also reported; with  nasal spray throat irritation, epistaxis, nasal ulcer,  rhinorrhoea  Dose   • Chronic intractable pain, by transdermal route, apply  to dry, non-irritated, non-irradiated, non-hairy skin on  torso or upper arm, removing after 72 hours and siting  replacement patch on a different area (avoid using the    same area for several days). ADULT over 16 years not  currently treated with a strong opioid analgesic (but  see Transdermal Fentanyl, p. 267), initial dose, one  ‘12’ or ‘25 micrograms/hour’ patch replaced after 72  hours; ADULT and CHILD over 2 years currently treated  with a strong opioid analgesic, initial dose based on  previous 24-hour opioid requirement (consult product  literature)   Dose adjustment When starting, evaluation of the analge-  sic effect should not be made before the system has been  worn for 24 hours (to allow for the gradual increase in  plasma-fentanyl concentration) — previous analgesic therapy  should be phased out gradually from time of first patch  application; if necessary dose should be adjusted at 48-72-  hour intervals in steps of 12-25 micrograms/hour. More than  one patch may be used at a time for doses greater than  100 micrograms /hour (but applied at the same time to avoid  confusion) — consider additional or alternative analgesic  therapy if dose required exceeds 300 micrograms/hour  (important: it may take up to 25 hours for the plasma-  fentanyl concentration to decrease by 50% — replacement  opioid therapy should be initiated at a low dose and  increased gradually).   Long duration of action In view of the long duration of  action, patients who have had severe side-effects should be  monitored for up to 24 hours after patch removal  • Breakthrough pain, see under oral preparations  Conversion (from oral morphine to transdermal fentanyl) see  Prescribing in Palliative Care, p. 2 1   B Tablets (sublingual), fentanyl (as citrate) 100 micr-  ograms, net price 10-tab pack = £49.99, 30-tab pack =  £149.70; 200 micrograms, 10-tab pack = £49.99, 30-  tab pack = £149.70; 300 micrograms, 10-tab pack =  £49.99, 30-tab pack = £149.70; 400 micrograms, 10-  tab pack = £49.99, 30-tab pack = £149.70; 600 micr-  ograms, 30-tab pack = £149.70; 800 micrograms, 30-  tab pack = £149.70. Label: 2, 26  Dose breakthrough pain in patients receiving opioid therapy for  chronic cancer pain, ADULT over 18 years, initially 100 micrograms  repeated if necessary after 15-30 minutes; adjust dose according  to response — consult product literature; no more than 2 dose  units, 15-30 minutes apart, for each pain episode; max.   Note If more than 4 episodes of breakthrough pain each day,   The Scottish Medicines Consortium (p. 4) has advised (January  2009) that Abstral ® sublingual tablets should be restricted for the  management of breakthrough pain in adult patients using opioid  therapy for chronic cancer pain, when other short-acting opioids  are unsuitable   Effentora® (Cephalon) ▼ GU  Tablets (buccal), fentanyl (as citrate) 100 micr-  ograms, net price 4-tab pack = £19.96, 28-tab pack =  £139.72; 200 micrograms, 4-tab pack = £19.96, 28-tab  pack = £139.72; 400 micrograms, 4-tab pack = £19.96,  28-tab pack = £139.72; 600 micrograms, 4-tab pack =  £19.96; 800 micrograms, 4-tab pack = £19.96, 28-tab  pack = £139.72. Label: 2, counselling, administration   Electrolytes Na + 0.35 mmol/ 100 microgram tablet, Na + 0.70 mmol/  tablet (all other strengths)   Dose breakthrough pain in patients receiving opioid therapy for  chronic cancer pain, ADULT over 18 years, initially 100 micrograms  repeated if necessary 30 minutes after first dose (no more than 2  dose units for each pain episode); adjust dose according to  response — consult product literature; max. 800 micrograms per  episode of breakthrough pain; leave at least 4 hours between  treatment of episodes of breakthrough pain during titration  Counselling Place tablet between cheek and gum and leave to  dissolve; if more than 1 tablet required, place second tablet on the  other side of the mouth; tablet may alternatively be placed under  the tongue (sublingually)   The Scottish Medicines Consortium (p. 4) has advised that  Effentora ® buccal tablets should be restricted for the manage-    ment of breakthrough pain in adult patients using opioid therapy  for chronic cancer pain, when other short-acting opioids are  unsuitable   Lozenge (buccal), with oromucosal applicator,  fentanyl (as citrate) 200 micrograms, net price 3 =  £17.52, 30 = £175.16; 400 micrograms, 3 = £17.52, 30  = £175.16; 600 micrograms, 3 =£17.52, 30 =£175.16;  800 micrograms, 3 =£17.52, 30 =£175.16; 1.2 mg, 3 =  £17.52, 30 = £175.16; 1.6 mg, 3 = £17.52, 30 =  £175.16. Label: 2   Dose breakthrough pain in patients receiving opioid therapy for  chronic cancer pain, initially 200 micrograms (over 15 minutes)  repeated if necessary 15 minutes after first dose (no more than 2  dose units for each pain episode); adjust dose according to  response; max. 4 dose units daily   Note If more than 4 episodes of breakthrough pain each day,  adjust background analgesia    A Nasal spray  Instanyl® (Nycomed) T CM  Nasal spray, fentanyl (as citrate) 50 micrograms/  metered spray, net price 10-dose pack = £59.50, 20-  dose pack = £1 19.00; 100 micrograms/metered spray,  10-dose pack = £59.50, 20-dose pack = £119.00;   200 micrograms/metered spray, 10-dose pack =  £59.50, 20-dose pack = £119.00. Label: 2, counselling,  administration   Dose breakthrough pain in patients receiving opioid therapy for  chronic cancer pain, ADULT over 18 years, initially 50 micrograms  into one nostril, repeated once if necessary after 10 minutes;  adjust dose according to response; max. 2 sprays for each pain  episode and minimum 4 hours between treatment of each pain  episode   Note If more than 4 breakthrough pain episodes daily, adjust  background analgesia   Counselling Patient should sit or stand during administration.  Avoid concomitant use of other nasal preparations  The Scottish Medicines Consortium (p. 4) has advised that  Instanyl ® nasal spray should be restricted for use within NHS  Scotland for the management of breakthrough pain in adult  patients using opioid therapy for chronic cancer pain, when other  short-acting opioids are unsuitable    PecFent® (Archimedes) T CM . I  Nasal spray, fentanyl (as citrate) 100 micrograms/  metered spray, net price 8-dose pack = £30.40, 32-  dose pack = £121.60; 400 micrograms /metered spray,  8-dose pack = £30.40, 32-dose pack = £121.60.   Label: 2, counselling, administration  Dose breakthrough pain in patients receiving opioid therapy for  chronic cancer pain, ADULT over 18 years, initially 100 micrograms  into one nostril; adjust dose according to response; max. 2 sprays  for each pain episode and minimum 4 hours between treatment of  each pain episode   Note If more than 4 breakthrough pain episodes daily, adjust  background analgesia   Prescriptions Prescriptions for fentanyl patches can be  written to show the strength in terms of the release rate  and it is acceptable to write ‘Fentanyl 25 patches to pre-  scribe patches that release fentanyl 25 micrograms per hour.  The dosage should be expressed in terms of the interval  between applying a patch and replacing it with a new one,  e.g. 'one patch to be applied every 72 hours’. The total  quantity of patches to be supplied should be written in words  and figures.   Fever or external heat Monitor patients using patches  for increased side-effects if fever present (increased  absorption possible); avoid exposing application site to  external heat, for example a hot bath or sauna (may also  increase absorption)   Respiratory depression Risk of fatal respiratory  depression, particularly in patients not previously treated  with a strong opioid analgesic; manufacturer recom-  mends use only in opioid tolerant patients  Counselling Patients and carers should be informed  about safe use, including correct administration and  disposal, strict adherence to dosage instructions, and the  symptoms and signs of opioid overdosage. Patches  should be removed immediately in case of breathing  difficulties, marked drowsiness, confusion, dizziness, or  impaired speech, and patients and carers should seek  prompt medical attention.    Fentanyl (Non-proprietary) (ZEI  Patches, self-adhesive, fentanyl, ‘12’ patch (releasing  approx. 12 micrograms /hour for 72 hours), net price 5  = £17.76; ‘25’ patch (releasing approx. 25 micr-  ograms/hour for 72 hours), 5 = £25.38; ‘50’ patch  (releasing approx. 50 micrograms/hour for 72 hours),  5 = £47.40; ‘75’ patch (releasing approx. 75 micr-  ograms/hour for 72 hours), 5 = £66.08; ‘100’ patch  (releasing approx. 100 micrograms/hour for 72  hours), 5 = £81.45. Label: 2, counselling, administra-  tion   Brands include Fentalis ®, Matrifen ®, Mezolar ®, Osmanil ®,  Tilofyl ®, Victanyl ®   Patches, self-adhesive, transparent, fentanyl, ‘12’  patch (releasing approx. 12 micrograms /hour for 72  hours), net price 5 = £17.76; ‘25’ patch (releasing  approx. 25 micrograms /hour for 72 hours), 5 =  £25.38; ‘50’ patch (releasing approx. 50 micrograms/  hour for 72 hours), 5 = £47.40; ‘75’ patch (releasing  approx. 75 micrograms /hour for 72 hours), 5 =  £66.08; ‘100’ patch (releasing approx. 100 micr-  ograms/hour for 72 hours), 5 = £81.45. Label: 2,  counselling, administration   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding avoid — no information available  Side-effects see notes above; also paralytic ileus,  peripheral oedema, seizures, asthenia, dyskinesia,  agitation, and tremor  Dose   Capsules, hydromorphone hydrochloride 1.3 mg  (orange/clear), net price 56-cap pack = £8.82; 2.6 mg  (red/clear), 56-cap pack = £17.64. Label: 2, counsel-  ling, see below   Dose 1.3 mg every 4 hours, increased if necessary according to  severity of pain; CHILD under 12 years not recommended  Counselling Swallow whole or open capsule and sprinkle con-  tents on soft food   Palladone® SR (Napp) dEI  Capsules, m/r, hydromorphone hydrochloride 2 mg  (yellow/ clear), net price 56-cap pack = £20.98; 4 mg  (pale blue/clear), 56-cap pack = £28.75; 8 mg (pink/  clear), 56-cap pack = £56.08; 16 mg (brown/clear),  56-cap pack = £106.53; 24 mg (dark blue/clear), 56-  cap pack = £159.82. Label: 2, counselling, see below  Dose 4 mg every 12 hours, increased if necessary according to  severity of pain; CHILD under 12 years not recommended  Counselling Swallow whole or open capsule and sprinkle con-  tents on soft food    Indications moderate to severe pain, including post-  operative and obstetric pain and renal colic; peri-  operative analgesia, section 15.1.4.3   Side-effects see notes above; can induce withdrawal  symptoms in patients dependent on opioids; also  diarrhoea, abdominal pain, dyspepsia, and hypo-  thermia   • By mouth, 200 mg every 3-6 hours as required; CHILD  not recommended   • By intramuscular injection, 75-100 mg every 2-4  hours if necessary; obstetric analgesia, 100-150 mg  according to patient’s weight (2 mg/kg); CHILD not  recommended   • By slow intravenous injection, 50-100 mg every 2-4  hours if necessary; CHILD not recommended   Tablets, orange, f/c, meptazinol 200 mg, net price  112-tab pack = £22.11. Label: 2  Injection, meptazinol 100 mg (as hydrochloride) /mL,  net price 1-mL amp = £1.92   Indications severe pain, see notes above; cough in  terminal disease (section 3.9.1); adjunct in treatment  of opioid dependence (section 4.10.3)   Cautions see notes above; also history of cardiac  conduction abnormalities, family history of sudden  death (ECG monitoring recommended; see also QT  Interval Prolongation, below)   QT interval prolongation Patients with the following risk  factors for QT interval prolongation should be carefully  monitored while taking methadone: heart or liver disease,  electrolyte abnormalities, or concomitant treatment with  drugs that can prolong QT interval; patients requiring more  than 100 mg daily should also be monitored  Contra-indications see notes above; also phaeo-  chromocytoma   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding withdrawal symptoms in infant;  breast-feeding permissible during maintenance but  dose should be as low as possible and infant mon-  itored to avoid sedation    Side-effects see notes above; also QT interval pro-  longation, torsade de pointes, hypothermia, restless-  ness, raised intracranial pressure, dysmenorrhoea, dry  eyes, and hyperprolactinaemia   • By mouth or by subcutaneous or intramuscular  injection, 5-10 mg every 6-8 hours, adjusted accord-  ing to response; on prolonged use not to be given  more frequently than every 12 hours; CHILD not  recommended   Methadone (Non-proprietary) dLl  Tablets, methadone hydrochloride 5 mg, net price 50  = £2.84. Label: 2  Brands include Physeptone ®   Injection ▼, methadone hydrochloride, lOmg/mL,  net price 1-mL amp = £1.00, 2-mL amp = £1.67, 3.5-  mL amp = £2.11, 5-mL amp = £2.28  Brands include Physeptone ® , Synastone ®   Indications see notes above and under Dose; acute  diarrhoea (section 1.4.2); cough in terminal care  (section 3.9.1)   Cautions see notes above; also pancreatitis, cardiac  arrhythmias, severe cor pulmonale   Contra-indications see notes above; also delayed  gastric emptying, acute abdomen; heart failure sec-  ondary to chronic lung disease; phaeochromocytoma   Breast-feeding therapeutic doses unlikely to affect  infant; withdrawal symptoms in infants of dependent  mothers; breast-feeding not best method of treating  dependence in offspring   Side-effects see notes above; also paralytic ileus,  abdominal pain, anorexia, dyspepsia, exacerbation of  pancreatitis, taste disturbance; hypertension, hypo-  thermia, syncope; bronchospasm, inhibition of cough  reflex; restlessness, seizures, paraesthesia, asthenia,  malaise, disorientation, excitation, agitation, delirium,  raised intracranial pressure; amenorrhoea; myoclo-  nus, muscle fasciculation, rhabdomyolysis, and nys-  tagmus   The patient should be closely monitored for pain relief  as well as for side-effects especially respiratory  depression. See also notes above.   • Acute pain, by subcutaneous injection (not suitable  for oedematous patients) or by intramuscular injec-  tion, initially 10 mg (ELDERLY or frail 5 mg) every 4  hours (or more frequently during titration), adjusted  according to response; NEONATE initially 100 micr-  ograms/kg every 6 hours, adjusted according to  response; CHILD 1-6 months initially 100-200 micr-  ograms/kg every 6 hours, adjusted according to  response; CHILD 6 months-2 years initially 100—   200 micrograms/kg every 4 hours, adjusted according  to response; CHILD 2-12 years initially 200 micr-  ograms/kg every 4 hours, adjusted according to    response; CHILD 12-18 years initially 2.5-10 mg every  4 hours, adjusted according to response  By slow intravenous injection, initially 5 mg (reduce  dose in ELDERLY or frail) every 4 hours (or more  frequently during titration), adjusted according to  response; NEONATE initially 50 micrograms/kg every 6  hours, adjusted according to response; CHILD 1-6  months initially 100 micrograms/kg every 6 hours,  adjusted according to response; CHILD 6 months-12  years initially 100 micrograms/kg every 4 hours,  adjusted according to response   • Premedication, by subcutaneous or intramuscular  injection, up to 10 mg 60-90 minutes before opera-  tion; CHILD, by intramuscular injection, 150 micr-  ograms/kg   • Myocardial infarction, by slow intravenous injection  (1-2 mg/minute), 5-10 mg followed by a further 5-  10 mg if necessary; ELDERLY or frail patients, reduce  dose by half   • Acute pulmonary oedema, by slow intravenous  injection (2 mg/minute) 5-10 mg; ELDERLY or frail  patients, reduce dose by half   • Chronic pain, by mouth or by subcutaneous injection  (not suitable for oedematous patients) or by intra-  muscular injection, initially 5-10 mg every 4 hours,  adjusted according to response; see also Prescribing  in Palliative Care, p. 20   By rectum, initially 15-30 mg every 4 hours, adjusted  according to response   Note For advice on transfer from oral solutions of morphine to   Oral solutions of morphine can be prescribed by writing the  formula:   Note The proportion of morphine hydrochloride may be altered  when specified by the prescriber; if above 13 mg per 5 mL the  solution becomes fdT]. For sample prescription see Controlled  Drugs and Drug Dependence, p. 8. It is usual to adjust the  strength so that the dose volume is 5 or 10 mL.   Oramorph® oral solution morphine sulphate  10 mg/5 mL, net price 100-mL pack = £1.78; 300-mL  pack = £4.95; 500-mL pack = £7.47. Label: 2  Oramorph® concentrated oral solution fcp~l, sugar-  free, morphine sulphate 100 mg/5 mL, net price 30-  mL pack = £4.98; 120-mL pack = £18.59 (both with  calibrated dropper). Label: 2   Tablets, f/c, scored, morphine sulphate 10 mg (blue),  net price 56-tab pack = £5.28; 20 mg (pink), 56-tab  pack = £10.55; 50 mg (pale green), 56-tab pack =  £28.02. Label: 2   Morphgesic® SR (Amdipharm) dD  Tablets, m/r, f/c, morphine sulphate 10 mg (buff), net  price 60-tab pack = £3.85; 30 mg (violet), 60-tab pack    = £9.24; 60 mg (orange), 60-tab pack = £18.04; 100 mg  (grey), 60-tab pack = £28.54. Label: 2, 25  Dose every 12 hours, dose adjusted according to daily morphine  requirements; for further advice on determining dose, see Pre-  scribing in Palliative Care, p. 20; dosage requirements should be  reviewed if the brand is altered   Morphine Sulphate (Non-proprietary) C3EI  Injection, morphine sulphate 10, 15, 20, and 30 mg/  mL, net price 1- and 2-mL amp (all) = 72p-£1.40  Intravenous infusion, morphine sulphate lmg/mL,  net price 50-mL vial = £5.00; 2 mg/mL, 50-mL vial =  £5.89    MST Continus® (Napp) C1D  Tablets, m/r, f/c, morphine sulphate 5 mg (white), net  price 60-tab pack = £3.29; 10 mg (brown), 60-tab pack  = £5.16; 15 mg (green), 60-tab pack = £9.61; 30 mg  (purple), 60-tab pack = £12.40; 60 mg (orange), 60-tab  pack = £24.20; 100 mg (grey), 60-tab pack = £38.30;  200 mg (green), 60-tab pack = £76.62. Label: 2, 25  Suspension (= sachet of granules to mix with water),  m/r, pink, morphine sulphate 20 mg/sachet, net price  30-sachet pack = £24.58; 30 mg/sachet, 30-sachet  pack = £25.54; 60 mg/sachet, 30-sachet pack =  £51.09; 100 mg/sachet, 30-sachet pack = £85.15;   200 mg/ sachet pack, 30-sachet pack = £170.30.  Label: 2, 13   Dose every 12 hours, dose adjusted according to daily morphine  requirements; for further advice on determining dose, see Pre-  scribing in Palliative Care, p. 20; dosage requirements should be  reviewed if the brand is altered   Zomorph® (Archimedes) d Ll  Capsules, m/r, morphine sulphate 10 mg (yellow/  clear enclosing pale yellow pellets), net price 60-cap  pack = £3.47; 30 mg (pink/ clear enclosing pale yellow  pellets), 60-cap pack = £8.30; 60 mg (orange/clear  enclosing pale yellow pellets), 60-cap pack = £16.20;  100 mg (white/clear enclosing pale yellow pellets),  60-cap pack = £25.65; 200 mg (clear enclosing pale  yellow pellets), 60-cap pack = £51.30. Label: 2,  counselling, see below   Dose every 12 hours, dose adjusted according to daily morphine  requirements; for further advice on determining doses, see Pre-  scribing in Palliative Care, p. 20; dosage requirements should be  reviewed if the brand is altered   Capsules, m/r, morphine sulphate 30 mg (light blue),  net price 28-cap pack = £10.91; 60 mg (brown), 28-cap  pack = £14.95; 90 mg (pink), 28-cap pack = £22.04;  120 mg (green), 28-cap pack = £29.15; 150 mg (blue),  28-cap pack = £36.43; 200 mg (red-brown), 28-cap  pack = £46.15. Label: 2, counselling, see below  Dose every 24 hours, dose adjusted according to daily morphine  requirements; for further advice on determining dose, see Pre-  scribing in Palliative Care, p. 20; dosage requirements should be  reviewed if the brand is altered    ^Suppositories  Morphine (Non-proprietary) d Ll  Suppositories, morphine hydrochloride or sulphate  10 mg, net price 12 = £11.21; 15 mg, 12 = £8.85;   20 mg, 12 = £33.22; 30 mg, 12 = £13.47. Label: 2  Note Both the strength of the suppositories and the morphine salt  contained in them must be specified by the prescriber    Minijet® Morphine Sulphate (UCB Pharma) dD  Injection, morphine sulphate 1 mg/mL, net price 10-  mL disposable syringe = £15.00   Caution In myocardial infarction cyclizine may aggravate  severe heart failure and counteract the haemodynamic  benefits of opioids, section 4.6. Not recommended in pal-  liative care, see Nausea and Vomiting, p. 22    Cyclimorph® (Amdipharm) GEI  Cyclimorph-10® Injection, morphine tartrate 10 mg,  cyclizine tartrate 50 mg/mL, net price 1-mL amp =  £1.75   Dose ADULT and CHILD over 12 years, moderate to severe pain  (short-term use only) by subcutaneous, intramuscular, or intra-  venous injection, 1 mL, repeated not more often than every 4  hours; max. 3 doses in any 24-hour period    Cyclimorph-15® Injection, morphine tartrate 15 mg,  cyclizine tartrate 50 mg/mL, net price 1-mL amp =  £1.82   Dose ADULT and CHILD over 12 years, moderate to severe pain  (short-term use only) by subcutaneous, intramuscular, or intra-  venous injection, 1 mL, repeated not more often than every 4  hours; max. 3 doses in any 24-hour period   Indications moderate to severe pain in patients with  cancer; postoperative pain; severe pain  Cautions see notes above; also toxic psychosis; pan-  creatitis   Contra-indications see notes above; also acute  abdomen; delayed gastric emptying; chronic consti-  pation; cor pulmonale; acute porphyria (section 9.8.2)  Hepatic impairment avoid in moderate to severe  impairment; see also notes above  Renal impairment avoid if eGFR less than 10 mL/  minute/ 1.73m 2 ; see also notes above  Pregnancy see notes above  Breast-feeding present in milk — avoid  Side-effects see notes above; also diarrhoea, abdo-  minal pain, anorexia, dyspepsia; bronchospasm, dys-  pnoea, impaired cough reflex; asthenia, anxiety; chills;  muscle fasciculation; less commonly paralytic ileus,  cholestasis, gastritis, flatulence, dysphagia, taste dis-  turbance, belching, hiccups, vasodilatation, supra-  ventricular tachycardia, syncope, amnesia,  hypoaesthesia, restlessness, seizures, pyrexia, amen-  orrhoea, hypotonia, paraesthesia, disorientation,  malaise, agitation, speech disorder, tremor, thirst, and  dry skin  Dose   • By mouth, initially 5 mg every 4-6 hours, increased if  necessary according to severity of pain, usual max.  400 mg daily, but some patients may require higher  doses; CHILD under 18 years, see BNF for Children   • By slow intravenous injection, 1-10 mg every 4 hours  when necessary; CHILD under 18 years, not recom-  mended    • By intravenous infusion, initially 2 mg/hour, adjusted  according to response; CHILD under 18 years not  recommended   • By subcutaneous infusion, initially 7.5 mg/24 hours  adjusted according to response; CHILD under 18 years,  not recommended   Note 2 mg oral oxycodone is approximately equivalent to 1 mg   Injection, oxycodone hydrochloride lOmg/mL, net  price 1-mL amp = £1.60, 2-mL amp = £3.20   Capsules, oxycodone hydrochloride 5 mg (orange/  beige), net price 56-cap pack = £1 1.36; 10 mg (white/  beige), 56-cap pack = £22.73; 20 mg (pink/beige), 56-  cap pack = £45.47. Label: 2  Liquid (=oral solution), sugar-free, oxycodone  hydrochloride 5mg/5mL, net price 250 mL = £9.66.  Label: 2   Injection, oxycodone hydrochloride lOmg/mL, net  price 1-mL amp = £1.60, 2-mL amp = £3.20; 50 mg/  mL, 1-mL amp = £14.02   Note The Scottish Medicines Consortium (p. 4) has advised  (October 2004 and November 2010) that OxyNorm ®  injection is restricted for use within NHS Scotland for  patients with cancer who have difficulty in tolerating  morphine or diamorphine   Tablets, f/c, m/r, oxycodone hydrochloride 5 mg  (blue), net price 28-tab pack = £12.46; 10 mg (white),  56-tab pack = £24.91; 20 mg (pink), 56-tab pack =  £49.82; 40 mg (yellow), 56-tab pack = £99.66; 80 mg  (green), 56-tab pack = £199.33. Label: 2, 25  Dose initially, 10 mg every 12 hours, increased if necessary  according to severity of pain, usual max. 200 mg every 12 hours,  but some patients may require higher doses; CHILD under 18 years  see BNF for Children    ^With naloxone  Targinact® (Napp) ▼ LIO  Tablets 5 mg/2.5 mg, f/c, m/r, oxycodone hydro-  chloride 5 mg, naloxone hydrochloride 2.5 mg (blue),  net price 28-tab pack = £17.56. Label: 2, 25  Tablets 10 mg/5 mg, f/c, m/r, oxycodone hydro-  chloride 10 mg, naloxone hydrochloride 5 mg (white),  net price 56-tab pack = £35.11. Label: 2, 25  Tablets 20 mg/10 mg, f/c, m/r, oxycodone hydro-  chloride 20 mg, naloxone hydrochloride 10 mg (pink),  net price 56-tab pack = £70.22. Label: 2, 25  Tablets 40 mg/20 mg, f/c, m/r, oxycodone hydro-  chloride 40 mg, naloxone hydrochloride 20 mg (yel-  low), net price 56-tab pack = £140.44. Label: 2, 25  Dose severe pain responsive only to opioid analgesics, ADULT  over 18 years not currently treated with opioid analgesics, initially  10 mg/ 5 mg every 12 hours, increased according to response;  patients already receiving opioid analgesics can start with a higher    dose of Targinact ®; max. Targinact ® 40 mg/20 mg every 12  hours   Note Supplemental modified-release oxycodone (without nal-  oxone) can be prescribed for patients who need higher doses —  consult product literature   A mixture of 253 parts of morphine hydrochloride, 23 parts of  papaverine hydrochloride and 20 parts of codeine hydro-  chloride   To avoid confusion, the figures of 7.7 mg/ml or 15.4 mg/ml  should be used for prescribing purposes   Contra-indications see notes above; heart failure  secondary to chronic lung disease; phaeochromo-  cytoma   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding therapeutic doses unlikely to affect  infant; withdrawal symptoms in infants of dependent  mothers; breast-feeding not best method of treating  dependence in offspring   • By subcutaneous, intramuscular, or intravenous  injection, 7.7-15.4 mg repeated every 4 hours if  necessary (ELDERLY initially 7.7 mg); CHILD up to 1  month 115 micrograms /kg, 1-12 months 154 micr-  ograms/kg, 1-5 years 1.93-3.85 mg, 6-12 years, 3.85-  7.7 mg   Intravenous dose In general the intravenous dose should  be 25-50% of the corresponding subcutaneous or intra-  muscular dose   Injection, papaveretum 15.4mg/mL (providing the  equivalent of 10 mg of anhydrous morphine/mL), net  price 1-mL amp = £1.64   Note The name Omnopon ® was formerly used for papaveretum  preparations   Injection, papaveretum 15.4 mg (providing the  equivalent of 10 mg of anhydrous morphine), hyoscine  hydrobromide 400 micrograms/mL, net price 1-mL  amp = £3.57   Cautions see notes above; also pancreatitis, arterial or  pulmonary hypertension, cardiac arrhythmias, myo-  cardial infarction, phaeochromocytoma; effects only  partially reversed by naloxone   Contra-indications see notes above; patients depen-  dent on opioids (can precipitate withdrawal); heart   Side-effects see notes above; also abdominal pain,  hypertension, syncope, seizures, paraesthesia, tremor,  raised intracranial pressure, disorientation, hypo-  thermia, chills, blood disorders, myalgia, and toxic  epidermal necrolysis   • By mouth, pentazocine hydrochloride 50 mg every 3-  4 hours preferably after food (range 25-100 mg); max.  600 mg daily; CHILD 6-12 years 25 mg   • By subcutaneous, intramuscular, or intravenous  injection, moderate pain, pentazocine 30 mg, severe  pain 45-60 mg every 3-4 hours when necessary; max.  360 mg daily; CHILD over 1 year, by subcutaneous or  intramuscular injection, up to 1 mg/kg, by intra-  venous injection up to 500 micrograms/kg   Injection, pentazocine 30 mg (as lactate)/mL, net  price 1-mL amp = £1.67; 2-mL amp = £3.21  Brands include Fortral ® CM1   Indications moderate to severe pain, obstetric  analgesia; peri-operative analgesia  Cautions see notes above; not suitable for severe  continuing pain; accumulation of metabolites may  result in neurotoxicity; cardiac arrhythmias, severe  cor pulmonale   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding present in milk but not known to be  harmful   Side-effects see notes above; also restlessness, tre-  mor, and hypothermia; convulsions reported in   • Acute pain, by mouth, 50-150 mg every 4 hours;  CHILD 0.5-2 mg/kg   By subcutaneous or intramuscular injection, 25-  100 mg (ELDERLY or debilitated, initially 25 mg),  repeated after 4 hours; CHILD, by intramuscular injec-  tion, 0.5-2 mg/kg   By slow intravenous injection, 25-50 mg (ELDERLY or  debilitated, initially 25 mg), repeated after 4 hours   • Obstetric analgesia, by subcutaneous or intramuscu-  lar injection, 50-100 mg, repeated 1-3 hours later if  necessary; max. 400 mg in 24 hours   • Premedication, by intramuscular injection, 25-  100 mg 1 hour before operation (ELDERLY or debili-  tated, 25 mg); CHILD 0.5-2 mg/kg    • Postoperative pain, by subcutaneous or intramuscu-  lar injection, 25-100 mg (ELDERLY or debilitated, initi-  ally 25 mg), every 2-3 hours if necessary; CHILD, by  intramuscular injection, 0.5-2 mg/kg  Note In the postoperative period, the patient should be  closely monitored for pain relief as well as for side-effects  especially respiratory depression   Pethidine (Non-proprietary) (3EI  Tablets, pethidine hydrochloride 50 mg, net price 50  = £6.68. Label: 2   Injection, pethidine hydrochloride 50mg/mL, net  price 1-mL amp = 48p, 2-mL amp = 5 lp; lOmg/mL,  5-mL amp = £3.17, 10-mL amp = £2.18   Injection, pethidine hydrochloride 50 mg, prometh-  azine hydrochloride 25 mg/mL, net price 2-mL amp =  £1.44   Dose by intramuscular injection, premedication, 2mL 60-90  minutes before operation; CHILD 8-12 years 0.75 mL, 13-16 years  1 mL   Obstetric analgesia, 1-2 mL every 4 hours if necessary  Severe pain, 1-2 mL every 4-6 hours if necessary  Note Although usually given intramuscularly, may be given intra-  venously after dilution to at least lOmL with water for injections   Indications moderate to severe pain  Cautions see notes above; impaired consciousness;  excessive bronchial secretions; not suitable as a sub-  stitute in opioid-dependent patients  General anaesthesia Not recommended for analgesia dur-  ing potentially light planes of general anaesthesia (possibly  increased intra-operative recall reported)  Contra-indications see notes above; uncontrolled  epilepsy   Side-effects see notes above; also diarrhoea; fatigue;  less commonly retching, gastritis, and flatulence;  rarely anorexia, syncope, hypertension, broncho-  spasm, dyspnoea, wheezing, seizures, paraesthesia,  and muscle weakness; blood disorders also reported  Dose    • ADULT and CHILD over 12 years, by mouth, 50-100 mg  not more often than every 4 hours; total of more than  400 mg daily not usually required   • ADULT and CHILD over 12 years, by intramuscular  injection or by intravenous injection (over 2-3 min-  utes) or by intravenous infusion, 50-100 mg every 4-  6 hours   Postoperative pain, 100 mg initially then 50 mg every  10-20 minutes if necessary during first hour to total  max. 250 mg (including initial dose) in first hour, then  50-100 mg every 4-6 hours; max. 600 mg daily    Tramadol Hydrochloride (Non-proprietary) (Ml  Capsules, tramadol hydrochloride 50 mg, net price  30-cap pack = £1.22, 100-cap pack = £2.07. Label: 2  Brands include Tramake ®   Capsules, tramadol hydrochloride 50 mg, net price  100-cap pack = £8.00. Label: 2  Orodispersible tablets {Zamadol Melt®), tramadol  hydrochloride 50 mg, net price 60-tab pack = £7.12.  Label: 2, counselling, administration   Capsules, green/yellow, tramadol hydrochloride  50 mg, net price 30-cap pack = £2.29, 100-cap pack =  £7.63. Label: 2   Soluble tablets, tramadol hydrochloride 50 mg, net  price 20-tab pack = £2.79, 100-tab pack = £13.33.  Label: 2, 13   Larapam® SR (Sandoz) (Ml  Tablets, m/r, tramadol hydrochloride 100 mg, net  price 60-tab pack = £17.55; 150 mg, 60-tab pack =  £27.35; 200 mg, 60-tab pack = £36.50. Label: 2, 25  Dose ADULT and CHILD over 12 years, initially 100 mg twice daily  increased if necessary; usual max. 200 mg twice daily    Mabron® (Morningside) (Ml  Tablets, m/r, tramadol hydrochloride 100 mg, net  price 60-tab pack = £18.26; 150 mg, 60-tab pack =  £27.39; 200 mg, 60-tab pack = £36.52. Label: 2, 25  Dose ADULT and CHILD over 12 years, 100 mg twice daily  increased if necessary; usual max. 200 mg twice daily    Marol® (Morningside) [Ml  Tablets, m/r, tramadol hydrochloride 100 mg, net  price 60-tab pack = £9.12; 150 mg, 60-tab pack =  £13.68; 200 mg, 60-tab pack = £18.24. Label: 2, 25  Dose ADULT and CHILD over 12 years, 100 mg twice daily  increased if necessary; usual max. 200 mg twice daily   Maxitram SR® (Chiesi) (Ml  Capsules, m/r, tramadol hydrochloride 50 mg  (white), net price 60-cap pack = £4.55; 100 mg (yel-  low), 60-cap pack = £12.14; 150 mg (yellow), 60-cap  pack = £18.21; 200 mg (yellow), 60-cap pack = £24.28.  Label: 2, 25   Dose ADULT and CHILD over 12 years, 100-200 mg twice daily;  total of more than 400 mg daily not usually required   Tramquel® SR (Meda) (Ml  Capsules, m/r, tramadol hydrochloride 50 mg (dark  green), net price 60-cap pack = £7.20; 100 mg (white),  60-cap pack = £14.39; 150 mg (dark green), 60-cap  pack = £21.59; 200 mg (yellow), 60-cap pack = £28.78.  Label: 2, counselling, administration  Dose ADULT and CHILD over 12 years, 50-100 mg twice daily  increased if necessary to 150-200 mg twice daily; total of more  than 400 mg daily not usually required   Zamadol® SR (Meda) (Ml  Capsules, m/r, tramadol hydrochloride 50 mg  (green), net price 60-cap pack = £7.20; 100 mg, 60-cap  pack = £14.39; 150 mg (dark green), 60-cap pack =   Label: 2, counselling, administration  Dose ADULT and CHILD over 12 years, 50-100 mg twice daily  increased if necessary to 150-200 mg twice daily; total of more  than 400 mg daily not usually required   Zeridame® SR (Actavis) Ml  Tablets, m/r, tramadol hydrochloride 100 mg, net  price 60-tab pack = £17.21; 150 mg, 60-tab pack =  £25.82; 200 mg, 60-tab pack = £34.43. Label: 2, 25  Dose ADULT and CHILD over 12 years, 100 mg twice daily  increased if necessary to 150-200 mg twice daily; usual max.   Zydol SR® (Griinenthal) (M  Tablets, m/r, f/c, tramadol hydrochloride 100 mg, net  price 60-tab pack = £18.26; 150 mg (beige), 60-tab  pack = £27.39; 200 mg (orange), 60-tab pack = £36.52.  Label: 2, 25   Dose ADULT and CHILD over 12 years, 100 mg twice daily  increased if necessary to 150-200 mg twice daily; total of more  than 400 mg daily not usually required   Tradorec XL® (MSD) M  Tablets, m/r, tramadol hydrochloride 100 mg, net  price 30-tab pack = £14.10; 200 mg, 30-tab pack =  £14.98; 300 mg, 30-tab pack = £22.47. Label: 2, 25  Dose ADULT and CHILD over 12 years, initially 100 mg once daily,  increased if necessary; usual max. 400 mg once daily   Zamadol® 24hr (Meda) M  Tablets, all f/c, all m/r, tramadol hydrochloride  150 mg, net price 28-tab pack = £10.70; 200 mg, 28-  tab pack = £14.26; 300 mg, 28-tab pack = £21.39;   400 mg, 28-tab pack = £28.51. Label: 2, 25  Dose ADULT and CHILD over 12 years, 150 mg once daily  increased if necessary; max. 400 mg once daily   Zydol XL® (Griinenthal) Ml  Tablets, m/r, f/c, tramadol hydrochloride 150 mg, net  price 30-tab pack = £12.18; 200 mg, 30-tab pack =  £17.98; 300 mg, 30-tab pack = £24.94; 400 mg, 30-tab  pack = £32.47. Label: 2, 25  Dose ADULT and CHILD over 12 years, 150 mg once daily  increased if necessary; usual max. 400 mg once daily    Neuropathic pain, which occurs as a result of damage to  neural tissue, includes phantom limb pain, compression  neuropathies, peripheral neuropathies (e.g. due to dia-  betes (section 6.1.5), alcoholism, HIV infection, chemo-  therapy, idiopathic neuropathy), trauma, central pain  (e.g. pain following stroke, spinal cord injury, and syr-  ingomyelia), and postherpetic neuralgia (peripheral  nerve damage following acute herpes zoster infection  (shingles)). The pain occurs in an area of sensory deficit  and may be described as burning, shooting or scalding  and is sometimes accompanied by pain that is evoked  by a non-noxious stimulus (allodynia).    Trigeminal neuralgia is also caused by dysfunction of  neural tissue, but its management (see below) is distinct  from other forms of neuropathic pain.    Neuropathic pain is generally managed with a tricyclic  antidepressant or with certain antiepileptic drugs. Ami-    triptyline (p. 235) [unlicensed indication] and pregaba-  lin (p. 284) are effective treatments for neuropathic  pain. Amitriptyline and pregabalin can be used in com-  bination if the patient has an inadequate response to  either drug at the maximum tolerated dose.   Nortriptyline [unlicensed indication] (p. 236) may be  better tolerated than amitriptyline.   Gabapentin (p. 284) is also effective for the treatment  of neuropathic pain.   Neuropathic pain may respond to opioid analgesics.  There is evidence of efficacy for tramadol (p. 271),  morphine (p. 268), and oxycodone (p. 269); however,  treatment with morphine or oxycodone should be  initiated only under specialist supervision. Tramadol  can be prescribed when other treatments have been  unsuccessful, while the patient is waiting for assessment  by a specialist.   Patients with localised pain who are unable to take oral  medicines may benefit from topical local anaesthetic  preparations, such as lidocaine medicated plasters (sec-  tion 15.2), while awaiting specialist review.   Capsaicin (p. 664) is licensed for neuropathic pain (but  the intense burning sensation during initial treatment  may limit use). Capsaicin 0.075% cream is licensed for  the symptomatic relief of postherpetic neuralgia. A self-  adhesive patch containing capsaicin 8% is licensed for  the treatment of peripheral neuropathic pain in non-  diabetic patients.   A corticosteroid may help to relieve pressure in com-  pression neuropathy and thereby reduce pain.   Neuromodulation by spinal cord stimulation may be of  benefit in some patients. Many patients with chronic  neuropathic pain require multidisciplinary manage-  ment, including physiotherapy and psychological sup-  port.   The management of trigeminal neuralgia and chronic  facial pain are outlined below; for the management of  neuropathic pain in palliative care, see p. 21; for the  management of diabetic neuropathy, see section 6.1.5.   Surgery may be the treatment of choice in many  patients; a neurological assessment will identify those  who stand to benefit. Carbamazepine (p. 281) taken  during the acute stages of trigeminal neuralgia, reduces  the frequency and severity of attacks. It is very effective  for the severe pain associated with trigeminal neuralgia  and (less commonly) glossopharyngeal neuralgia. Blood  counts and electrolytes should be monitored when high  doses are given. Small doses should be used initially to  reduce the incidence of side-effects e.g. dizziness. Some  cases respond to phenytoin (p. 288); the drug may be  given by intravenous infusion (possibly as fosphenytoin)  in a crisis (specialist use only).   Chronic oral and facial pain including persistent idio-  pathic facial pain (also termed ‘atypical facial pain’) and  temporomandibular dysfunction (previously termed  temporomandibular joint pain dysfunction syndrome)  may call for prolonged use of analgesics or for other  drugs. Tricyclic antidepressants (section 4.3.1) may be  useful for facial pain [unlicensed indication], but are not    on the Dental Practitioners’ List. Disorders of this type  require specialist referral and psychological support to  accompany drug treatment. Patients on long-term ther-  apy need to be monitored both for progress and for side-  effects.   Treatment of acute migraine  Prophylaxis of migraine  Cluster headache and the trigeminal  autonomic cephalalgias    Treatment of a migraine attack should be guided by  response to previous treatment and the severity of the  attacks. A simple analgesic such as aspirin, paraceta-  mol (preferably in a soluble or dispersible form) or a  NS AID is often effective; concomitant antiemetic treat-  ment may be required. If treatment with an analgesic is  inadequate, an attack may be treated with a specific  antimigraine compound such as a 5HTi-receptor ago-  nist (‘triptan’). Ergot alkaloids are rarely required now;  oral and rectal preparations are associated with many  side-effects and they should be avoided in cerebrovasc-  ular or cardiovascular disease.   Excessive use of acute treatments for migraine (opioid  and non-opioid analgesics, 5HTj receptor agonists, and  ergotamine) is associated with medication-overuse  headache (analgesic-induced headache); therefore,  increasing consumption of these medicines needs care-  ful management.   Most migraine headaches respond to analgesics such as  aspirin (p. 258) or paracetamol (p. 259) but because  peristalsis is often reduced during migraine attacks the  medication may not be sufficiently well absorbed to be  effective; dispersible or effervescent preparations are  therefore preferred. Compound preparations containing  analgesics and antiemetics are available (section 4.7.1).  The NSAID tolfenamic acid is licensed specifically for  the treatment of an acute attack of migraine; diclofenac  potassium, flurbiprofen, ibuprofen, and naproxen  sodium (section 10.1.1) are also licensed for use in  migraine.   Indications treatment of acute migraine  Cautions see NSAIDs, section 10.1.1  Contra-indications see NSAIDs, section 10.1.1  Hepatic impairment section 10.1.1  Renal impairment section 10.1.1  Pregnancy section 10.1.1  Breast-feeding amount too small to be harmful  Side-effects see NSAIDs, section 10.1.1; also dysuria  (most commonly in men), confusion, malaise, hallu-  cination, paraesthesia, tremor, euphoria, fatigue, and  visual disturbances reported   • ADULT over 18 years, 200 mg at onset repeated once  after 1-2 hours if necessary   Tablets, tolfenamic acid 200 mg, net price 10-tab pack  = £15.00. Label: 21   A 5HT r receptor agonist is of considerable value in the  treatment of an acute migraine attack. The 5HT,-recep-  tor agonists (‘triptans’) act on the 5HT (serotonin) IB/  ID receptors and they are therefore sometimes referred  to as 5HT 1B/1D -receptor agonists. A 5HT,-receptor ago-  nist may be used during the established headache phase  of an attack and is the preferred treatment in those who  fail to respond to conventional analgesics. 5HT,-recep-  tor agonists are not indicated for the treatment of  hemiplegic, basilar, or opthalmoplegic migraine.   The 5HT,-receptor agonists available for treating  migraine are almotriptan, eletriptan, frovatriptan,  naratriptan, rizatriptan, sumatriptan, and zolmitrip-  tan. If a patient does not respond to one 5HT r receptor  agonist, an alternative 5HT]-receptor agonist should be  tried. For patients who have prolonged attacks that  frequently recur despite treatment with a 5HT r receptor  agonist, combination therapy with a NS AID such as  naproxen should be considered. Sumatriptan or zolmi-  triptan are also used to treat cluster headache (section  4. 7.4.3).   Cautions 5HT,-receptor agonists should be used with  caution in the elderly [unlicensed], and in conditions  which predispose to coronary artery disease (pre-exist-  ing cardiac disease, see Contra-indications below);  interactions: Appendix 1 (5HT! agonists).   Contra-indications 5HT r receptor agonists are con-  tra-indicated in ischaemic heart disease, previous myo-  cardial infarction, coronary vasospasm (including Prinz-  metal’s angina), and uncontrolled or severe  hypertension.   Pregnancy There is limited experience of using SHTj-  receptor agonists during pregnancy; manufacturers  advise that they should be avoided unless the potential  benefit outweighs the risk.   Side-effects Side-effects of the 5HT r receptor ago-  nists include sensations of tingling, heat, heaviness,  pressure, or tightness of any part of the body (including  throat and chest — discontinue if intense, may be due to  coronary vasoconstriction or to anaphylaxis), flushing,  dizziness, feeling of weakness; fatigue; nausea and vomi-  ting also reported.   Indications treatment of acute migraine  Cautions see under 5HT r receptor agonists above;  sensitivity to sulfonamides; interactions: Appendix 1  (5HTi agonists)   Contra-indications see under 5HT r receptor agonists  above; previous cerebrovascular accident or transient  ischaemic attack; peripheral vascular disease  Hepatic impairment caution in mild to moderate  impairment; avoid in severe impairment    Renal impairment max. 12.5 mg in 24 hours if eGFR  less than 30 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding present in milk in animal studies —  withhold breast-feeding for 24 hours  Side-effects see under 5HT,-receptor agonists above;  also transient increase in blood pressure, drowsiness;  less commonly diarrhoea, dyspepsia, dry mouth, chest  pain, palpitation, paraesthesia, headache, myalgia,  bone pain, tinnitus; very rarely myocardial infarction,  and tachycardia  Dose   • 12.5 mg as soon as possible after onset repeated after  2 hours if migraine recurs (patient not responding  should not take second dose for same attack); max.  25 mg in 24 hours; CHILD and ADOLESCENT under 18  years not recommended   12.5 mg, net price 3-tab pack = £9.07; 6-tab pack =  £18.14; 9-tab pack = £27.20. Label: 3   Contra-indications see under 5HT r receptor agonists  above; previous cerebrovascular accident or transient  ischaemic attack; arrhythmias; heart failure; periph-  eral vascular disease   Renal impairment reduce initial dose to 20 mg; max.  40 mg in 24 hours; avoid if eGFR less than 30 mL/  minute/ 1.73 m 2   Side-effects see under 5HT,-receptor agonists above;  also abdominal pain, dry mouth, dyspepsia; tachy-  cardia, palpitation; drowsiness, headache; pharyngitis,  rhinitis, chills; myasthenia, myalgia; sweating; less  commonly diarrhoea, glossitis, thirst, anorexia, taste  disturbance; dyspnoea, yawning, oedema, agitation,  confusion, euphoria, depression, insomnia, deperso-  nalisation, tremor, dysarthria, stupor, movement dis-  orders, hypertonia, urinary frequency, arthralgia,  photophobia, visual disturbances, tinnitus, rash, and  pruritus; rarely constipation, oesophagitis, brady-  cardia, asthma, syncope, lymphadenopathy, and  menorrhagia; ischaemic colitis and hypertension also  reported  Dose   • ADULT over 18 years, 40 mg repeated after 2 hours if  migraine recurs (patient not responding to initial dose  should not take second dose for same attack);  increase to 80 mg for subsequent attacks if 40-mg  dose inadequate; max. 80 mg in 24 hours   20 mg, net price 6-tab pack = £22.50; 40 mg, 6-tab  pack = £22.50. Label: 3   interactions: Appendix 1 (5HT! agonists)  Contra-indications see under 5HT r receptor agonists  above; previous cerebrovascular attack or transient  ischaemic attack; peripheral vascular disease  Hepatic impairment avoid in severe impairment  Pregnancy see notes above  Breast-feeding present in milk in animal studies —  withhold breast-feeding for 24 hours  Side-effects see under 5HTj-receptor agonists above;  also dry mouth, dyspepsia, abdominal pain, paraes-  thesia, drowsiness, headache, visual disturbances,  sweating; less commonly diarrhoea, dysphagia, flatu-  lence, tachycardia, palpitation, hypertension, rhinitis,  pharyngitis, sinusitis, laryngitis, tremor, anxiety, asth-  enia, insomnia, confusion, nervousness, impaired  concentration, agitation, depression, depersonalisa-  tion, taste disturbances, micturition disorders, thirst,  dehydration, arthralgia, muscle stiffness, tinnitus,  vertigo, pruritus; rarely constipation, gastro-oeso-  phageal reflux, irritable bowel syndrome, hiccup,  peptic ulcer, stomatitis, bradycardia, hyperventilation,  amnesia, abnormal dreams, hypertonia, hypotonia,  breast tenderness, hypocalcaemia, hypoglycaemia,  bilirubinaemia, epistaxis, urticaria, pyrexia, and  purpura  Dose   • 2.5 mg as soon as possible after onset repeated after 2  hours if migraine recurs (patient not responding  should not take second dose for same attack); max.   5 mg in 24 hours; CHILD and ADOLESCENT under 18  years not recommended   Tablets, f/c, frovatriptan (as succinate) 2.5 mg, net  price 6-tab pack = £16.67. Label: 3   Contra-indications see under 5HT r receptor agonists  above; previous cerebrovascular accident or transient  ischaemic attack; peripheral vascular disease  Hepatic impairment max. 2.5 mg in 24 hours in  moderate impairment; avoid if severe  Renal impairment max. 2.5 mg in 24 hours; avoid if  eGFR less than 15 mL/minute/ 1.73 m 2  Pregnancy see notes above   Breast-feeding withhold breast-feeding for 24 hours  Side-effects see under 5HT r receptor agonists above;  also less commonly bradycardia, tachycardia, palpi-  tation, and visual disturbance; rarely ischaemic colitis,  rash, and pruritus  Dose   • 2.5 mg, repeated after at least 4 hours if migraine  recurs (patient not responding should not take second  dose for same attack); max. 5 mg in 24 hours; CHILD  and ADOLESCENT under 18 years not recommended   2.5 mg, net price 6-tab pack = £24.55, 12-tab pack =  £49.10. Label: 3   Driving Drowsiness may affect performance of skilled tasks  (e g. driving)   Contra-indications see under 5HT r receptor agonists  above; previous cerebrovascular accident or transient  ischaemic attack; peripheral vascular disease  Hepatic impairment reduce dose to 5 mg in mild to  moderate impairment; avoid in severe impairment  Renal impairment reduce dose to 5 mg in mild to  moderate impairment; avoid in severe impairment  Pregnancy see notes above  Breast-feeding present in milk in animal studies —  withhold breast-feeding for 24 hours  Side-effects see under 5HT,-receptor agonists above;  drowsiness, palpitation, tachycardia, dry mouth,  diarrhoea, dyspepsia, thirst, pharyngeal discomfort,  dyspnoea, headache, paraesthesia, decreased alert-  ness, insomnia, tremor, ataxia, nervousness, vertigo,  confusion, myalgia and muscle weakness, sweating,  urticaria, pruritus, blurred vision; rarely syncope,  hypertension, toxic epidermal necrolysis; seizures and  taste disturbance reported    • 10 mg as soon as possible after onset repeated after 2  hours if migraine recurs (patient not responding  should not take second dose for same attack); max.  20 mg in 24 hours; CHILD and ADOLESCENT under 18  years not recommended   Tablets, pink, rizatriptan (as benzoate) 5 mg, net price  6-tab pack = £26.74; 10 mg, 3-tab pack = £13.37, 6-tab  pack = £26.74. Label: 3   Oral lyophilisates {Maxalt Melt Wafers), rizatriptan  (as benzoate) 10 mg, net price 3-wafer pack = £13.37,  6-wafer pack = £26.74. Label: 3, counselling, admin-  istration   Counselling Maxalt 9 Melt wafers should be placed on the tongue  and allowed to dissolve   Driving Drowsiness may affect performance of skilled tasks  (e g. driving)   Contra-indications see under 5HT r receptor agonists  above; previous cerebrovascular accident or transient  ischaemic attack; peripheral vascular disease; mod-  erate and severe hypertension  Hepatic impairment reduce oral dose to 25-50 mg;    Breast-feeding present in milk but amount probably  too small to be harmful; withhold breast-feeding for  12 hours   Side-effects see under 5HT r receptor agonists above;  also dyspnoea, drowsiness, transient increase in blood  pressure, myalgia; also reported diarrhoea, ischaemic  colitis, hypotension, bradycardia or tachycardia, pal-  pitation, arrhythmias, myocardial infarction,  Raynaud’s syndrome, anxiety, seizures, tremor, dys-  tonia, nystagmus, arthralgia, visual disturbances, and  sweating; epistaxis with nasal spray   • By mouth, 50 mg (some patients may require 100 mg);  dose may be repeated after at least 2 hours if migraine  recurs; max. 300 mg in 24 hours; CHILD under 18 years,  see BNF for Children   • By subcutaneous injection using auto-injector, 6 mg;  dose may be repeated once after at least 1 hour if  headache recurs; max. 12 mg in 24 hours; CHILD 10-18  years see BNF for Children   Important Not for intravenous injection which may cause  coronary vasospasm and angina   • Intranasally, 10-20 mg into one nostril; dose may be  repeated once after at least 2 hours if migraine recurs;  max. 40 mg in 24 hours; CHILD 12-18 years [unli-  censed dose], 10-20 mg into one nostril; dose may be  repeated once after at least 2 hours if migraine recurs;  max. 40 mg in 24 hours   Sumatriptan (Non-proprietary) (Ml  Tablets, sumatriptan (as succinate) 50 mg, net price 6-  tab pack = £1.71, 12-tab pack = £2.49; 100 mg, 6-tab  pack = £2.43. Label: 3, 10, patient information leaflet   1 . Sumatriptan 50 mg tablets can be sold to the public to treat  previously diagnosed migraine; max. daily dose 100 mg   Tablets, sumatriptan (as succinate) 50 mg, net price 6-  tab pack = £26.54; 100 mg, 6-tab pack = £42.90.  Label: 3, 10, patient information leaflet  Injection, sumatriptan (as succinate) 12mg/mL (=  6mg/0.5-mL syringe), net price, treatment pack (2 x  0.5-mL prefilled syringes and auto-injector) = £42.47;  refill pack 2 x 0.5-mL prefilled cartridges = £40.41.  Label: 3, 10, patient information leaflet  Nasal spray, sumatriptan lOmg/O.l-mL actuation,  net price 2 unit-dose spray device = £11.80; 20 mg/  0.1-mL actuation, 2 unit-dose spray device = £1 1.80, 6  unit-dose spray device = £35.39. Label: 3, 10, patient  information leaflet   Imigran® Radis (GSK) (Ml  Tablets, f/c, sumatriptan (as succinate) 50 mg (pink),  net price 6-tab pack = £23.90; 100 mg (white), 6-tab  pack = £42.90. Label: 3, 10, patient information leaflet   Cautions see under 5HT r receptor agonists above;  should not be taken within 12 hours of any other  5HT r receptor agonist; interactions: Appendix 1  (5HT! agonists)   Contra-indications see under 5HT r receptor agonists  above; Wolff-Parkinson- White syndrome or arrhyth-  mias associated with accessory cardiac conduction  pathways; previous cerebrovascular accident or tran-  sient ischaemic attack   Side-effects see under 5HT,-receptor agonists above;  also abdominal pain, dry mouth; palpitation; drowsi-  ness, paraesthesia, headache; myalgia, muscle weak-  ness; less commonly tachycardia, transient increase in  blood pressure, polyuria; rarely urticaria; very rarely  gastro-intestinal and splenic infarction, ischaemic  colitis, angina, myocardial infarction; with nasal  spray, taste disturbance, and epistaxis   • By mouth, migraine, ADULT over 18 years, 2.5 mg  repeated after not less than 2 hours if migraine per-  sists or recurs (increase to 5 mg for subsequent  attacks in patients not achieving satisfactory relief  with 2.5-mg dose); max. 10 mg in 24 hours; CHILD 12-  18 years see BNF for Children   • Intranasally, cluster headache [unlicensed] or  migraine, ADULT over 18 years, 5 mg (1 spray) into one  nostril as soon as possible after onset, repeated after  not less than 2 hours if headache persists or recurs;  max. 10 mg in 24 hours; CHILD 12-18 years see BNF  for Children   Tablets, f/c, yellow, zolmitriptan 2.5 mg, net price 6-  tab pack = £18.00, 12-tab pack = £36.00  Orodispersible tablets (Zomig Rapimelt®), zolmi-  triptan 2.5 mg, net price 6-tab pack = £17.90; 5 mg, 6-  tab pack = £22.80 Counselling, administration  Counselling Zomig Rapimelt® should be placed on the tongue,  allowed to disperse and swallowed   Excipients include aspartame equivalent to phenylalanine 2.81 mg/  tablet (section 9.4.1)   Nasal spray, zolmitriptan 5mg/0.1-mL unit-dose  spray device, net price 6 unit-dose sprays = £36.50   The value of ergotamine for migraine is limited by  difficulties in absorption and by its side-effects, particu-  larly nausea, vomiting, abdominal pain, and muscular  cramps', it is best avoided. The recommended doses of  ergotamine preparations should not be exceeded and  treatment should not be repeated at intervals of less  than 4 days.   To avoid habituation the frequency of administration of  ergotamine should be limited to no more than twice a  month. It should never be prescribed prophylactically  but in the management of cluster headache a low dose  (e.g. ergotamine lmg at night for 6 nights in 7) is  occasionally given for 1 to 2 weeks [unlicensed indica-  tion],   Indications treatment of acute migraine and migraine  variants unresponsive to analgesics  Cautions risk of peripheral vasospasm (see below);  elderly; dependence (see Ergot Alkaloids above);  cardiac disease; anaemia; interactions: Appendix 1  (ergot alkaloids)   Peripheral vasospasm Warn patient to stop treatment  immediately if numbness or tingling of extremities devel-  ops and to contact doctor.    Contra-indications peripheral vascular disease, cor-  onary heart disease, obliterative vascular disease and  Raynaud’s syndrome, temporal arteritis, sepsis, severe  or inadequately controlled hypertension, hyper-  thyroidism, acute porphyria (section 9.8.2)   Pregnancy avoid; oxytocic effect on the uterus  Breast-feeding avoid; ergotism may occur in infant;   repeated doses may inhibit lactation  Side-effects abdominal pain, nausea, vomiting; dizzi-  ness; less commonly diarrhoea, pain and weakness in  extremities, cyanosis, peripheral vasoconstriction,  paraesthesia, and hypoaesthesia; rarely intestinal  ischaemia, arrhythmias, increased blood pressure,  bradycardia, tachycardia, dyspnoea, ergotism  (including absence of pulse and numbness in extre-  mities), myalgia, rash, and urticaria; very rarely  myocardial ischaemia, myocardial infarction, heart-  valve fibrosis, and gangrene; constipation, dry mouth,  cerebral ischaemia, thrombosis, drowsiness, sleep  disturbances, tremor, seizures, extrapyramidal effects,  anxiety, depression, confusion, hallucinations, renal  artery spasm, urinary retention, blood disorders,  blurred vision, and arthralgia also reported; with  suppositories rectal and anal ulcers on prolonged use  Dose   Cafergot® (Alliance) ® CM  Tablets, s/c, ergotamine tartrate 1 mg, caffeine  100 mg, net price 30-tab pack = £5.02. Label: 18,  counselling, dosage   Dose ADULT and CHILD over 12 years, 1-2 tablets at onset; max. 4  tablets in 24 hours; not to be repeated at intervals of less than 4  days; max. 8 tablets in one week (but see also notes above)  Suppositories, ergotamine tartrate 2 mg, caffeine  100 mg, net price 30 = £10.13. Label: 18, counselling,  dosage   Dose ADULT and CHILD over 12 years, 1 suppository at onset;  max. 2 in 24 hours; max. 4 suppositories in one week (but see also  notes above)   Tablets, scored, ergotamine tartrate 2 mg, cyclizine  hydrochloride 50 mg, caffeine hydrate 100 mg, net  price 100 = £51.00. Label: 2, 18, counselling, dosage  Dose 1 tablet at onset, followed after 30 minutes by Vz-l tablet,  repeated every 30 minutes if necessary; max. 3 tablets in 24 hours,  4 tablets per attack, 6 tablets in one week (but see also notes  above); CHILD not recommended   Antiemetics (section 4.6), such as metoclopramide or  domperidone, or phenothiazine and antihistamine anti-  emetics, relieve the nausea associated with migraine  attacks. Antiemetics may be given by intramuscular  injection or rectally if vomiting is a problem. Metoclo-  pramide and domperidone have the added advantage of  promoting gastric emptying and normal peristalsis; a  single dose should be given at the onset of symptoms.  Oral analgesic preparations containing metoclopramide  are a convenient alternative (important: for warnings  relating to extrapyramidal effects of metoclopramide  particularly in children and young adults, see p. 249).   Where migraine attacks are frequent, possible provok-  ing factors such as stress, irregular life-style (e.g. lack of  sleep), or chemical triggers (e.g. alcohol and nitrates)  should be sought; combined oral contraceptives may  also provoke migraine, see section 7.3.1 for advice.  Preventive treatment for migraine should be considered  for patients who:   • cannot take suitable treatment for migraine attacks.  Prophylaxis is also necessary in some rare migraine  subtypes and those at risk of migrainous infarction.   The beta-blockers propranolol, atenolol, metoprolol,  nadolol, and timolol (section 2.4) are all effective.  Propranolol is the most commonly used.   Tricyclic antidepressants (section 4.3.1) [unlicensed  indication], topiramate (section 4.8.1), sodium val-  proate (section 4.8.1) [unlicensed indication], valproic  acid (section 4.2.3) [unlicensed indication], and gaba-  pentin (section 4.8.1) [unlicensed indication] are also  effective for preventing migraine.   Pizotifen is an antihistamine and a serotonin-receptor  antagonist, structurally related to the tricyclic anti-  depressants. It is of limited value and may cause weight  gain.   Botulinum toxin type A is licensed for the prophylaxis  of headaches in adults with chronic migraine, defined as  headache on at least 15 days per month, of which at  least 8 of those days are with migraine.   Clonidine ( Dixarit ®) is not recommended; it can  aggravate depression and cause insomnia. Methy-  sergide, a semi-synthetic ergot alkaloid, has dangerous  side-effects (retroperitoneal fibrosis and fibrosis of the  heart valves and pleura); important: it should only be  administered under hospital supervision.   Indications prevention of vascular headache including  classical migraine, common migraine, and cluster  headache   Cautions urinary retention; susceptibility to angle-  closure glaucoma; history of epilepsy; interactions:  Appendix 1 (pizotifen)   Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced   Breast-feeding amount probably too small to be  harmful, but manufacturer advises avoid   Side-effects dry mouth, nausea; dizziness, drowsi-  ness, increased appetite, weight gain; less commonly  constipation; rarely anxiety, aggression, insomnia,  paraesthesia, hallucination, depression, arthralgia,  myalgia; very rarely seizures  Dose   • Initially 500 micrograms at night increased gradually  to usual dose of 1.5 mg at night or in 3 divided doses;  may be further increased up to max. daily dose 4.5 mg  (but rarely necessary), max. single dose 3 mg; CHILD    over 5 years, up to 1.5 mg daily in divided doses; max.  single dose at night 1 mg   Pizotifen (Non-proprietary) [Ml  Tablets, pizotifen (as hydrogen malate), 500 micr-  ograms, net price 28-tab pack = £1.28; 1.5 mg, 28-tab  pack = £2.17. Label: 2   Sanomigran® (Novartis) (Ml  Tablets, both ivory-yellow, s/c, pizotifen (as hydrogen  malate), 500 micrograms, net price 60-tab pack =  £2.06; 1.5 mg, 28-tab pack = £3.42. Label: 2  Elixir, pizotifen (as hydrogen malate) 250 micr-  ograms/5 mL, net price 300 mL = £3.61. Label: 2   Cautions depressive illness; heart failure; Raynaud’s  syndrome; concurrent antihypertensive therapy;  cerebrovascular disease; polyneuropathy; constipa-  tion; interactions: Appendix 1 (clonidine)  Contra-indications severe bradyarrhythmia  Renal impairment use with caution in severe impair-  ment — reduce initial dose and increase gradually  Pregnancy avoid unless potential benefit outweighs  risk   Side-effects constipation, dry mouth, nausea, vomi-  ting; postural hypotension; depression, sleep disorder,  dizziness, headache, drowsiness; erectile dysfunction;  less commonly Raynaud’s syndrome, paraesthesia,  hallucination, rash, and pruritus; rarely AV block,  gynaecomastia, and alopecia  Dose   • 50 micrograms twice daily, increased after 2 weeks to  75 micrograms twice daily if necessary; CHILD not  recommended   Clonidine (Non-proprietary) (M  Tablets, clonidine hydrochloride 25 micrograms, net  price 112-tab pack = £13.84   Dixarit® (Boehringer Ingelheim) (Ml  Tablets, blue, s/c, clonidine hydrochloride 25 micr-  ograms, net price 112-tab pack = £6.75   Indications prevention of severe recurrent migraine,  cluster headache and other vascular headaches in  patients who are refractory to other treatment and  whose lives are seriously disrupted (important: hos-  pital supervision only, see notes above); diarrhoea  associated with carcinoid syndrome  Cautions history of peptic ulceration; avoid abrupt  withdrawal of treatment; after 6 months withdraw  (gradually over 2 to 3 weeks) for reassessment for at  least 1 month (see also notes above); interactions:  Appendix 1 (ergot alkaloids)   Contra-indications pulmonary and cardiovascular  disease, severe hypertension, collagen disease, cellu-  litis, urinary-tract disorders, cachectic or septic con-  ditions   Side-effects nausea, vomiting, heartburn, abdominal  discomfort, drowsiness, and dizziness occur fre-  quently in initial treatment; mental and behavioural  disturbances, insomnia, oedema, weight gain, rashes,  loss of scalp hair, cramps, arterial spasm (including  coronary artery spasm with angina and possible  myocardial infarction), paraesthesias of extremities,  postural hypotension, and tachycardia also occur;  retroperitoneal and other abnormal fibrotic reactions  may occur on prolonged administration, requiring  immediate withdrawal of treatment  Dose   • Initially 1 mg at bedtime, increased gradually over  about 2 weeks to 1-2 mg 3 times daily with food (see  notes above); CHILD not recommended   • Diarrhoea associated with carcinoid syndrome, usual  range, 12-20 mg daily (hospital supervision); CHILD  not recommended   Tablets, s/c, methysergide (as maleate) lmg, net  price 60-tab pack = £12.94. Label: 2, 21   Cluster headache rarely responds to standard anal-  gesics. Sumatriptan (p. 275) given by subcutaneous  injection is the drug of choice for the treatment of  cluster headache. If an injection is unsuitable, sumatrip-  tan nasal spray or zolmitriptan nasal spray [both unli-  censed use] may be used. Alternatively, 100% oxygen at  a rate of 10-15 litres/minute for 10-20 minutes is useful  in aborting an attack.   Prophylaxis of cluster headache is considered if the  attacks are frequent, last over 3 weeks, or if they cannot  be treated effectively. Verapamil (p. 133) or lithium  [both unlicensed use] are used for prophylaxis.  Prednisolone (section 6.3.2) can be used for short-term  prophylaxis of episodic cluster headache [unlicensed  use] either as monotherapy, or in combination with  verapamil during verapamil titration. The dose of pred-  nisolone for monotherapy or adjunctive therapy is 60-  100 mg once daily for 2-5 days followed by a dose  reduction of 10 mg every 2-3 days until prednisolone  is discontinued.   Ergotamine, used on an intermittent basis is an alter-  native for patients with short bouts, but it should not be  used for prolonged periods. Methysergide is effective  but must be used with extreme caution (section 4. 7.4.2)  and only if other drugs cannot be used or if they are not  effective.   The other trigeminal autonomic cephalalgias, paroxys-  mal hemicrania (sensitive to indometacin), and short-  lasting unilateral neuralgiform headache attacks with  conjunctival injection and tearing, are seen rarely and  are best managed by a specialist.   Control of the epilepsies  Drugs used in status epilepticus  Febrile convulsions   The object of treatment is to prevent the occurrence of  seizures by maintaining an effective dose of one or more  antiepileptic drugs. Careful adjustment of doses is  necessary, starting with low doses and increasing gra-  dually until seizures are controlled or there are signifi-  cant adverse effects.   When choosing an antiepileptic drug, the seizure type,  concomitant medication, co-morbidity, age, and sex  should be taken into account. For women of child-  bearing age, see Pregnancy, p. 280.   The dosage frequency is often determined by the  plasma-drug half-life, and should be kept as low as  possible to encourage adherence with the prescribed  regimen. Most antiepileptics, when used in the usual  dosage, can be given twice daily. Lamotrigine, pheno-  barbital, and phenytoin, which have long half-lives, can  be given once daily at bedtime. However, with large  doses, some antiepileptics may need to be given more  frequently to avoid adverse effects associated with high  peak plasma-drug concentration. Young children meta-  bolise some antiepileptics more rapidly than adults and  therefore may require more frequent doses and a higher  dose in proportion to their body-weight.   Management When monotherapy with a first-line  antiepileptic drug has failed, monotherapy with a sec-  ond drug should be tried; the diagnosis should be  checked before starting an alternative drug if the first  drug showed lack of efficacy. The change from one  antiepileptic drug to another should be cautious, slowly  withdrawing the first drug only when the new regimen  has been established. Combination therapy with two or  more antiepileptic drugs may be necessary, but the  concurrent use of antiepileptic drugs increases the risk  of adverse effects and drug interactions (see below). If  combination therapy does not bring about worthwhile  benefits, revert to the regimen (monotherapy or combi-  nation therapy) that provided the best balance between  tolerability and efficacy.   Interactions Interactions between antiepileptics are  complex and may increase toxicity without a corre-  sponding increase in antiepileptic effect. Interactions  are usually caused by hepatic enzyme induction or  hepatic enzyme inhibition', displacement from protein  binding sites is not usually a problem. These interac-  tions are highly variable and unpredictable.   For interactions of antiepileptic drugs, see Appendix 1;  for advice on hormonal contraception and enzyme-  inducing drugs, see section 7.3.1 and section 7.3.2  Significant interactions that occur between antiepilep-  tics and that may affect dosing requirements are as  follows:   often lowers plasma concentration of clobazam, clon-  azepam, lamotrigine, phenytoin (but may also raise  phenytoin concentration), tiagabine, topiramate, val-  proate, zonisamide, and an active metabolite of oxcar-  bazepine   sometimes lowers plasma concentration of eslicarbaze-  pine, ethosuximide, primidone (but tendency for corre-  sponding increase in phenobarbital level), and rufina-  mide   sometimes raises plasma concentration of an active  metabolite of carbamazepine (but evidence is conflict-   sometimes lowers plasma concentration of carbamaze-  pine (but may raise concentration of an active metabo-  lite of carbamazepine)   sometimes raises plasma concentration of phenytoin  often raises plasma concentration of phenobarbital   often lowers plasma concentration of carbamazepine,  clonazepam, lamotrigine, phenytoin (but may also raise  phenytoin concentration), tiagabine, valproate, and  zonisamide   often lowers plasma concentration of clonazepam,  carbamazepine, eslicarbazepine, lamotrigine, tiagabine,  topiramate, valproate, zonisamide, and an active meta-  bolite of oxcarbazepine   often raises plasma concentration of phenobarbital  sometimes lowers plasma concentration of ethosux-  imide, primidone (by increasing conversion to pheno-  barbital), and rufinamide   often raises plasma concentration of lamotrigine,  primidone, phenobarbital, phenytoin (but may also  lower), and an active metabolite of carbamazepine  sometimes raises plasma concentration of ethosuximide,  primidone (and tendency for significant increase in  phenobarbital level), and rufinamide  Vigabatrin   often lowers plasma concentration of phenytoin  sometimes lowers plasma concentration of phenobarbi-  tal and primidone    Withdrawal Antiepileptic drugs should be withdrawn  under specialist supervision. Avoid abrupt withdrawal,  particularly of barbiturates and benzodiazepines,  because this may precipitate severe rebound seizures.  Reduction in dosage should be gradual and, in the case  of barbiturates, withdrawal of the drug may take  months.   The decision to withdraw antiepileptic drugs from a  seizure-free patient, and its timing, is often difficult  and depends on individual circumstances. Even in  patients who have been seizure-free for several years,  there is a significant risk of seizure recurrence on drug  withdrawal.   In patients receiving several antiepileptic drugs, only  one drug should be withdrawn at a time.    Driving Patients with epilepsy may drive a motor  vehicle (but not a large goods or passenger carrying  vehicle) provided that they have been seizure-free for  one year or, if subject to attacks only while asleep, have  established a 3-year period of asleep attacks without  awake attacks. Those affected by drowsiness should not  drive or operate machinery.   Guidance issued by the Drivers Medical Unit of the  Driver and Vehicle Licensing Agency (DVLA) recom-  mends that patients should be advised not to drive  during medication changes or withdrawal of antiepilep-  tic drugs, and for 6 months afterwards (see also Drugs  and Driving under General Guidance, p. 3).   Patients who have had a first or single epileptic seizure  must not drive for 6 months (5 years in the case of large  goods or passenger carrying vehicles) after the event;  driving may then be resumed, provided the patient has  been assessed by a specialist as fit to drive because no  abnormality was detected on investigation.    Pregnancy Women of child-bearing potential should  discuss the impact of both epilepsy and the treatment of  epilepsy on the outcome of pregnancy with a specialist.  There is an increased risk of teratogenicity associated  with the use of antiepileptic drugs (especially if used  during the first trimester and if the patient takes two or  more antiepileptic drugs). Valproate is associated with  the highest risk of major and minor congenital malfor-  mations, and with developmental delay. Valproate  should not be prescribed unless there is no safer alter-  native and only after a careful discussion of the risks;  doses greater than 1 g daily are associated with an  increased risk of teratogenicity. There is also an  increased risk of teratogenicity with phenytoin, primid-  one, phenobarbital, lamotrigine, and carbamazepine.  There is not enough evidence to establish the risk of  teratogenicity with other antiepileptic drugs.   Women of child-bearing potential who take antiepileptic  drugs should be given contraceptive advice. Some anti-  epileptic drugs can reduce the efficacy of hormonal  contraceptives, and the efficacy of some antiepileptics  may be affected by hormonal contraceptives (see sec-  tion 7.3.1 and interactions of antiepileptics, Appendix 1).  Women who want to become pregnant should be  referred to a specialist for advice in advance of concep-  tion. For some women, the severity of seizure or the  seizure type may not pose a serious threat, and drug  withdrawal may be considered; therapy may be  resumed after the first trimester. If treatment with anti-  epileptic drugs must continue throughout pregnancy,   Once an unplanned pregnancy is discovered it is usually  too late for changes to be made to the treatment regi-  men; the risk of harm to the mother and fetus from  convulsive seizures outweighs the risk of continued  therapy. The likelihood of a woman who is taking anti-  epileptic drugs having a baby with no malformations is  at least 90%, and it is important that women do not stop  taking essential treatment because of concern over  harm to the fetus.   To reduce the risk of neural tube defects, folate supple-  mentation (section 9.1.2) is advised before conception  and throughout the first trimester.   The concentration of antiepileptic drugs in the plasma  can change during pregnancy, particularly in the later  stages. Doses of phenytoin (see p. 288), carbamazepine,  and lamotrigine should be adjusted on the basis of  plasma-drug concentration monitoring; the dose of  other antiepileptic drugs should be monitored carefully  during pregnancy and after birth, and adjustments made  on a clinical basis. Plasma-drug concentration monitor-  ing during pregnancy is also useful to check compliance.  Additionally, in patients taking topiramate or levetira-  cetam, it is recommended that fetal growth should be  monitored.   Women who have seizures in the second half of  pregnancy should be assessed for eclampsia before  any change is made to antiepileptic treatment. Status  epilepticus should be treated according to the standard  protocol, see section 4.8.2.   Routine injection of vitamin K (section 9.6.6) at birth  minimises the risk of neonatal haemorrhage associated  with antiepileptics.   Withdrawal effects in the newborn may occur with some  antiepileptic drugs, in particular benzodiazepines and  phenobarbital.   Epilepsy and Pregnancy Register  All pregnant women with epilepsy, whether taking  medication or not, should be encouraged to notify  the UK Epilepsy and Pregnancy Register (Tel: 0800  389 1248).    Breast-feeding Breast-feeding is acceptable with all  antiepileptic drugs taken in normal doses, with the  possible exception of the barbiturates and some of the  newer antiepileptics (see under individual drugs).   Carbamazepine, lamotrigine, oxcarbazepine, and  sodium valproate are the drugs of choice for focal  seizures; second-line drugs include clobazam, gabapen-  tin, levetiracetam, pregabalin, tiagabine, topiramate,  and zonisamide.   Tonic-clonic seizures The drugs of choice for tonic-  clonic seizures are carbamazepine, lamotrigine, and  sodium valproate. Clobazam, levetiracetam, oxcarba-  zepine, and topiramate are second-line drugs.    Absence seizures Ethosuximide and sodium val-  proate are the drugs of choice in typical absence  seizures; alternatives include clonazepam and lamotri-  gine. Sodium valproate is also highly effective in treating  the generalised tonic-clonic seizures which can co-exist  with absence seizures in idiopathic primary generalised  epilepsy.   Myoclonic seizures Myoclonic seizures (myoclonic  jerks) occur in a variety of syndromes, and response to  treatment varies considerably. Sodium valproate is the  drug of choice; clonazepam and levetiracetam can  also be used. Alternatives include lamotrigine and topir-  amate, but lamotrigine may occasionally exacerbate  myoclonic seizures. For reference to the adjunctive  use of piracetam, see section 4.9.3.   Sodium valproate and levetiracetam are effective in  treating the generalised tonic-clonic seizures that co-  exist with myoclonic seizures in idiopathic generalised  epilepsy.   Atypical absence, atonic, and tonic seizures are usually  seen in childhood, in specific epilepsy syndromes, or  associated with cerebral damage or mental retardation.  They may respond poorly to the traditional drugs. Sod-  ium valproate, lamotrigine, and clonazepam can be  tried. Second-line drugs that are occasionally helpful  include clobazam, ethosuximide, levetiracetam, and  topiramate.   Some drugs are licensed for use in particular epilepsy  syndromes, such as lamotrigine and rufinamide in Len-  nox-Gastaut syndrome. The epilepsy syndromes are  specific types of epilepsy that are characterised accord-  ing to a number of features including seizure type, age of  onset, and EEG characteristics.   For more information on epilepsy syndromes in chil-  dren, see BNF for Children, section 4.8.1. Prescribing  information for stiripentol ( Diacomit ®) in severe myo-  clonic epilepsy of infancy (Dravet syndrome) can also be  found in BNF for Children.   Carbamazepine is a drug of choice for simple and  complex focal seizures and for tonic-clonic seizures  secondary to a focal discharge. It is essential to initiate  carbamazepine therapy at a low dose and build this up  slowly with increments of 100-200 mg every two weeks.  Some side-effects (such as headache, ataxia, drowsi-  ness, nausea, vomiting, blurring of vision, dizziness,  unsteadiness, and allergic skin reactions) are dose-  related, and may be dose-limiting. These side-effects  are more common at the start of treatment and in the  elderly. They may be reduced by altering the timing of  medication; use of modified-release tablets also signifi-  cantly lessens the incidence of dose-related side-effects.  Oxcarbazepine is licensed as monotherapy or adjunc-  tive therapy for the treatment of focal seizures with or  without secondary generalised tonic-clonic seizures.  Eslicarbazepine is licensed for adjunctive treatment in  adults with focal seizures with or without secondary  generalisation.    The Scottish Medicines Consortium (p. 4) has advised  (October 2010) that eslicarbazepine ( Zebinix -®) is  accepted for restricted use within NHS Scotland as  adjunctive therapy in adults with focal seizures with or  without secondary generalisation. It is restricted for use  in refractory epilepsy.    Indications focal and secondary generalised tonic-  clonic seizures, primary generalised tonic-clonic sei-  zures; trigeminal neuralgia; prophylaxis of bipolar  disorder unresponsive to lithium; adjunct in acute  alcohol withdrawal [unlicensed] (section 4.10.1); dia-  betic neuropathy [unlicensed] (section 6.1.5)  Cautions cardiac disease (see also Contra-indications);  skin reactions (see also Blood, Hepatic, or Skin Dis-  orders, below and under Side-effects); test for HLA-  B*1502 allele in individuals of Han Chinese or Thai  origin (avoid unless no alternative — risk of Stevens-  Johnson syndrome in presence of HLA-B*1502  allele); history of haematological reactions to other  drugs; manufacturer recommends blood counts and  hepatic and renal function tests (but evidence of  practical value uncertain); may exacerbate absence  and myoclonic seizures; consider vitamin D supple-  mentation in patients who are immobilised for long  periods or who have inadequate sun exposure or  dietary intake of calcium; susceptibility to angle-clo-  sure glaucoma; cross-sensitivity reported with oxcar-  bazepine and with phenytoin; avoid abrupt with-  drawal; interactions: see p. 279 and Appendix 1  (carbamazepine)   Blood, hepatic, or skin disorders Patients or their carers  should be told how to recognise signs of blood, liver, or skin  disorders, and advised to seek immediate medical attention if  symptoms such as fever, rash, mouth ulcers, bruising, or  bleeding develop. Carbamazepine should be withdrawn  immediately in cases of aggravated liver dysfunction or acute  liver disease. Leucopenia that is severe, progressive, or  associated with clinical symptoms requires withdrawal (if  necessary under cover of a suitable alternative).  Contra-indications AV conduction abnormalities  (unless paced); history of bone marrow depression,  acute porphyria (section 9.8.2); hypersensitivity to  tricyclic antidepressants  Hepatic impairment metabolism impaired in  advanced liver disease; see also Blood, Hepatic, or  Skin Disorders, above  Renal impairment use with caution  Pregnancy see Pregnancy, p. 280  Breast-feeding amount probably too small to be  harmful but monitor infant for possible adverse  reactions; see also Breast-feeding, p. 280  Side-effects see notes above; dry mouth, nausea,  vomiting; oedema; ataxia, dizziness, drowsiness, fati-  gue, headache; hyponatraemia (leading in rare cases  to water intoxication); blood disorders (including  eosinophilia, leucopenia, thrombocytopenia, haemo-  lytic anaemia, and aplastic anaemia); dermatitis, and  urticaria; less commonly diarrhoea, constipation,  involuntary movements (including nystagmus), visual  disturbances; rarely abdominal pain, anorexia,  hepatitis, jaundice, vanishing bile duct syndrome,  cardiac conduction disorders, hypertension, hypo-  tension, peripheral neuropathy, dysarthria, aggres-  sion, agitation, confusion, depression, hallucinations,  restlessness, paraesthesia, lymph node enlargement,  muscle weakness, systemic lupus erythematosus, and  delayed multi-organ hypersensitivity disorder; very    rarely pancreatitis, stomatitis, hepatic failure, taste  disturbance, exacerbation of coronary artery disease,  AV block with syncope, circulatory collapse, hyper-  cholesterolaemia, thrombophlebitis, thromboembo-  lism, pulmonary hypersensitivity (with dyspnoea,  pneumonitis, or pneumonia), psychosis, neuroleptic  malignant syndrome, osteomalacia (see Cautions),  osteoporosis, galactorrhoea, gynaecomastia,  impaired male fertility, interstitial nephritis, renal  failure, sexual dysfunction, urinary frequency, urinary  retention, arthralgia, muscle pain, muscle spasm,  conjunctivitis, angle-closure glaucoma, hearing dis-  orders, acne, alterations in skin pigmentation, alo-  pecia, hirsutism, sweating, photosensitivity, purpura,  Stevens- Johnson syndrome, toxic epidermal necro-  lysis, and aseptic meningitis; suicidal ideation  Dose   Note Different preparations may vary in bioavailability; to  avoid reduced effect or excessive side-effects, it may be  prudent to avoid changing the formulation   • By mouth, epilepsy, initially, 100-200 mg 1-2 times  daily, increased slowly (see notes above) to usual dose  of 0.8-1. 2 g daily in divided doses; in some cases 1.6-  2 g daily in divided doses may be needed; ELDERLY  reduce initial dose; CHILD daily in divided doses, up to  1 year 100-200 mg, 1-5 years 200-400 mg, 5-10 years  400-600 mg, 10-15 years 0.6-1 g   Trigeminal neuralgia, initially 100 mg 1-2 times daily  (but some patients may require higher initial dose),  increased gradually according to response; usual dose  200 mg 3-4 times daily, up to 1.6 g daily in some  patients   Diabetic neuropathy [unlicensed indication], initially  100 mg 1-2 times daily, increased gradually according  to response; usual dose 200 mg 3-4 times daily, up to  1.6 g daily in some patients   Prophylaxis of bipolar disorder unresponsive to lith-  ium (see also section 4.2.3), initially 400 mg daily in  divided doses increased until symptoms controlled;  usual range 400-600 mg daily; max. 1.6 g daily  Treatment of alcohol withdrawal [unlicensed indica-  tion], initially 800 mg daily in divided doses, reduced  gradually over 5 days to 200 mg daily; usual treatment  duration 7-10 days   • By rectum, epilepsy, for short-term use (max. 7 days)  when oral therapy temporarily not possible; 125-mg  suppository approx, equivalent to 100-mg tablet, but  final adjustment should always depend on clinical  response (plasma concentration monitoring recom-  mended); max. 1 g daily in 4 divided doses    Carbamazepine (Non-proprietary) (Ml  Tablets, carbamazepine 100 mg, net price 28 = £5.69;  200 mg, 28 = £4.99; 400 mg, 28 = £6.59. Label: 3, 8,  counselling, blood, hepatic or skin disorder symptoms  (see above), driving (see notes above)   Tablets, scored, carbamazepine 100 mg, net price 84-  tab pack = £2.07; 200 mg, 84-tab pack = £3.83;   400 mg, 56-tab pack = £5.02. Label: 3, 8, counselling,  blood, hepatic or skin disorder symptoms (see above),  driving (see notes above)   Chewtabs, orange, carbamazepine 100 mg, net price  56-tab pack = £3.16; 200 mg, 56-tab pack = £5.88.    Label: 3, 8, 21, 24, counselling, blood, hepatic or skin  disorder symptoms (see above), driving (see notes  above)   Liquid, sugar-free, carbamazepine 100 mg/5 mL. Net  price 300-mL pack = £6.12. Label: 3, 8, counselling,  blood, hepatic or skin disorder symptoms (see above),  driving (see notes above)   Suppositories, carbamazepine 125 mg, net price 5 =  £8.03; 250 mg, 5 = £10.71. Label: 3, 8, counselling,  blood, hepatic or skin disorder symptoms (see above),  driving (see notes above)   Carbagen® SR (Generics) (Ml  Tablets, m/r, f/c, scored, carbamazepine 200 mg, net  price 56-tab pack = £5.20; 400 mg, 56-tab pack =  £10.24. Label: 3, 8, 25, counselling, blood, hepatic or  skin disorder symptoms (see above), driving (see  notes above)   Dose epilepsy, ADULT and CHILD over 5 years, as above; tri-  geminal neuralgia, as above; bipolar disorder, as above; total daily  dose given in 1-2 divided doses   Tegretol® Retard (Novartis) (Ml  Tablets, m/r, scored, carbamazepine 200 mg (beige-  orange), net price 56-tab pack = £5.20; 400 mg  (brown-orange), 56-tab pack = £10.24. Label: 3, 8, 25,  counselling, blood, hepatic or skin disorder symptoms  (see above), driving (see notes above)   Dose epilepsy, ADULT and CHILD over 5 years, as above; tri-  geminal neuralgia, as above; bipolar disorder, as above; total daily  dose given in 2 divided doses   Cautions avoid abrupt withdrawal; hyponatraemia  (monitor plasma-sodium concentration in patients at  risk and discontinue treatment if hyponatraemia  occurs); PR-interval prolongation (avoid concomitant  administration of drugs that prolong PR interval);  elderly; interactions: see p. 279 and Appendix 1  (eslicarbazepine)   Renal impairment reduce initial dose to 400 mg  every other day for 2 weeks then 400 mg once daily if  eGFR 30-60 mL/minute/ 1.73 m 2 , adjusted according  to response; avoid if eGFR less than 30 mL/minute/  1.73 m 2   Side-effects gastro-intestinal disturbances; dizziness,  drowsiness, headache, impaired coordination, tremor,  visual disturbances, fatigue; rash; less commonly dry  mouth, dehydration, gingival hyperplasia, stomatitis;  palpitation, bradycardia, hypertension, hypotension,  epistaxis, appetite changes, weight changes, agitation,  hyperactivity, confusion, mood changes, psychosis,  impaired memory, insomnia, dysaesthesia, dystonia,  parosmia, movement disorders, convulsions, periph-  eral neuropathy, nystagmus, dysarthria, taste distur-  bance, liver disorders, hypothyroidism, anaemia,  hyponatraemia (see Cautions), electrolyte imbalance,  tinnitus, alopecia, sweating, nail disorder, myalgia,  nocturia, menstruation changes, malaise, chills, per-    ipheral oedema; very rarely pancreatitis, thrombocy-  topenia, and leucopenia; PR-interval prolongation  also reported; suicidal ideation   • ADULT over 18 years, initially 400 mg once daily,  increased after 1-2 weeks to 800 mg once daily; max.  1.2 g   Tablets, scored, eslicarbazepine acetate 800 mg, net  price 30-tab pack = £154.20. Label: 8, counselling,  driving (see notes above)   Cautions hypersensitivity to carbamazepine; avoid  abrupt withdrawal; hyponatraemia (monitor plasma-  sodium concentration in patients at risk), heart failure  (monitor body-weight), cardiac conduction disorders;  avoid in acute porphyria (section 9.8.2); interactions:  see p. 279 and Appendix 1 (oxcarbazepine)   Blood, hepatic, or skin disorders Patients or their carers  should be told how to recognise signs of blood, liver, or skin  disorders, and advised to seek immediate medical attention if  symptoms such as lethargy, confusion, muscular twitching,  fever, sore throat, rash, blistering, mouth ulcers, bruising, or  bleeding develop   Renal impairment halve initial dose if eGFR less than  30mL/minute/1.73m 2 ; increase according to  response at intervals of at least 1 week   Side-effects nausea, vomiting, constipation, diarr-  hoea, abdominal pain; dizziness, headache, drowsi-  ness, agitation, amnesia, asthenia, ataxia, confusion,  impaired concentration, depression, tremor; hypo-  natraemia; acne, alopecia, rash, nystagmus, visual  disorders including diplopia; less commonly urticaria,  leucopenia; very rarely hepatitis, pancreatitis, arrhy-  thmias, blood disorders, systemic lupus erythemato-  sus, Stevens- Johnson syndrome, and toxic epidermal  necrolysis; hypertension and hypothyroidism also  reported; suicidal ideation   • Initially 300 mg twice daily increased according to  response in steps of up to 600 mg daily at weekly  intervals; usual dose range 0.6-2.4 g daily in divided  doses; CHILD 6-18 years, 8-10 mg/kg daily in 2  divided doses increased according to response in  steps of up to 10 mg/kg daily at weekly intervals (in  adjunctive therapy, maintenance dose approx. 30 mg/  kg daily); max. 46 mg/kg daily in divided doses  Note In adjunctive therapy, the dose of concomitant anti-  epileptics may need to be reduced when using high doses of  oxcarbazepine   Tablets, oxcarbazepine 150 mg, net price 50-tab pack  = £11.02; 300 mg, 50-tab pack = £22.38; 600 mg, 50-  tab pack = £44.72. Label: 3, 8, counselling, blood,  hepatic, or skin disorders (see above), driving (see  notes above)   Tablets, f/c, scored, oxcarbazepine 150 mg (green),  net price 50-tab pack = £8.50; 300 mg (yellow), 50-tab    pack = £17.00; 600 mg (pink), 50-tab pack = £34.00.  Label: 3, 8, counselling, blood, hepatic or skin dis-  orders (see above), driving (see notes above)   Oral suspension, sugar-free, oxcarbazepine 300 mg/  5mL, net price 250 mL (with oral syringe) = £34.00.  Label: 3, 8, counselling, blood, hepatic or skin dis-  orders (see above), driving (see notes above)   Ethosuximide is used for typical absence seizures; it  may also be used for atypical absence seizures. Etho-  suximide is rarely used for myoclonic or tonic seizures.    Cautions avoid abrupt withdrawal avoid in acute por-  phyria (section 9.8.2); interactions: see p. 279 and  Appendix 1 (ethosuximide)   Blood disorders Patients or their carers should be told how  to recognise signs of blood disorders, and advised to seek  immediate medical attention if symptoms such as fever, sore  throat, mouth ulcers, bruising, or bleeding develop    Hepatic impairment use with caution  Renal impairment use with caution  Pregnancy see Pregnancy, p. 280  Breast-feeding present in milk; hyperexcitability and  sedation reported; see also Breast-feeding, p. 280  Side-effects gastro-intestinal disturbances (including  nausea, vomiting, diarrhoea, abdominal pain, ano-  rexia, weight loss); less frequently headache, fatigue,  drowsiness, dizziness, hiccup, ataxia, euphoria, irrit-  ability, aggression, impaired concentration; rarely  tongue swelling, sleep disturbances, night terrors,  depression, psychosis, photophobia, dyskinesia,  increased libido, vaginal bleeding, myopia, gingival  hypertrophy, and rash; also reported hyperactivity,  increase in seizure frequency, blood disorders such as  leucopenia, agranulocytosis, pancytopenia, and  aplastic anaemia (blood counts required if features of  infection), systemic lupus erythematosus, and Ste-  vens-Johnson syndrome; suicidal ideation    • ADULT and CHILD over 6 years, initially 500 mg daily in 2  divided doses, increased by 250 mg every 4-7 days to  usual dose of 1-1.5 g daily in 2 divided doses; occa-  sionally up to 2 g daily may be needed;   250 mg) daily in 2 divided doses, increased gradually  over 2-3 weeks to usual dose of 20-40 mg/kg (max.  1 g) daily in 2 divided doses; total daily dose may be  given in 3 divided doses    Ethosuximide (Non-proprietary) (Ml  Capsules, ethosuximide 250 mg, net price 56-cap  pack = £38.23. Label: 8, counselling, blood disorders  (see above), driving (see notes above)   Syrup, black currant, ethosuximide 250 mg/5 mL, net  price 200-mL pack = £6.60. Label: 8, counselling,  blood disorders (see above), driving (see notes above)   Syrup, yellow, ethosuximide 250 mg/5 mL, net price  200-mL pack = £4.22. Label: 8, counselling, blood  disorders (see above), driving (see notes above)   Gabapentin and pregabalin are used for the treatment  of focal seizures with or without secondary general-  isation. They are also licensed for the treatment of  neuropathic pain (p. 272). Pregabalin is licensed for  the treatment of generalised anxiety disorder (p. 233).  Gabapentin is an effective treatment for migraine  prophylaxis [unlicensed] (p. 277).   The Scottish Medicines Consortium (p. 4) has advised  (July 2007) that pregabalin ( Lyrica ®) is not recom-  mended for the treatment of central neuropathic pain.  The Scottish Medicines Consortium (p. 4) has advised  (April 2009) that pregabalin (Lyrica®) is accepted for  restricted use within NHS Scotland for the treatment of  peripheral neuropathic pain in adults who have not  achieved adequate pain relief with, or have not  tolerated, first- or second-line treatments; discontinue  treatment if sufficient benefit is not achieved within 8  weeks of reaching the maximum tolerated dose.   Indications monotherapy and adjunctive treatment of  focal seizures with or without secondary generalisa-  tion; peripheral neuropathic pain (section 4.7.3);  migraine prophylaxis (section 4.7.4. 2)   Cautions avoid abrupt withdrawal (may cause anxiety,  insomnia, nausea, pain, and sweating — taper off over  at least 1 week); elderly; diabetes mellitus; false  positive readings with some urinary protein tests;  history of psychotic illness; interactions: Appendix 1  (gabapentin)   Renal impairment reduce dose to 600-1 800 mg daily  in 3 divided doses if eGFR 50-80 mL/minute/   1.73 m 2 ; reduce dose to 300-900 mg daily in 3 divided  doses if eGFR 30-50 mL/minute/ 1.73 m 2 ; reduce  dose to 300 mg on alternate days (up to max. 600 mg  daily) in 3 divided doses if eGFR 15-30 mL/minute/  1.73 m 2 ; reduce dose to 300 mg on alternate days (up  to max. 300 mg daily) in 3 divided doses if eGFR less  than 15 mL/minute/ 1.73 m 2 — consult product litera-  ture    Pregnancy see Pregnancy, p. 280  Breast-feeding present in milk — manufacturer  advises use only if potential benefit outweighs risk;  see also Breast-feeding, p. 280  Side-effects diarrhoea, dry mouth, dyspepsia, nausea,  vomiting, constipation, abdominal pain, flatulence,  appetite changes, gingivitis, weight gain; hyper-  tension, vasodilation, oedema; dyspnoea, cough,  rhinitis; confusion, depression, hostility, sleep distur-  bances, headache, dizziness, anxiety, amnesia, ataxia,  dysarthria, nystagmus, tremor, asthenia, paraesthesia,  hyperkinesia; influenza-like symptoms; impotence,  urinary incontinence; leucopenia; myalgia, arthralgia;  diplopia, amblyopia; rash, purpura, pruritus, acne;  rarely pancreatitis, hepatitis, jaundice, palpitation,  hallucinations, movement disorders, thrombocytope-  nia, blood-glucose fluctuations in patients with dia-  betes, tinnitus, acute renal failure, Stevens- Johnson  syndrome, and alopecia; suicidal ideation; psychosis  also reported  Dose   • Epilepsy, 300 mg once daily on day 1, then 300 mg  twice daily on day 2, then 300 mg 3 times daily on day  3 or initially 300 mg 3 times daily on day 1; then    increased according to response in steps of 300 mg (in  3 divided doses) every 2-3 days; usual dose 0.9-3. 6 g  daily in 3 divided doses; CHILD 6-12 years (adjunctive  therapy only) initially 10-15 mg/kg (max. 300 mg)  once daily, then increased according to response over  3 days to usual dose 25-35 mg/kg daily in 3 divided  doses; max. 50 mg/kg daily in 3 divided doses; CHILD  2-6 years see BNF for Children   • Neuropathic pain, ADULT over 18 years, 300 mg once  daily on day 1, then 300 mg twice daily on day 2, then  300 mg 3 times daily on day 3 or initially 300 mg 3  times daily on day 1, then increased according to  response in steps of 300 mg (in 3 divided doses) every  2-3 days up to max. 3.6 g daily   • Migraine prophylaxis [unlicensed], initially 300 mg  daily, increased according to response up to 2.4 g  daily in divided doses   Capsules, gabapentin 100 mg, net price 100-cap pack  = £3.57; 300 mg, 100-cap pack = £8.83; 400 mg, 100-  cap pack = £5.53. Label: 3, 5, 8, counselling, driving  (see notes above)   Tablets, gabapentin 600 mg, net price 100-tab pack =  £24.85; 800 mg, 100-tab pack = £36.42. Label: 3, 5, 8,  counselling, driving (see notes above)   Capsules, gabapentin 100 mg (white), net price 100-  cap pack = £18.29; 300 mg (yellow), 100-cap pack =  £42.40; 400 mg (orange), 100-cap pack = £49.06.  Label: 3, 5, 8, counselling, driving (see notes above)  Tablets, f/c, gabapentin 600 mg, net price 100-tab  pack = £84.80; 800 mg, 100-tab pack = £98.13.   Indications peripheral and central neuropathic pain  (section 4.7.3); adjunctive therapy for focal seizures  with or without secondary generalisation; generalised  anxiety disorder (section 4.3)   Cautions avoid abrupt withdrawal (taper over at least  1 week); severe congestive heart failure; conditions  that may precipitate encephalopathy  Renal impairment initially 75 mg daily and max.   300 mg daily if eGFR 30-60 mL/minute/ 1.73 m 2 ;  initially 25-50 mg daily and max. 150 mg daily in 1-2  divided doses if eGFR 15-30 mL/minute/ 1.73 m 2 ;  initially 25 mg once daily and max. 75 mg once daily if  eGFR less than 15 mL/minute/ 1.73 m 2  Pregnancy see Pregnancy, p. 280  Breast-feeding present in milk in animal studies —  manufacturer advises avoid; see also Breast-feeding,   Side-effects dry mouth, constipation, vomiting,  flatulence, oedema, dizziness, drowsiness, irritability,  impaired attention, disturbances in muscle control  and movement, speech disorder, impaired memory,  paraesthesia, euphoria, confusion, malaise, appetite  changes, insomnia, weight gain, sexual dysfunction,  visual disturbances (including blurred vision, diplopia,  visual field defects); less commonly abdominal dis-  tension, hypersalivation, gastro-oesophageal reflux  disease, thirst, taste disturbance, flushing, hypo-  tension, hypertension, tachycardia, syncope, first-  degree AV block, dyspnoea, nasal dryness, stupor,  depersonalisation, depression, abnormal dreams,  hallucinations, agitation, cognitive impairment, panic    attacks, chills, hypoglycaemia, thrombocytopenia,  urinary incontinence, dysuria, myalgia, arthralgia, dry  eye, lacrimation, hyperacusis, nasopharyngitis,  sweating, rash; rarely ascites, dysphagia, pancreatitis,  weight loss, cold extremities, arrhythmia, bradycardia,  cough, epistaxis, rhinitis, parosmia, hyperglycaemia,  renal failure, oliguria, menstrual disturbances, breast  pain, breast discharge, breast hypertrophy, neutrope-  nia, hypokalaemia, leucopenia, rhabdomyolysis, urti-  caria; also reported diarrhoea, nausea, congestive  heart failure, QT-interval prolongation, aggression,  headache, convulsions, encephalopathy, urinary  retention, keratitis, Stevens- Johnson syndrome, pru-  ritus; suicidal ideation  Dose   • Neuropathic pain, ADULT over 18 years, initially 150 mg  daily in 2-3 divided doses, increased if necessary after  3-7 days to 300 mg daily in 2-3 divided doses,  increased further if necessary after 7 days to max.  600 mg daily in 2-3 divided doses   • Epilepsy, ADULT over 18 years, initially 25 mg twice  daily, increased at 7-day intervals in steps of 50 mg  daily to 300 mg daily in 2-3 divided doses, increased  further if necessary after 7 days to max. 600 mg daily  in 2-3 divided doses   • Generalised anxiety disorder, ADULT over 18 years,  initially 150 mg daily in 2-3 divided doses, increased if  necessary at 7-day intervals in steps of 150 mg daily;  max. 600 mg daily in 2-3 divided doses   Note Pregabalin doses in BNF may differ from those in product   Capsules, pregabalin 25 mg (white), net price 56-cap  pack = £64.40, 84-cap pack = £96.60; 50 mg (white),  84-cap pack = £96.60; 75 mg (white/orange), 56-cap  pack = £64.40; 100 mg (orange), 84-cap pack =  £96.60; 150 mg (white), 56-cap pack = £64.40; 200 mg  (orange), 84-cap pack = £96.60; 225 mg (white/  orange), 56-cap pack = £64.40; 300 mg (white/  orange), 56-cap pack = £64.40. Label: 3, 8, counsel-  ling, driving (see notes above)   Lacosamide is licensed for adjunctive treatment of  focal seizures with or without secondary generalisation.   The Scottish Medicines Consortium (p. 4) has advised  (January 2009) that lacosamide ( Vimpat ®) is accepted  for restricted use within NHS Scotland as adjunctive  treatment for focal seizures with or without secondary  generalisation in patients from 16 years. It is restricted  for specialist use in refractory epilepsy.   Indications see notes above  Cautions risk of PR-interval prolongation (including  conduction problems, severe cardiac disease, and  concomitant use of drugs that prolong PR interval),  elderly; interactions: Appendix 1 (lacosamide)  Contra-indications second- or third-degree AV block  Hepatic impairment caution in severe impairment —  no information available   250 mg daily if eGFR less than 30 mL/minute/1.73 m 2  Pregnancy see Pregnancy, p. 280   Side-effects nausea, vomiting, constipation, flatu-  lence, dizziness, headache, impaired coordination,  cognitive disorder, drowsiness, tremor, depression,  fatigue, abnormal gait, blurred vision, nystagmus,  pruritus; also reported dyspepsia, dry mouth, first-  degree AV block, bradycardia, PR-interval prolonga-  tion, confusion, hypoesthesia, dysarthria, irritability,  muscle spasm, tinnitus, rash; suicidal ideation   • By intravenous infusion over 15-60 minutes (for up to  5 days) or by mouth, ADULT and CHILD over 16 years,  initially 50 mg twice daily, increased weekly by 50 mg  twice daily; max. 200 mg twice daily    Vimpat® (UCB Pharma) T (Ml  Tablets, f/c, lacosamide 50 mg (pink), net price 14-tab  pack = £10.81; 100 mg (yellow), 14-tab pack = £21.62,  56-tab pack = £86.50; 150 mg (pink), 14-tab pack =  £32.44, 56-tab pack £129.74; 200 mg (blue), 56-tab  pack = £144.16. Label: 8, counselling, driving (see  notes above)   Syrup, lacosamide 15mg/mL, net price 200 mL =  £38.61. Label: 8, counselling, driving (see notes above)   Electrolytes Na + 0.4 mmol/5 mL  Excipients include aspartame (section 9.4.1)   Lamotrigine is an antiepileptic for focal seizures and  primary and secondary generalised tonic-clonic sei-  zures. It is also licensed for typical absence seizures in  children (but efficacy may not be maintained in all  children). Lamotrigine may cause serious rashes espe-  cially in children; dose recommendations should be  adhered to closely.   Lamotrigine is used either as sole treatment or as an  adjunct to treatment with other antiepileptic drugs. Val-  proate increases plasma-lamotrigine concentration,  whereas the enzyme-inducing antiepileptics reduce it;  care is therefore required in choosing the appropriate  initial dose and subsequent titration. When the potential  for interaction is not known, treatment should be  initiated with lower doses, such as those used with  valproate.   Indications monotherapy and adjunctive treatment of  focal seizures and generalised seizures including  tonic-clonic seizures; seizures associated with Len-  nox-Gastaut syndrome; monotherapy of typical  absence seizures in children; prevention of depressive  episodes associated with bipolar disorder  Cautions closely monitor and consider withdrawal if  rash, fever, or other signs of hypersensitivity  syndrome develop; avoid abrupt withdrawal (taper off  over 2 weeks or longer) unless serious skin reaction  occurs; myoclonic seizures (may be exacerbated);  Parkinson’s disease (may be exacerbated); interac-  tions: see p. 279 and Appendix 1 (lamotrigine)   Blood disorders Be alert for symptoms and signs sugges-  tive of bone-marrow failure such as anaemia, bruising, or    infection. Aplastic anaemia, bone-marrow depression and  pancytopenia have been associated rarely with lamotrigine  Hepatic impairment halve dose in moderate impair-  ment; quarter dose in severe impairment  Renal impairment caution in renal failure; metabolite  may accumulate; consider reducing maintenance  dose in significant impairment  Pregnancy see Pregnancy, p. 280  Breast-feeding present in milk but limited data sug-  gest no harmful effects on infants; see also Breast-  feeding, p. 280    Side-effects nausea, vomiting, diarrhoea, dry mouth,  aggression, agitation, headache, drowsiness, dizzi-  ness, tremor, insomnia, ataxia, back pain, arthralgia,  nystagmus, diplopia, blurred vision, rash (see Skin  Reactions, below); rarely conjunctivitis; very rarely  hepatic failure, aseptic meningitis, movement disor-  ders, unsteadiness, increase in seizure frequency,  exacerbation of Parkinson’s disease, confusion, hal-   lucination, blood disorders (including anaemia,  leucopenia, thrombocytopenia, pancytopenia — see  Blood Disorders, above), hypersensitivity syndrome  (possibly including rash, fever, facial oedema, lym-  phadenopathy, hepatic dysfunction, blood disorders,  disseminated intravascular coagulation, and multi-  organ dysfunction), lupus erythematosus-like reac-  tions; also reported suicidal ideation  Skin reactions Serious skin reactions including Stevens-  Johnson syndrome and toxic epidermal necrolysis have  developed especially in children; most rashes occur in the  first 8 weeks. Rash is sometimes associated with hyper-  sensitivity syndrome (see Side-effects, above) and is more  common in patients with history of allergy or rash from other  antiepileptic drugs. Consider withdrawal if rash or signs of  hypersensitivity syndrome develop. Factors associated with  increased risk of serious skin reactions include concomitant  use of valproate, initial lamotrigine dosing higher than  recommended, and more rapid dose escalation than  recommended.    Counselling Warn patients to see their doctor immediately  if rash or signs or symptoms of hypersensitivity syndrome  develop   Note Dose titration should be repeated if restarting after an  interval of more than 5 days   • Monotherapy of seizures, ADULT and CHILD over 12  years, initially 25 mg once daily for 14 days, increased  to 50 mg once daily for further 14 days, then increased  by max. 100 mg every 7-14 days; usual maintenance  100-200 mg daily in 1-2 divided doses (up to 500 mg  daily has been required)   • Adjunctive therapy of seizures with valproate, ADULT  and CHILD over 12 years, initially 25 mg on alternate  days for 14 days then 25 mg once daily for further 14  days, thereafter increased by max. 50 mg every 7-14  days; usual maintenance, 100-200 mg daily in 1-2  divided doses; CHILD 2-12 years initially 150 micr-  ograms/kg once daily for 14 days (those weighing  under 13 kg may receive 2 mg on alternate days for  first 14 days) then 300 micrograms/kg once daily for  further 14 days, thereafter increased by max.   300 micrograms/kg every 7-14 days; usual mainte-  nance 1-5 mg/kg daily in 1-2 divided doses (max.  single dose 100 mg)   • Adjunctive therapy of seizures (with enzyme inducing  drugs) without valproate, ADULT and CHILD over 12  years, initially 50 mg once daily for 14 days then    50 mg twice daily for further 14 days, thereafter  increased by max. 100 mg every 7-14 days; usual  maintenance 200-400 mg daily in 2 divided doses (up  to 700 mg daily has been required); CHILD 2-12 years  initially 600 micrograms/kg daily in 2 divided doses  for 14 days then 1.2 mg/kg daily in 2 divided doses for  further 14 days, thereafter increased by max. 1.2 mg/  kg every 7-14 days; usual maintenance 5-15 mg/kg  daily in 2 divided doses (max. single dose 200 mg)   • Adjunctive therapy of seizures (without enzyme  inducing drugs) without valproate, ADULT and CHILD  over 12 years, initially 25 mg once daily for 14 days,  increased to 50 mg once daily for further 14 days, then  increased by max. 100 mg every 7-14 days; usual  maintenance 100-200 mg daily in 1-2 divided doses;  CHILD 2-12 years initially 300 micrograms/kg daily in  1-2 divided doses for 14 days then 600 micrograms/  kg daily in 1-2 divided doses for further 14 days,  thereafter increased by max. 600 micrograms/kg  every 7-14 days; usual maintenance 1-10 mg/kg  daily in 1-2 divided doses; max. 200 mg daily   • Monotherapy or adjunctive therapy of bipolar disor-  der (without enzyme inducing drugs) without val-  proate, ADULT over 18 years, initially 25 mg once daily  for 14 days, then 50 mg daily in 1-2 divided doses for  further 14 days, then 100 mg daily in 1-2 divided  doses for further 7 days; usual maintenance 200 mg  daily in 1-2 divided doses; max. 400 mg daily   • Adjunctive therapy of bipolar disorder with valproate,  ADULT over 18 years, initially 25 mg on alternate days  for 14 days, then 25 mg once daily for further 14 days,  then 50 mg daily in 1-2 divided doses for further 7  days; usual maintenance 100 mg daily in 1-2 divided  doses; max. 200 mg daily   • Adjunctive therapy of bipolar disorder (with enzyme  inducing drugs) without valproate, ADULT over 18  years, initially 50 mg once daily for 14 days, then  50 mg twice daily for further 14 days, then 100 mg  twice daily for further 7 days, then 150 mg twice daily  for further 7 days; usual maintenance 200 mg twice  daily   Note Patients stabilised on lamotrigine for bipolar disorder  may require dose adjustments if other drugs are added to or  withdrawn from their treatment regimens — consult product  literature    Lamotrigine (Non-proprietary) T  Tablets, lamotrigine 25 mg, net price 56-tab pack =  £2.25; 50 mg, 56-tab pack = £3.07; 100 mg, 56-tab  pack = £4.53; 200 mg, 30-tab pack = £27.53, 56-tab  pack = £7.51. Label: 8, counselling, driving (see notes  above), skin reactions (see above)   Dispersible tablets, lamotrigine 5 mg, net price 28-  tab pack = £2.27; 25 mg, 56-tab pack = £2.91; 100 mg,  56-tab pack = £5.86. Label: 8, 13, counselling, driving  (see notes above), skin reactions (see above)   Tablets, yellow, lamotrigine 25 mg, net price 56-tab  pack = £19.61; 50 mg, 56-tab pack = £33.35; 100 mg,  56-tab pack = £57.53; 200 mg, 56-tab pack = £97.79.  Label: 8, counselling, driving (see notes above), skin  reactions (above)   Dispersible tablets, chewable, lamotrigine 2 mg, net  price 30-tab pack = £10.45; 5 mg, 28-tab pack = £7.82;  25 mg, 56-tab pack = £19.61; 100 mg, 56-tab pack =  £57.53. Label: 8, 13, counselling, , driving (see notes  above), skin reactions (above)   Levetiracetam is licensed for monotherapy and adjunc-  tive treatment of focal seizures with or without second-  ary generalisation, and for adjunctive therapy of myo-  clonic seizures in patients with juvenile myoclonic  epilepsy and primary generalised tonic-clonic seizures.   Hepatic impairment halve dose in severe hepatic  impairment if eGFR less than 60mL/minute/1.73 m 2  Renal impairment max. 2 g daily if eGFR 50-80 mL/  minute/1.73 m 2 ; max. 1.5 g daily if eGFR 30-50 mL/  minute/ 1.73 m 2 ; max. 1 g daily if eGFR less than  30 mL/minute/ 1 .73 m 2  Pregnancy see Pregnancy, p. 280  Breast-feeding present in milk — manufacturer  advises avoid; see also Breast-feeding, p. 280  Side-effects anorexia, weight changes, abdominal  pain, nausea, vomiting, dyspepsia, diarrhoea, cough,  drowsiness, amnesia, ataxia, convulsion, dizziness,  headache, tremor, hyperkinesia, malaise, impaired  attention, aggression, agitation, depression, insomnia,  anxiety, irritability, personality disorder, thrombocy-  topenia, myalgia, diplopia, blurred vision, rash; also  reported pancreatitis, hepatic failure, paraesthesia,  confusion, psychosis, suicidal ideation, leucopenia,  neutropenia, pancytopenia, alopecia, toxic epidermal  necrolysis, Stevens-Johnson syndrome  Dose   • Monotherapy of focal seizures with or without sec-  ondary generalisation, by mouth or by intravenous  infusion, ADULT and CHILD over 16 years, initially  250 mg once daily increased after 1-2 weeks to   250 mg twice daily; thereafter, increased according to  response in steps of 250 mg twice daily every 2 weeks;  max. 1.5 g twice daily   • Adjunctive therapy of focal seizures with or without  secondary generalisation, by mouth, ADULT and CHILD  over 12 years, body-weight over 50 kg, initially 250 mg  twice daily, adjusted in steps of 500 mg twice daily  every 2-4 weeks; max. 1.5 g twice daily; CHILD over 6  months, body-weight under 50 kg, initially 10 mg/kg  once daily, adjusted in steps not exceeding 10 mg/kg  twice daily every 2 weeks; max. 30 mg/kg twice daily;  CHILD 1-6 months, initially 7 mg/kg once daily,  adjusted in steps not exceeding 7 mg/kg twice daily  every 2 weeks; max. 2 1 mg/kg twice daily   By intravenous infusion, ADULT and CHILD over 12  years, body-weight over 50 kg, initially 250 mg twice  daily, adjusted in steps of 500 mg twice daily every 2-  4 weeks; max. 1.5 g twice daily; CHILD over 4 years,  body-weight under 50 kg, initially 10 mg/kg once  daily, adjusted in steps not exceeding 10 mg/kg twice  daily every 2 weeks; max. 30 mg/kg twice daily   • Adjunctive therapy of myoclonic seizures and tonic-  clonic seizures, by mouth or by intravenous infusion,  ADULT and CHILD over 12 years, body-weight over   50 kg, initially 250 mg twice daily, adjusted in steps of  500 mg twice daily every 2-4 weeks; max. 1.5 g twice  daily; CHILD 12-18 years, body-weight under 50kg,  initially 10 mg/kg once daily, adjusted in steps not  exceeding 10 mg/kg twice daily every 2 weeks; max.  30 mg/kg twice daily    • If switching from oral to intravenous therapy (because  oral route temporarily unavailable), by intravenous  infusion, same as established oral dose  Note Levetiracetam doses in BNF may differ from those in  product literature   Tablets, f/c, levetiracetam 250 mg (blue), net price  60-tab pack = £29.70; 500 mg (yellow), 60-tab pack =  £52.30; 750 mg (orange) 60-tab pack = £89.10; 1 g  (white), 60-tab pack = £101.10. Label: 8  Oral solution, sugar-free, levetiracetam lOOmg/mL,  net price 150 mL (with 1 mL or 3 mL syringe) =  £42.60, 300 mL = £71.00. Label: 8  Concentrate for intravenous infusion, levetiracetam  lOOmg/mL, net price 5-mL vial = £13.50    Phenobarbital is effective for tonic-clonic and focal  seizures but may be sedative in adults and cause  behavioural disturbances and hyperkinesia in children.  It may be tried for atypical absence, atonic, and tonic  seizures. Rebound seizures may be a problem on with-  drawal. For therapeutic purposes phenobarbital and  phenobarbital sodium should be considered equivalent  in effect. Plasma-phenobarbital concentration for opti-  mum response is 15-40 mg/litre (60-180 micromol/  litre); however, monitoring the plasma concentration is  less useful than with other drugs because tolerance  occurs.   Primidone is largely converted to phenobarbital and  this is probably responsible for its antiepileptic action. A  low initial dose of primidone is essential, and the drug  should be introduced over several weeks.   Indications all forms of epilepsy except typical  absence seizures; status epilepticus (section 4.8.2)  Cautions see notes above; elderly; debilitated; chil-  dren; respiratory depression (avoid if severe); avoid  abrupt withdrawal (dependence with prolonged use);  history of drug or alcohol abuse; consider vitamin D  supplementation in patients who are immobilised for  long periods or who have inadequate sun exposure or  dietary intake of calcium; avoid in acute porphyria  (section 9.8.2); interactions: see p. 279 and Appendix  1 (barbiturates)   Hepatic impairment may precipitate coma; avoid in  severe impairment  Renal impairment use with caution  Pregnancy see Pregnancy, p. 280  Breast-feeding avoid if possible; drowsiness may  occur; see also Breast-feeding, p. 280  Side-effects hepatitis, cholestasis; hypotension; resp-  iratory depression; behavioural disturbances, nystag-  mus, irritability, drowsiness, lethargy, depression,  ataxia, paradoxical excitement, hallucinations,  impaired memory and cognition, hyperactivity parti-  cularly in the elderly and in children; osteomalacia  (see Cautions); megaloblastic anaemia (may be trea-  ted with folic acid), agranulocytosis, thrombocytope-  nia; allergic skin reactions; very rarely Stevens- John-    son syndrome and toxic epidermal necrolysis; suicidal  ideation; overdosage: see Emergency Treatment of  Poisoning, p. 33   • By mouth, 60-180 mg at night; CHILD 5-8 mg/kg daily   Tablets, phenobarbital 15 mg, net price 28-tab pack =  95p; 30 mg, 28-tab pack = 96p; 60 mg, 28-tab pack =  71p. Label: 2, 8, counselling, driving (see notes above)  Elixir, phenobarbital 15 mg/5 mL in a suitable fla-  voured vehicle, containing alcohol 38%, net price  100 mL = 78p. Label: 2, 8, counselling, driving (see  notes above)   Cautions see under Phenobarbital; interactions: see  p. 279 and Appendix 1 (primidone)   Renal impairment see Phenobarbital  Pregnancy see Phenobarbital  Breast-feeding see Phenobarbital  Side-effects see Phenobarbital; also nausea, visual  disturbances; less commonly vomiting, headache,  dizziness; rarely psychosis, lupus erythematosus,  arthralgia; also reported Dupuytren’s contracture   • Epilepsy, ADULT and CHILD over 9 years, initially 125 mg  daily at bedtime, increased by 125 mg every 3 days to  500 mg daily in 2 divided doses, then increased  according to response by 250 mg every 3 days to  usual maintenance 0.75-1.5 g daily in 2 divided doses;  CHILD under 9 years, initially 125 mg daily at bedtime,  increased by 125 mg every 3 days according to  response; usual maintenance, CHILD under 2 years,  250-500 mg daily in 2 divided doses; 2-5 years, 500-  750 mg daily in 2 divided doses; 5-9 years 0.75-1 g  daily in 2 divided doses   • Essential tremor, initially 50 mg daily increased gra-  dually over 2-3 weeks according to response; max.  750 mg daily   Tablets, scored, primidone 50 mg, net price 100-tab  pack = £12.60; 250 mg, 100-tab pack = £12.60.  Label: 2, 8, counselling, driving (see notes above)   Phenytoin is effective for tonic-clonic and focal sei-  zures. It has a narrow therapeutic index and the relation-  ship between dose and plasma concentration is non-  linear; small dosage increases in some patients may  produce large increases in plasma concentration with  acute toxic side-effects. Similarly, a few missed doses or  a small change in drug absorption may result in a  marked change in plasma concentration. Monitoring  of plasma concentration improves dosage adjustment.  Symptoms of phenytoin toxicity include nystagmus,   Phenytoin may cause coarsening of the facial appear-  ance, acne, hirsutism, and gingival hyperplasia and so  may be particularly undesirable in adolescent patients.  When only parenteral administration is possible,  fosphenytoin (section 4.8.2), a pro-drug of phenytoin,  may be convenient to give. Whereas phenytoin can be  given intravenously only, fosphenytoin may also be  given by intramuscular injection.   Indications all forms of epilepsy except absence sei-  zures; status epilepticus (section 4.8.2); trigeminal  neuralgia if carbamazepine inappropriate (see also  section 4.7.3)   Cautions cross-sensitivity reported with carbamaze-  pine; avoid abrupt withdrawal; HLA-B*1502 allele in  individuals of Han Chinese or Thai origin — avoid  unless essential (increased risk of Stevens- Johnson  syndrome); manufacturer recommends blood counts  (but evidence of practical value uncertain); consider  vitamin D supplementation in patients who are  immobilised for long periods or who have inadequate  sun exposure or dietary intake of calcium; enteral  feeding (interrupt feeding for 2 hours before and after  dose; more frequent monitoring may be necessary);  avoid in acute porphyria (section 9.8.2); interactions:  see p. 279 and Appendix 1 (phenytoin)   Blood or skin disorders Patients or their carers should be  told how to recognise signs of blood or skin disorders, and  advised to seek immediate medical attention if symptoms  such as fever, rash, mouth ulcers, bruising, or bleeding  develop. Leucopenia that is severe, progressive, or asso-  ciated with clinical symptoms requires withdrawal (if  necessary under cover of a suitable alternative)   Breast-feeding small amount present in milk, but not  known to be harmful; see also Breast-feeding, p. 280  Side-effects nausea, vomiting, constipation, drowsi-  ness, insomnia, transient nervousness, tremor,  paraesthesia, dizziness, headache, anorexia; gingival  hypertrophy and tenderness (maintain good oral  hygiene); rash (discontinue; if mild re-introduce cau-  tiously but discontinue immediately if recurrence),  acne, hirsutism, coarsening of facial appearance;  rarely hepatotoxicity, peripheral neuropathy, dys-  kinesia, lymphadenopathy, osteomalacia (see Cau-  tions); blood disorders (including megaloblastic  anaemia, leucopenia, thrombocytopenia, and aplastic  anaemia), polyarteritis nodosa, lupus erythematosus,  Stevens- Johnson syndrome, and toxic epidermal  necrolysis; also reported polyarthropathy, pneumoni-  tis, and interstitial nephritis; suicidal ideation  Dose   • By mouth, initially 3-4 mg/kg daily or 150-300 mg  daily (as a single dose or in 2 divided doses) increased  gradually as necessary (with plasma-phenytoin con-  centration monitoring); usual dose 200-500 mg daily  (exceptionally, higher doses may be used); CHILD  initially 5 mg/kg daily in 2 divided doses, usual dose  range 4-8 mg/kg daily (max. 300 mg daily)   Note Plasma concentration for optimum response 10-  20 mg/litre (40-80 micromol/litre)    Phenytoin (Non-proprietary) (Ml  Tablets, coated, phenytoin sodium 100 mg, net price  28-tab pack = £30.00. Label: 8, counselling, adminis-  tration, blood or skin disorder symptoms (see above),  driving (see notes above)   Note On the basis of single dose tests there are no clinically  relevant differences in bioavailability between available phenytoin  sodium tablets and capsules but there may be a pharmacokinetic  basis for maintaining the same brand of phenytoin in some  patients   Capsules, phenytoin sodium 25 mg (white/purple),  net price 28-cap pack = 66p; 50 mg (white/pink), 28-  cap pack = 67p; 100 mg (white/orange), 84-cap pack  = £2.83; 300 mg (white/green), 28-cap pack = £2.83.  Label: 8, counselling, administration, blood or skin  disorder symptoms (see above), driving (see notes  above)   Chewable tablets ( Infatabs ®), yellow, scored,  phenytoin 50 mg, net price 112 = £7.38. Label: 8, 24,  counselling, blood or skin disorder symptoms (see  above), driving (see notes above)   Note Contain phenytoin 50 mg (as against phenytoin sodium)  therefore care is needed on changing to capsules or tablets  containing phenytoin sodium   Suspension, red, phenytoin 30 mg/5 mL, net price  500 mL = £4.27. Label: 8, counselling, administration,  blood or skin disorder symptoms (see above), driving  (see notes above)   Note Suspension of phenytoin 90 mg in 15 mL may be considered  to be approximately equivalent in therapeutic effect to capsules or  tablets containing phenytoin sodium 100 mg, but nevertheless  care is needed in making changes   Rufinamide is licensed for the adjunctive treatment of  seizures in Lennox-Gastaut syndrome.   The Scottish Medicines Consortium (p. 4) has advised  (October 2008) that rufinamide ( Inovelon ®) is accepted  for restricted use within NHS Scotland as adjunctive  therapy in the treatment of seizures associated with  Lennox-Gastaut syndrome in patients 4 years and  above. It is restricted for use when alternative traditional  antiepileptic drugs are unsatisfactory.   Indications see notes above  Cautions closely monitor and consider withdrawal if  rash, fever, or other signs of hypersensitivity  syndrome develop; avoid abrupt withdrawal; inter-  actions: see p. 279 and Appendix 1 (rufinamide)  Hepatic impairment caution and careful dose titra-  tion in mild to moderate impairment; avoid in severe  impairment   Pregnancy see Pregnancy, p. 280  Breast-feeding manufacturer advises avoid — no  information available; see also Breast-feeding, p. 280  Side-effects nausea, vomiting, constipation, diarr-  hoea, dyspepsia, abdominal pain, weight loss, ano-  rexia; rhinitis, epistaxis; dizziness, headache, drowsi-  ness, insomnia, anxiety, fatigue, increase in seizure  frequency, impaired coordination, hyperactivity, tre-  mor, gait disturbances; influenza-like symptoms; oli-  gomenorrhoea; back pain; nystagmus, diplopia,  blurred vision; rash and acne; hypersensitivity  syndrome (possibly including rash, fever, lymphade-    nopathy, hepatic dysfunction, haematuria, and multi-  organ dysfunction) also reported  Hypersensitivity syndrome Serious hypersensitivity  syndrome (see Side-effects) has developed, especially in  children and upon initiation of therapy; consider withdrawal  if rash or signs or symptoms of hypersensitivity syndrome  develop   Counselling Warn patients to seek immediate medical  attention if signs or symptoms of hypersensitivity develop   • ADULT and CHILD over 4 years body-weight over 30 kg,  initially 200 mg twice daily increased according to  response in steps of 200 mg twice daily at intervals of  not less than 2 days; body-weight 30-50 kg max.   900 mg twice daily; body-weight 50-70 kg max. 1.2 g  twice daily; body-weight over 70 kg max. 1.6 g twice  daily; CHILD over 4 years body-weight less than 30 kg,  initially 100 mg twice daily increased according to  response in steps of 100 mg twice daily at intervals of  not less than 2 days; max. 500 mg twice daily (max.  300 mg twice daily if adjunctive therapy with val-  proate)   Tablets, pink, f/c, scored, rufinamide 100 mg, net  price 10-tab pack = £5.15; 200 mg, 60-tab pack =  £61.77; 400 mg, 60-tab pack = £102.96. Label: 21,  counselling, driving (see notes above), hypersensi-  tivity syndrome (see above)   Tiagabine is used as adjunctive treatment for focal  seizures with or without secondary generalisation that  are not satisfactorily controlled by other antiepileptics.   Hepatic impairment maintenance dose 5-10 mg 1-2  times daily initially in mild to moderate impairment;  avoid in severe impairment  Pregnancy see Pregnancy, p. 280  Breast-feeding manufacturer advises use only if  potential benefit outweighs risk; see also Breast-  feeding, p. 280   Side-effects diarrhoea; dizziness, tiredness, nervous-  ness, tremor, impaired concentration, emotional labi-  lity, speech impairment; rarely confusion, depression,  drowsiness, psychosis, non-convulsive status epi-  lepticus, bruising, and visual disturbances; suicidal  ideation; leucopenia also reported  Dose   • Adjunctive therapy, ADULT and CHILD over 12 years,  with enzyme-inducing drugs, 5 mg twice daily for 1  week, then increased at weekly intervals in steps of 5-  10 mg daily; usual maintenance dose 30-45 mg daily  (doses above 30 mg given in 3 divided doses); in  patients receiving non-enzyme-inducing drugs, initial  maintenance dose 15-30 mg daily   Tablets, f/c, tiagabine (as hydrochloride) 5 mg, net  price 100-tab pack = £40.89; 10 mg, 100-tab pack =  £81.77; 15 mg, 100-tab pack = £122.66. Label: 21   Topiramate can be given alone or as adjunctive treat-  ment in generalised tonic-clonic seizures or focal sei-  zures with or without secondary generalisation. It can  be used as adjunctive treatment for seizures associated  with Lennox-Gastaut syndrome. Topiramate is also  licensed for prophylaxis of migraine (section 4.7.4.2).   Cautions avoid abrupt withdrawal; risk of metabolic  acidosis; risk of nephrolithiasis — ensure adequate  hydration (especially in strenuous activity or warm  environment); avoid in acute porphyria (section 9.8.2);  interactions: see p. 279 and Appendix 1 (topiramate)  Important Topiramate has been associated with acute myo-  pia with secondary angle-closure glaucoma, typically  occurring within 1 month of starting treatment. Choroidal  effusions resulting in anterior displacement of the lens and  iris have also been reported. If raised intra-ocular pressure  occurs:    Hepatic impairment use with caution in moderate to  severe impairment — clearance may be reduced  Renal impairment use with caution if eGFR less than  60 mL/minute/ 1.73 m 2 — reduced clearance and  longer time to steady-state plasma concentration  Pregnancy see Pregnancy, p. 280  Breast-feeding manufacturer advises avoid — present  in milk; see also Breast-feeding, p. 280  Side-effects nausea, diarrhoea, vomiting, constipa-  tion, dyspepsia, abdominal pain, dry mouth, taste  disturbance, gastritis, appetite changes, dyspnoea,  impaired attention, cognitive impairment, movement  disorders, seizures, tremor, malaise, impaired coordi-  nation, speech disorder, drowsiness, dizziness, sleep  disturbance, anxiety, confusion, paraesthesia, aggres-  sion, mood changes, depression, agitation, irritability,  nephrolithiasis, urinary disorders, anaemia, arthralgia,  muscle spasm, myalgia, muscular weakness, visual  disturbances, nystagmus, tinnitus, epistaxis, alopecia,  rash, pruritus; less commonly pancreatitis, flatulence,  abdominal distension, gingival bleeding, salivation,  halitosis, thirst, glossodynia, bradycardia, palpitation,  hypotension, postural hypotension, flushing, altered  sense of smell, peripheral neuropathy, suicidal idea-  tion, psychosis, panic attack, influenza-like symptoms,  sexual dysfunction, urinary calculus, haematuria,  blood disorders (including leucopenia, neutropenia,  and thrombocytopenia), hypokalaemia, metabolic  acidosis, dry eye, photophobia, blepharospasm,  increased lacrimation, mydriasis, hearing loss,  reduced sweating, skin discoloration; rarely  Raynaud’s syndrome, periorbital oedema, unilateral  blindness, Stevens- Johnson syndrome, abnormal skin    odour, calcinosis; very rarely angle-closure glaucoma;  also reported maculopathy, toxic epidermal necroly-  sis   • Monotherapy, initially 25 mg at night for 1 week then  increased in steps of 25-50 mg taken in 2 divided  doses at intervals of 1-2 weeks; usual dose 100-  200 mg daily in 2 divided doses, adjusted according to  response; max. 500 mg daily (doses of 1 g daily have  been used in refractory epilepsy); CHILD 6-18 years,  initially 0.5-1 mg/kg (max. 25 mg) at night for 1 week  then increased in steps of 0.5-1 mg/kg taken in 2  divided doses at intervals of 1-2 weeks; initial target  dose 100 mg daily in 2 divided doses; max. 15 mg/kg  (max. 500 mg) daily   • Adjunctive therapy, initially 25-50 mg at night for 1  week then increased in steps of 25-50 mg taken in 2  divided doses at intervals of 1-2 weeks; usual dose  200-400 mg daily in 2 divided doses; max. 400 mg  daily; CHILD 2-18 years, initially 1-3 mg/kg (max.   25 mg) at night for 1 week then increased in steps of  1-3 mg/kg (max. 50 mg) taken in 2 divided doses at  intervals of 1-2 weeks; usual dose 5-9 mg/kg daily in  2 divided doses; max. 15 mg/kg (max. 400 mg) daily   • Migraine prophylaxis, ADULT, initially 25 mg daily at  night for 1 week then increased in steps of 25 mg at  intervals of 1 week; usual dose 50-100 mg daily in 2  divided doses; max. 200 mg daily    Topiramate (Non-proprietary) ▼ (Ml  Tablets, topiramate 25 mg, net price 60-tab pack =  £6.17; 50 mg, 60-tab pack = £10.74; 100 mg, 60-tab  pack = £12.52; 200 mg, 60-tab pack = £17.21. Label: 3,  8, counselling, driving (see notes above)   Capsules, topiramate 15 mg, net price 60-cap pack =  £16.61; 25 mg, 60-cap pack = £24.91; 50 mg, 60-cap  pack = £40.93. Label: 3, 8, counselling, driving (see  notes above)   Tablets, f/c, topiramate 25 mg, net price 60-tab pack  = £19.29; 50 mg (light yellow), 60-tab pack = £31.69;  100 mg (yellow), 60-tab pack = £56.76; 200 mg (sal-  mon), 60-tab pack = £110.23. Label: 3, 8, counselling,  driving (see notes above)   Capsules (Sprinkle®), topiramate 15 mg, net price  60-cap pack = £14.79; 25 mg, 60-cap pack = £22.18;  50 mg, 60-cap pack = £36.45. Label: 3, 8, counselling,  administration, driving (see notes above)   Sodium valproate is effective in controlling tonic-clon-  ic seizures, particularly in primary generalised epilepsy.  It is a drug of choice in primary generalised epilepsy,  generalised absences and myoclonic seizures, and can  be tried in atypical absence, atonic, and tonic seizures.  Sodium valproate has widespread metabolic effects and  monitoring is essential (see Cautions below).   Valproic acid (as semisodium valproate) (section 4.2.3)  is licensed for acute mania associated with bipolar  disorder.   Cautions monitor liver function before therapy and  during first 6 months especially in patients most at  risk (see also below); measure full blood count and  ensure no undue potential for bleeding before starting  and before surgery; systemic lupus erythematosus;  false-positive urine tests for ketones; avoid abrupt  withdrawal; consider vitamin D supplementation in  patients that are immobilised for long periods or who  have inadequate sun exposure or dietary intake of  calcium; interactions: see p. 279 and Appendix 1  (valproate)   Liver toxicity Liver dysfunction (including fatal hepatic fail-  ure) has occurred in association with valproate (especially in  children under 3 years and in those with metabolic or  degenerative disorders, organic brain disease or severe sei-  zure disorders associated with mental retardation) usually in  first 6 months and usually involving multiple antiepileptic  therapy. Raised liver enzymes during valproate treatment are  usually transient but patients should be reassessed clinically  and liver function (including prothrombin time) monitored  until return to normal — discontinue if abnormally prolonged  prothrombin time (particularly in association with other  relevant abnormalities).   Blood or hepatic disorders Patients or their carers should  be told how to recognise signs and symptoms of blood or  liver disorders and advised to seek immediate medical  attention if symptoms develop   Pancreatitis Patients or their carers should be told how to  recognise signs and symptoms of pancreatitis and advised to  seek immediate medical attention if symptoms such as  abdominal pain, nausea, or vomiting develop; discontinue if  pancreatitis is diagnosed   Contra-indications family history of severe hepatic  dysfunction; acute porphyria (section 9.8.2)   Hepatic impairment avoid if possible — hepatotoxi-  city and hepatic failure may occasionally occur  (usually in first 6 months); avoid in active liver disease;  see also under Cautions   Breast-feeding amount too small to be harmful; see  also Breast-feeding, p. 280  Side-effects nausea, gastric irritation, diarrhoea;  weight gain; hyperammonaemia, thrombocytopenia;  transient hair loss (regrowth may be curly); less fre-  quently increased alertness, aggression, hyperactivity,  behavioural disturbances, ataxia, tremor, and vascu-  litis; rarely hepatic dysfunction (see under Cautions;  withdraw treatment immediately if persistent vomi-  ting and abdominal pain, anorexia, jaundice, oedema,  malaise, drowsiness, or loss of seizure control),  lethargy, drowsiness, confusion, stupor, hallucina-  tions, blood disorders (including anaemia, leucopenia,  pancytopenia), hearing loss, and rash; very rarely  pancreatitis (see under Cautions), peripheral oedema,  increase in bleeding time, extrapyramidal symptoms,  dementia, encephalopathy, coma, gynaecomastia,  Fanconi’s syndrome, hirsutism, acne, enuresis, hypo-  natraemia, toxic epidermal necrolysis, and Stevens-  Johnson syndrome; suicidal ideation; reduced bone  mineral density (see Cautions); also reported men-  strual disturbances  Dose   • Epilepsy, by mouth, initially 600 mg daily in 1-2  divided doses, increased by 200 mg daily every 3    days; usual maintenance dose 1-2 g daily (20-30 mg/  kg daily), max. 2.5 g daily; CHILD body-weight up to  20 kg, initially 20 mg/kg daily in 1-2 divided doses,  increased according to response (dose above 40 mg/  kg daily monitor clinical chemistry and haematologi-  cal parameters); CHILD under 12 years body- weight  over 20 kg, initially 400 mg daily in 1-2 divided doses  increased according to response; usual maintenance  dose 20-30 mg/kg daily, max. 35 mg/kg daily  Initiation of valproate treatment, by intravenous  injection (over 3-5 minutes), up to 10 mg/kg (usually  400-800 mg) followed by intravenous infusion up to  max. 2.5 g daily; CHILD under 12 years, usually 20-  30 mg/kg daily, increased according to response  (dose above 40 mg/kg daily monitor clinical chemis-  try and haematological parameters)   Continuation of valproate treatment by intravenous  injection (over 3-5 minutes) in 2 divided doses or by  intravenous infusion, same as established oral dose  • Migraine prophylaxis [unlicensed], by mouth, initially  200 mg twice daily, increased if necessary to 1.2-1. 5 g  daily in divided doses    Sodium Valproate (Non-proprietary) (Ml  Tablets (crushable), scored, sodium valproate  100 mg, net price 100-tab pack = £5.60. Label: 8, 21,  counselling, pancreatitis, blood, or hepatic disorder  symptoms (see above), driving (see notes above)  Tablets, e/c, sodium valproate 200 mg, net price 100-  tab pack = £4.83; 500 mg, 100-tab pack = £10.09.  Label: 5, 8, 25, counselling, pancreatitis, blood, or  hepatic disorder symptoms (see above), driving (see  notes above)   Oral solution, sodium valproate 200 mg/5 mL, net  price 300 mL = £5.42. Label: 8, 21, counselling, pan-  creatitis, blood, or hepatic disorder symptoms (see  above), driving (see notes above)    Epilim® (Sanofi-Aventis) (Ml  Tablets (crushable), scored, sodium valproate  100 mg, net price 100 = £5.60. Label: 8, 21, counsel-  ling, pancreatitis, blood, or hepatic disorder symp-  toms (see above), driving (see notes above)   Tablets, e/c, lilac, sodium valproate 200 mg, net price  100 = £7.70; 500 mg, 100 = £19.25. Label: 5, 8, 25,  counselling, pancreatitis, blood, or hepatic disorder  symptoms (see above), driving (see notes above)  Liquid, red, sugar-free, sodium valproate 200 mg/  5mL, net price 300-mL pack = £9.33. Label: 8, 21,  counselling, pancreatitis, blood, or hepatic disorder  symptoms (see above), driving (see notes above)  Syrup, red, sodium valproate 200 mg/ 5 mL, net price  300-mL pack = £7.78. Label: 8, 21, counselling, pan-  creatitis, blood, or hepatic disorder symptoms (see  above), driving (see notes above)   Epilim Chrono® (Sanofi-Aventis) (EM  Tablets, m/r, lilac, sodium valproate 200 mg (as sod-  ium valproate and valproic acid), net price 100-tab  pack = £11.65; 300 mg, 100-tab pack = £17.47;    counselling, pancreatitis, blood, or hepatic disorder  symptoms (see above), driving (see notes above)   Dose ADULT and CHILD over 20 kg, as above, total daily dose  given in 1-2 divided doses   Epilim Chronosphere® (Sanofi-Aventis) (Ml  Granules, m/r, sodium valproate 50 mg (as sodium  valproate and valproic acid), net price 30-sachet pack  = £30.00; 100 mg, 30-sachet pack = £30.00; 250 mg,  30-sachet pack = £30.00; 500 mg, 30-sachet pack =  £30.00; 750 mg, 30-sachet pack = £30.00; 1000 mg,  30-sachet pack = £30.00. Label: 8, 21, 25, counselling,  administration, pancreatitis, blood, or hepatic disor-  der symptoms (see above), driving (see notes above)  Dose ADULT and CHILD, as above to the nearest whole 50-mg  sachet; total daily dose given in 1-2 divided doses  Counselling Granules may be mixed with soft food or drink that is  cold or at room temperature, and swallowed immediately without  chewing   Capsules, enclosing m/r granules, sodium valproate  150 mg, net price 100-cap pack = £7.00; 300 mg, 100-  cap pack = £13.00. Label: 8, 21, 25, counselling,  administration, pancreatitis, blood, or hepatic disor-  der symptoms (see above), driving (see notes above)  Dose ADULT and CHILD, as above, total daily dose given in 1-2  divided doses   Counselling Contents of capsule may be mixed with cold food or  drink and swallowed immediately without chewing  Granules, m/r, sodium valproate 500 mg, net price   B 100-sachet pack = £21.00; 1 g, 100-sachet pack =  £41.00. Label: 8, 21, 25, counselling, administration,  pancreatitis, blood, or hepatic disorder symptoms (see  above), driving (see notes above)   Dose ADULT and CHILD, as above, total daily dose given in 1-2  divided doses   Counselling Granules may be mixed with cold food or drink and  swallowed immediately without chewing   Epilim® Intravenous (Sanofi-Aventis) (Ml  Injection, powder for reconstitution, sodium val-  proate, net price 400-mg vial (with 4-mL amp water  for injections) = £11.58   ^Valproic acid  Convulex® (Pharmacia) (Ml  Capsules, e/c, valproic acid 150 mg, net price 100-  cap pack = £3.68; 300 mg, 100-cap pack = £7.35;   500 mg, 100-cap pack = £12.25. Label: 8, 21, 25,  counselling, pancreatitis, blood, or hepatic disorder  symptoms (see above), driving (see notes above)   Dose epilepsy, ADULT and CHILD over 12 years, initially 600 mg  daily in 2-4 divided doses, increased by 300 mg every 3 days to  max. 2.5 g daily, usual maintenance dose 1-2 g daily (20-30 mg/  kg daily); CHILD body-weight up to 20 kg, initially 20 mg/kg daily  in 2-4 divided doses, increased according to response (dose  above 40 mg/kg daily monitor clinical chemistry and haemato-  logical parameters); CHILD body-weight over 20 kg, initially  300 mg daily in 2-4 divided doses increased according to  response (usual range 20-30 mg/kg daily); max. 35 mg/kg daily  Equivalence to sodium valproate Convulex ® has a 1:1 dose  relationship with products containing sodium valproate, but  nevertheless care is needed if switching   Vigabatrin can be prescribed in combination with other  antiepileptic treatment for focal epilepsy with or without  secondary generalisation. It should not be prescribed  unless all other appropriate drug combinations are  ineffective or have not been tolerated, and it should  be initiated and supervised by an appropriate specialist.  Vigabatrin can be prescribed as monotherapy in the  management of infantile spasms in West’s syndrome.  About one-third of patients treated with vigabatrin have  suffered visual field defects; counselling and careful  monitoring for this side-effect are required (see also  Visual Field Defects under Cautions below). Vigabatrin  has prominent behavioural side-effects in some patients.   Indications see notes above  Cautions elderly; closely monitor neurological func-  tion; avoid sudden withdrawal (taper off over 2-4  weeks); history of psychosis, depression or  behavioural problems; absence seizures (may be  exacerbated); interactions: see p. 279 and Appendix  1 (vigabatrin)   Visual field defects Vigabatrin is associated with visual  field defects. The onset of symptoms varies from 1 month to  several years after starting. In most cases, visual field defects  have persisted despite discontinuation, and further dete-  rioration after discontinuation cannot be excluded. Product  literature advises visual field testing before treatment and at  6-month intervals. Patients should be warned to report any  new visual symptoms that develop and those with symptoms  should be referred for an urgent ophthalmological opinion.  Gradual withdrawal of vigabatrin should be considered.  Contra-indications visual held defects  Renal impairment consider reduced dose or  increased dose interval if eGFR less than 60 mL/  minute/ 1.73 m 2   Pregnancy see Pregnancy, p. 280  Breast-feeding present in milk — manufacturer  advises avoid; see also Breast-feeding, p. 280  Side-effects nausea, abdominal pain; oedema; drow-  siness ( rarely encephalopathic symptoms including  marked sedation, stupor, and confusion with non-  specific slow wave EEG — reduce dose or withdraw),  fatigue, excitation (in children), agitation, dizziness,  headache, nervousness, depression, aggression, irrit-  ability, paranoia, impaired concentration, impaired  memory, tremor, paraesthesia, speech disorder,  weight gain; visual field defects (see under Cautions),  blurred vision, nystagmus, diplopia; less commonly  ataxia, psychosis, mania, and rash; occasional  increase in seizure frequency (especially if myo-  clonic); rarely suicidal ideation and retinal disorders  (including peripheral retinal neuropathy); very rarely  hepatitis, optic neuritis, and optic atrophy; also  reported movement disorders in infantile spasms  Dose   • With current antiepileptic therapy, initially 1 g daily in  single or 2 divided doses then increased according to  response in steps of 500 mg at weekly intervals; usual  range 2-3 g daily (max. 3 g daily); CHILD initially  40 mg/kg daily in single or 2 divided doses then  adjusted according to body-weight 10-15 kg, 0.5-1 g  daily; body-weight 15-30 kg, 1-1.5 g daily; body-  weight 30-50 kg, 1.5-3 g daily; body-weight over  50 kg, 2-3 g daily   50 mg/kg daily, adjusted according to response over 7  days; up to 150 mg/kg daily used with good toler-  ability   Sabril® (Sanofi-Aventis) (Ml  Tablets, f/c, scored, vigabatrin 500 mg, net price 100-  tab pack = £30.84. Label: 3, 8, counselling, driving (see  notes above)   Powder, sugar-free, vigabatrin 500 mg/sachet. Net  price 50-sachet pack = £17.08. Label: 3, 8, 13, coun-  selling, driving (see notes above)   Note The contents of a sachet should be dissolved in water or a  soft drink immediately before taking   Zonisamide can be used as adjunctive treatment for  refractory focal seizures with or without secondary  generalisation.   Indications see notes above  Cautions elderly; ensure adequate hydration (espe-  cially if predisposition to nephrolithiasis or in stren-  uous activity or warm environment); concomitant use  of drugs that increase risk of hyperthermia or  nephrolithiasis; metabolic acidosis (consider dose  reduction or discontinuation); avoid abrupt with-  drawal; interactions: see p. 279 and Appendix 1  (zonisamide)   Contra-indications hypersensitivity to sulfonamides  Hepatic impairment initially increase dose at 2-week  intervals if mild or moderate impairment; avoid in  severe impairment   Renal impairment initially increase dose at 2-week  intervals; discontinue if renal function deteriorates  Pregnancy see Pregnancy, p. 280  Breast-feeding manufacturer advises avoid for 4  weeks after administration; see also Breast-feeding,   Side-effects nausea, diarrhoea, abdominal pain, con-  stipation, dyspepsia, anorexia, weight loss; drowsi-  ness, dizziness, confusion, agitation, irritability,  depression, psychosis, ataxia, speech disorder,  impaired memory and attention, fatigue, nystagmus,  paraesthesia, tremor, pyrexia, insomnia; diplopia;  ecchymosis; rash (consider withdrawal); less com-  monly vomiting, cholelithiasis, cholecystitis, aggres-  sion, suicidal ideation, seizures, pneumonia, urinary  tract infection, urinary calculus, and hypokalaemia;  very rarely hepatitis, pancreatitis, aspiration, dys-  pnoea, hallucinations, amnesia, coma, myasthenic  syndrome, neuroleptic malignant syndrome, heat  stroke, hydronephrosis, renal failure, metabolic aci-  dosis, renal tubular acidosis, blood disorders, rhab-  domyolysis, impaired sweating, pruritus, Stevens-  Johnson syndrome, and toxic epidermal necrolysis  Dose   • ADULT over 18 years, initially 50 mg daily in 2 divided  doses, increased after 7 days to 100 mg daily in 2  divided doses; then increase if necessary by 100 mg  every 7 days; usual maintenance 300-500 mg daily in  1-2 divided doses   Capsules, zonisamide 25 mg (white), net price 14-cap  pack = £8.82; 50 mg (white/grey), 56-cap pack =  £47.04; 100 mg (white/red), 56-cap pack = £62.72.  Label: 3   Clobazam may be used as adjunctive therapy in the  treatment of epilepsy. Clonazepam is occasionally used  in tonic-clonic or focal seizures, but its sedative side-  effects may be prominent.   The effectiveness of clobazam and clonazepam may  decrease significantly after weeks or months of contin-  uous therapy.   Cautions see Diazepam, section 4.1.2  Contra-indications see Diazepam, section 4.1.2  Hepatic impairment see Benzodiazepines, section  4.1.2    Renal impairment see Benzodiazepines, section 4.1.2  Pregnancy see Benzodiazepines, section 4.1.2  Breast-feeding see Benzodiazepines, section 4.1.2  Side-effects see Diazepam, section 4.1.2   • Epilepsy, 20-30 mg daily; max. 60 mg daily; CHILD over  3 years, not more than half adult dose   • Anxiety, 20-30 mg daily in divided doses or as a single  dose at bedtime, increased in severe anxiety (in hos-  pital patients) to a max. of 60 mg daily in divided  doses; ELDERLY (or debilitated) 10-20 mg daily   1 Clobazam (Non-proprietary) (Ml (Ml  Tablets, clobazam 10 mg. Net price 30-tab pack =  £4.68. Label: 2 or 19, 8, counselling, driving (see notes  above)   Cautions see notes above; elderly and debilitated,  respiratory disease, spinal or cerebellar ataxia; history  of alcohol or drug abuse, depression or suicidal  ideation; avoid sudden withdrawal; myasthenia gravis  (avoid if unstable); acute porphyria (section 9.8.2);  interactions: Appendix 1 (anxiolytics and hypnotics)  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced  Contra-indications respiratory depression; acute  pulmonary insufficiency; sleep apnoea syndrome;  marked neuromuscular respiratory weakness includ-  ing unstable myasthenia gravis  Hepatic impairment see Benzodiazepines, section  4.1.2   Renal impairment see Benzodiazepines, section 4.1.2  Pregnancy see Benzodiazepines, section 4.1.2  Breast-feeding see Benzodiazepines, section 4.1.2    Side-effects drowsiness, fatigue, dizziness, muscle  hypotonia, co-ordination disturbances; also poor  concentration, restlessness, confusion, amnesia, dep-  endence, and withdrawal; salivary or bronchial  hypersecretion in infants and small children; rarely  gastro-intestinal symptoms, respiratory depression,  headache, paradoxical effects including aggression  and anxiety, sexual dysfunction, urinary incontinence,  urticaria, pruritus, reversible hair loss, skin pigmen-  tation changes; dysarthria, and visual disturbances on  long-term treatment; blood disorders reported; suici-  dal ideation; overdosage: see Emergency Treatment  of Poisoning, p. 37   • 1 mg (ELDERLY 500 micrograms) initially at night for 4  nights, increased according to response over 2-4  weeks to usual maintenance dose of 4-8 mg usually at  night (may be given in 3-4 divided doses if necessary);  CHILD up to 1 year, initially 250 micrograms increased  as above to usual maintenance dose of 0.5-1 mg, 1-5  years, initially 250 micrograms increased as above to  1-3 mg, 5-12 years, initially 500 micrograms  increased as above to 3-6 mg   Note Clonazepam doses in BNF may differ from those in  product literature   Tablets, both scored, clonazepam 500 micrograms  (beige), net price 100-tab pack = £3.69; 2 mg (white),  100-tab pack = £4.93. Label: 2, 8, counselling, driving  (see notes above)   Acetazolamide (section 11.6), a carbonic anhydrase  inhibitor, has a specific role in treating epilepsy asso-  ciated with menstruation. It can also be used with other  antiepileptics for refractory tonic-clonic, absence, and  focal seizures. It is occasionally helpful in atypical  absence, atonic, and tonic seizures.   Piracetam (section 4.9.3) is used as adjunctive treat-  ment for cortical myoclonus.   Convulsive status epilepticus Immediate measures  to manage status epilepticus include positioning the  patient to avoid injury, supporting respiration including  the provision of oxygen, maintaining blood pressure,  and the correction of any hypoglycaemia. Parenteral  thiamine should be considered if alcohol abuse is  suspected; pyridoxine (section 9.6.2) should be given  if the status epilepticus is caused by pyridoxine defi-  ciency.   Convulsive status epilepticus should be treated urgently  with intravenous lorazepam, repeated once after 10  minutes if seizures recur or fail to respond. Intravenous  diazepam is effective but it carries a high risk of throm-  bophlebitis (reduced by using an emulsion formulation).  Absorption of diazepam from intramuscular injection or  from suppositories is too slow for treatment of status   Where facilities for resuscitation are not immediately  available, diazepam can be administered as a rectal  solution or midazolam [unlicensed use] can be given  into the buccal cavity.   If, after initial treatment with benzodiazepines, sei-  zures recur or fail to respond 20 minutes after onset,  phenytoin sodium, fosphenytoin, or phenobarbital  sodium should be used; contact intensive care unit if  seizures continue at 30 minutes after onset.   If these measures fail to control seizures 40 minutes  after onset, anaesthesia with thiopental (section  15.1.1), midazolam (section 15.1.4), or in adults, a  non-barbiturate anaesthetic such as propofol [unli-  censed indication] (section 15.1.1), should be insti-  tuted with full intensive care support.    Phenytoin sodium may be given by slow intravenous  injection, followed by the maintenance dosage if appro-  priate; monitor ECG and blood pressure and reduce rate  of administration if bradycardia or hypotension occurs.  Intramuscular use of phenytoin is not recommended  (absorption is slow and erratic).   Alternatively, fosphenytoin, a pro-drug of phenytoin,  can be given more rapidly and when given intravenously  causes fewer injection-site reactions than phenytoin.  Intravenous administration requires ECG monitoring.  Although it can also be given intramuscularly, absorp-  tion is too slow by this route for treatment of status  epilepticus. Doses of fosphenytoin should be expressed  in terms of phenytoin sodium.   Paraldehyde also remains a valuable drug. Given  rectally it causes little respiratory depression and is  therefore useful where facilities for resuscitation are  poor.   For advice on the management of epileptic seizures in  dental practice, see p. 27.   Non-convulsive status epilepticus The urgency to  treat non-convulsive status epilepticus depends upon  the severity of the patient’s condition. If there is incom-  plete loss of awareness, usual oral antiepileptic therapy  should be continued or restarted. Patients who fail to  respond to oral antiepileptic therapy or have complete  lack of awareness can be treated in the same way as for  convulsive status epilepticus, although anaesthesia is  rarely needed.   Indications status epilepticus; other forms of epilepsy,  and myoclonus (section 4.8.1)   Cautions see Clonazepam, section 4.8.1; facilities for  reversing respiratory depression with mechanical  ventilation must be at hand (but see also notes above)  Intravenous infusion Intravenous infusion of clonazepam  is potentially hazardous (especially if prolonged), calling for  close and constant observation and best carried out in  specialist centres with intensive care facilities. Prolonged  infusion may lead to accumulation and delay recovery  Contra-indications see Clonazepam, section 4.8.1;  avoid injections containing benzyl alcohol in neonates  (see under preparations below)   Breast-feeding see Benzodiazepines, section 4.1.2  Side-effects see Clonazepam, section 4.8.1; hypo-  tension and apnoea   • By intravenous injection into a large vein (over at least  2 minutes) or by intravenous infusion, 1 mg, repeated  if necessary; CHILD all ages, 500 micrograms   Injection, clonazepam lmg/mL in solvent, for dilu-  tion with 1 mL water for injections immediately before  injection or as described in Appendix 6. Net price 1-  mL amp (with 1 mL water for injections) = 60p   Excipients include benzyl alcohol (avoid in neonates unless there is no  safer alternative available, see Excipients, p. 2), ethanol, propylene glycol   Indications status epilepticus; febrile convulsions  (section 4.8.3); convulsions due to poisoning (see  p. 33); other indications (section 4.1.2, section 10.2.2,  and section 15.1.4.1)   Cautions see Diazepam, section 4.1.2; when given  intravenously facilities for reversing respiratory  depression with mechanical ventilation must be at  hand (but see also notes above)   Contra-indications see Diazepam, section 4.1.2  Hepatic impairment see Benzodiazepines, section  4.1.2   Renal impairment see Benzodiazepines, section 4.1.2  Pregnancy see Benzodiazepines, section 4.1.2, and  Pregnancy, p. 280   Breast-feeding see Benzodiazepines, section 4.1.2  Side-effects see Diazepam, section 4.1.2; hypotension  and apnoea   • Status epilepticus (but see notes above), febrile con-  vulsions, and convulsions due to poisoning, by intra-  venous injection, 10 mg at a rate of 1 mL (5 mg) per  minute, repeated once after 10 minutes if necessary;  CHILD under 12 years, 300-400 micrograms/kg (max.  10 mg) [unlicensed dose], repeated once after 10  minutes if necessary   By rectum as rectal solution, ADULT and CHILD over 12  years, 10-20 mg, repeated once after 10-15 minutes if  necessary; ELDERLY 10 mg; NEONATE [unlicensed] 1.25—  2.5 mg; CHILD 1 month-1 year [unlicensed] 5 mg; 1-2  years 5 mg; 2-12 years 5-10 mg   Diazepam (Non-proprietary) (Ml  Injection (solution), diazepam 5mg/mL. See Appen-  dix 6. Net price 2-mL amp = 45p   Excipients may include benzyl alcohol (avoid in neonates, see Excipi-  ents, p. 2), ethanol, propylene glycol   Injection (emulsion), diazepam 5mg/mL (0.5%). See  Appendix 6. Net price 2-mL amp = 91p  Brands include Diazemuls ®   Rectal tubes (= rectal solution), diazepam 2mg/mL,  net price 1.25-mL (2.5-mg) tube = 90p, 2.5-mL (5-mg)  tube = £1.41; 4mg/mL, 2.5-mL (10-mg) tube = £1.88    Indications status epilepticus; seizures associated  with neurosurgery or head injury; when phenytoin by  mouth not possible   Hepatic impairment consider 10-25% reduction in  dose or infusion rate (except initial dose for status  epilepticus)   Renal impairment consider 10-25% reduction in  dose or infusion rate (except initial dose for status  epilepticus)    Side-effects see Phenytoin Sodium; also dry mouth,  taste disturbance, vasodilatation, asthenia, euphoria,  incoordination; chills; visual disturbances; tinnitus;  pruritus, ecchymosis; less commonly dysarthria,  hypoaesthesia, increased or decreased reflexes, stu-  por, muscle weakness, pain, and hypoacusis; also  reported extrapyraidal disorder, twitching, confusion,  hyperglycaemia   Important Intravenous infusion of fosphenytoin has been  associated with severe cardiovascular reactions including  asystole, ventricular fibrillation, and cardiac arrest. Hypo-  tension, bradycardia and heart block have also been  reported. The following are recommended:   • monitor heart rate, blood pressure, and respiratory  function for duration of infusion;   • reduce dose or infusion rate in elderly, and in renal or  hepatic impairment.   Note Prescriptions for fosphenytoin sodium should state  the dose in terms of phenytoin sodium equivalent (PE);  fosphenytoin sodium 1.5 mg = phenytoin sodium 1 mg    • Status epilepticus, by intravenous infusion (at a rate of  100-150 mg(PE)/minute), initially 20 mg(PE)/kg then  by intravenous infusion (at a rate of 50-100 mg(PE)/  minute), 4-5 mg(PE)/kg daily in 1-2 divided doses,  dose adjusted according to response and trough  plasma-phenytoin concentration   CHILD 5 years and over, by intravenous infusion (at a  rate of 2-3 mg(PE) /kg/minute), initially 20mg(PE)/  kg then by intravenous infusion (at a rate of 1-  2 mg(PE)/kg/minute), 4-5mg(PE)/kg daily in 1-4  divided doses, dose adjusted according to response  and trough plasma-phenytoin concentration   • Prophylaxis or treatment of seizures associated with  neurosurgery or head injury, by intramuscular injec-  tion or by intravenous infusion (at a rate of 50-  100 mg(PE) /minute), initially 10-15 mg(PE)/kg then  by intramuscular injection or by intravenous infusion  (at a rate of 50-100 mg(PE)/minute), 4-5mg(PE)/kg  daily (in 1-2 divided doses), dose adjusted according  to response and trough plasma-phenytoin concen-  tration   CHILD 5 years and over, by intravenous infusion (at a  rate of 1-2 mg(PE) /kg/minute), initially 10-  15mg(PE)/kg then 4-5mg(PE)/kg daily in 1-4    divided doses, dose adjusted according to response  and trough plasma-phenytoin concentration   • Temporary substitution for oral phenytoin, by intra-  muscular injection or by intravenous infusion (at a  rate of 50-100 mg(PE)/minute), same dose and dos-  ing frequency as oral phenytoin therapy; CHILD 5 years  and over, by intravenous infusion (at a rate of 1-   2 mg(PE) /kg/minute, max. 100mg(PE)/minute),  same dose and dosing frequency as oral phenytoin  therapy   Note Fosphenytoin sodium doses in BNF may differ from those  in product literature   Injection, fosphenytoin sodium 75mg/mL (equiva-  lent to phenytoin sodium 50 mg/mL), net price 10-mL  vial = £40.00   Electrolytes phosphate 3.7 micromol/mg fosphenytoin sodium (phos-  phate 5.6 micromol/mg phenytoin sodium)   Indications status epilepticus; febrile convulsions  (section 4.8.3); convulsions due to poisoning (see  p. 33); other indications (section 4.1.2 and section  15.1.4.1)   Cautions see Diazepam, section 4.1.2  Contra-indications see Diazepam, section 4.1.2  Hepatic impairment see Benzodiazepines, section  4.1.2   Renal impairment see Benzodiazepines, section 4.1.2  Pregnancy see Benzodiazepines, section 4.1.2, and  Pregnancy, p. 280   • By slow intravenous injection (into large vein), 4 mg  repeated once after 10 minutes if necessary; CHILD  under 12 years 100 micrograms/kg (max. 4 mg)  repeated once after 10 minutes if necessary   Indications status epilepticus [unlicensed indication];  febrile convulsions [unlicensed] (section 4.8.3); other  indications (section 15.1.4.1)   Cautions see Midazolam, section 15.1.4.1  Contra-indications see Midazolam, section 15.1.4.1  Hepatic impairment see Midazolam, section 15.1.4.1  Renal impairment see Midazolam, section 15.1.4.1  Pregnancy see Midazolam, section 15.1.4.1, and  Pregnancy, p. 280   • By buccal administration [unlicensed], ADULT and  CHILD over 10 years, 10 mg repeated once after 10  minutes if necessary; CHILD up to 6 months,   300 micrograms/kg (max. 2.5 mg); 6 months-1 year,  2.5 mg; 1-5 years, 5 mg; 5-10 years, 7.5 mg  Note Midazolam injection solution may be given by buccal  administration   • By rectum (doses expressed as undiluted par-  aldehyde), ADULT 20 mL as a single dose; NEONATE  0.4mL/kg; CHILD 1 month-18 years 0.4mL/kg (max.  10 mL) as a single dose   Indications status epilepticus; other forms of epilepsy  except absence seizures (section 4.8.1)   Cautions see Phenobarbital, section 4.8.1; interac-  tions: see p. 279 and Appendix 1 (phenobarbital)  Hepatic impairment see Phenobarbital, section 4.8.1  Renal impairment see Phenobarbital, section 4.8.1  Pregnancy see Pregnancy, p. 280  Breast-feeding see Phenobarbital, section 4.8.1  Side-effects see Phenobarbital, section 4.8.1  Dose   • Status epilepticus, by intravenous injection (dilute  injection 1 in 10 with water for injections), 10 mg/kg  at a rate of not more than 100 mg/minute; max. 1 g  Note For therapeutic purposes phenobarbital and phenobar-  bital sodium may be considered equivalent in effect   Cautions see notes above; respiratory depression;  hypotension and heart failure; resuscitation facilities  must be available; injection solutions alkaline (irritant  to tissues); see also p. 288; interactions: see p. 279  and Appendix 1 (phenytoin)   Contra-indications sinus bradycardia, sino-atrial  block, and second- and third-degree heart block;  Stokes-Adams syndrome; acute porphyria (section  9.8.2)   Side-effects intravenous injection may cause cardio-  vascular and CNS depression (particularly if injection  too rapid) with arrhythmias, hypotension, and cardi-  ovascular collapse; alterations in respiratory function  (including respiratory arrest); also reported tonic  seizures, purple glove syndrome; see also p. 288  Dose   • By slow intravenous injection or infusion (with blood  pressure and ECG monitoring), status epilepticus,   20 mg/kg at a rate not exceeding 50 mg per minute,  as a loading dose (see also notes above); maintenance  doses of about 100 mg should be given thereafter at  intervals of every 6-8 hours, monitored by measure-  ment of plasma concentrations; rate and dose  reduced according to weight; CHILD 20 mg/kg as a  loading dose (NEONATE 20 mg/kg at rate of 1-3 mg/  kg/minute)   Note To avoid local venous irritation each injection or  infusion should be preceded and followed by an injection  of sterile physiological saline through the same needle or  catheter   Note Phenytoin sodium doses in BNF may differ from those  in product literature   Phenytoin (Non-proprietary) LmD  Injection, phenytoin sodium 50mg/mL with propy-  lene glycol 40% and alcohol 10% in water for injec-  tions, net price 5-mL amp = £3.40   Epanutin® Ready-Mixed Parenteral (Pfizer) (Ml  Injection, phenytoin sodium 50mg/mL with propy-  lene glycol 40% and alcohol 10% in water for injec-  tions, net price 5-mL amp = £4.88    Brief febrile convulsions need no specific treatment;  antipyretic medication, e.g. paracetamol (section  4.7.1) is commonly used to reduce fever and prevent  further convulsions but evidence to support this practice  is lacking. Prolonged febrile convulsions (those lasting 5  minutes or longer), recurrent convulsions, or those  occurring in a child at known risk must be treated  more actively, as there is the possibility of resulting  brain damage. Diazepam is the drug of choice given  either by slow intravenous injection or preferably rect-    ally in solution (section 4.8.2). The rectal route is pre-  ferred as satisfactory absorption is achieved within  minutes and administration is much easier. Supposi-  tories are not suitable because absorption is too slow.   Intermittent prophylaxis (i.e. the anticonvulsant admi-  nistered at the onset of fever) is possible in only a small  proportion of children. Again diazepam is the treatment  of choice, orally or rectally.   Long-term anticonvulsant prophylaxis for febrile con-  vulsions is rarely indicated. Anticonvulsant treatment  needs to be considered only for children at risk from  prolonged or complex febrile convulsions, including  those whose first seizure occurred at under 14 months  or who have neurological abnormalities or who have  had previous prolonged or focal convulsions.   Dopaminergic drugs used in  Parkinson’s disease  Antimuscarinic drugs used in  parkinsonism   In idiopathic Parkinson’s disease, the progressive degen-  eration of pigmented neurones in the substantia nigra  leads to a deficiency of the neurotransmitter dopamine.  The resulting neurochemical imbalance in the basal  ganglia causes the characteristic signs and symptoms  of the illness. Drug therapy does not prevent disease  progression, but it improves most patients’ quality of  life.   Patients with suspected Parkinson’s disease should be  referred to a specialist to confirm the diagnosis; the  diagnosis should be reviewed every 6-12 months.   Features resembling those of Parkinson’s disease can  occur in diseases such as progressive supranuclear  palsy and multiple system atrophy, but they do not  normally show a sustained response to the drugs used  in the treatment of idiopathic Parkinson’s disease.   When initiating treatment, patients should be advised  about its limitations and possible side-effects. About 5-  10% of patients with Parkinson’s disease respond poorly  to treatment.   Treatment is usually not started until symptoms cause  significant disruption of daily activities. Levodopa  (p. 302), non-ergot-derived dopamine-receptor ago-  nists (p. 298), or monoamine-oxidase-B inhibitors  (p. 304) can be prescribed for initial treatment in early  Parkinson’s disease. Therapy with two or more anti-  parkinsonian drugs may be necessary as the disease  progresses. Most patients eventually require levodopa  and subsequently develop motor complications.    Elderly Antiparkinsonian drugs can cause confusion in  the elderly. It is particularly important to initiate treat-  ment with low doses and to increase the dose gradually    The dopamine-receptor agonists, bromocriptine,  cabergoline, pergolide, pramipexole, ropinirole, and  rotigotine have a direct action on dopamine receptors.  Initial treatment of Parkinson’s disease is often with  dopamine-receptor agonists. They are also used with  levodopa in more advanced disease. If a dopamine-  receptor agonist is added to levodopa therapy, the  dose of levodopa needs to be reduced (see individual  monographs).   When used alone, dopamine-receptor agonists cause  fewer motor complications in long-term treatment com-  pared with levodopa treatment but the overall motor  performance improves slightly less. The dopamine-  receptor agonists are associated with more psychiatric  side-effects than levodopa. The ergot-derived  dopamine-receptor agonists bromocriptine, cabergo-  line, and pergolide, are associated with fibrotic reactions  (see notes below). Patients should be monitored for  signs of cardiac fibrosis, before and at regular intervals  during treatment with cabergoline or pergolide. Ergot-  derived dopamine-receptor agonists should not be used  as first-line treatment for Parkinson’s disease.    Treatment with dopamine-receptor agonists is asso-  ciated with impulse control disorders, including patho-  logical gambling, binge eating, and hypersexuality.  Patients taking dopamine-receptor agonists, and their  carers, should be informed about the risk of impulse  control disorders. There is no evidence that ergot- and  non-ergot-derived dopamine-receptor agonists differ in  their propensity to cause impulse control disorders, so  switching between dopamine-receptor agonists to con-  trol these side-effects is not recommended. If the patient  develops an impulse control disorder, the dopamine-  receptor agonist should be discontinued or the dose  titrated downwards, until the symptoms resolve.   Apomorphine is a potent dopamine-receptor agonist  that is sometimes helpful in advanced disease for  patients experiencing unpredictable ‘off’ periods with  levodopa treatment. Apomorphine should be initiated in  a specialist clinic with at least two days pretreatment  with domperidone (p. 253) for nausea and vomiting.  After an overnight withdrawal of oral antiparkinsonian  medication to induce an ‘off’ episode, the threshold  dose of apomorphine is determined. Oral anti-  parkinsonian medication is then restarted. The patient  must be taught to self-administer apomorphine by sub-  cutaneous injection into the lower abdomen or outer  thigh at the first sign of an ‘off’ episode. Once treatment  has been established it may be possible to gradually  reduce other antiparkinsonian medications and reduce  or withdraw domperidone therapy. Treatment with apo-  morphine should remain under specialist supervision.   Antiparkinsonian drug therapy should never be stopped  abruptly as this carries a small risk of neuroleptic malig-  nant syndrome.   Ergot-derived dopamine-receptor agonists, bromo-  criptine, cabergoline, and pergolide, have been asso-  ciated with pulmonary, retroperitoneal, and pericar-  dial fibrotic reactions.   Exclude cardiac valvulopathy with echocardiogra-  phy before starting treatment with these ergot deri-  vatives for Parkinson’s disease or chronic endocrine  disorders (excludes suppression of lactation); it may  also be appropriate to measure the erythrocyte  sedimentation rate and serum creatinine and to  obtain a chest X-ray. Patients should be monitored  for dyspnoea, persistent cough, chest pain, cardiac  failure, and abdominal pain or tenderness. If long-  term treatment is expected, then lung-function tests  may also be helpful. Patients taking cabergoline or  pergolide should be regularly monitored for cardiac  fibrosis by echocardiography (within 3-6 months of  initiating treatment and subsequently at 6-12 month  intervals).   Sudden onset of sleep Excessive daytime sleepi-  ness and sudden onset of sleep can occur with co-  careldopa, co-beneldopa, and dopamine-receptor  agonists.   Patients starting treatment with these drugs should  be warned of the risk and of the need to exercise  caution when driving or operating machinery. Those  who have experienced excessive sedation or sudden  onset of sleep should refrain from driving or operat-  ing machines until these effects have stopped recur-  ring.   Management of excessive daytime sleepiness should  focus on the identification of an underlying cause,  such as depression or concomitant medication that  can disturb sleep. Patients should be counselled on  improving sleep behaviour.   Hypotensive reactions Hypotensive reactions can  occur in some patients taking dopamine-receptor  agonists; these can be particularly problematic dur-  ing the first few days of treatment and care should be  exercised when driving or operating machinery.   Indications refractory motor fluctuations in Parkin-  son’s disease (‘off episodes) inadequately controlled  by co-beneldopa or co-careldopa or other dopami-  nergics (for capable and motivated patients under  specialist supervision)   Cautions see notes above; pulmonary disease, cardi-  ovascular disease, history of postural hypotension  (special care on initiation); susceptibility to QT-inter-  val prolongation; neuropsychiatric conditions; moni-  tor hepatic, haemopoietic, renal, and cardiovascular  function; with concomitant levodopa test initially and  every 6 months for haemolytic anaemia and throm-  bocytopenia (development calls for specialist hae-  matological care with dose reduction and possible  discontinuation); interactions: Appendix 1 (apomor-  phine)    Contra-indications see Bromocriptine, section 6.7.1  Hepatic impairment see Bromocriptine, section 6.7.1  Pregnancy see Bromocriptine, section 6.7.1  Breast-feeding see Bromocriptine, section 6.7.1  Side-effects see notes above and Bromocriptine,  section 6.7.1  Dose   • First week 1-1.25 mg at night, second week 2-2.5 mg  at night, third week 2.5 mg twice daily, fourth week  2.5 mg 3 times daily then increasing by 2.5 mg every  3-14 days according to response to a usual range of  10-30 mg daily; taken with food   Indications alone or as adjunct to co-beneldopa or co-  careldopa in Parkinson’s disease where dopamine-  receptor agonists other than ergot derivative not  appropriate; endocrine disorders (section 6.7.1)  Cautions see Cabergoline in section 6.7.1 and notes  above   Contra-indications see Cabergoline, section 6.7.1  Hepatic impairment see Cabergoline, section 6.7.1  Pregnancy see Cabergoline, section 6.7.1  Breast-feeding see Cabergoline, section 6.7.1  Side-effects see notes above and Cabergoline, section  6.7.1  Dose   • Initially 1 mg daily, increased by increments of 0.5-  1 mg at 7 or 14 day intervals; max. 3 mg daily  Note Concurrent dose of levodopa may be decreased gra-  dually while dose of cabergoline is increased   Cabergoline (Non-proprietary) (Ml  Tablets, scored, cabergoline 1 mg, net price 20-tab  pack = £59.08; 2 mg, 20-tab pack = £71.13. Label: 10,  21, counselling, driving, see notes above  Note Dispense in original container (contains desiccant)   Cabaser® (Pharmacia) (Ml  Tablets, scored, cabergoline 1 mg, net price 20-tab  pack = £83.00; 2 mg, 20-tab pack = £83.00. Label: 10,  21, counselling, driving, see notes above  Note Dispense in original container (contains desiccant)   Side-effects see notes above; also nausea, vomiting  (see notes above); yawning; drowsiness (including  sudden onset of sleep), confusion, hallucinations; less  commonly postural hypotension, dyspnoea, dys-  kinesia during ‘on’ periods (may require discontinua-  tion), haemolytic anaemia and thrombocytopenia  with levodopa (see Cautions), and rash; rarely  eosinophilia; peripheral oedema, compulsive beha-  viour, and dizziness also reported  Dose   • By subcutaneous injection, ADULT over 18 years, to  determine threshold dose (see also notes above),  initially 1 mg at the first sign of ‘off’ episode; if  inadequate or no response after 30 minutes, then a  further 2 mg should be given; thereafter increase dose  at minimum 40-minute intervals until satisfactory  response obtained; usual range 3-30 mg daily in  divided doses; subcutaneous infusion may be prefer-  able in those requiring division of injections into more  than 10 doses daily; max. single dose 10 mg   • By continuous subcutaneous infusion, ADULT over 18  years, (those requiring division into more than 10  injections daily) initially 1 mg/hour increased  according to response (not more often than every 4  hours) in max. steps of 500 micrograms/hour, to usual  rate of 1-4 mg/hour (15-60 micrograms/kg/hour);  change infusion site every 12 hours and give during  waking hours only (tolerance may occur unless there  is a 4-hour treatment-free period at night — 24-hour  infusions not recommended unless severe night-time  symptoms); intermittent bolus boosts may be needed   Apomorphine (Non-proprietary) (Ml  Injection, apomorphine hydrochloride 10 mg/mL, net  price 2-mL amp = £7.21, 5-mL amp = £13.89.   Injection, apomorphine hydrochloride 10 mg/mL, net  price 2-mL amp = £7.59, 5-mL amp = £14.62.    Indications alone or as adjunct to co-beneldopa or co-  careldopa in Parkinson’s disease where dopamine-  receptor agonists other than ergot derivative not  appropriate   Cautions see notes above; arrhythmias or underlying  cardiac disease; history of confusion, psychosis, or  hallucinations, dyskinesia (may exacerbate); acute  porphyria (section 9.8.2); interactions: Appendix 1  (pergolide)   Side-effects see notes above; also nausea, vomiting,  dyspepsia, abdominal pain; dyspnoea, rhinitis; hallu-  cinations, dyskinesia, drowsiness (including sudden  onset of sleep); diplopia; also reported constipation,    diarrhoea, hiccups, tachycardia, atrial premature  contractions, palpitation, hypotension, syncope,  Raynaud’s phenomenon, compulsive behaviour,  insomnia, confusion, dizziness, fever, erythromelalgia,  and rash  Dose   • Monotherapy, 50 micrograms at night on day 1, then  50 micrograms twice daily on days 2-4, then  increased by 100-250 micrograms daily every 3-4  days to 1.5 mg daily in 3 divided doses at day 28; after  day 30, further increases every 3-4 days of up to  250 micrograms daily; usual maintenance dose 2.1-  2.5 mg daily; max. 3 mg daily   • Adjunctive therapy with levodopa, 50 micrograms  daily for 2 days, increased gradually by 100-   150 micrograms every 3 days over next 12 days,  usually given in 3 divided doses; further increases of  250 micrograms every 3 days; max. 3 mg daily; during  pergolide titration levodopa dose may be reduced  cautiously   Pergolide (Non-proprietary) (Ml  Tablets, pergolide (as mesilate) 50 micrograms, net  price 100-tab pack = £17.42; 250 micrograms, 100-tab  pack = £14.68; lmg, 100-tab pack = £41.95. Label: 10,  counselling, driving, see notes above   Tablets, scored, pergolide (as mesilate) 50 micr-  ograms (ivory), net price 100-tab pack = £20.70;   250 micrograms (green), 100-tab pack = £21.12; 1 mg  (pink), 100-tab pack = £43.44. Label: 10, counselling,  driving, see notes above   Indications Parkinson’s disease, used alone or as an  adjunct to co-beneldopa or co-careldopa; moderate to  severe restless legs syndrome   Cautions see notes above; psychotic disorders;  ophthalmological testing recommended (risk of visual  disorders); severe cardiovascular disease; risk of pos-  tural hypotension (especially on initiation) — monitor  blood pressure; interactions: Appendix 1 (pramipex-  ole)   • for immediate-release tablets in Parkinson’s disease,  initially 88 micrograms twice daily (max. 1.57 mg  daily in 2 divided doses) if eGFR 20-50 mL/min-  ute/ 1.73m 2 ; initially 88 micrograms once daily  (max. 1.1 mg once daily) if eGFR less than 20 mL/  minute/ 1.73 m 2 ; if renal function declines during  treatment, reduce dose by the same percentage as  the decline in eGFR   • for immediate-release tablets in restless legs  syndrome, reduce dose if eGFR less than 20 mL/  minute/ 1.73 m 2   • for modified-release tablets, initially 260 micr-  ograms on alternate days if eGFR 30-50 mL/min-  ute/ 1.73m 2 , increased to 260 micrograms once  daily after 1 week, further increased if necessary  by 260 micrograms daily at weekly intervals to max.  1.57 mg daily; avoid if eGFR less than 30mL/min-  ute/ 1.73m 2    Breast-feeding may suppress lactation; avoid — pre-  sent in milk in animal studies  Side-effects see notes above; also nausea, constipa-  tion, vomiting, weight changes, hypotension (includ-  ing postural hypotension), peripheral oedema, dizzi-  ness, dyskinesia, drowsiness (including sudden onset  of sleep), amnesia, headache, sleep disturbances,  confusion, hallucinations, restlessness, visual distur-  bances; less commonly syncope, pneumonia, dys-  pnoea, compulsive behaviour, delusion, paranoia,  pruritus, rash; also reported paradoxical worsening of  restless legs syndrome  Dose   Important Doses and strengths are stated in terms of  pramipexole (base); equivalent strengths in terms of prami-  pexole dihydrochloride monohydrate (salt) are as follows:   88 micrograms 3 times daily, dose doubled every 5-7  days if tolerated to 350 micrograms 3 times daily;  further increased if necessary by 180 micrograms 3  times daily at weekly intervals; max. 3.3 mg daily in 3  divided doses   Note During dose titration and maintenance, levodopa dose  may be reduced   • Restless legs syndrome, ADULT over 18 years, initially  88 micrograms once daily 2-3 hours before bedtime,  dose doubled every 4-7 days if necessary; max.   Note Repeat dose titration if restarting treatment after an  interval of more than a few days    Mirapexin® (Boehringer Ingelheim) [Ml  Tablets, pramipexole 88 micrograms, net price 30-tab  pack = £9.55; 180 micrograms (scored), 30-tab pack =  £19.10, 100-tab pack = £63.67; 350 micrograms  (scored), 30-tab pack = £38.20, 100-tab pack =  £127.34; 700 micrograms (scored), 30-tab pack =  £76.40, 100-tab pack = £254.69. Label: 10, counsel-  ling, driving, see notes above   Tablets, m/r, pramipexole 260 micrograms, net price  30-tab pack = £28.65; 520 micrograms, 30-tab pack =  £57.30; 1.05 mg, 30-tab pack = £114.60; 1.57 mg, 30-  tab pack = £171.90; 2.1 mg, 30-tab pack = £229.20;  2.62 mg, 30-tab pack = £286.50; 3. 15 mg, 30-tab pack  = £343.80. Label: 10, 25, counselling, driving, see  notes above   Important Doses and strengths are stated in terms of pramipexole  (base); equivalent strengths in terms of pramipexole dihy-  drochloride monohydrate (salt) are as follows:   Dose Parkinson’s disease (with or without co-beneldopa or co-  careldopa), ADULT over 18 years, initially 260 micrograms once  daily, dose doubled every 5-7 days to 1.05 mg once daily; further  increased if necessary by 520 micrograms daily at weekly inter-  vals; max. 3.15 mg once daily   Note During dose titration and maintenance, levodopa dose may  be reduced   Indications Parkinson’s disease, either used alone or  as adjunct to co-beneldopa or co-careldopa; moderate  to severe restless legs syndrome   Cautions see notes above; severe cardiovascular dis-  ease, major psychotic disorders; dose adjustment may  be necessary if smoking started or stopped during  treatment; interactions: Appendix 1 (ropinirole)   Renal impairment avoid if eGFR less than 30 mL/  minute /1.73m 2   Side-effects see notes above; also nausea, vomiting,  abdominal pain, dyspepsia, constipation; hypo-  tension; syncope, peripheral oedema; drowsiness  (including sudden onset of sleep, see p. 298), dizzi-  ness, nervousness, fatigue, dyskinesia, hallucinations,  confusion; less commonly psychosis, compulsive  behaviour; very rarely hepatic disorders; also  reported paradoxical worsening of restless legs  syndrome   • Parkinson’s disease, initially 750 micrograms daily in 3  divided doses, increased by increments of 750 micr-  ograms at weekly intervals to 3 mg daily; further  increased by increments of up to 3 mg at weekly  intervals according to response; usual range 9-16 mg  daily (but higher doses may be required if used with  levodopa); max. 24 mg daily   Note When administered as adjunct to levodopa, concurrent  dose of levodopa maybe reduced by approx. 20 %; ropinirole  doses in the BNF may differ from those in product literature   • Restless legs syndrome, ADULT over 18 years initially  250 micrograms at night for 2 days, increased if tol-  erated to 500 micrograms at night for 5 days and then  to 1 mg at night for 7 days; further increased at weekly  intervals in steps of 500 micrograms daily according  to response; usual dose 2 mg at night; max. 4 mg daily  Note Repeat dose titration if restarting after interval of more  than a few days   Ropinirole (Non-proprietary) (5°M1  Tablets, ropinirole (as hydrochloride) 250 micr-  ograms, net price 12-tab pack = £2.79; 500 micr-  ograms, 28-tab pack = £7.72; 1 mg, 84-tab pack =  £27.65; 2 mg, 84-tab pack = £54.43; 5 mg, 84-tab pack  = £107.55. Label: 10, 21, counselling, driving, see  notes above   Tablets, f/c, ropinirole (as hydrochloride) 250 micr-  ograms (white), net price 12-tab pack = £3.94;   500 micrograms (yellow), 28-tab pack = £15.75, 84-  tab pack = £47.26; 2 mg (pink), 28-tab pack = £31.51,  84-tab pack = £94.53. Label: 10, 21, counselling,  driving, see notes above   The Scottish Medicines Consortium has advised (June 2006) that  Adartrel ® should be restricted for use in patients with a baseline  score of 24 points or more on the International Restless Legs  Scale   Tablets, f/c, ropinirole (as hydrochloride) lmg  (green), net price 84-tab pack = £47.26; 2 mg (pink),  84-tab pack = £94.53; 5 mg (blue), 84-tab pack =  £163.27; 28-day starter pack of 42 x 250-microgram  (white) tablets, 42 x 500-microgram (yellow) tablets,    and 21 x 1-mg (green) tablets = £40.10; 28-day  follow-on pack of 42 x 500-microgram (yellow)  tablets, 42 x 1-mg (green) tablets, and 63 x 2-mg  (pink) tablets = £74.40. Label: 10, 21, counselling,  driving, see notes above   Tablets, m/r, f/c, ropinirole (as hydrochloride) 2 mg  (pink), net price 28-tab pack = £31.36; 4 mg (brown),  28-tab pack = £62.72; 8 mg (red), 28-tab pack =  £105.28. Label: 10, 25, counselling, driving, see notes  above   Dose stable Parkinson’s disease in patients transferring from  ropinirole immediate-release tablets, initially Requip ® XL once  daily substituted for total daily dose equivalent of ropinirole  immediate-release tablets; if control not maintained after switch-  ing, in patients receiving less than 8 mg once daily , increase in  steps of 2 mg at intervals of at least 1 week to 8 mg once daily  according to response; in patients receiving 8 mg once daily or  more, increase in steps of 2 mg at intervals of at least 2 weeks  according to response; max. 24 mg once daily  Note When administered as adjunct to levodopa, concurrent dose  of levodopa may be reduced    Indications Parkinson’s disease, either used alone or  as adjunct to co-beneldopa or co-careldopa; moderate  to severe restless legs syndrome  Cautions see notes above; ophthalmic testing recom-  mended; avoid exposure of patch to heat; withdraw  gradually; interactions: Appendix 1 (rotigotine)  Hepatic impairment caution in severe impairment —  no information available   Pregnancy avoid — no information available  Breast-feeding may suppress lactation; avoid — pre-  sent in milk in animal studies  Side-effects see notes above; also constipation, dry  mouth, dyspepsia, nausea, vomiting, weight changes;  hypertension, postural hypotension, palpitation, per-  ipheral oedema; hiccup; asthenia, dizziness, drowsi-  ness (including sudden onset of sleep), sleep distur-  bances, dyskinesia, hallucinations, headache,  syncope, sweating, rash, pruritus; less commonly  abdominal pain, atrial fibrillation, hypotension, con-  fusion, paranoia, compulsive behaviour, erectile dys-  function, and visual disturbances; rarely tachycardia,  seizures, irritability, obsessive compulsive disorder,  and psychotic disorder  Dose   24 hours at weekly intervals if required; max. 8 mg/  24 hours   • Adjunctive therapy with levodopa in Parkinson’s dis-  ease, initially apply ‘4 mg/24 hours’ patch, increased  in steps of 2 mg/ 24 hours at weekly intervals if  required; max. 16 mg/24 hours   24 hours’ patch, increased in steps of 1 mg/ 24 hours  at weekly intervals if required; max. 3 mg/ 24 hours  Note Apply patch to dry, non-irritated skin on torso, thigh, or  upper arm, removing after 24 hours and siting replacement  patch on a different area (avoid using the same area for 14  days)   Patches, self-adhesive, beige, rotigotine 1 mg/ 24  hours, net price 28 = £77.24; 2 mg/24 hours, 28 =  £77.24; 3 mg/24 hours, 28 = £97.48; 4 mg/24 hours,    28 =£117.71; 6 mg/24 hours, 28 = £142.79; 8 mg/  24 hours, 28 = £142.79; 28-day starter pack of 7 x  2 mg/24 hours, 7 x 4 mg/24 hours, 7 x 6 mg/24  hours, and 7 x 8 mg/24 hours patches = £142.79.  Label: 10, counselling, driving, see notes above  Note Remove patch (aluminium-containing) before magnetic  resonance imaging or cardioversion   Note The Scottish Medicines Consortium (p. 4) has advised that  Neupro ® is accepted as monotherapy for the treatment of early-  stage idiopathic Parkinson’s disease (June 2007) and for restricted  use for the treatment of advanced Parkinson’s disease in  combination with levodopa where the transdermal route would  facilitate treatment (July 2007)   Note The Scottish Medicines Consortium (p. 4) has advised (April  2009) that rotigotine (Neupro®) is accepted for restricted use  within NHS Scotland for the symptomatic treatment of moderate  to severe idiopathic resdess legs syndrome in adults with a  baseline score of 15 points or more on the International Restiess  Legs Scale   Levodopa, the amino-acid precursor of dopamine, acts  by replenishing depleted striatal dopamine; it is given  with an extracerebral dopa-decarboxylase inhibitor  that reduces the peripheral conversion of levodopa to  dopamine, thereby limiting side-effects such as nausea,  vomiting and cardiovascular effects. Additionally, effec-  tive brain-dopamine concentrations can be achieved  with lower doses of levodopa. The extracerebral dopa-  decarboxylase inhibitors used with levodopa are ben-  serazide (in co-beneldopa) and carbidopa (in co-carel-  dopa).    Levodopa, in combination with a dopa-decarboxylase  inhibitor, is useful in the elderly or frail, in patients with  other significant illnesses, and in those with more severe  symptoms. It is effective and well tolerated in the  majority of patients.    Levodopa therapy should be initiated at a low dose and  increased in small steps; the final dose should be as low  as possible. Intervals between doses should be chosen  to suit the needs of the individual patient.   Note When co-careldopa is used, the total daily dose of carbi-  dopa should be at least 70 mg. A lower dose may not achieve  full inhibition of extracerebral dopa-decarboxylase, with a  resultant increase in side-effects.    Nausea and vomiting with co-beneldopa or co-carel-  dopa are rarely dose-limiting but domperidone (section  4.6) may be useful in controlling these effects.  Levodopa treatment is associated with potentially trou-  blesome motor complications including response fluc-  tuations and dyskinesias. Response fluctuations are  characterised by large variations in motor performance,  with normal function during the ‘on’ period, and weak-  ness and restricted mobility during the ‘off period.  ‘End-of-dose’ deterioration with progressively shorter  duration of benefit also occurs. Modified-release pre-  parations may help with ‘end-of-dose’ deterioration or  nocturnal immobility and rigidity. Motor complications  are particularly problematic in young patients treated  with levodopa.    Cautions Levodopa should be used with caution in  severe pulmonary or cardiovascular disease (including  history of myocardial infarction with residual arrhyth-  mia), psychiatric illness (avoid if severe and discontinue  if deterioration), endocrine disorders (including hyper-  thyroidism, Cushing’s syndrome, diabetes mellitus,  osteomalacia, and phaeochromocytoma), and in those    with a history of convulsions or peptic ulcer. Levodopa  should be used with caution in patients susceptible to  angle-closure glaucoma, and in hepatic or renal impair-  ment. Patients should be advised to avoid abrupt with-  drawal (risk of neuroleptic malignant syndrome and  rhabdomyolysis), and to be aware of the potential for  excessive drowsiness and sudden onset of sleep (see  Driving, p. 298); interactions: Appendix 1 (levodopa).   Pregnancy Levodopa should be used with caution in  pregnancy — toxicity has occurred in animal studies.   Side-effects Side-effects of levodopa include nausea,  vomiting, taste disturbances, dry mouth, anorexia,  arrhythmias, palpitations, postural hypotension, syn-  cope, drowsiness (see Driving, p. 298), fatigue, demen-  tia, psychosis, confusion, euphoria, abnormal dreams,  insomnia, depression ( very rarely with suicidal idea-  tion), anxiety, dizziness, dystonia, dyskinesia, and  chorea.   Less commonly weight changes, constipation, diarr-  hoea, hypersalivation, dysphagia, flatulence, hyper-  tension, chest pain, oedema, hoarseness, ataxia, hand  tremor, malaise, weakness, muscle cramps, and reddish  discoloration of the urine and other body fluids may  occur. Rare side-effects include abdominal pain, gastro-  intestinal bleeding, duodenal ulcer, dyspepsia, phlebitis,  dyspnoea, agitation, paraesthesia, bruxism, trismus, hic-  cups, neuroleptic malignant syndrome (associated with  abrupt withdrawal), convulsions, reduced mental acuity,  disorientation, headache, urinary retention, urinary  incontinence, priapism, activation of malignant  melanoma, leucopenia, haemolytic and non-haemolytic  anaemia, thrombocytopenia, agranulocytosis, blurred  vision, blepharospasm, diplopia, activation of Homer’s  syndrome, pupil dilatation, oculogyric crisis, flushing,  alopecia, exanthema, Henoch-Schonlein purpura, and  sweating; very rarely angle-closure glaucoma may  occur; compulsive behaviour and false positive tests  for urinary ketones have also been reported.   A mixture of benserazide hydrochloride and levodopa in mass  proportions corresponding to 1 part of benserazide and 4 parts  of levodopa   Capsules {Madopar® -62.5 mg), blue/grey, co-  beneldopa 12.5/50 (benserazide 12.5 mg (as hydro-  chloride), levodopa 50 mg), net price 100-cap pack =  £4.96. Label: 10, 14, counselling, driving, see notes  above   Capsules {Madopar® -125 mg), blue/pink, co-benel-  dopa 25/100 (benserazide 25 mg (as hydrochloride),  levodopa 100 mg), net price 100-cap pack = £6.91.  Label: 10, 14, counselling, driving, see notes above    Capsules (Madopar® -250 mg), blue/caramel, co-  beneldopa 50/200 (benserazide 50 mg (as hydro-  chloride), levodopa 200 mg), net price 100-cap pack =  £11.78. Label: 10, 14, counselling, driving, see notes  above   Dispersible tablets, scored, co-beneldopa 12.5/50  (benserazide 12.5 mg (as hydrochloride), levodopa  50 mg), net price 100-tab pack = £5.90. Label: 10, 14,  counselling, administration, see below, driving, see  notes above   Dispersible tablets, scored, co-beneldopa 25/100  (benserazide 25 mg (as hydrochloride) levodopa  100 mg), net price 100-tab pack = £10.45. Label: 10,  14, counselling, administration, see below, driving, see  notes above   Counselling The dispersible tablets can be dispersed in water or  orange squash (not orange juice) or swallowed whole  Dose expressed as levodopa, initially 50 mg 3-4 times daily  (100 mg 3 times daily in advanced disease), increased by 100 mg  daily once or twice weekly according to response; usual main-  tenance dose 400-800 mg daily in divided doses; ELDERLY initially  50 mg once or twice daily, increased by 50 mg daily every 3-4  days according to response   Note When transferring patients from another levodopa/dopa-  decarboxylase inhibitor preparation, the previous preparation  should be discontinued 12 hours before (although interval can be  shorter)   Madopar® CR (Roche) (Ml  Capsules, m/r, dark green/light blue, co-beneldopa  25/100 (benserazide 25 mg (as hydrochloride), levo-  dopa 100 mg), net price 100-cap pack = £12.77.  Label: 5, 10, 14, 25, counselling, driving, see notes  above   Dose patients not taking levodopa/dopa-decarboxylase inhibi-  tor therapy, initially 1 capsule 3 times daily (max. initial dose 6  capsules daily)   Patients transferring from immediate-release levodopa/dopa-  decarboxylase inhibitor preparations, initially 1 capsule substi-  tuted for every 100 mg of levodopa and given at same dosage  frequency, increased every 2-3 days according to response;  average increase of 50% needed over previous levodopa dose and  titration may take up to 4 weeks   Supplementary dose of immediate-release Madopar 9 may be  needed with first morning dose; if response still poor to total daily  dose of Madopar ® CR plus Madopar * corresponding to 1.2 g  levodopa, consider alternative therapy   A mixture of carbidopa and levodopa; the proportions are  expressed in the form x/y where x and y are the strengths in  milligrams of carbidopa and levodopa respectively   • Expressed as levodopa, initially 100 mg (with carbi-  dopa 25 mg) 3 times daily, increased by 50-100 mg  (with carbidopa 12.5-25 mg) daily or on alternate  days according to response, up to 800 mg (with  carbidopa 200 mg) daily in divided doses   12.5 mg) 3-4 times daily, increased by 50-100 mg  daily or on alternate days according to response, up to  800 mg (with carbidopa 80-100 mg) daily in divided  doses   Note At least 70 mg carbidopa daily is necessary to achieve  full inhibition of peripheral dopa-decarboxylase. When  transferring patients from another levodopa/ dopa-decar-  boxylase inhibitor preparation, the previous preparation  should be discontinued at least 12 hours before   Co-careldopa (Non-proprietary) (Ml  Tablets, co-careldopa 10/100 (carbidopa 10 mg  (anhydrous), levodopa 100 mg), net price 100-tab  pack = £7.30. Label: 10, 14, counselling, driving, see  notes above   Tablets, co-careldopa 25/100 (carbidopa 25 mg  (anhydrous), levodopa 100 mg), net price 100-tab  pack = £24.45. Label: 10, 14, counselling, driving, see  notes above   Tablets, co-careldopa 25/250 (carbidopa 25 mg  (anhydrous), levodopa 250 mg), net price 100-tab  pack = £34.58. Label: 10, 14, counselling, driving, see  notes above   Tablets (Sinemet® -62.5), yellow, scored, co-carel-  dopa 12.5/50 (carbidopa 12.5 mg (anhydrous), levo-  dopa 50 mg), net price 90-tab pack = £6.28. Label: 10,  14, counselling, driving, see notes above  Note 2 tablets Sinemet 9 -62.5 = 1 tablet Sinemet Plus 9    Tablets (Sinemet® -110), blue, scored, co-careldopa  10/100 (carbidopa 10 mg (anhydrous), levodopa  100 mg), net price 90-tab pack = £6.57. Label: 10, 14,  counselling, driving, see notes above   Tablets (Sinemet® -Plus), yellow, scored, co-careldopa  25/100 (carbidopa 25 mg (anhydrous), levodopa  100 mg), net price 90-tab pack = £9.66. Label: 10, 14,  counselling, driving, see notes above  Note Co-careldopa 25/100 provides an adequate dose of carbi-  dopa when low doses of levodopa are needed    Tablets (Sinemet® -275), blue, scored, co-careldopa  25/250 (carbidopa 25 mg (anhydrous), levodopa  250 mg), net price 90-tab pack = £13.72. Label: 10, 14,  counselling, driving, see notes above    ^For use with enteral tube  Duodopa® (Abbott Healthcare) T (Ml  Intestinal gel, co-careldopa 5/20 (carbidopa 5 mg as  monohydrate, levodopa 20 mg)/mL, net price 100 mL  cassette (for use with Duodopa® portable pump) =  £77.00. Label: 10, 14, counselling, driving, see notes  above   Tablets, m/r, orange-brown, co-careldopa 25/100  (carbidopa 25 mg (as monohydrate), levodopa  100 mg), net price 60-tab pack = £1 1.47; co-careldopa  50/200 (carbidopa 50 mg (as monohydrate), levodopa  200 mg), 60-tab pack = £11.47. Label: 10, 14, 25,  counselling, driving, see notes above  Dose patients not receiving levodopa/dopa-decarboxylase inhi-  bitor preparations, expressed as levodopa, initially 100-200 mg  twice daily (at least 6 hours between doses); dose adjusted  according to response at intervals of at least 2 days  Patients transferring from immediate-release levodopa/dopa-  decarboxylase inhibitor preparations, discontinue previous pre-  paration at least 12 hours before first dose of Caramet 9 CR,  substitute Caramel :• CR to provide a similar amount of levodopa  daily and extend dosing interval by 30-50%; dose then adjusted  according to response at intervals of at least 2 days    Half Sinemet® CR (MSD) (Ml  Tablets, m/r, pink, co-careldopa 25/100 (carbidopa  25 mg (anhydrous), levodopa 100 mg), net price 60-  tab pack = £11.60. Label: 10, 14, 25, counselling,  driving, see notes above   Tablets, m/r, peach, scored, co-careldopa 50/200  (carbidopa 50 mg (anhydrous), levodopa 200 mg), net  price 60-tab pack = £11.60. Label: 10, 14, 25, coun-  selling, driving, see notes above  Dose patients not receiving levodopa/dopa-decarboxylase inhi-  bitor therapy, initially, 1 Sinemet? CR tablet twice daily; both dose  and interval then adjusted according to response at intervals of  not less than 3 days   Patients transferring from immediate-release levodopa/dopa-  decarboxylase inhibitor preparations, 1 Sinemet? CR tablet twice  daily can be substituted for a daily dose of levodopa 300-400 mg  in immediate-release Sinemet? tablets (substitute Sinemet? CR to  provide approx. 10% more levodopa per day and extend dosing  interval by 30-50%); dose and interval then adjusted according to  response at intervals of not less than 3 days   For Parkinson’s disease and end-of-dose motor fluc-  tuations not adequately controlled with levodopa and  dopa-decarboxylase inhibitor treatment   12.5 mg, entacapone 200 mg, net price 30-tab pack =  £20.79, 100-tab pack = £69.31. Label: 10, 14 (urine  reddish-brown), 25, counselling, driving, see notes  above   Dose only 1 tablet to be taken for each dose; max. 10 tablets  daily   Tablets, f/c, brown, levodopa 75 mg, carbidopa  18.75 mg, entacapone 200 mg, net price 30-tab pack =  £20.79, 100-tab pack = £69.31. Label: 10, 14 (urine  reddish-brown), 25, counselling, driving, see notes  above   Dose only 1 tablet to be taken for each dose; max. 10 tablets  daily   Tablets, f/c, brown, levodopa 100 mg, carbidopa  25 mg, entacapone 200 mg, net price 30-tab pack =  £20.79, 100-tab pack = £69.31. Label: 10, 14 (urine  reddish-brown), 25, counselling, driving, see notes  above   Dose only 1 tablet to be taken for each dose; max. 10 tablets  daily   Tablets, f/c, brown, levodopa 125 mg, carbidopa  31.25 mg, entacapone 200 mg, net price 30-tab pack =  £20.79, 100-tab pack = £69.31. Label: 10, 14 (urine  reddish-brown), 25, counselling, driving, see notes  above   Dose only 1 tablet to be taken for each dose; max. 10 tablets  daily   37.5 mg, entacapone 200 mg, net price 30-tab pack =  £20.79, 100-tab pack = £69.31. Label: 10, 14 (urine  reddish-brown), 25, counselling, driving, see notes  above   Dose only 1 tablet to be taken for each dose; max. 10 tablets  daily   Tablets, f/c, brown, levodopa 200 mg, carbidopa  50 mg, entacapone 200 mg, net price 30-tab pack =  £20.79, 100-tab pack = £69.31. Label: 10, 14 (urine   Dose only 1 tablet to be taken for each dose; max. 7 tablets daily  Note Patients receiving standard-release co-careldopa or co-  beneldopa alone, initiate Stalevo ® at a dose that provides  similar (or slightly lower) amount of levodopa  Patients with dyskinesia or receiving more than 800 mg  levodopa daily, introduce entacapone before transferring to  Stalevo ® (levodopa dose may need to be reduced by 10-  30% initially)   Patients receiving entacapone and standard-release co-  careldopa or co-beneldopa, initiate Stalevo ® at a dose that  provides similar (or slightly higher) amount of levodopa   Rasagiline, a monoamine-oxidase-B inhibitor, is  licensed for the management of Parkinson’s disease  used alone or as an adjunct to levodopa for ‘end-of-  dose’ fluctuations.   Selegiline is a monoamine-oxidase-B inhibitor used in  conjunction with levodopa to reduce ‘end-of-dose’ dete-  rioration in advanced Parkinson’s disease. Early treat-  ment with selegiline alone can delay the need for levo-  dopa therapy. When combined with levodopa, selegiline  should be avoided or used with great caution in postural  hypotension.   Indications Parkinson’s disease, used alone or as  adjunct to co-beneldopa or co-careldopa  Cautions avoid abrupt withdrawal; interactions:  Appendix 1 (rasagiline)   Hepatic impairment use with caution in mild impair-  ment; avoid in moderate to severe impairment  Pregnancy use with caution  Breast-feeding use with caution — may suppress  lactation   Side-effects dry mouth, dyspepsia, constipation,  flatulence; angina; headache, depression, anorexia,  weight loss, abnormal dreams, vertigo, hallucinations;  influenza-like symptoms; urinary urgency; leuco-  penia; arthralgia; conjunctivitis; rhinitis; rash, skin  carcinoma; less commonly myocardial infarction, and  cerebrovascular accident  Dose   Tablets, rasagiline (as mesilate) 1 mg, net price 28-tab  pack = £70.72   Indications Parkinson’s disease, used alone or as  adjunct to co-beneldopa or co-careldopa  Cautions avoid abrupt withdrawal; gastric and duo-  denal ulceration (avoid in active ulceration), uncon-  trolled hypertension, arrhythmias, angina, psychosis,  side-effects of levodopa may be increased, concurrent  levodopa dosage can be reduced by 10-30%; avoid in  acute porphyria (section 9.8.2); interactions: Appen-  dix 1 (selegiline)    Pregnancy avoid — no information available  Breast-feeding avoid — no information available  Side-effects nausea, constipation, diarrhoea, dry  mouth; postural hypotension; dyskinesia, vertigo,  sleeping disorders, confusion, hallucinations; arthr-  algia, myalgia; mouth ulcers with oral lyophilisate;  rarely arrhythmias, agitation, headache, micturition  difficulties, skin reactions; very rarely hypersexuality;  also reported chest pain  Dose   • 10 mg in the morning, or 5 mg at breakfast and mid-  day; ELDERLY see below   Elderly To avoid initial confusion and agitation, it may be  appropriate to start treatment with a dose of 2.5 mg daily  Note 1.25-mg oral lyophilisate is equivalent to 10-mg tablet   Selegiline Hydrochloride (Non-proprietary) (Ml  Tablets, selegiline hydrochloride 5 mg, net price 60-  tab pack = £5.59; 10 mg, 30-tab pack = £6.87   Tablets, scored, selegiline hydrochloride 5 mg, net  price 60-tab pack = £9.91; 10 mg, 30-tab pack = £9.67  Oral liquid, selegiline hydrochloride 10mg/5mL, net  price 200 mL = £17.93   Oral lyophilisates (= freeze-dried tablets), yellow,  selegiline hydrochloride 1.25 mg, net price 30-tab  pack = £43.16. Counselling, administration   Counselling Tablets should be placed on the tongue and allowed  to dissolve. Advise patient not to drink, rinse, or wash mouth out  for 5 minutes after taking the tablet   Note Patients receiving 10 mg conventional selegiline hydro-  chloride tablets can be switched to Zelapar ® 1.25 mg   Entacapone and tolcapone prevent the peripheral  breakdown of levodopa, by inhibiting catechol-O-  methyltransferase, allowing more levodopa to reach  the brain. They are licensed for use as an adjunct to  co-beneldopa or co-careldopa for patients with Parkin-  son’s disease who experience ‘end-of-dose’ deteriora-  tion and cannot be stabilised on these combinations.  Due to the risk of hepatotoxicity, tolcapone should be  prescribed under specialist supervision only, when other  catechol-O-methyltransferase inhibitors combined with  co-beneldopa or co-careldopa are ineffective.   Cautions ischaemic heart disease; avoid abrupt with-  drawal; concurrent levodopa dose may need to be  reduced by about 10-30%; interactions: Appendix 1  (entacapone)   Side-effects nausea, vomiting, abdominal pain, con-  stipation, diarrhoea, urine may be coloured reddish-  brown, dry mouth; ischaemic heart disease; confu-  sion, dizziness, abnormal dreams, fatigue, insomnia,  dystonia, dyskinesia, hallucinations; sweating; less  commonly myocardial infarction; rarely rash; very  rarely anorexia, weight loss, agitation, and urticaria;  also reported hepatitis, colitis, neuroleptic malignant  syndrome, rhabdomyolysis, and skin, hair, and nail  discoloration  Dose   • 200 mg with each dose of levodopa with dopa-  decarboxylase inhibitor; max. 2 g daily   Tablets, f/c, brown/orange, entacapone 200 mg, net  price 30-tab pack = £17.24, 100-tab pack = £57.45.  Label: 14, (urine reddish-brown), counselling, driving,  see notes above, avoid iron-containing products at the  same time of day   Cautions avoid abrupt withdrawal; most patients  receiving more than 600 mg levodopa daily require  reduction of levodopa dose by about 30%; interac-  tions: Appendix 1 (tolcapone)   Hepatotoxicity Potentially life-threatening hepatotoxicity  including fulminant hepatitis reported rarely, usually in  women and during the first 6 months, but late-onset liver  injury also reported; test liver function before treatment, and  monitor every 2 weeks for first year, every 4 weeks for next 6  months and then every 8 weeks thereafter (restart monitor-  ing schedule if dose increased); discontinue if abnormal liver  function tests or symptoms of liver disorder (counselling, see  below); do not re-introduce tolcapone once discontinued  Counselling Patients should be told how to recognise signs  of liver disorder and advised to seek immediate medical  attention if symptoms such as anorexia, nausea, vomiting,  fatigue, abdominal pain, dark urine, or pruritus develop   Contra-indications severe dyskinesia, phaeochromo-  cytoma, previous history of neuroleptic malignant  syndrome, rhabdomyolysis, or hyperthermia  Hepatic impairment avoid; see also under Cautions    Renal impairment caution if eGFR less than 30 mL/  minute/ 1.73 m 2    Side-effects diarrhoea, constipation, dyspepsia,  abdominal pain, nausea, vomiting, anorexia, xero-  stomia, hepatotoxicity (see above); chest pain; con-  fusion, dystonia, dyskinesia, drowsiness, headache,  dizziness, sleep disturbances, excessive dreaming,  hallucinations; syncope; urine discoloration; sweating;  neuroleptic malignant syndrome and rhabdomyolysis  reported on dose reduction or withdrawal   • 100 mg 3 times daily, leave 6 hours between each  dose; max. 200 mg 3 times daily in exceptional cir-  cumstances; first daily dose should be taken at the  same time as levodopa with dopa-decarboxylase  inhibitor   Amantadine is a weak dopamine agonist with modest  antiparkinsonian effects. Tolerance to its effects may  develop and confusion and hallucinations may occa-  sionally occur.   Cautions congestive heart disease (may exacerbate  oedema), confused or hallucinatory states, elderly;  avoid abrupt withdrawal in Parkinson’s disease;  interactions: Appendix 1 (amantadine)   Hepatic impairment caution  Renal impairment reduce dose; avoid if eGFR less  than 15 mL/minute/ 1.73 m 2  Pregnancy avoid; toxicity in animal studies  Breast-feeding avoid; present in milk; toxicity in  infant reported   Side-effects gastro-intestinal disturbances, anorexia,  dry mouth; palpitation, peripheral oedema, postural  hypotension; anxiety, mood changes, dizziness,  headache, lethargy, hallucinations, insomnia, impaired  concentration, slurred speech; myalgia; sweating and  livedo reticularis; less commonly confusion, psycho-  sis, tremor, movement disorders, seizure, neuroleptic  malignant syndrome, urinary retention, urinary  incontinence, visual disturbances, and rash; heart  failure, leucopenia, and photosensitisation also  reported   • Parkinson’s disease, 100 mg daily increased after one  week to 100 mg twice daily, usually in conjunction  with other treatment; some patients may require  higher doses, max. 400 mg daily; ELDERLY 65 years and  over, 100 mg daily adjusted according to response   • Post-herpetic neuralgia, 100 mg twice daily for 14  days, continued for a further 14 days if necessary   Antimuscarinic drugs exert their antiparkinsonian  action by reducing the effects of the relative central  cholinergic excess that occurs as a result of dopamine  deficiency. Antimuscarinic drugs can be useful in drug-  induced parkinsonism, but they are generally not used  in idiopathic Parkinson’s disease because they are less  effective than dopaminergic drugs and they are asso-  ciated with cognitive impairment.   The antimuscarinic drugs orphenadrine, procyclidine,  and trihexyphenidyl reduce the symptoms of  parkinsonism induced by antipsychotic drugs, but  there is no justification for giving them routinely in the  absence of parkinsonian side-effects. Tardive dyskinesia  is not improved by antimuscarinic drugs and may be  made worse.   In idiopathic Parkinson’s disease, antimuscarinic drugs  reduce tremor and rigidity but they have little effect on  bradykinesia. They may be useful in reducing sialor-  rhoea.   No important differences exist between the anti-  muscarinic drugs, but some patients tolerate one better  than another.   Procyclidine can be given parenterally and is effective  emergency treatment for acute drug-induced dystonic  reactions.   Cautions Antimuscarinics should be used with caution  in cardiovascular disease, hypertension, psychotic dis-  orders, prostatic hypertrophy, pyrexia, in those suscep-  tible to angle-closure glaucoma, and in the elderly.  Antimuscarinics should not be withdrawn abruptly in  patients receiving long-term treatment. Antimuscarinics  are liable to abuse. Interactions: Appendix 1 (Anti-  muscarinics)   Contra-indications Antimuscarinics should be  avoided in gastro-intestinal obstruction and myasthenia  gravis.   Hepatic and renal impairment Orphenadrine, pro-  cyclidine, and trihexyphenidyl should be used with cau-  tion in patients with hepatic or renal impairment.   Side-effects Side-effects of antimuscarinics include  constipation, dry mouth, nausea, vomiting, tachycardia,  dizziness, confusion, euphoria, hallucinations, impaired  memory, anxiety, restlessness, urinary retention, blurred  vision, and rash. Angle-closure glaucoma may occur  very rarely.   Symmetrel® (Alliance) (Ml  Capsules, red-brown, amantadine hydrochloride  100 mg. Net price 56-cap pack = £16.22. Counselling,  driving, see Cautions   Syrup, amantadine hydrochloride 50 mg/5 mL. Net  price 150-mL pack = £5.33. Counselling, driving, see  Cautions   Indications parkinsonism; drug-induced extrapyra-  midal symptoms (but not tardive dyskinesia, see notes  above)   Side-effects see notes above; less commonly seizures,  drowsiness, insomnia, and impaired coordination   • Initially 150 mg daily in divided doses, increased  gradually in steps of 50 mg every 2-3 days according  to response; usual dose range 150-300 mg daily in  divided doses; max. 400 mg daily; ELDERLY preferably  lower end of range   Orphenadrine Hydrochloride (Non-proprietary) (Ml  Tablets, orphenadrine hydrochloride 50 mg, net price  100-tab pack = £63.68. Counselling, driving, see notes  above   Liquid, sugar-free, orphenadrine hydrochloride  25 mg/5 mL, net price 200 mL = £8.48. Counselling,  driving, see notes above   Tablets, yellow, s/c, orphenadrine hydrochloride  50 mg, net price 250-tab pack = £8.59. Counselling,  driving, see notes above   Indications parkinsonism; drug-induced extrapyra-  midal symptoms (but not tardive dyskinesia, see notes  above)   • By mouth, 2.5 mg 3 times daily, increased gradually in  steps of 2.5-5 mg daily every 2-3 days if necessary;  usual max. 30 mg daily in 2-4 divided doses (60 mg  daily in exceptional circumstances); ELDERLY prefer-  ably lower end of range   • By intramuscular or intravenous injection, acute  dystonia, 5-10 mg (occasionally more than 10 mg),  usually effective in 5-10 minutes but may need 30  minutes for relief; ELDERLY preferably lower end of  range   Arpicolin® (Rosemont) (Ml  Syrup, sugar-free, procyclidine hydrochloride 2.5 mg/  5mL, net price 150 mL = £4.22; 5mg/5mL, 150 mL  pack = £7.54. Counselling, driving, see notes above    Kemadrin® (Auden Mckenzie) [Ml  Injection, procyclidine hydrochloride 5mg/mL, net  price 2-mL amp = £1.49   Indications parkinsonism; drug-induced extrapyra-  midal symptoms (but not tardive dyskinesia, see notes  above)   • 1 mg daily, increased gradually; usual maintenance  dose 5-15 mg daily in 3-4 divided doses (max. 20 mg  daily); ELDERLY preferably lower end of range; CHILD  under 18 years see BNF for Children    Trihexyphenidyl (Non-proprietary) (Ml  Tablets, trihexyphenidyl hydrochloride 2 mg, net  price 84-tab pack = £19.60; 5 mg, 84-tab pack =  £18.59, 100-tab pack = £15.60. Counselling, with or  after food, driving, see notes above   Syrup, pink, black currant, trihexyphenidyl hydro-  chloride 5mg/5mL, net price 200 mL = £7.44.  Counselling, driving, see notes above   Tetrabenazine is mainly used to control movement  disorders in Huntington’s chorea and related disorders.  Tetrabenazine can also be prescribed for the treatment  of tardive dyskinesia if switching or withdrawing the  causative antipsychotic drug is not effective. It may act  by depleting nerve endings of dopamine. It is effective in  only a proportion of patients and its use may be limited  by the development of depression.   Haloperidol (p. 219) can improve motor tics and symp-  toms of Tourette syndrome and related choreas. Other  treatments for Tourette syndrome include pimozide  (p. 220) [unlicensed indication] (important: ECG mon-  itoring required), clonidine (p. 278) [unlicensed indica-  tion], and sulpiride (p. 221) [unlicensed indication].  Trihexyphenidyl (above) in high dosage can also  improve some movement disorders; it is sometimes  necessary to build the dose up over many weeks, to  20 to 30 mg daily or higher. Chlorpromazine (p. 218)  and haloperidol (p. 219) are used to relieve intractable  hiccup.   Propranolol or another beta-adrenoceptor blocking  drug (section 2.4) may be useful in treating essential  tremor or tremors associated with anxiety or thyrotoxic-  osis.    Primidone (p. 288) in some cases provides relief from  benign essential tremor; the dose is increased slowly to  reduce side-effects.   Piracetam is used as an adjunctive treatment for myo-  clonus of cortical origin.   Riluzole is used to extend life in patients with motor  neurone disease who have amyotrophic lateral sclerosis.   Riluzole is recommended for treating the amyo-  trophic lateral sclerosis (ALS) form of motor neurone  disease (MND). Treatment should be initiated by a  specialist in MND but it can then be supervised  under a shared-care arrangement involving the gen-  eral practitioner.   Cautions avoid abrupt withdrawal; elderly; haemosta-  sis, major surgery, or severe haemorrhage   Renal impairment use two-thirds of normal dose if  eGFR 50-80 mL/minute/ 1.73 m 2 ; use one-third of  normal dose in 2 divided doses if eGFR 30-50 mL/  minute/ 1.73 m 2 ; use one-sixth normal dose as a single  dose if eGFR 20-30 mL/minute/ 1.73 m 2 ; avoid if  eGFR less than 20 mL/minute/ 1.73 m 2   Side-effects weight gain, nervousness, hyperkinesia;  less commonly drowsiness, depression, asthenia,; also  reported abdominal pain, nausea, vomiting, diarr-  hoea, headache, anxiety, confusion, hallucination,  vertigo, ataxia, insomnia, and rash   • Initially 7.2 g daily in 2-3 divided doses, increased  according to response by 4.8 g daily every 3-4 days to  max. 20 g daily (subsequently, attempts should be  made to reduce dose of concurrent therapy); CHILD  under 16 years not recommended  Oral solution Follow the oral solution with a glass of water  (or soft drink) to reduce bitter taste.   Nootropil® (UCB Pharma) (Ml  Tablets, f/c, scored, piracetam 800 mg, net price 90-  tab pack = £11.75; 1.2 g, 60-tab pack = £10.97.   Indications to extend life in patients with amyotrophic  lateral sclerosis, initiated by specialists experienced in  the management of motor neurone disease   Blood disorders Patients or their carers should be told how  to recognise signs of neutropenia and advised to seek  immediate medical attention if symptoms such as fever  occur; white blood cell counts should be determined in   Interstitial lung disease Perform chest radiography if  symptoms such as dry cough or dyspnoea develop; discon-  tinue if interstitial lung disease is diagnosed  Driving Dizziness or vertigo may affect performance of  skilled tasks (e.g. driving)   Side-effects nausea, vomiting, diarrhoea, abdominal  pain; tachycardia; asthenia, headache, dizziness,  drowsiness, oral paraesthesia; less commonly inter-  stitial lung disease, pancreatitis, angioedema, and  anaemia; rarely neutropenia; very rarely hepatitis   Rilutek® (Sanofi-Aventis) (Ml  Tablets, f/c, riluzole 50 mg. Net price 56-tab pack =  £278.55. Counselling, blood disorders, driving, see  Cautions   Cautions interactions: Appendix 1 (tetrabenazine)  Driving May affect performance of skilled tasks (e.g. driving)   Side-effects drowsiness, gastro-intestinal distur-  bances, depression, extrapyramidal dysfunction,  hypotension; rarely parkinsonism; neuroleptic malig-  nant syndrome reported   • Movement disorders due to Huntington’s chorea,  hemiballismus, senile chorea, and related neurological  conditions, initially 12.5 mg twice daily (elderly   12.5 mg daily) gradually increased to 12.5-25 mg 3  times daily; max. 200 mg daily   • Moderate to severe tardive dyskinesia, initially  12.5 mg daily, gradually increased according to  response   Botox® and Dysport® are licensed for the treatment of  focal spasticity (including arm symptoms in conjunction  with physiotherapy, dynamic equinus foot deformity  caused by spasticity in ambulant paediatric cerebral  palsy patients over 2 years, and hand and wrist disability  associated with stroke), blepharospasm, hemifacial  spasm, and spasmodic torticollis. Botox® is also  licensed for severe hyperhidrosis of the axillae, and for  the prophylaxis of headaches in adults with chronic  migraine (section 4.7.4.2).   Azzalure®, Bocouture®, and Vistabel® are licensed for  the temporary improvement of moderate to severe  wrinkles between the eyebrows in adults under 65 years.    Xeomin® is licensed for the treatment of blepharos-  pasm, spasmodic torticollis, and post-stroke spasticity  of the upper limb.   Indications see notes above; preparations are not  interchangeable and should be used under specialist  supervision   Cautions history of dysphagia or aspiration; chronic  respiratory disorder; neurological disorders (can lead  to increased sensitivity and exaggerated muscle  weakness)   Specific cautions for blepharospasm or hemifacial  spasm Caution if risk of angle-closure glaucoma; reduced  blinking can lead to comeal exposure, persistent epithelial  defect and comeal ulceration (especially in those with Vllth  nerve disorders) — careful testing of comeal sensation in  previously operated eyes, avoidance of injection in lower lid  area to avoid ectropion, and vigorous treatment of epithelial  defect needed   Contra-indications generalised disorders of muscle  activity (e.g. myasthenia gravis); infection at injection  site   Side-effects increased electrophysiologic jitter in  some distant muscles; misplaced injections may  paralyse nearby muscle groups and excessive doses  may paralyse distant muscles; influenza-like symp-  toms; rarely arrhythmias, myocardial infarction, sei-  zures, and antibody formation (substantial deteriora-  tion in response); very rarely exaggerated muscle  weakness, dysphagia, and aspiration (seek medical  attention if swallowing, speech, or respiratory disor-  ders)   Specific side-effects for blepharospasm or hemifacial  spasm ptosis; keratitis, lagophthalmos, dry eye, irritation,  photophobia, lacrimation; facial oedema; less commonly dry  mouth, facial weakness (including drooping), dizziness,  paraesthesia, headache, tiredness, ectropion, entropion,  diplopia, visual disturbances, conjunctivitis, dermatitis;  rarely eyelid bruising and swelling (minimised by applying  gentle pressure at injection site immediately after injection);  very rarely angle-closure glaucoma, corneal ulceration  Specific side-effects in paediatric cerebral palsy drow-  siness, paraesthesia, urinary incontinence, myalgia  Specific side-effects for temporary improvement of  moderate to severe wrinkles between the eyebrows  facial oedema, headache; ptosis; less commonly nausea, dry  mouth, dizziness, asthenia, anxiety, paraesthesia, muscle  cramp, visual disturbances, tinnitus, blepharitis, photo-  sensitivity reactions, and dry skin  Specific side-effects in spasmodic torticollis dysphagia  and pooling of saliva (occurs most frequently after injection  into stemomastoid muscle), nausea, dry mouth; rhinitis;  drowsiness, headache, dizziness, malaise, numbness, stiff-  ness, hypertonia, back pain, weakness; less commonly  diarrhoea, vomiting, colitis, dyspnoea, voice alteration, tre-  mor, skeletal pain, myalgia, diplopia, eye pain, ptosis, and  sweating   Specific side-effects in axillary hyperhidrosis non-axil-  lary sweating, hot flushes; less commonly myalgia and joint  pain   Specific side-effects in focal upper-limb spasticity  associated with stroke dysphagia; hypertonia, purpura;  less commonly nausea, dry mouth, cough, haematoma, per-  ipheral oedema, depression, insomnia, vertigo, amnesia,  malaise, paraesthesia, dysaesthesia, headache, pain in  extremities, arthralgia, and bursitis   Injection, powder for reconstitution, botulinum toxin  type A complex, net price 50-unit vial = £77.50, 100-  unit vial = £138.20, 200-unit vial = £276.40   Injection, powder for reconstitution, botulinum toxin  type A, net price 100-unit vial = £129.90   Side-effects increased electrophysiologic jitter in  some distant muscles; dry mouth, dyspepsia, wor-  sening torticollis, neck pain, myasthenia, voice  changes, taste disturbances; very rarely exaggerated  muscle weakness, dysphagia, and aspiration (seek  medical attention if swallowing, speech, or respiratory  disorders)   • By intramuscular injection, initially 5000-10 000 units  divided between 2-4 most affected muscles; adjust  dose and frequency according to response; impor-  tant: not interchangeable with other botulinum toxin  preparations   Injection, botulinum toxin type B 5000units/mL, net  price 0.5-mL vial = £111.20; 1-mL vial = £148.27; 2-  mL vial = £197.69   This section includes drugs used in alcohol dependence,  cigarette smoking, and opioid dependence.   The UK health departments have produced guidance on  the treatment of drug misuse in the UK. Drug Misuse  and Dependence: UK Guidelines on Clinical Manage-  ment (2007) is available at www.nta.nhs.uk/uploads/  clinical_guidelines_2007.pdf.   Excessive drinking of alcoholic beverages over a pro-  longed period of time can result in an alcohol with-  drawal syndrome on abrupt cessation of, or marked  reduction in, drinking; for some patients the withdrawal  syndrome can be severe and even fatal.   Acute alcohol withdrawal Long-acting benzodiaz-  epines, usually chlordiazepoxide (p. 214), are used to  attenuate alcohol withdrawal symptoms. In primary  care, fixed-dose reducing regimens are usually used,  whilst a symptom-triggered flexible regimen is used in  hospital or other settings where continued assessment  and monitoring is carried out for 24-48 hours, usually  followed by a fixed 5-day reducing dose schedule.  Patients with decompensated liver disease should be  treated under specialist supervision.   Carbamazepine [unlicensed indication] (p. 281) is  sometimes used as an alternative treatment in acute  alcohol withdrawal when benzodiazepines are contra-  indicated or not tolerated. Clomethiazole (p. 211) is  licensed for use in acute alcohol withdrawal, but benzo-  diazepines are preferred. It should only be used in an  inpatient setting and should not be prescribed if the  patient is liable to continue drinking alcohol.   Patients with marked agitation or hallucinations and  those at risk of delirium tremens (characterised by  delirium, hallucinations, course tremor, and disorienta-  tion) may be prescribed antipsychotic drugs, such as  haloperidol (p. 219) or olanzapine (p. 224) [unlicensed  indication], as adjunctive therapy to benzodiazepines;  antipsychotics should not be used alone because they  do not treat alcohol withdrawal and may lower the  seizure threshold. Delirium tremens is a medical emer-  gency that requires specialist inpatient care.    If a patient taking a benzodiazepine as part of a with-  drawal regimen develops alcohol withdrawal seizures, a  fast-acting benzodiazepine (such as intravenous loraze-  pam [unlicensed indication] (p. 296) or rectal diazepam  (p. 295)) should be prescribed; thereafter an increase in  the dose of oral benzodiazepine should be considered to  prevent further seizures from occurring.   are effective treatments for relapse prevention in  patients with alcohol dependence (see below).   Patients with alcohol dependence are at risk of devel-  oping Wernicke’s encephalopathy; patients at high-risk  are those who are malnourished, at risk of malnourish-  ment, or have decompensated liver disease. Parenteral  thiamine (as Pabrinex®, section 9.6.2) should be  prescribed for treatment of suspected or confirmed  Wernicke’s encephalopathy, and for prophylaxis in  alcohol-dependent patients attending hospital for  acute treatment (including treatment unrelated to  alcohol dependence); parenteral prophylaxis may also  be considered for high-risk patients being treated in  primary care. High-dose oral thiamine (p. 616) should  be prescribed following parenteral treatment until  cognitive function is maximised. In primary care,  prophylactic high-dose oral thiamine should be pre-  scribed during acute withdrawal of alcohol, before  planned withdrawal, and for patients not undergoing  withdrawal but who are at high-risk of developing  Wernicke’s encephalopathy.   Patients with chronic alcohol-related pancreatitis who  have symptoms of steatorrhoea or who have poor    nutritional status due to exocrine pancreatic insuffi-  ciency should be prescribed pancreatic enzyme sup-  plements (section 1.9.4); supplements are not indicated  when pain is the only symptom.   Corticosteroids (section 6.3.2) are used in patients with  severe acute alcohol-related hepatitis.   Acamprosate, in combination with counselling, may be  helpful for maintaining abstinence in alcohol-dependent  patients. It is useful for patients who are concerned that  strong cravings will result in relapse. It should be  initiated as soon as possible after abstinence has been  achieved and continued for 1 year; treatment should be  maintained if the patient has a temporary relapse.  Acamprosate is not effective in all patients, so efficacy  should be regularly assessed.   Side-effects diarrhoea, nausea, vomiting, abdominal  pain; fluctuation in libido; pruritus, maculopapular  rash; rarely bullous skin reactions   666 mg 3 times daily; body-weight less than 60 kg,  666 mg at breakfast, 333 mg at midday and 333 mg at  night   Campral EC® (Merck Serono) (Ml  Tablet, e/c, acamprosate calcium 333 mg, net price  168-tab pack = £24.00. Label: 21, 25   Disulfiram is used as an adjunct in the treatment of  alcohol dependence (under specialist supervision). It  gives rise to an extremely unpleasant systemic reaction  after the ingestion of even a small amount of alcohol  because it causes accumulation of acetaldehyde in the  body; it is only effective if taken daily. Symptoms can  occur within 10 minutes of ingesting alcohol and include  flushing of the face, throbbing headache, palpitation,  tachycardia, nausea, vomiting, and, with large doses of  alcohol, arrhythmias, hypotension, and collapse; these  reactions can last several hours. Small amounts of  alcohol such as those included in many oral medicines  may be sufficient to precipitate a reaction — even toile-  tries and mouthwashes that contain alcohol should be  avoided. Alcohol should be avoided for at least 1 week  after stopping treatment.   Before initiating disulfiram, prescribers should evaluate  the patient’s suitability for treatment, because some  patient factors, for example memory impairment or  social circumstances, make compliance to treatment  or abstinence from alcohol difficult.   Cautions ensure that alcohol not consumed for at least  24 hours before initiating treatment; see also notes  above; alcohol challenge not recommended on rou-  tine basis (if considered essential — specialist units  only with resuscitation facilities); respiratory disease,  diabetes mellitus, epilepsy; avoid in acute porphyria  (section 9.8.2); interactions: Appendix 1 (disulfiram)   Contra-indications cardiac failure, coronary artery  disease, history of cerebrovascular accident, hyper-  tension, psychosis, severe personality disorder, sui-  cide risk   Pregnancy high concentrations of acetaldehyde which  occur in presence of alcohol may be teratogenic;  avoid in first trimester   Side-effects initially drowsiness and fatigue; nausea,  vomiting, halitosis, reduced libido; rarely psychotic  reactions (depression, paranoia, schizophrenia,  mania), allergic dermatitis, peripheral neuritis, hepatic  cell damage   • 800 mg as a single dose on first day, reducing over 5  days to 100-200 mg daily; should not be continued for  longer than 6 months without review; CHILD not  recommended   Tablets, scored, disulfiram 200 mg. Net price 50-tab  pack = £24.78. Label: 2, counselling, alcohol reaction   Smoking cessation interventions are a cost-effective  way of reducing ill health and prolonging life. Smokers  should be advised to stop and offered help with follow-  up when appropriate. If possible, smokers should have  access to smoking cessation services for behavioural  support.   Therapy to aid smoking cessation is chosen according  to the smoker’s likely compliance, availability of coun-  selling and support, previous experience of smoking-  cessation aids, contra-indications and adverse effects of  the products, and the smoker’s preferences. Nicotine  replacement therapy, bupropion, and varenicline are  effective aids to smoking cessation. The use of nicotine  replacement preparations in an individual who is  already accustomed to nicotine introduces few new  risks and it is widely accepted that there are no circum-  stances in which it is safer to smoke than to use nicotine  replacement therapy.   Some patients benefit from having more than one type  of nicotine replacement therapy prescribed, such as a  combination of transdermal and oral preparations. The  combination of nicotine replacement therapy with var-  enicline or bupropion is not recommended.   Concomitant medication Cigarette smoking  increases the metabolism of some medicines by stimu-  lating the hepatic enzyme CYP1A2. When smoking is  discontinued, the dose of these drugs, in particular  theophylline (p. 181), cinacalcet (p. 610), ropinirole  (p. 301), and some antipsychotics (including clozapine   (p. 223), olanzapine (p. 224), chlorpromazine (p. 218),  and haloperidol (p. 219)), may need to be reduced.  Regular monitoring for adverse effects is advised.   Bupropion has been used as an antidepressant but its  mode of action in smoking cessation is not clear and  may involve an effect on noradrenaline and dopamine  neurotransmission.   Cautions elderly; predisposition to seizures (prescribe  only if benefit clearly outweighs risk) including con-  comitant use of drugs that lower seizure threshold,  alcohol abuse, history of head trauma, and diabetes;  measure blood pressure before and during treatment;  interactions: Appendix 1 (bupropion)   Driving May impair performance of skilled tasks (e.g. driving)  Contra-indications acute alcohol or benzodiazepine  withdrawal; severe hepatic cirrhosis; CNS tumour;  history of seizures, eating disorders, or bipolar dis-  order   avoid in severe hepatic cirrhosis  Renal impairment reduce dose to 150 mg daily  Pregnancy avoid — no information available  Breast-feeding present in milk — avoid  Side-effects dry mouth, gastro-intestinal distur-  bances, taste disturbance; agitation, anxiety, dizziness,  depression, headache, impaired concentration,  insomnia (reduced by avoiding dose at bedtime),  tremor; fever; pruritus, rash, sweating; less commonly  chest pain, flushing, hypertension, tachycardia, ano-  rexia, asthenia, confusion, tinnitus, and visual distur-  bances; rarely hepatitis, jaundice, palpitation, postural  hypotension, vasodilatation, abnormal dreams, ataxia,  dystonia, depersonalisation, hallucinations, hostility,  incoordination, irritability, impaired memory, paraes-  thesia, seizures, twitching, blood-glucose changes,  urinary frequency, urinary retention, exacerbation of  psoriasis, and Stevens- Johnson syndrome; very rarely  aggression, delusions, paranoid ideation, and rest-  lessness; also reported suicidal ideation  Dose   • ADULT over 18 years, start 1-2 weeks before target stop  date, initially 150 mg daily for 6 days then 150 mg  twice daily (max. single dose 150 mg, max. daily dose  300 mg; minimum 8 hours between doses); period of  treatment 7-9 weeks; discontinue if abstinence not  achieved at 7 weeks; consider max. 150 mg daily in  patients with risk factors for seizures; ELDERLY max.  150 mg daily   Tablets, m/r, f/c, bupropion hydrochloride 150 mg,  net price 60-tab pack = £47.82. Label: 25, counselling,  driving, see Cautions   Nicotine replacement therapy can be used in place of  cigarettes after abrupt cessation of smoking, or alterna-  tively to reduce the amount of cigarettes used in    advance of making a quit attempt. Nicotine replacement  therapy can also be used to minimise passive smoking,  and to treat cravings and reduce compensatory smoking  after enforced abstinence in smoke-free environments.  Smokers who find it difficult to achieve abstinence  should consult a healthcare professional for advice.   Choice Nicotine patches are a prolonged-release for-  mulation and are applied for 16 hours (with the patch  removed overnight) or for 24 hours. If patients experi-  ence strong cravings for cigarettes on waking, a 24-hour  patch may be more suitable. Immediate-release nicotine  preparations (gum, lozenges, sublingual tablets, inhala-  tor, nasal spray) are used whenever the urge to smoke  occurs.   The choice of nicotine replacement preparation  depends largely on patient preference, and should take  into account what preparations, if any, have been tried  before. Patients with a high level of nicotine depend-  ence, or who have failed with nicotine replacement  therapy previously, may benefit from using a combina-  tion of an immediate-release preparation and patches to  achieve abstinence.   All preparations are licensed for adults and children  over 12 years (with the exception of Nicotinell®  lozenges which are licensed for children under 18  years only when recommended by a doctor).   Cautions Most warnings for nicotine replacement  therapy also apply to continued cigarette smoking, but  the risk of continued smoking outweighs any risks of  using nicotine preparations. Nicotine replacement ther-  apy should be used with caution in haemodynamically  unstable patients hospitalised with severe arrhythmias,  myocardial infarction, or cerebrovascular accident, and  in patients with phaeochromocytoma or uncontrolled  hyperthyroidism. Care is also needed in patients with  diabetes mellitus — blood-glucose concentration should  be monitored closely when initiating treatment.    Specific cautions for individual preparations are usually  related to the local effect of nicotine. Oral preparations  should be used with caution in patients with oeso-  phagitis, gastritis, or peptic ulcers because swallowed  nicotine can aggravate these conditions. The gum may  also stick to and damage dentures. Acidic beverages,  such as coffee or fruit juice, may decrease the absorp-  tion of nicotine through the buccal mucosa and should  be avoided for 15 minutes before the use of oral nicotine  replacement therapy. Care should be taken with the  inhalation cartridges in patients with obstructive lung  disease, chronic throat disease, or bronchospastic dis-  ease. The nasal spray can cause worsening of bronchial  asthma. Patches should not be placed on broken skin  and should be used with caution in patients with skin  disorders.    Hepatic impairment Nicotine replacement therapy  should be used with caution in moderate to severe  hepatic impairment.   Renal impairment Nicotine replacement therapy  should be used with caution in severe renal impairment.   Pregnancy The use of nicotine replacement therapy  in pregnancy is preferable to the continuation of  smoking, but should be used only if smoking cessation  without nicotine replacement fails. Intermittent therapy  is preferable over patches but avoid liquorice-flavoured  nicotine products. Patches are useful, however, if the  patient is experiencing pregnancy-related nausea and    vomiting. If patches are used, they should be removed  before bed.   Breast-feeding Nicotine is present in milk; however,  the amount to which the infant is exposed is small and  less hazardous than second-hand smoke. Intermittent  therapy is preferred.   Side-effects Some systemic effects occur on initiation  of therapy, particularly if the patient is using high-  strength preparations; however, the patient may confuse  side-effects of the nicotine-replacement preparation  with nicotine withdrawal symptoms. Common symp-  toms of nicotine withdrawal include malaise, headache,  dizziness, sleep disturbance, coughing, influenza-like  symptoms, depression, irritability, increased appetite,  weight gain, restlessness, anxiety, drowsiness, aphthous  ulcers, decreased heart rate, and impaired concentra-  tion.   Mild topical reactions at the beginning of treatment are  common because of the irritant effect of nicotine. Oral  preparations and inhalation cartridges can cause irrita-  tion of the throat, gum and lozenges can cause increased  salivation, and patches can cause minor skin irritation.  The nasal spray commonly causes coughing, nasal  irritation, epistaxis, sneezing, and watery eyes.  Gastro-intestinal disturbances are common and may be  caused by swallowed nicotine. Nausea, vomiting, dys-  pepsia, and hiccup occur most frequently. Ulcerative  stomatitis has also been reported. Dry mouth is a  common side-effect of lozenges, patches and sublingual  tablets. Lozenges cause diarrhoea, constipation, dys-  phagia, oesophagitis, gastritis, mouth ulcers, bloating,  flatulence, and less commonly, taste disturbance, thirst,  gingival bleeding, and halitosis.   Palpitations may occur with nicotine replacement ther-  apy and rarely patches can cause arrhythmia. Patches  and lozenges can cause chest pain.   Abnormal dreams can occur with patches', removal of  the patch before bed may help. Lozenges may cause hot  flushes; sweating, arthralgia, and myalgia can occur with  patches.   Nicotine medicated chewing gum Individuals who  smoke fewer than 20 cigarettes each day should use one  piece of 2-mg strength gum when the urge to smoke  occurs; individuals who smoke more than 20 cigarettes  each day or who require more than 15 pieces of 2-mg  strength gum each day should use the 4-mg strength.  Patients should not exceed 15 pieces of 4-mg strength  gum daily. If attempting smoking cessation, treatment  should continue for 3 months before reducing the dose.   Administration Chew the gum until the taste becomes  strong, then rest it between the cheek and gum; when  the taste starts to fade, repeat this process. One piece of  gum lasts for approximately 30 minutes.   Nicotine inhalation cartridge The cartridges can be  used when the urge to smoke occurs or to prevent  cravings, up to a maximum of 12 cartridges daily.   Administration Insert the cartridge into the device and  draw in air through the mouthpiece. The amount of  nicotine from 1 puff of the cartridge is less than that  from a cigarette, therefore it is necessary to inhale more  often than when smoking a cigarette. A single cartridge  lasts for approximately 20 minutes of intense use.   Nicotine lozenge One lozenge should be used every  1-2 hours when the urge to smoke occurs. Individuals    who smoke less than 20 cigarettes each day should  usually use the lower-strength lozenges; individuals  who smoke more than 20 cigarettes each day and  those who fail to stop smoking with the low-strength  lozenges should use the higher-strength lozenges.  Patients should not exceed 15 lozenges daily If attempt-  ing smoking cessation, treatment should continue for 6-  12 weeks before attempting a reduction in dose.  Administration Slowly allow each lozenge to dissolve  in the mouth; periodically move the lozenge from one  side of the mouth to the other. Lozenges last for 10-30  minutes, depending on their size.   Nicotine sublingual tablets Individuals who smoke  fewer than 20 cigarettes each day should initially use 1  tablet each hour, increased to 2 tablets each hour if  necessary; individuals who smoke more than 20 cigar-  ettes each day should use 2 tablets each hour. Patients  should not exceed 40 tablets daily. If attempting  smoking cessation, treatment should continue for up  to 3 months before reducing the dose.   Administration Each tablet should be placed under the  tongue and allowed to dissolve.   Nicotine nasal spray Patients can use 1 spray in each  nostril when the urge to smoke occurs, up to twice every  hour for 16 hours daily (maximum 64 sprays daily). If  attempting smoking cessation, treatment should con-  tinue for 8 weeks before reducing the dose.  Administration Initially 1 spray should be used in both  nostrils but when withdrawing from therapy, the dose  can be gradually reduced to 1 spray in 1 nostril.   Nicotine transdermal patches As a general guide  for smoking cessation, individuals who smoke more  than 10 cigarettes daily should apply a high-strength  patch daily for 6-8 weeks, followed by the medium-  strength patch for 2 weeks, and then the low-strength  patch for the final 2 weeks; individuals who smoke fewer  than 10 cigarettes daily can usually start with the  medium-strength patch for 6-8 weeks, followed by the  low-strength patch for 2-4 weeks. A slower titration  schedule can be used in patients who are not ready to  quit but want to reduce cigarette consumption before a  quit attempt.   If abstinence isn’t achieved, or if withdrawal symptoms  are experienced, the strength of the patch used should  be maintained or increased until the patient is stabilised.  Patients using the high-strength patch who experience  excessive side-effects, that do not resolve within a few  days, should change to a medium-strength patch for the  remainder of the initial period and then use the low-  strength patch for 2-4 weeks.   Administration Patches should be applied on waking to  dry, non-hairy skin on the hip, trunk, or upper arm and  held in position for 10-20 seconds; place next patch on  a different area and avoid using the same site for several  days.   Indications see notes above  Cautions see notes above; interactions: Appendix 1  (nicotine)   Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   Tablets (sublingual) (Nicorette Microtab®), nicotine  (as a cyclodextrin complex) 2 mg, net price starter  pack of 2 x 15-tablet discs with dispenser = £4.46;  pack of 100 = £12.12. Label: 26  Note Also available in lemon flavour; also available as NicAssist 9  Excipients lemon flavour includes aspartame (section 9.4.1)   Chewing gum, sugar-free, nicotine (as resin) 2 mg, net  price pack of 30 = £3.41, pack of 105 = £9.37, pack of  210 = £14.82; 4 mg, pack of 30 = £3.99, pack of 105 =  £11.48, pack of 210 =£18.24   Note Also available in mint, freshfruit, freshmint, and icy white  flavours. Also available as NicAssist 9   Patches, self-adhesive, beige, nicotine, ‘5 mg’ patch  (releasing approx. 5 mg/ 16 hours), net price 7 = £9.07;  ‘10 mg’ patch (releasing approx. 10 mg/ 16 hours), 7 =  £9.07; ‘15 mg’ patch (releasing approx. 15 mg/16  hours), 2 = £2.85, 7 = £9.07  Note Also available as NicAssist 9    Invisi patches, self-adhesive, beige, nicotine, ‘10mg  patch (releasing approx. 10 mg/ 16 hours), net price 7  = £9.97; ‘15 mg’ patch (releasing approx. 15 mg/   16 hours), 7 = £9.97; ‘25 mg’ patch (releasing approx.  25 mg/ 16 hours), 7 = £9.97    Inhalator (nicotine-impregnated plug for use in inha-  lator mouthpiece), nicotine 10 mg/cartridge, net price  6-cartridge (starter) pack = £4.46, 42-cartridge (refill)  pack = £14.01. Counselling, administration, see notes  above   Chewing gum, sugar-free, nicotine (as polacrilin  complex) 2 mg, net price pack of 12 = £1.71, pack of  24 = £3.01, pack of 96 = £8.26, pack of 204 = £14.23;  4 mg, pack of 12 = £1.70, pack of 24 = £3.30, pack of  96 = £10.26   Note Also available in fruit, liquorice and mint flavours  Mint lozenge, sugar-free, nicotine (as bitartrate) 1 mg,  net price pack of 12 = £1.71, pack of 36 = £4.27, pack  of 96 = £9.12; 2 mg, net price pack of 12 =£1.99, pack  of 36 = £4.95, pack of 96 = £10.60. Label: 24   TTS Patches, self-adhesive, all yellowish-ochre, nico-  tine, ‘10’ patch (releasing approx. 7 mg/24 hours), net  price 7 = £9.12; ‘20’ patch (releasing approx. 14 mg/  24 hours), net price 2 = £2.57, 7 = £9.40; ‘30’ patch  (releasing approx. 21 mg/ 24 hours), net price 2 =  £2.85, 7 = £9.97, 21 =£24.51   Chewing gum, sugar-free, mint-flavour, nicotine 2 mg  (white), net price pack of 12 = £1.71, pack of 24 =  £2.85, pack of 96 = £8.55; 4 mg (yellow), net price  pack of 12 = £1.71, pack of 24 = £2.85, pack of 96 =  £8.55   Lozenges, sugar-free, nicotine (as resinate) 1.5 mg  (cherry- and mint-flavoured), net price pack of 20 =    £3.18, pack of 60 = £8.93; nicotine (as polacrilex) 2 mg  (mint-flavoured), pack of 36 = £ 5.12, pack of 72 =  £9.97; nicotine (as resinate) 4 mg (mint-flavoured),  pack of 20 = £3.18, pack of 60 = £8.93, nicotine (as  polacrilex) 4 mg (mint-flavoured) pack of 36 = £5.12,  pack of 72 = £9.97. Label: 24   Excipients include aspartame (section 9.4.1); contains 0.65 mmol Na + /  lozenge   Patches, self-adhesive, pink/beige, nicotine 7 mg’  patch (releasing approx. 7 mg/24 hours), net price 7 =  £9.97; '14 mg’ patch (releasing approx. 14mg/24  hours), 7 = £9.97; ‘21 mg’ patch (releasing approx.   21 mg/24 hours), 7 = £9.97, 14 = £18.79  Note Also available as a clear patch   Varenicline is a selective nicotine-receptor partial ago-  nist used as an aid for smoking cessation.   Cautions risk of relapse, irritability, depression, and  insomnia on discontinuation (consider dose tapering  on completion of 12-week course); history of psy-  chiatric illness (may exacerbate underlying illness  including depression)   MHRA/CHM advice  Suicidal behaviour and varenicline  Patients should be advised to discontinue treatment  and seek prompt medical advice if they develop agita-  tion, depressed mood, or suicidal thoughts. Patients  with a history of psychiatric illness should be mon-  itored closely while taking varenicline    Renal impairment if eGFR less than 30mL/minute/  1.73 m 2 , initial dose 500 micrograms once daily,  increased after 3 days to 1 mg once daily  Pregnancy avoid — toxicity in animal studies  Breast-feeding present in milk in animal studies  Side-effects gastro-intestinal disturbances, appetite  changes, dry mouth, taste disturbance; headache,  drowsiness, dizziness, sleep disorders, abnormal  dreams; less commonly thirst, weight gain, aphthous  stomatitis, gingival pain, chest pain, hypertension,  tachycardia, atrial fibrillation, palpitation, panic  attack, mood swings, dysarthria, asthenia, tremor,  incoordination, hypertonia, restlessness, hypoaesthe-  sia, impaired temperature regulation, menorrhagia,  vaginal discharge, sexual dysfunction, dysuria, arthr-  algia, muscle spasm, visual disturbances, eye pain,  lacrimation, tinnitus, acne, sweating, rash, and pru-  ritus; myocardial infarction, anxiety, depression,  aggression, irrational behaviour, psychosis, suicidal  ideation (see MHRA/CHM advice above), and Ste-  vens- Johnson syndrome also reported  Dose   • ADULT over 18 years, start 1-2 weeks before target stop  date, initially 500 micrograms once daily for 3 days,  increased to 500 micrograms twice daily for 4 days,  then 1 mg twice daily for 1 1 weeks (reduce to  500 micrograms twice daily if not tolerated); 12-week  course can be repeated in abstinent individuals to  reduce risk of relapse   Tablets, f/c, varenicline (as tartrate) 500 micrograms  (white), net price 56-tab pack = £54.60; 1 mg (blue)    28-tab pack = £27.30, 56-tab pack = £54.60; starter  pack of 1 1 x 500-microgram tabs with 14 x 1-mg tabs  = £27.30. Label: 3   The management of opioid dependence requires med-  ical, social, and psychological treatment; access to a  multidisciplinary team is recommended. Treatment for  opioid dependence should be initiated under the super-  vision of an appropriately qualified prescriber.  Untreated heroin dependence shows early withdrawal  symptoms within 8 hours, with peak symptoms at 36-72  hours; symptoms subside substantially after 5 days.  Methadone or buprenorphine withdrawal occurs later,  with longer-lasting symptoms.   Methadone and buprenorphine are used as substitu-  tion therapy in opioid dependence. Substitute medica-  tion should be commenced with a short period of  stabilisation, followed by either a withdrawal regimen  or by maintenance treatment. Maintenance treatment  enables patients to achieve stability, reduces drug use  and crime, and improves health; it should be regularly  reviewed to ensure the patient continues to derive  benefit. The prescriber should monitor for signs of  toxicity, and the patient should be told to be aware of  warning signs of toxicity on initiation and during titra-  tion.   A withdrawal regimen after stabilisation with metha-  done or buprenorphine should be attempted only after  careful consideration. Enforced withdrawal is ineffective  for sustained abstinence, and it increases the risk of  patients relapsing and subsequently overdosing because  of loss of tolerance. Complete withdrawal from opioids  usually takes up to 4 weeks in an inpatient or residential  setting, and up to 12 weeks in a community setting. If  abstinence is not achieved, illicit drug use is resumed, or  the patient cannot tolerate withdrawal, the withdrawal  regimen should be stopped and maintenance therapy  should be resumed at the optimal dose. Following  successful withdrawal treatment, further support and  monitoring to maintain abstinence should be provided  for a period of at least 6 months.   In younger patients (under 18 years), the harmful effects  of drug misuse are more often related to acute intoxica-  tion than to dependence, and substitution therapy is  therefore usually inappropriate. Maintenance treatment  with opioid substitution therapy is therefore controver-  sial in young people; however, it may be useful for the  older adolescent who has a history of opioid use to  undergo a period of stabilisation with buprenorphine or  methadone before starting a withdrawal regimen.   Patients who miss 3 days or more of their regular  prescribed dose of opioid maintenance therapy are  at risk of overdose because of loss of tolerance.  Consider reducing the dose in these patients.   If the patient misses 5 or more days of treatment, an  assessment of illicit drug use is also recommended  before restarting substitution therapy; this is parti-  cularly important for patients taking buprenorphine,  because of the risk of precipitated withdrawal.   Methadone and buprenorphine for the  management of opioid dependence (January  2007)   Oral methadone and buprenorphine are recom-  mended for maintenance therapy in the manage-  ment of opioid dependence. Patients should be  committed to a supportive care programme includ-  ing a flexible dosing regimen administered under  supervision for at least 3 months, until compliance is  assured. Selection of methadone or buprenorphine  should be made on a case-by-case basis, but metha-  done should be prescribed if both drugs are equally  suitable.    Buprenorphine Buprenorphine is an opioid-receptor  partial agonist (it has opioid agonist and antagonist  properties). Buprenorphine is preferred by some  patients because it is less sedating than methadone;  for this reason it may be more suitable for employed  patients or those undertaking other skilled tasks such as  driving. Buprenorphine is safer than methadone when  used in conjunction with other sedating drugs, and has  fewer drug interactions. Dose reductions may be easier  than with methadone because the withdrawal symp-  toms are milder, and patients generally require fewer  adjunctive medications; there is also a lower risk of  overdose. Buprenorphine can be given on alternate  days in higher doses and it requires a shorter drug-  free period than methadone before induction with  naltrexone for prevention of relapse (p. 317).   Patients dependent on high doses of opioids may be at  increased risk of precipitated withdrawal. Precipitated  withdrawal may occur in any patient if buprenorphine is  administered when other opioid agonist drugs are in  circulation. Precipitated opioid withdrawal, if it occurs,  starts within 1-3 hours of the first buprenorphine dose  and peaks at around 6 hours. Non-opioid adjunctive  therapy, such as lofexidine (p. 317), may be required if  symptoms are severe.   The first dose of buprenorphine should be given when  the patient is exhibiting signs of withdrawal, or 6-12  hours after the last use of heroin (or other short-acting  opioid), or 24-48 hours after the last dose of methadone.  It is possible to titrate the dose of buprenorphine within  one week — more rapidly than with methadone ther-  apy — but care is still needed to avoid toxicity or pre-  cipitated withdrawal; dividing the dose on the first day  may be useful.   In patients taking methadone who want to switch to  buprenorphine, the dose of methadone should be  reduced to a maximum of 30 mg daily before starting  buprenorphine treatment. If the dose of methadone is  over 10 mg daily, buprenorphine can be started at a dose  of 4 mg daily and titrated according to requirements; if  the methadone dose is below 10 mg daily, bupren-  orphine can be started at a dose of 2 mg daily.  Buprenorphine should not normally be used in patients  with liver dysfunction. Baseline liver function tests and  documentation of viral hepatitis status is recommended  prior to commencing therapy, and regular liver function  tests should be performed throughout treatment.   A combination preparation containing buprenorphine  with naloxone (Suboxone ® , p. 316) can be prescribed  for patients when there is a risk of dose diversion for    parenteral administration; the naloxone component  precipitates withdrawal if the preparation is injected,  but it has little effect when the preparation is taken  sublingually.    Methadone Methadone, a long-acting opioid agonist,  is usually administered in a single daily dose as metha-  done oral solution 1 mg/mL. Patients with a long history  of opioid misuse, those who typically abuse a variety of  sedative drugs and alcohol, and those who experience  increased anxiety during withdrawal of opioids may  prefer methadone to buprenorphine because it has a  more pronounced sedative effect.   Methadone is initiated at least 8 hours after the last  heroin dose, provided that there is objective evidence of  withdrawal symptoms. A supplementary dose on the  first day may be considered if there is evidence of  persistent opioid withdrawal symptoms. Because of  the long half-life, blood levels progressively rise during  initial treatment even if the patient remains on the same  daily dose (it takes 3-10 days for plasma levels to reach  steady-state in patients on a stable dose); a dose toler-  ated on the first day of treatment may become a toxic  dose on the third day as cumulative toxicity develops.  Thus, titration to the optimal dose in methadone main-  tenance treatment may take several weeks.    Pregnancy Acute withdrawal of opioids should be  avoided in pregnancy because it can cause fetal death.  Opioid substitution therapy is recommended during  pregnancy because it carries a lower risk to the fetus  than continued use of illicit drugs. If a woman who is  stabilised on methadone or buprenorphine for treatment  of opioid dependence becomes pregnant, therapy  should be continued [buprenorphine is not licensed for  use in pregnancy]. Many pregnant patients choose a  withdrawal regimen, but withdrawal during the first  trimester should be avoided because it is associated  with an increased risk of spontaneous miscarriage.  Withdrawal of methadone or buprenorphine should be  undertaken gradually during the second trimester; for  example, the dose of methadone may be reduced by 2-  3 mg every 3-5 days. If illicit drug use occurs, the  patient should be re-stabilised at the optimal mainte-  nance dose and consideration should be given to stop-  ping the withdrawal regimen.   Further withdrawal of methadone or buprenorphine in  the third trimester is not recommended because mater-  nal withdrawal, even if mild, is associated with fetal  distress, stillbirth, and the risk of neonatal mortality.  Drug metabolism can be increased in the third trimester;  it may be necessary to either increase the dose of  methadone or change to twice-daily consumption (or  a combination of both strategies) to prevent withdrawal  symptoms from developing.    The neonate should be monitored for respiratory  depression and signs of withdrawal if the mother is  prescribed high doses of opioid substitute.    Signs of neonatal withdrawal from opioids usually devel-  op 24-72 hours after delivery but symptoms may be  delayed for up to 14 days, so monitoring may be  required for several weeks. Symptoms include a high-  pitched cry, rapid breathing, hungry but ineffective  suckling, and excessive wakefulness; severe, but rare,  symptoms include hypertonicity and convulsions.    Breast-feeding The dose of methadone should be  kept as low as possible in breast-feeding mothers and  the infant should be monitored for sedation (high doses  of methadone carry an increased risk of sedation and  respiratory depression in the neonate).   Buprenorphine is excreted in low levels in breast milk  and has low oral bioavailability; however, neonates  should be monitored for drowsiness, adequate weight  gain, and developmental milestones.   Increased sleepiness, breathing difficulties, or limpness  in breast-fed babies of mothers taking opioid substitutes  should be reported urgently to a healthcare professional.   Indications adjunct in the treatment of opioid dep-  endence; premedication, peri-operative analgesia,  analgesia in other situations (section 4.7.2)   Cautions see Buprenorphine in section 4.7.2 and notes  above; caution if pre-existing liver enzyme abnorm-  alities, hepatitis B or C infection, or concomitant use  of hepatotoxic drugs   • By sublingual administration, ADULT and CHILD over 16  years, initially, 0.8-4 mg on day 1, adjusted if neces-  sary by 2-4 mg daily to usual dose of 12-24 mg daily  (max. 32 mg daily); withdraw gradually   Tablets (sublingual), buprenorphine (as hydro-  chloride) 400 micrograms, net price 7-tab pack =  £1.57; 2 mg, 7-tab pack = £7.74; 8 mg, 7-tab pack =  £20.54. Label: 2, 26   Tablets (sublingual), buprenorphine (as hydro-  chloride) 400 micrograms, net price 7-tab pack =  £1.54; 2 mg, 7-tab pack = £6.46; 8 mg, 7-tab pack =  £19.40. Label: 2, 26   Suboxone® (Schering-Plough) T (S. Ll  Suboxone 2 mg/500 micrograms tablets (sublin-  gual), buprenorphine (as hydrochloride) 2 mg, nal-  oxone (as hydrochloride) 500 micrograms, net price  28-tab pack = £25.87. Label: 2, 26  Suboxone 8 mg/2 mg tablets (sublingual), bupren-  orphine (as hydrochloride) 8 mg, naloxone (as hydro-  chloride) 2 mg, net price 28-tab pack = £77.61.   Dose expressed as buprenorphine, ADULT and CHILD over 15  years, initially 2-4 mg once daily (an additional dose of 2-4 mg  may be administered on day 1 depending on the individual  patient’s requirement), increased in steps of 2-8 mg according to  response; max. 24 mg daily; total weekly dose may be divided and  given on alternate days or 3 times weekly (but max. 24 mg daily)  Note The Scottish Medicines Consortium (p. 4) has advised (Feb-  ruary 2007) that Suboxone ® should be restricted for use in  patients in whom methadone is not suitable   Indications adjunct in treatment of opioid depend-  ence, see notes above; analgesia (section 4.7.2); cough  in terminal disease (section 3.9.1)   Cautions see Methadone, section 4.7.2  Contra-indications see Methadone, section 4.7.2  Hepatic impairment see notes in section 4.7.2  Renal impairment see notes in section 4.7.2  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see Methadone, section 4.7.2; overdo-  sage: see Emergency Treatment of Poisoning, p. 36  Important Methadone, even in low doses is a special  hazard for children; non-dependent adults are also at risk  of toxicity; dependent adults are at risk if tolerance is  incorrectly assessed during induction  Incompatibility Syrup preserved with hydroxybenzoate  (parabens) esters may be incompatible with methadone  hydrochloride.   • Initially 10-40 mg daily, increased by up to 10 mg  daily (max. weekly increase 30 mg) until no signs of  withdrawal or intoxication; usual dose range 60-  120 mg daily; CHILD not recommended (see also  important note above)   Note Methadone hydrochloride doses in the BNF may differ  from those in the product literature   Methadone (Non-proprietary) 69 l 1  Oral solution 1 mg/mL, methadone hydrochloride  1 mg/mL, net price 20 mL = 29p, 30 mL = 62p, 40 mL  = 58p, 50 mL = £1.04, 60 mL = 87p, 100 mL = £1.27,  500 mL = £11.34. Label: 2   Brands include Metharose® (sugar-free), Physeptone (sugar-free)  Important Methadone oral solution 1 mg/mL is 2'A times the  strength of Methadone Linctus (section 3.9.1). Many preparations  of Methadone oral solution are licensed for opioid drug addiction  only but some are also licensed for analgesia in severe pain   Injection, methadone hydrochloride 25 mg/mL, net  price 2-mL amp = £2.05; 50 mg/mL, 1-mL amp =  £2.05   Oral concentrate, methadone hydrochloride 10 mg/  mL (blue), net price 150mL = £12.01; 20 mg/mL  (brown), 150 mL = £24.02. Label: 2  Note The final strength of the methadone mixture to be dispensed  to the patient must be specified on the prescription  Important Care is required in prescribing and dispensing the  correct strength since any confusion could lead to an overdose;  this preparation should be dispensed only after dilution as  appropriate with Methadose® Diluent (life of diluted solution 3  months) and is for drug dependent persons (see also p. 8)   Adjunctive therapy may be required for the manage-  ment of opioid withdrawal symptoms. Loperamide  (p. 58) may be used for the control of diarrhoea; mebe-  verine (p. 48) for controlling stomach cramps; para-  cetamol (p. 259) and non-steroidal anti-inflammatory  drugs (p. 630) for muscular pains and headaches; meto-  clopramide (p. 253) or prochlorperazine (p. 252) may  be useful for nausea or vomiting. Topical rubefacients  (p. 664) can be helpful for relieving muscle pain asso-  ciated with methadone withdrawal. If a patient is suffer-  ing from insomnia, benzodiazepines (section 4.1) or  zopiclone (p. 210) may be prescribed, but because of    the potential for abuse, prescriptions should be limited  to a short course of a few days only. If anxiety or  agitation is severe, specialist advice should be sought.   Lofexidine Lofexidine is an alpha 2 -adrenergic ago-  nist. It may alleviate some of the physical symptoms of  opioid withdrawal by attenuating the increase in adr-  energic neurotransmission that occurs during opioid  withdrawal. Lofexidine can be prescribed as an adjuvant  to opioid substitution therapy, initiated either at the  same time as the opioid substitute, or during withdrawal  of the opioid substitute. Alternatively, lofexidine may be  prescribed instead of an opioid substitute in patients  who have mild or uncertain dependence (including  young people), and those with a short history of illicit  drug use. The patient should take part of the dose at  bedtime to offset insomnia associated with opioid with-  drawal.   Monitoring of blood pressure and pulse rate is recom-  mended on initiation, for at least 72 hours or until a  stable dose is achieved, and on discontinuation; treat-  ment should be discontinued gradually over 2-4 days to  reduce the risk of rebound hypertension.   Cautions severe coronary insufficiency, recent myo-  cardial infarction, cerebrovascular disease, brady-  cardia, hypotension (monitor pulse rate and blood  pressure); history of QT prolongation, concomitant  administration of drugs that prolong QT interval;  metabolic disturbances; withdraw gradually over 2-4  days (or longer) to minimise risk of rebound hyper-  tension and associated symptoms; depression; inter-  actions: Appendix 1 (lofexidine)   Side-effects dry mucous membranes; hypotension,  bradycardia; dizziness, drowsiness; QT-interval pro-  longation also reported   • Initially, 800 micrograms daily in divided doses,  increased as necessary in steps of 400-800 micr-  ograms daily to max. 2.4 mg daily in divided doses;  max. single dose 800 micrograms; recommended  duration of treatment 7-10 days if no opioid use (but  longer may be required)   Naloxone is an opioid-receptor antagonist used to  reverse opioid overdose. Patients dependant on opioids  can be given a supply of naloxone to be used in case of  accidental overdose; see Emergency Treatment of Pois-  oning, p. 36.   Naltrexone is an opioid-receptor antagonist that pre-  cipitates withdrawal symptoms in opioid-dependent    subjects. Because the effects of opioid-receptor agonists  are blocked by naltrexone, it is prescribed as an aid to  prevent relapse in formerly opioid-dependent patients.   Naltrexone is recommended for the prevention of  relapse in formerly opioid-dependent patients who  are motivated to remain in a supportive care absti-  nence programme. Naltrexone should be adminis-  tered under supervision and its effectiveness in  preventing opioid misuse reviewed regularly.    Indications adjunct to prevent relapse in formerly  opioid-dependent patients (who have remained  opioid-free for at least 7-10 days)   Cautions liver function tests needed before and during  treatment; test for opioid dependence with naloxone  before treatment; avoid concomitant use of opioids  but increased dose of opioid analgesic may be  required for pain (monitor for opioid intoxication)  Note Patients should be warned that an attempt to overcome  the blockade of opioid receptors by overdosing could result  in acute opioid intoxication   Hepatic impairment avoid in acute hepatitis, hepatic  failure, or severe impairment  Renal impairment avoid in severe impairment  Pregnancy use only if benefit outweighs risk  Breast-feeding avoid — present in milk in animal  studies   Side-effects nausea, vomiting, abdominal pain, diarr-  hoea, constipation, reduced appetite, increased thirst;  chest pain; anxiety, sleep disorders, headache,  reduced energy, increased energy, irritability, emo-  tional lability, dizziness; chills; urinary retention;  delayed ejaculation, decreased potency; arthralgia,  myalgia; increased lacrimation; rash, and increased  sweating; rarely hepatic dysfunction, suicidal idea-  tion, and speech disorders; very rarely hallucinations,  tremor, and idiopathic thrombocytopenia  Dose    • ADULT over 18 years (initiate in specialist clinics only),  25 mg initially then 50 mg daily; total weekly dose  (350 mg) may be divided and given on 3 days of the  week for improved compliance (e.g. 100 mg on Mon-  day and Wednesday, and 150 mg on Friday)    Nalorex® (Bristol-Myers Squibb) (Ml  Tablets, yellow, f/c, scored, naltrexone hydrochloride  50 mg, net price 28-tab pack = £22.34   Tablets, beige, f/c, scored, naltrexone hydrochloride  50 mg, net price 28-tab pack = £23.00   Acetylcholinesterase inhibiting drugs are used in the  treatment of Alzheimer’s disease, specifically for mild  to moderate disease. Rivastigmine is also licensed for    mild to moderate dementia associated with Parkinson’s  disease. The evidence to support the use of these drugs  relates to their cognitive enhancement.   Treatment with drugs for dementia should be initiated  and supervised only by a specialist experienced in the  management of dementia.   Benefit is assessed by repeating the cognitive assess-  ment at around 3 months. Such assessment cannot  demonstrate how the disease may have progressed in  the absence of treatment but it can give a good guide to  response. Up to half the patients given these drugs will  show a slower rate of cognitive decline. Drugs for  dementia should be discontinued in those thought not  to be responding. Many specialists repeat the cognitive  assessment 4 to 6 weeks after discontinuation to assess  deterioration; if significant deterioration occurs during  this short period, consideration should be given to  restarting therapy.   Donepezil is a reversible inhibitor of acetylcholinester-  ase. Galantamine is a reversible inhibitor of acetylcho-  linesterase and it also has nicotinic receptor agonist  properties. Rivastigmine is a reversible non-competi-  tive inhibitor of acetylcholinesterases; it is also licensed  for treating mild to moderate dementia in Parkinson’s  disease.   Acetylcholinesterase inhibitors can cause unwanted  dose-related cholinergic effects and should be started  at a low dose and the dose increased according to  response and tolerability.   Memantine is a glutamate receptor antagonist; it is  licensed for treating moderate to severe Alzheimer’s  disease.   Donepezil, galantamine, and rivastigmine can be  used for the treatment of moderate Alzheimer’s  disease in patients whose mini mental-state exam-  ination (MMSE) score is 10-20 points under the  following conditions:   • Alzheimer’s disease must be diagnosed in a  specialist clinic; cognitive, global, and  behavioural functioning, activities of daily living,  and the likelihood of compliance with treatment  must be assessed;   • treatment should be initiated by specialists but  can be continued by general practitioners under  a shared-care protocol;   • the patient should be assessed every 6 months  and drug treatment should continue only if the  MMSE score remains at or above 10 points and  if treatment is considered to have a worthwhile  effect on the global, functional, and behavioural  condition.   Healthcare professionals should not rely solely on  the MMSE score to assess the severity of Alzhei-  mer’s disease when the patient has learning or other  disabilities, or other communication difficulties.  NICE does not recommend initiation of memantine  for Alzheimer’s disease except as part of clinical  studies.   Cautions sick sinus syndrome or other supraventricu-  lar conduction abnormalities; susceptibility to peptic  ulcers; asthma, chronic obstructive pulmonary dis-  ease; interactions: Appendix 1 (parasympatho-  mimetics)   Hepatic impairment caution in mild to moderate  impairment, no information available for severe  impairment   Side-effects nausea, vomiting, anorexia, diarrhoea;  fatigue, insomnia, headache, dizziness, syncope, hal-  lucinations, agitation, aggression; muscle cramps;  urinary incontinence; rash, pruritus; less commonly  gastric and duodenal ulcers, gastro-intestinal  haemorrhage, bradycardia, seizures; rarely sino-atrial  block, AV block, hepatitis, extrapyramidal symptoms;  potential for bladder outflow obstruction   • Initially 5 mg once daily at bedtime, increased if  necessary after one month to max. 10 mg daily   Tablets, f/c, donepezil hydrochloride 5 mg (white),  net price 28-tab pack = £59.85; 10 mg (yellow), 28-tab  pack = £83.89.   Orodispersible tablets, donepezil hydrochloride  5 mg (white), net price 28-tab pack = £59.85; 10 mg  (yellow), 28-tab pack = £83.89. Counselling, admin-  istration   Counselling Aricept Evess® should be placed on the tongue,  allowed to disperse, and swallowed   Cautions cardiac disease (including sick sinus  syndrome or other supraventricular conduction  abnormalities, unstable angina, congestive heart fail-  ure); electrolyte disturbances; susceptibility to peptic  ulcers; asthma, chronic obstructive pulmonary dis-  ease, pulmonary infection; avoid in urinary retention,  gastro-intestinal obstruction, and while recovering  from bladder or gastro-intestinal surgery; interac-  tions: Appendix 1 (parasympathomimetics)   • for immediate-release preparations in moderate  impairment, initially 4 mg once daily (preferably in  the morning) for at least 7 days, then 4 mg twice  daily for at least 4 weeks; max. 8 mg twice daily;  avoid in severe impairment   • for modified-release preparations in moderate  impairment, initially 8 mg on alternate days (pre-  ferably in the morning) for 7 days, then 8 mg once  daily for 4 weeks; max. 16 mg daily; avoid in severe  impairment   Renal impairment avoid if eGFR less than 9 mL/  minute/ 1.73m 2   Side-effects vomiting, nausea, abdominal pain, diarr-  hoea, dyspepsia, anorexia, weight loss, bradycardia,  hypertension, syncope, hallucination, depression,  dizziness, tremor, headache, drowsiness, malaise,  muscle spasm, sweating; less commonly taste distur-  bance, palpitation, arrhythmias, first-degree AV block,    hypotension, flushing, paraesthesia, dehydration,  muscular weakness, blurred vision, tinnitus; rarely  hepatitis, exacerbation of Parkinson’s disease, seizures   • Initially 4 mg twice daily for 4 weeks increased to  8 mg twice daily for 4 weeks; maintenance 8-12 mg  twice daily   Tablets, f/c, galantamine (as hydrobromide) 8 mg  (pink), net price 56-tab pack = £68.32; 12 mg (orange-  brown), 56-tab pack = £84.00 Label: 3, 21  Oral solution, galantamine (as hydrobromide) 4 mg/  mL, net price 100 mL with pipette = £120.00. Label: 3,  21   Capsules, m/r, galantamine (as hydrobromide) 8 mg  (white), net price 28-cap pack = £51.88; 16 mg (pink),  28-cap pack = £64.90; 24 mg (beige), 28-cap pack =  £79.80. Label: 3, 21, 25   Dose initially 8 mg once daily for 4 weeks increased to 16 mg  once daily for 4 weeks; maintenance 16-24 mg daily   Renal impairment reduce dose to 10 mg daily if eGFR  30-49 mL/minute/ 1.73 m 2 , if well tolerated after at  least 7 days dose can be increased in steps to 20 mg  daily; reduce dose to 10 mg daily if eGFR 5-29 mL/  minute/1.73 m 2 ; avoid if eGFR less than 5 mL/min-  ute/ 1.73m 2   Side-effects constipation; hypertension; dyspnoea;  headache, dizziness, drowsiness; less commonly  vomiting, thrombosis, heart failure, confusion, fatigue,  hallucinations, and abnormal gait; very rarely sei-  zures; pancreatitis, psychosis, depression, and suicidal  ideation also reported   • Initially 5 mg once daily, increased in steps of 5 mg at  weekly intervals; max. 20 mg daily   Tablets, f/c, scored, memantine hydrochloride 10 mg,  net price 28-tab pack = £34.50, 56-tab pack = £69.01,  112-tab pack = £138.01; 20 mg, 28-tab pack = £69.01;  treatment initiation pack, 7 x 5 mg, 7 x 10 mg, 7 x  15 mg, and 7 x 20 mg = £43.13  Oral solution, memantine hydrochloride 5 mg/  actuation (lOmg/mL), net price 50-g pump pack =  £61.61, 100-g pump pack = £123.23  Counselling Solution should be dosed onto a spoon or into a glass  of water   Side-effects nausea, vomiting, diarrhoea, dyspepsia,  anorexia, weight loss, increased salivation, abdominal  pain, bradycardia, dizziness, headache, drowsiness,  malaise, agitation, anxiety, restlessness, confusion,  insomnia, extrapyramidal symptoms (and worsening  of Parkinson’s disease), dehydration, sweating; less  commonly atrial fibrillation, AV block, depression,  syncope; rarely gastric and duodenal ulceration,  angina, seizures, rash; very rarely gastro-intestinal  haemorrhage, pancreatitis, tachycardia, hypertension,  hallucinations   Capsules, rivastigmine (as hydrogen tartrate) 1.5 mg  (yellow), net price 28-cap pack = £33.25, 56-cap pack  = £66.51; 3 mg (orange), 28-cap pack = £33.25, 56-cap  pack = £66.51; 4.5 mg (red), 28-cap pack = £33.25, 56-  cap pack = £66.51; 6 mg (red/orange), 28-cap pack =  £33.25, 56-cap pack = £66.51. Label: 21, 25   Oral solution, rivastigmine (as hydrogen tartrate)  2mg/mL, net price 120 mL (with oral syringe) =  £99.14. Label: 21   Dose initially 1.5 mg twice daily, increased in steps of 1.5 mg  twice daily at intervals of at least 2 weeks according to response  and tolerance; usual range 3-6 mg twice daily; max. 6 mg twice  daily; if treatment interrupted for more than several days, treat-  ment should be retitrated from 1.5 mg twice daily    Patches, self-adhesive, beige, rivastigmine 4.6 mg/24  hours, net price 30 = £77.97; 9.5 mg/24 hours, 30 =  £77.97   Dose initially apply 4.6 mg/24 hours patch to clean, dry, non-  hairy, non-irritated skin on back, upper arm, or chest, removing  after 24 hours and siting a replacement patch on a different area  (avoid using the same area for 14 days); if well tolerated increase  to 9.5 mg/24 hours patch daily after at least 4 weeks; if treatment  interrupted for more than several days, treatment should be  retitrated from 4.6 mg/24 hours patch   Note When switching from oral to transdermal therapy, patients  taking 3-6 mg by mouth daily should initially switch to 4.6 mg/24  hours patch (then titrate as above); patients taking 9-12 mg by  mouth daily should switch to 9.5 mg/24 hours patch. The first  patch should be applied on the day following the last oral dose  Note The Scottish Medicines Consortium (p. 4) has advised  (October 2007) that Exelon ® patches should be restricted for  use in patients with moderately severe Alzheimer’s disease under  the conditions of the NICE guidance (September 2007) and when  a transdermal patch is an appropriate choice of formulation   Indications mild to moderate dementia in Alzheimer’s  disease or in Parkinson’s disease  Cautions gastric or duodenal ulcers (or susceptibility  to ulcers); monitor body-weight; sick sinus syndrome,  conduction abnormalities; history of asthma or  chronic obstructive pulmonary disease; history of    This chapter also includes advice on the drug man-  agement of the following:  anthrax, p. 368   Clostridium difficile infection, p. 322  bacterial infections: table 1, summary of anti-  bacterial treatment, p. 322  bacterial infections: table 2, summary of anti-  bacterial prophylaxis, p. 330  Lyme disease, p. 336  MRSA infections, p. 334  oral infections, p. 321, p. 328, p. 373   Doctors must notify the Proper Officer of the local  authority (usually the consultant in communicable  disease control) when attending a patient suspected  of suffering from any of the diseases listed below; a  form is available from the Proper Officer.    Note It is good practice for doctors to also inform the con-  sultant in communicable disease control of instances of other  infections (e.g. psittacosis) where there could be a public health  risk.   Choice of a suitable drug Before selecting an anti-  bacterial the clinician must first consider two factors —  the patient and the known or likely causative organism.  Factors related to the patient which must be considered  include history of allergy, renal and hepatic function,  susceptibility to infection (i.e. whether immunocompro-  mised), ability to tolerate drugs by mouth, severity of  illness, ethnic origin, age, whether taking other medica-  tion and, if female, whether pregnant, breast-feeding or  taking an oral contraceptive.   The known or likely organism and its antibacterial  sensitivity, in association with the above factors, will  suggest one or more antibacterials, the final choice  depending on the microbiological, pharmacological,  and toxicological properties.   An example of a rational approach to the selection of an  antibacterial is treatment of a urinary-tract infection in a  patient complaining of nausea and symptoms of a  urinary-tract infection in early pregnancy. The organism  is reported as being resistant to ampicillin but sensitive  to nitrofurantoin (can cause nausea), gentamicin (can be  given only by injection and best avoided in pregnancy),  tetracycline (causes dental discoloration) and trimetho-  prim (folate antagonist therefore theoretical teratogenic  risk), and cefalexin. The safest antibiotics in pregnancy  are the penicillins and cephalosporins; therefore, cefa-  lexin would be indicated for this patient.   The principles involved in selection of an antibacterial  must allow for a number of variables including changing  renal and hepatic function, increasing bacterial resis-  tance, and new information on side-effects. Duration of  therapy, dosage, and route of administration depend on  site, type and severity of infection and response.   Antibacterial policies Local policies often limit the  antibacterials that may be used to achieve reasonable  economy consistent with adequate cover, and to reduce  the development of resistant organisms. A policy may  indicate a range of drugs for general use, and permit  other drugs only on the advice of the microbiologist or  physician responsible for the control of infectious dis-  eases.   Before starting therapy The following precepts  should be considered before starting:   • Viral infections should not be treated with antibac-  terials. However, antibacterials may be used to treat  secondary bacterial infection (e.g. bacterial pneu-  monia secondary to influenza);   • Knowledge of prevalent organisms and their cur-  rent sensitivity is of great help in choosing an anti-  bacterial before bacteriological confirmation is  available. Generally, narrow-spectrum antibac-  terials are preferred to broad-spectrum antibac-  terials unless there is a clear clinical indication  (e.g. life-threatening sepsis);   • The dose of an antibacterial varies according to a  number of factors including age, weight, hepatic  function, renal function, and severity of infection.  The prescribing of the so-called ‘standard’ dose in  serious infections may result in failure of treatment   or even death of the patient; therefore it is important  to prescribe a dose appropriate to the condition. An  inadequate dose may also increase the likelihood of  antibacterial resistance. On the other hand, for an  antibacterial with a narrow margin between the  toxic and therapeutic dose (e.g. an aminoglycoside)  it is also important to avoid an excessive dose and  the concentration of the drug in the plasma may  need to be monitored;   • The route of administration of an antibacterial often  depends on the severity of the infection. Life-threa-  tening infections require intravenous therapy. Anti-  bacterials that are well absorbed may be given by  mouth even for some serious infections. Parenteral  administration is also appropriate when the oral  route cannot be used (e.g. because of vomiting) or  if absorption is inadequate. Whenever possible,  painful intramuscular injections should be avoided  in children;   • Duration of therapy depends on the nature of the  infection and the response to treatment. Courses  should not be unduly prolonged because they  encourage resistance, they may lead to side-effects  and they are costly. However, in certain infections  such as tuberculosis or osteomyelitis it may be  necessary to treat for prolonged periods. Conver-  sely a single dose of an antibacterial may cure  uncomplicated urinary-tract infections.    Oral bacterial infections Antibacterial drugs should  only be prescribed for the treatment of oral infections on  the basis of defined need. They may be used in con-  junction with (but not as an alternative to) other appro-  priate measures, such as providing drainage or extract-  ing a tooth.   The ‘blind’ prescribing of an antibacterial for unex-  plained pyrexia, cervical lymphadenopathy, or facial  swelling can lead to difficulty in establishing the diag-  nosis. In severe oral infections, a sample should always  be taken for bacteriology.    Oral infections which may require antibacterial treat-  ment include acute periapical or periodontal abscess,  cellulitis, acutely created oral-antral communication  (and acute sinusitis), severe pericoronitis, localised  osteitis, acute necrotising ulcerative gingivitis, and  destructive forms of chronic periodontal disease. Most  of these infections are readily resolved by the early  establishment of drainage and removal of the cause  (typically an infected necrotic pulp). Antibacterials  may be required if treatment has to be delayed, in  immunocompromised patients, or in those with condi-  tions such as diabetes or Paget’s disease. Certain rarer  infections including bacterial sialadenitis, osteomyelitis,  actinomycosis, and infections involving fascial spaces  such as Ludwig’s angina, require antibiotics and specia-  list hospital care.    Antibacterial drugs may also be useful after dental  surgery in some cases of spreading infection. Infection  may spread to involve local lymph nodes, to fascial  spaces (where it can cause airway obstruction), or into  the bloodstream (where it can lead to cavernous sinus  thrombosis and other serious complications). Extension  of an infection can also lead to maxillary sinusitis;  osteomyelitis is a complication, which usually arises  when host resistance is reduced.    If the oral infection fails to respond to antibacterial  treatment within 48 hours the antibacterial should be  changed, preferably on the basis of bacteriological    investigation. Failure to respond may also suggest an  incorrect diagnosis, lack of essential additional mea-  sures (such as drainage), poor host resistance, or poor  patient compliance.   Combination of a penicillin (or erythromycin) with  metronidazole may sometimes be helpful for the treat-  ment of severe oral infections or oral infections that  have not responded to initial antibacterial treatment.   See also Penicillins (section 5.1.1), Cephalosporins  (section 5.1.2), Tetracyclines (section 5.1.3), Macro-  lides (section 5.1.5), Clindamycin (section 5.1.6),  Metronidazole (section 5.1.11), Fusidic acid (section  13.10.1.2).    Superinfection In general, broad-spectrum anti-  bacterial drugs such as the cephalosporins are more  likely to be associated with adverse reactions related to  the selection of resistant organisms e.g. fungal infec-  tions or antibiotic-associated colitis (pseudomembran-  ous colitis); other problems associated with superinfec-  tion include vaginitis and pruritus ani.   Therapy Suggested treatment is shown in table 1.  When the pathogen has been isolated treatment may  be changed to a more appropriate antibacterial if neces-  sary. If no bacterium is cultured the antibacterial can be  continued or stopped on clinical grounds. Infections for  which prophylaxis is useful are listed in table 2.    If treating a patient suspected of suffering from a notifiable disease, the consultant in communicable  disease control should be informed (see p. 320)   Treat invasive or severe infection. Do not treat less severe infection unless there is a risk of developing invasive  infection (e.g. immunocompromised patients, those with haemoglobinopathy, the elderly, or children under 6  months of age).   Infections from Middle-East, South Asia, and South-East Asia may be multiple-antibacterial-resistant and sensitivity  should be tested.   Azithromycin may be an alternative in mild or moderate disease caused by multiple-antibacterial-resistant  organisms.   For third or subsequent episode of infection, for severe infection, for infection not responding  to metronidazole, or in patients intolerant of metronidazole, oral vancomycin  Suggested duration of treatment 10-14 days   For infection not responding to vancomycin, or for life-threatening infection, or in patients  •with ileus, oral vancomycin + i/v metronidazole  Suggested duration of treatment 10-14 days    1. Where clarithromycin is suggested azithromycin or erythromycin may be used   A cephalosporin + metronidazole or gentamicin + metronidazole or gentamicin + clindamycin  or piperacillin with tazobactam alone   Vancomycin 1 + ceftazidime added to dialysis fluid or vancomycin added to dialysis fluid +  ciprofloxacin by mouth   If cardiac prostheses present, or if penicillin-allergic, or if meticillin-resistant Staphylococcus   Add rifampicin for at least 2 weeks in prosthetic valve endocarditis.   Suggested duration of treatment at least 4 weeks (at least 6 weeks for prosthetic valve endocarditis)   If penicillin-allergic or if meticillin-resistant Staphylococcus aureus, vancomycin + rifampicin  Suggested duration of treatment at least 4 weeks (at least 6 weeks for prosthetic valve endocarditis)   Alternative if a large vegetation, intracardial abscess, or infected emboli are absent, benzyl-  penicillin + gentamicin   Suggested duration of treatment 4-6 weeks (stop gentamicin after 2 weeks for micro-organisms moderately  sensitive to penicillin)   If aminoglycoside cannot be used and if streptococci moderately sensitive to penicillin,  benzylpenicillin   Suggested duration of treatment 4-6 weeks (stop gentamicin after 2 weeks for micro-organisms moderately  sensitive to penicillin)   Suggested duration of treatment at least 6 weeks (stop gentamicin after 2 weeks if micro-organisms fully  sensitive to penicillin)   Suggested duration of treatment at least 6 weeks (stop gentamicin after 2 weeks if micro-organisms fully  sensitive to penicillin)   Suggested duration of treatment at least 4 weeks (at least 6 weeks for prosthetic valve endocarditis)  If penicillin-allergic or penicillin-resistant, vancomycin 1 + gentamicin  If gentamicin-resistant, substitute gentamicin with streptomycin.   Suggested duration of treatment at least 4 weeks (at least 6 weeks for prosthetic valve endocarditis)    Endocarditis caused by haemophilus, actinobacillus, cardiobacterium, eikenella, and king-  ella species (‘HACEK’ micro-organisms)   Suggested duration of treatment 4 weeks (6 weeks for prosthetic valve endocarditis); stop gentamicin after 2  weeks   Suggested duration of treatment 4 weeks (6 weeks for prosthetic valve endocarditis); stop gentamicin after 2  weeks   If history of immediate hypersensitivity reaction to penicillin or to cephalosporins, chloram-  phenicol   Treat if increase in sputum purulence accompanied by an increase in sputum volume or increase in dyspnoea.   Some pneumococci and Haemophilus influenzae strains tetracycline-resistant; approx. 20% H. influenzae  strains amoxicillin-resistant.   Suggested duration of treatment 5 days; longer treatment may be necessary in severely ill patients   Suggested duration of treatment 5 days; longer treatment may be necessary in severely ill patients   Pneumococci with decreased penicillin sensitivity being isolated, but not yet common in UK.  If atypical pathogens suspected, add clarithromycin 3 .   Suggested duration of treatment 7 days (14-21 days for infections caused by staphylococci)   Suggested duration of treatment 7 days (14-21 days for infections caused by staphylococci)   Pneumococci with decreased penicillin sensitivity being isolated, but not yet common in UK.  If meticillin-resistant Staphylococcus aureus suspected, add vancomycin 4 .   Suggested duration of treatment 7 days (14-21 days for infections caused by staphylococci)   Suggested duration of treatment 7-10 days (may extend treatment to 14-21 days in some cases e.g. if  staphylococci or Gram-negative enteric bacilli suspected)    Alternatives, cefuroxime + clarithromycin 3 or cefotaxime 1 + clarithromycin 3   Suggested duration of treatment 7-10 days (may extend treatment to 14-21 days in some cases e.g. if  staphylococci or Gram-negative enteric bacilli suspected)   If high-severity Legionella infection, add rifampicin for the first few days.   Suggested duration of treatment 14 days (usually 7-10 days for Legionella)   If high-severity Legionella infection, add clarithromycin 3 or rifampicin for the first few days.  Suggested duration of treatment usually 7-10 days  Alternative for chlamydial or mycoplasma infections, doxycycline  Suggested duration of treatment 14 days   Early-onset infection (less than 5 days after admission to hospital), co-amoxiclav or cefur-  oxime   If life-threatening infection, or if history of antibacterial treatment in the last 3 months, or if resistant micro-  organisms suspected, treat as for late-onset hospital-acquired pneumonia.   Late-onset infection (more than 5 days after admission to hospital), an antipseudomonal  penicillin (e.g. piperacillin with tazobactam) or a broad-spectrum cephalosporin (e.g. ceft-  azidime) or another antipseudomonal beta-lactam or a quinolone (e.g. ciprofloxacin)   For severe illness caused by Pseudomonas aeruginosa, consider adding an aminoglycoside.   Suggested duration of treatment 7 days (longer if Pseudomonas aeruginosa confirmed)   3. Where clarithromycin is suggested azithromycin or erythromycin may be used   • If meningococcal disease (meningitis with non-blanching rash or meningococcal septicaemia) suspected,  benzylpenicillin (see p. 334 for dose) can be given before transfer to hospital, so long as this does not delay the  transfer. If a patient with suspected bacterial meningitis without non-blanching rash cannot be transferred to  hospital urgently, benzylpenicillin (see p. 334 for dose) can be given before the transfer. Cefotaxime (section  5.1.2) may be an alternative in penicillin allergy; chloramphenicol (section 5.1.7) may be used if history of  immediate hypersensitivity reaction to penicillin or to cephalosporins.   • In hospital, consider adjunctive treatment with dexamethasone (particularly if pneumococcal meningitis  suspected in adults; section 6.3.2), preferably starting before or with first dose of antibacterial, but no later  than 12 hours after starting antibacterial; avoid dexamethasone in septic shock, meningococcal septicaemia, or  if immunocompromised, or in meningitis following surgery.   Consider adding vancomycin if prolonged or multiple use of other antibacterials in the last 3 months, or if  travelled, in the last 3 months, to areas outside the UK with highly penicillin- and cephalosporin-resistant  pneumococci.   Consider adding vancomycin if prolonged or multiple use of other antibacterials in the last 3 months, or if  travelled, in the last 3 months, to areas outside the UK with highly penicillin- and cephalosporin-resistant  pneumococci.   To eliminate nasopharyngeal carriage give rifampicin for 2 days (see Table 2, section 5.1)    If history of immediate hypersensitivity reaction to penicillin or to cephalosporins, chloram-  phenicol   To eliminate nasopharyngeal carriage give rifampicin for 2 days (see Table 2, section 5.1)   Consider adjunctive treatment with dexamethasone (section 6.3.2), preferably starting before or with first  dose of antibacterial, but no later than 12 hours after starting antibacterial (may reduce penetration of  vancomycin into cerebrospinal fluid).   If micro-organism highly penicillin- and cephalosporin-resistant, add vancomycin and if necessary rif-  ampicin.   Consider adjunctive treatment with dexamethasone (section 6.3.2), preferably starting before or with first  dose of antibacterial, but no later than 12 hours after starting antibacterial.   For H. influenzae type b give rifampicin for 4 days before hospital discharge (see Table 2, section 5.1)   If history of immediate hypersensitivity reaction to penicillin or to cephalosporins, or if micro-  organism resistant to cefotaxime, chloramphenicol   Consider adjunctive treatment with dexamethasone (section 6.3.2), preferably starting before or with first  dose of antibacterial, but no later than 12 hours after starting antibacterial.   For H. influenzae type b give rifampicin for 4 days before hospital discharge (see Table 2, section 5.1)   Suggested duration of treatment 10-14 days (longer treatment may be necessary in complicated pyelo-  nephritis)   Suggested duration of treatment 7 days, but a short course (e.g. 3 days) is usually adequate for  uncomplicated urinary-tract infections in women. See also section 5.1.13  Alternative, amoxicillin 1 or oral cephalosporin   Suggested duration of treatment 7 days, but a short course (e.g. 3 days) is usually adequate for  uncomplicated urinary-tract infections in women. See also section 5.1.13   Suggested duration of treatment single-dose (repeat dose after 7 days for women in the third trimester of  pregnancy)   Late latent syphilis (asymptomatic infection of more than 2 years)  Contact tracing recommended.   Suggested duration of treatment single-dose  Alternative if micro-organism sensitive, ciprofloxacin  Suggested duration of treatment single-dose  Pharyngeal infection, ceftriaxone   Suggested duration of treatment azithromycin as a single dose or doxycycline for 7 days   Suggested duration of treatment 14 days (use i/m ceftriaxone as a single dose).   In severely ill patients initial treatment with doxycycline + i/v ceftriaxone (as a single dose) + i/v  metronidazole, then switch to oral treatment with doxycycline + metronidazole to complete 14 days’  treatment   Suggested duration of treatment 5-7 days (or high-dose metronidazole as a single dose)   Suggested duration of treatment 5 days with metronidazole or 7 days with clindamycin   A broad-spectrum antipseudomonal penicillin (e.g. piperacillin with tazobactam, ticarcillin  with clavulanic acid) or a broad-spectrum cephalosporin (e.g. cefiiroxime)   If other resistant micro-organisms suspected, use a more broad-spectrum beta-lactam antibacterial (e.g.  meropenem)   A broad-spectrum antipseudomonal beta-lactam antibacterial (e.g. piperacillin with tazo-  bactam, ticarcillin with clavulanic acid, ceftazidime, imipenem with cilastatin, or meropenem)  If meticillin-resistant Staphylococcus aureus suspected, add vancomycin 1 .   If Gram-negative sepsis suspected, especially in the immunocompromised, add a broad-spectrum anti-  pseudomonal beta-lactam.   Consider removing vascular catheter, particularly if infection caused by Staphylococcus aureus, pseudo-  monas, or Candida species   If meningococcal disease suspected, a single dose of benzylpenicillin (see p. 334 for dose) can be given before  urgent transfer to hospital, so long as this does not delay the transfer; cefotaxime (section 5.1.2) may be an  alternative in penicillin allergy; chloramphenicol may be used if history of immediate hypersensitivity reaction to  penicillin or to cephalosporins.   To eliminate nasopharyngeal carriage give rifampicin for 2 days (see Table 2, section 5.1)   If history of immediate hypersensitivity reaction to penicillin or to cephalosporins, chloram-  phenicol   To eliminate nasopharyngeal carriage give rifampicin for 2 days (see Table 2, section 5.1)   Suggested duration of treatment 6 weeks for acute infection  If meticillin-resistant Staphylococcus aureus suspected, vancomycin 1  Consider adding fusidic acid or rifampicin for initial 2 weeks.   Suggested duration of treatment 4-6 weeks (longer if infection complicated; treat gonococcal infection for  2 weeks)   Antibacterial required only in presence of systemic features of infection, or of trismus, or persistent swelling despite  local treatment.   Antibacterial used as an adjunct to debridement in severe disease or disease unresponsive to local treatment alone.   Most throat infections are caused by viruses and many do not require antibacterial therapy. Consider antibacterial, if  history of valvular heart disease, if marked systemic upset, if peritonsillar cellulitis or abscess, or if at increased risk  from acute infection (e.g. in immunosuppression, cystic fibrosis); prescribe antibacterial for beta-haemolytic  streptococcal pharyngitis.   In severe infection, initial parenteral therapy with benzylpenicillin, then oral therapy with phenoxymethyl-  penicillin or amoxicillin 1 . Avoid amoxicillin if possibility of glandular fever, see section 5. 1.1. 3.   Suggested duration of treatment 10 days  If penicillin-allergic, clarithromycin 2  Suggested duration of treatment 10 days   Antibacterial should usually be used only for persistent symptoms and purulent discharge lasting at least 7 days or if  severe symptoms. Also, consider antibacterial for those at high risk of serious complications (e.g. in immunosup-  pression, cystic fibrosis).   In severe infection, initial parenteral therapy with co-amoxiclav or cefuroxime may be required   2. Where clarithromycin is suggested azithromycin or erythromycin may be used   Many infections caused by viruses. Most uncomplicated cases resolve without antibacterial treatment. In children  without systemic features, antibacterial treatment may be started after 72 hours if no improvement. Consider earlier  treatment if deterioration, if systemically unwell, if at high risk of serious complications (e.g. in immunosuppression,  cystic fibrosis), if mastoiditis present, or in children under 2 years of age with bilateral otitis media.   Suggested duration of treatment 7 days is usually adequate (max. 10 days)  Alternative if meticillin-resistant Staphylococcus aureus, topical mupirocin  Suggested duration of treatment 7 days is usually adequate (max. 10 days)   If streptococci suspected in severe infection, add phenoxymethylpenicillin.  Suggested duration of treatment 7 days  If penicillin-allergic, oral clarithromycin 2  Suggested duration of treatment 7 days   If staphylococci suspected, replace phenoxymethylpenicillin or benzylpenicillin with flucloxacillin.  Suggested duration of treatment at least 7 days  If penicillin-allergic, clindamycin or clarithromycin 2  Suggested duration of treatment at least 7 days   If streptococcal infection confirmed, replace flucloxacillin with phenoxymethylpenicillin or benzylpeni-  cillin.   Cleanse wound thoroughly. For tetanus-prone wound, give human tetanus immunoglobulin (with a tetanus-  containing vaccine if necessary, according to immunisation history and risk of infection), see under Tetanus  Vaccines, section 14.4. Consider rabies prophylaxis (section 14.4) for bites from animals in endemic countries;  assess risk of blood-borne viruses.   2. Where clarithromycin is suggested azithromycin or erythromycin may be used   Phenoxymethylpenicillin 250 mg twice daily or sulfadia-  zine 1 g daily (500 mg daily for patients under 30 kg)    Prevention of secondary case of pertussis in  non-immune patient or partially immune  patient   Erythromycin 3 ADULT and CHILD over 8 years, 250-  500 mg every 6 hours for 7 days; CHILD under 2 years  125 mg every 6 hours, 2-8 years 250 mg every 6 hours    Prevention of secondary case of invasive  group A streptococcal infection 1   Phenoxymethylpenicillin 250-500 mg every 6 hours for  10 days; CHILD under 1 year 62.5 mg every 6 hours, 1-5  years 125 mg every 6 hours, 6-12 years 250 mg every 6  hours   either erythromycin ADULT and CHILD over 8 years, 250-  500 mg every 6 hours for 10 days; CHILD under 2 years  125 mg every 6 hours, 2-8 years 250 mg every 6 hours   or azithromycin [unlicensed indication] 500 mg once  daily for 5 days; CHILD over 6 months, 12 mg/kg (max.  500 mg) once daily   Rifampicin 600 mg every 12 hours for 2 days; CHILD  10 mg/kg (under 1 year, 5 mg/kg) every 12 hours for  2 days   or ciprofloxacin 500 mg as a single dose; CHILD [unli-  censed] 2-5 years 125 mg; 5-12 years 250 mg   or i/m ceftriaxone [unlicensed indication] 250 mg as a  single dose; CHILD under 12 years 125 mg    Prevention of secondary case of  Haemophilus influenzae type b disease 2   Rifampicin 600 mg once daily for 4 days (regimen of  choice for adults); CHILD 1-3 months 10 mg/kg once  daily for 4 days, over 3 months 20 mg/kg once daily for  4 days (max. 600 mg daily)   Erythromycin 3 500 mg every 6 hours for 7 days; CHILD  up to 2 years 125 mg every 6 hours, 2-8 years 250 mg  every 6 hours    1. For details of those who should receive chemoprophylaxis  contact a consultant in communicable disease control (or a  consultant in infectious diseases or the local Health  Protection Agency Laboratory)   2. For details of those who should receive chemoprophylaxis  contact a consultant in communicable disease control (or a  consultant in infectious diseases or the local Health  Protection Agency laboratory). Unless there has been  direct exposure of the mouth or nose to infectious droplets  from a patient with meningococcal disease who has  received less than 24 hours of antibacterial treatment,  healthcare workers do not generally require chemopro-  phylaxis   3. Where erythromycin is suggested another macrolide (e.g.  azithromycin or clarithromycin) may be used    Prevention of pneumococcal infection in  asplenia or in patients with sickle-cell  disease   Phenoxymethylpenicillin 500 mg every 12 hours; CHILD  under 5 years 125 mg every 12 hours, 6-12 years  250 mg every 12 hours — if cover also needed for H.  influenzae in CHILD give amoxicillin instead (under 5  years 125 mg every 12 hours, over 5 years 250 mg every  12 hours)   Benzylpenicillin 300-600 mg every 6 hours for 5 days or  if penicillin-allergic metronidazole 400-500 mg every 8  hours    Prevention of tuberculosis in susceptible  close contacts or those who have become  tuberculin positive*   Isoniazid 300 mg daily for 6 months; CHILD 5 mg/kg  daily (max. 300 mg daily)   or isoniazid 300 mg daily + rifampicin 600 mg daily  (450 mg if less than 50 kg) for 3 months; CHILD isoniazid  5 mg/kg daily (max. 300 mg daily) + rifampicin 10 mg/  kg daily (max. 450 mg daily if body-weight less than  50 kg; max. 600 mg daily if body-weight over 50 kg)  or (if isoniazid-resistant tuberculosis in patients under  35 years) rifampicin 600 mg daily (450 mg if less than  50 kg) for 6 months; CHILD 10 mg/kg daily (max. 450 mg  daily if body-weight less than 50 kg; max. 600 mg daily if  body-weight over 50 kg)   Single dose 6 of i/v gentamicin or i/v cefuroxime or i/v   Add i/v teicoplanin 7 if high risk of meticillin-resistant Sta-  phylococcus aureus   4. For details of those who should receive chemoprophylaxis  contact the lead clinician for local tuberculosis services (or  a consultant in communicable disease control). See also  section 5.1.9, for advice on immunocompromised patients  and on prevention of tuberculosis   5. Intravenous antibacterial prophylaxis should be given up to  30 minutes before the procedure   6. Additional intra-operative or postoperative doses of anti-  bacterial may be given for prolonged procedures or if there  is major blood loss   Single dose 2 of i/v cefuroxime + i/v metronidazole 3 or  i/v gentamicin + i/v metronidazole 3 or i/v co-amoxi-  clav alone   Add i/v teicoplanin 4 if high risk of meticillin-resistant Sta-  phylococcus aureus   Resections of colon and rectum for carcinoma, and  resections in inflammatory bowel disease, and  appendicectomy 1   Single dose 2 of i/v gentamicin + i/v metronidazole 3 or  i/v cefuroxime + i/v metronidazole 3 or i/v co-amoxi-  clav alone   Add i/v teicoplanin 4 if high risk of meticillin-resistant Sta-  phylococcus aureus   Single dose of i/v gentamicin or oral or i/v ciproflox-  acin   Prophylaxis recommended if pancreatic pseudocyst, immu-  nocompromised, history of liver transplantation, or risk of  incomplete biliary drainage. For biliary complications fol-  lowing liver transplantation, add i/v amoxicillin or i/v  vancomycin   Single dose of i/v co-amoxiclav or i/v cefuroxime  Use single dose of i/v teicoplanin 4 if history of allergy to  penicillins or cephalosporins, or if high risk of meticillin-  resistant Staphylococcus aureus   Single dose 2 of i/v cefuroxime alone or i/v flucloxacillin  + i/v gentamicin   If history of allergy to penicillins or to cephalosporins or if  high risk of meticillin-resistant Staphylococcus aureus, use  single dose 2 of i/v teicoplanin 4 + i/v gentamicin   Single dose 2 of i/v cefuroxime or i/v flucloxacillin  If history of allergy to penicillins or to cephalosporins or if  high risk of meticillin-resistant Staphylococcus aureus, use  single dose 2 of i/v teicoplanin 4   i/v co-amoxiclav alone or i/v cefuroxime + i/v metro-  nidazole [or i/v clindamycin alone if history of allergy to  penicillins or to cephalosporins)   Add i/v teicoplanin 4 if high risk of meticillin-resistant Sta-  phylococcus aureus. Start prophylaxis within 3 hours of  injury and continue until soft tissue closure (max. 72 hours);  at first debridement also use a single dose of i/v cefuroxime  + i/v metronidazole + i/v gentamicin or i/v co-amoxiclav +  i/v gentamicin [or i/v clindamycin + i/v gentamicin if  history of allergy to penicillins or to cephalosporins). At time  of skeletal stabilisation and definitive soft tissue closure 1 use  a single dose of i/v gentamicin + i/v teicoplanin 4    1. Intravenous antibacterial prophylaxis should be given up to  30 minutes before the procedure   2. Additional intra-operative or postoperative doses of anti-  bacterial may be given for prolonged procedures or if there  is major blood loss   3 . Metronidazole may alternatively be given by suppository  but to allow adequate absorption, it should be given 2  hours before surgery   Single dose 2 of oral ciprofloxacin + oral metronidazole  or i/v gentamicin + i/v metronidazole 3  Use single dose 2 of i/v gentamicin + i/v metronidazole 3 if  high risk of meticillin-resistant Staphylococcus aureus   Single dose 2 of oral ciprofloxacin or i/v gentamicin or  i/v cefuroxime   Use single dose 2 of i/v gentamicin if high risk of meticillin-  resistant Staphylococcus aureus    Single dose 2 of i/v cefuroxime  Administer immediately after umbilical cord is clamped.  Substitute i/v clindamycin if history of allergy to penicillins  or cephalosporins. Add i/v teicoplanin 4 if high risk of meti-  cillin-resistant Staphylococcus aureus    Single dose 2 of i/v cefuroxime + i/v metronidazole 3 or  i/v gentamicin + i/v metronidazole 3 or i/v co-amoxi-  clav alone   Use single dose 2 of i/v gentamicin + i/v metronidazole 3 or  add i/v teicoplanin 4 to other regimens if high risk of meti-  cillin-resistant Staphylococcus aureus   Single dose 2 of oral metronidazole  If genital chlamydial infection cannot be ruled out, give  doxycycline (section 5.1.3) postoperatively   Single dose 2 of i/v cefuroxime alone or i/v flucloxacillin  + i/v gentamicin or i/v teicoplanin 4 + i/v gentamicin  Use single dose 2 of i/v teicoplanin 4 + i/v cefuroxime or i/v  teicoplanin 4 + i/v gentamicin if high risk of meticillin-resis-  tant Staphylococcus aureus   Single dose 2 of i/v cefuroxime alone or i/v flucloxacillin  + i/v gentamicin   Add i/v metronidazole for patients at risk from anaerobic  infections including those with diabetes, gangrene, or  undergoing amputation. Use single dose 2 of i/v teicoplanin 4  + i/v gentamicin if history of allergy to penicillins or ceph-  alosporins, or if high risk of meticillin-resistant Staphylo-  coccus aureus   Antimicrobial prophylaxis against infective  endocarditis in adults and children  undergoing interventional procedures  (March 2008)   Antibacterial prophylaxis and chlorhexidine  mouthwash are not recommended for the preven-  tion of endocarditis in patients undergoing dental  procedures.   Antibacterial prophylaxis is not recommended for  the prevention of endocarditis in patients under-  going procedures of the:   • upper and lower respiratory tract (including ear,  nose, and throat procedures and bronchoscopy);   Whilst these procedures can cause bacteraemia,  there is no clear association with the development  of infective endocarditis. Prophylaxis may expose  patients to the adverse effects of antimicrobials  when the evidence of benefit has not been proven.   Any infection in patients at risk of endocarditis 1  should be investigated promptly and treated appro-  priately to reduce the risk of endocarditis.   If patients at risk of endocarditis 1 are undergoing a  gastro-intestinal or genito-urinary tract procedure at  a site where infection is suspected, they should  receive appropriate antibacterial therapy that  includes cover against organisms that cause endo-  carditis.   • told how to recognise signs of infective endo-  carditis, and advised when to seek expert  advice.    Dermatological procedures  Advice of a Working Party of the British Society for  Antimicrobial Chemotherapy is that patients who  undergo dermatological procedures 2 do not require  antibacterial prophylaxis against endocarditis.    1. Patients at risk of endocarditis include those with valve  replacement, acquired valvular heart disease with stenosis  or regurgitation, structural congenital heart disease (in-  cluding surgically corrected or palliated structural condi-  tions, but excluding isolated atrial septal defect, fully  repaired ventricular septal defect, fully repaired patent  ductus arteriosus, and closure devices considered to be  endothelialised), hypertrophic cardiomyopathy, or a pre-  vious episode of infective endocarditis   2. The British Association of Dermatologists Therapy Guide-  lines and Audit Subcommittee advise that such dermato-  logical procedures include skin biopsies and excision of  moles or of malignant lesions    Joint prostheses and dental treatment  Advice of a Working Party of the British Society for  Antimicrobial Chemotherapy is that patients with  prosthetic joint implants (including total hip replace-  ments) do not require antibiotic prophylaxis for  dental treatment. The Working Party considers that  it is unacceptable to expose patients to the adverse  effects of antibiotics when there is no evidence that  such prophylaxis is of any benefit, but that those who  develop any intercurrent infection require prompt  treatment with antibiotics to which the infecting  organisms are sensitive.   The Working Party has commented that joint infec-  tions have rarely been shown to follow dental pro-  cedures and are even more rarely caused by oral  streptococci.   Advice of a Working Party of the British Society for  Antimicrobial Chemotherapy is that patients who  are immunosuppressed (including transplant  patients) and patients with indwelling intraperitoneal  catheters do not require antibiotic prophylaxis for  dental treatment provided there is no other indica-  tion for prophylaxis.   The Working Party has commented that there is little  evidence that dental treatment is followed by infec-  tion in immunosuppressed and immunodeficient  patients nor is there evidence that dental treatment  is followed by infection in patients with indwelling  intraperitoneal catheters.   The penicillins are bactericidal and act by interfering  with bacterial cell wall synthesis. They diffuse well into  body tissues and fluids, but penetration into the cere-  brospinal fluid is poor except when the meninges are  inflamed. They are excreted in the urine in therapeutic  concentrations.   Hypersensitivity reactions The most important  side-effect of the penicillins is hypersensitivity which  causes rashes and anaphylaxis and can be fatal. Allergic  reactions to penicillins occur in 1-10% of exposed  individuals; anaphylactic reactions occur in fewer than  0.05% of treated patients. Patients with a history of  atopic allergy (e.g. asthma, eczema, hay fever) are at a  higher risk of anaphylactic reactions to penicillins. Indi-    viduals with a history of anaphylaxis, urticaria, or rash  immediately after penicillin administration are at risk of  immediate hypersensitivity to a penicillin; these indivi-  duals should not receive a penicillin. Patients who are  allergic to one penicillin will be allergic to all because  the hypersensitivity is related to the basic penicillin  structure. As patients with a history of immediate hyper-  sensitivity to penicillins may also react to the cephalo-  sporins and other beta-lactam antibiotics, they should  not receive these antibiotics; aztreonam may be less  likely to cause hypersensitivity in penicillin-sensitive  patients and can be used with caution. If a penicillin  (or another beta-lactam antibiotic) is essential in an  individual with immediate hypersensitivity to penicillin  then specialist advice should be sought on hypersensi-  tivity testing or using a beta-lactam antibiotic with a  different structure to the penicillin that caused the  hypersensitivity (see also p. 340).   Individuals with a history of a minor rash (i.e. non-  confluent, non-pruritic rash restricted to a small area  of the body) or a rash that occurs more than 72 hours  after penicillin administration are probably not allergic  to penicillin and in these individuals a penicillin should  not be withheld unnecessarily for serious infections; the  possibility of an allergic reaction should, however, be  borne in mind. Other beta-lactam antibiotics (including  cephalosporins) can be used in these patients.   Other side-effects A rare but serious toxic effect of  the penicillins is encephalopathy due to cerebral irrita-  tion. This may result from excessively high doses or in  patients with severe renal failure. The penicillins should  not be given by intrathecal injection because they can  cause encephalopathy which may be fatal.   Another problem relating to high doses of penicillin, or  normal doses given to patients with renal failure, is the  accumulation of electrolyte since most injectable peni-  cillins contain either sodium or potassium.   Diarrhoea frequently occurs during oral penicillin ther-  apy. It is most common with broad-spectrum penicillins,  which can also cause antibiotic-associated colitis.   Benzylpenicillin sodium (Penicillin G) remains an  important and useful antibiotic but is inactivated by  bacterial beta-lactamases. It is effective for many strep-  tococcal (including pneumococcal), gonococcal, and  meningococcal infections and also for anthrax (section  5.1.12), diphtheria, gas-gangrene, leptospirosis, and  treatment of Lyme disease (section 5. 1.1.3). Pneumo-  cocci, meningococci, and gonococci which have  decreased sensitivity to penicillin have been isolated;  benzylpenicillin is no longer the drug of first choice for  pneumococcal meningitis. Although benzylpenicillin is  effective in the treatment of tetanus, metronidazole  (section 5.1.11) is preferred. Benzylpenicillin is inacti-  vated by gastric acid and absorption from the gut is low;  therefore it is best given by injection.   Benzathine benzylpenicillin (available from ‘special-  order’ manufacturers or specialist importing companies,  see p. 988) is used for the treatment of early syphilis and  late latent syphilis; it is given by intramuscular injection.   Phenoxymethylpenicillin (Penicillin V) has a similar  antibacterial spectrum to benzylpenicillin, but is less   active. It is gastric acid-stable, so is suitable for oral  administration. It should not be used for serious infec-  tions because absorption can be unpredictable and  plasma concentrations variable. It is indicated princi-  pally for respiratory-tract infections in children, for  streptococcal tonsillitis, and for continuing treatment  after one or more injections of benzylpenicillin when  clinical response has begun. It should not be used for  meningococcal or gonococcal infections. Phenoxy-  methylpenicillin is used for prophylaxis against strepto-  coccal infections following rheumatic fever and against  pneumococcal infections following splenectomy or in  sickle-cell disease.    Indications throat infections, otitis media, endocard-  itis, meningococcal disease, pneumonia, cellulitis  (Table 1, section 5.1); anthrax; intrapartum prophy-  laxis against group B streptococcal infection;  prophylaxis in limb amputation (Table 2, section 5.1);  see also notes above    Cautions history of allergy; false-positive urinary glu-  cose (if tested for reducing substances); interactions:  Appendix 1 (penicillins)   Pregnancy not known to be harmful  Breast-feeding trace amounts in milk  Side-effects hypersensitivity reactions including urti-  caria, fever, joint pains, rashes, angioedema, anaphy-  laxis, serum sickness-like reaction; rarely CNS toxicity  including convulsions (especially with high doses or in  severe renal impairment), interstitial nephritis,  haemolytic anaemia, leucopenia, thrombocytopenia,  and coagulation disorders; also reported diarrhoea  (including antibiotic-associated colitis)    • By intramuscular or by slow intravenous injection or  by infusion, 0.6-1.2g every 6 hours, increased if  necessary in more serious infections (single doses  over 1.2 g intravenous route only; see also below);  NEONATE under 7 days, 25 mg/kg every 12 hours, dose  doubled in severe infection; NEONATE 7-28 days,   25 mg/kg every 8 hours, dose doubled in severe  infection; CHILD 1 month-18 years, 25 mg/kg every 6  hours (increased in severe infection to 50 mg/kg  every 4-6 hours (max. 2.4 g every 4 hours); intra-  venous route recommended in neonates and infants   • Endocarditis (in combination with another anti-  bacterial if necessary, see Table 1, section 5.1), by  slow intravenous injection or by infusion, 1.2 g every  4 hours, increased if necessary (e.g. in enterococcal  endocarditis or if benzylpenicillin used alone) to 2.4 g  every 4 hours; CHILD 1 month- 18 years see BNF for  Children   • Anthrax (in combination with other antibacterials, see  also section 5.1.12), by slow intravenous injection or  by infusion, 2.4 g every 4 hours; CHILD 37.5 mg/kg  every 6 hours    • Intrapartum prophylaxis against group B streptococ-  cal infection, by slow intravenous injection or by  infusion, initially 3 g then 1.5 g every 4 hours until  delivery   • Meningitis, meningococcal disease, by slow intra-  venous injection or by infusion, 2.4 g every 4 hours;  NEONATE, 75 mg/kg every 8 hours; CHILD 1 month-18  years, 50 mg/kg every 4-6 hours (max. 2.4 g every 4  hours)   Important. If meningococcal disease (meningitis with non-  blanching rash or meningococcal septicaemia) is suspected,  a single dose of benzylpenicillin can be given before trans-  ferring the patient to hospital urgently, so long as this does  not delay the transfer. If a patient with suspected bacterial  meningitis without non-blanching rash cannot be transferred  to hospital urgently, a single dose of benzylpenicillin can be  given before the transfer. Suitable doses of benzylpenicillin  by intravenous injection (or by intramuscular injection) are:  ADULT 1.2 g; INFANT under 1 year 300 mg; CHILD 1-9 years  600 mg, 10 years and over as for adult. In penicillin allergy,  cefotaxime (section 5.1.2) may be an alternative; chloram-  phenicol (section 5.1.7) may be used if there is a history of  anaphylaxis to penicillins   Indications oral infections (see notes above); tonsill-  itis, otitis media, erysipelas, cellulitis; group A strep-  tococcal infection, rheumatic fever and pneumo-  coccal infection prophylaxis (Table 2, section 5.1)  Cautions see under Benzylpenicillin; interactions:  Appendix 1 (penicillins)   Contra-indications see under Benzylpenicillin  Pregnancy not known to be harmful  Breast-feeding trace amounts in milk  Side-effects see under Benzylpenicillin   • 500 mg every 6 hours increased up to 1 g every 6  hours in severe infections; CHILD up to 1 year 62.5 mg  every 6 hours, increased up to 12.5 mg/kg every 6  hours in severe infections; 1-6 years, 125 mg every 6  hours, increased up to 12.5 mg/kg every 6 hours in  severe infections; 6-12 years, 250 mg every 6 hours,  increased up to 12.5 mg/kg every 6 hours in severe  infections   Note Phenoxymethylpenicillin doses in the BNF may differ  from those in product literature   Phenoxymethylpenicillin (Non-proprietary) fMl  Tablets, phenoxymethylpenicillin (as potassium salt)  250 mg, net price 28-tab pack = £1.27. Label: 9, 23  Dental prescribing on NHS Phenoxymethylpenicillin  Tablets may be prescribed   Oral solution, phenoxymethylpenicillin (as potassium  salt) for reconstitution with water, net price 125 mg/  5mL, 100 mL = £1.90; 250 mg/5 mL, 100 mL = £2.59.  Label: 9, 23   Most staphylococci are now resistant to benzylpenicillin  because they produce penicillinases. Flucloxacillin,  however, is not inactivated by these enzymes and is  thus effective in infections caused by penicillin-resistant  staphylococci, which is the sole indication for its use.  Flucloxacillin is acid-stable and can, therefore, be given  by mouth as well as by injection.   Flucloxacillin is well absorbed from the gut. For a  warning on hepatic disorders see under Flucloxacillin.  Temocillin is active against Gram-negative bacteria and  is stable against a wide range of beta-lactamases. It  should be reserved for the treatment of infections  caused by beta-lactamase-producing strains of Gram-  negative bacteria, including those resistant to third-gen-  eration cephalosporins. Temocillin is not active against  Pseudomonas aeruginosa or Acinetobacter spp.    MRS A Infection from Staphylococcus aureus strains  resistant to meticillin [now discontinued] (meticillin-  resistant Staph, aureus, MRSA) and to flucloxacillin  can be difficult to manage. Treatment is guided by the  sensitivity of the infecting strain.   Rifampicin (section 5.1.9) or sodium fusidate (section  5.1.7) should not be used alone because resistance may  develop rapidly. A tetracycline alone or a combination  of rifampicin and sodium fusidate can be used for skin  and soft-tissue infections caused by MRSA; clindamycin  alone is an alternative. A glycopeptide (e.g. vanco-  mycin, section 5.1.7) can be used for severe skin and  soft-tissue infections associated with MRSA; if a glyco-  peptide is unsuitable, linezolid (section 5.1.7) can be  used on expert advice. As linezolid is not active against  Gram-negative organisms, it can be used for mixed skin  and soft-tissue infections only when other treatments  are not available; linezolid must be given with other  antibacterials if the infection also involves Gram-nega-  tive organisms. A combination of a glycopeptide and  sodium fusidate or a glycopeptide and rifampicin can be  considered for skin and soft-tissue infections that have  failed to respond to a single antibacterial.   Tigecycline (section 5.1.3) and daptomycin (section  5.1.7) are licensed for the treatment of complicated skin  and soft-tissue infections involving MRSA.   A tetracycline or clindamycin can be used for bronchi-  ectasis caused by MRSA. A glycopeptide can be used  for pneumonia associated with MRSA; if a glycopeptide  is unsuitable, linezolid can be used on expert advice.  Linezolid must be given with other antibacterials if the  infection also involves Gram-negative organisms.   A tetracycline can be used for urinary-tract infections  caused by MRSA; trimethoprim or nitrofurantoin are  alternatives. A glycopeptide can be used for urinary-  tract infections that are severe or resistant to other  antibacterials.   For the management of endocarditis, osteomyelitis, or  septic arthritis associated with MRSA, see Table 1,  section 5.1.   Prophylaxis with vancomycin or teicoplanin (alone or in  combination with another antibacterial active against   • there is a history of MRSA colonisation or infection  without documented eradication;   • there is a risk that the patient’s MRSA carriage has  recurred;   • the patient comes from an area with a high pre-  valence of MRSA.   Indications infections due to beta-lactamase-produ-  cing staphylococci including otitis externa; adjunct in  pneumonia, impetigo, cellulitis, osteomyelitis and in  staphylococcal endocarditis (Table 1, section 5.1)  Cautions see under Benzylpenicillin (section 5. 1.1.1);  risk of kemicterus in jaundiced neonates when high  doses given parenterally; interactions: Appendix 1  (penicillins)   Cholestatic jaundice and hepatitis may occur very  rarely, up to two months after treatment with fluclox-  acillin has been stopped. Administration for more than  2 weeks and increasing age are risk factors. Healthcare  professionals are reminded that:   • flucloxacillin should not be used in patients with a history  of hepatic dysfunction associated with flucloxacillin;   • flucloxacillin should be used with caution in patients with  hepatic impairment;   • careful enquiry should be made about hypersensitivity  reactions to beta-lactam antibacterials.   Renal impairment reduce dose if eGFR less than  10 mL/minute/ 1.73 m 2   Side-effects see under Benzylpenicillin (section  5. 1.1.1); also gastro-intestinal disturbances; very  rarely hepatitis and cholestatic jaundice (see also  Hepatic disorders above)   • By mouth, 250-500 mg every 6 hours, at least 30  minutes before food; NEONATE see BNF for Children ;  CHILD 1 month-2 years, 62.5-125 mg every 6 hours, at  least 30 minutes before food; 2-10 years, 125-250 mg  every 6 hours, at least 30 minutes before food   • By intramuscular injection, 250-500 mg every 6  hours; CHILD 1 month-18 years see BNF for Children   • By slow intravenous injection or by intravenous  infusion, 0.25-2 g every 6 hours; CHILD under 18 years  see BNF for Children   Endocarditis (in combination with another anti-  bacterial, see Table 1, section 5.1), body-weight under  85 kg, 8 g daily in 4 divided doses; body-weight over  85 kg, 12 g daily in 6 divided doses; CHILD 1 month-18  years see BNF for Children   Osteomyelitis (see Table 1, section 5.1), up to 8 g daily  in 3-4 divided doses; CHILD under 18 years see BNF  for Children   • Surgical prophylaxis, by slow intravenous injection or  by intravenous infusion, 1-2 g up to 30 minutes  before the procedure; up to 4 further doses of 500 mg    may be given every 6 hours by mouth, or by intra-  muscular injection, or by slow intravenous injection  or by intravenous infusion for high risk procedures   Flucloxacillin (Non-proprietary) £mD  Capsules, flucloxacillin (as sodium salt) 250 mg, net  price 28 = £2.07; 500 mg, 28 = £3.21. Label: 9, 23  Brands include Floxapen® , Fluclomix ®, Ladropen ®   Oral solution (= elixir or syrup), flucloxacillin (as  sodium salt) for reconstitution with water, 125 mg/  5mL, net price 100 mL = £4.41; 250 mg/5 mL,   Note Sugar-free versions are available and can be ordered by  specifying ‘sugar-free’ on the prescription  Injection, powder for reconstitution, flucloxacillin (as  sodium salt), net price 250-mg vial = £1.23; 500-mg  vial = £2.45; 1-g vial = £4.90    Indications septicaemia, urinary-tract infections,  lower respiratory-tract infections caused by suscep-  tible Gram-negative bacteria  Cautions see under Benzylpenicillin (section 5. 1.1.1);   interactions: Appendix 1 (penicillins)  Contra-indications see under Benzylpenicillin (sec-  tion 5. 1.1.1)   Renal impairment 1 g every 12 hours if eGFR 30-  60mL/minute/1.73m 2 ; 1 g every 24 hours if eGFR  10-30 mL/minute/1. 73m 2 ; 1 g every 48 hours or  500 mg every 24 hours if eGFR less than 10 mL/  minute/ 1.73 m 2   • ADULT over 18 years, by intramuscular injection or by  intravenous injection over 3-4 minutes, or by intra-  venous infusion, 1-2 g every 12 hours    Negaban® (Eumedica) (Ml  Injection, powder for reconstitution, temocillin (as  sodium salt), net price 1-g vial = £25.45   active against certain Gram-positive and  Gram-negative organisms but is inactivated by peni-  cillinases including those produced by Staphylococcus  aureus and by common Gram-negative bacilli such as  Escherichia coli. Almost all staphylococci, approx. 60%  of E. coli strains and approx. 20% of Haemophilus  influenzae strains are now resistant. The likelihood of  resistance should therefore be considered before using  ampicillin for the “blind’ treatment of infections; in  particular, it should not be used for hospital patients  without checking sensitivity.   Ampicillin is well excreted in the bile and urine. It is  principally indicated for the treatment of exacerbations  of chronic bronchitis and middle ear infections, both of  which may be due to Streptococcus pneumoniae and H.  influenzae, and for urinary-tract infections (section  5.1.13).    Ampicillin can be given by mouth but less than half the  dose is absorbed, and absorption is further decreased by  the presence of food in the gut.   Maculopapular rashes commonly occur with ampicillin  (and amoxicillin) but are not usually related to true  penicillin allergy. They almost always occur in patients  with glandular fever; broad-spectrum penicillins should  not therefore be used for ‘blind’ treatment of a sore  throat. The risk of rash is also increased in patients with  acute or chronic lymphocytic leukaemia or in cyto-  megalovirus infection.   Amoxicillin is a derivative of ampicillin and has a  similar antibacterial spectrum. It is better absorbed  than ampicillin when given by mouth, producing higher  plasma and tissue concentrations; unlike ampicillin,  absorption is not affected by the presence of food in  the stomach. Amoxicillin may also be used for the  treatment of Lyme disease [not licensed], see below.  Co-amoxiclav consists of amoxicillin with the beta-  lactamase inhibitor clavulanic acid. Clavulanic acid itself  has no significant antibacterial activity but, by inactivat-  ing beta-lactamases, it makes the combination active  against beta-lactamase-producing bacteria that are  resistant to amoxicillin. These include resistant strains  of Staph, aureus, E. coli, and H. influenzae, as well as  many Bacteroides and Klebsiella spp. Co-amoxiclav  should be reserved for infections likely, or known, to  be caused by amoxicillin-resistant beta-lactamase-pro-  ducing strains.   A combination of ampicillin with flucloxacillin (as co-  fluampicil) is available to treat infections involving  either streptococci or staphylococci (e.g. cellulitis).   Lyme disease Lyme disease should generally be  treated by those experienced in its management. Dox-  ycycline (p. 348), amoxicillin [unlicensed indication] or  cefuroxime axetil are the antibacterials of choice for  early Lyme disease or Lyme arthritis. If these antibac-  terials are contra-indicated, a macrolide (e.g. clarithro-  mycin) can be used for early Lyme disease. Intravenous  administration of ceftriaxone, cefotaxime (p. 340), or  benzylpenicillin (p. 333) is recommended for Lyme  disease associated with cardiac or neurological compli-  cations. The duration of treatment is usually 2-4 weeks;  Lyme arthritis may require further treatment.    Oral infections Amoxicillin or ampicillin are as effec-  tive as phenoxymethylpenicillin (section 5. 1.1.1) but  they are better absorbed; however, they may encourage  emergence of resistant organisms. Like phenoxymethyl-  penicillin, amoxicillin and ampicillin are ineffective  against bacteria that produce beta-lactamases. Amox-  icillin may be useful for short-course oral regimens. Co-  amoxiclav is active against beta-lactamase-producing  bacteria that are resistant to amoxicillin. Co-amoxiclav  may be used for severe dental infection with spreading  cellulitis or dental infection not responding to first-line  antibacterial treatment.   Indications see under Ampicillin; also oral infections,  Lyme disease (see notes above); endocarditis treat-  ment (Table 1, section 5.1); anthrax (section 5.1.12);  adjunct in listerial meningitis (Table 1, section 5.1);  Helicobacter pylori eradication (section 1.3)  Cautions see under Ampicillin; maintain adequate  hydration with high doses (particularly during par-   Contra-indications see under Ampicillin  Renal impairment risk of crystalluria with high doses  (particularly during parenteral therapy). Reduce dose  in severe impairment; rashes more common  Pregnancy not known to be harmful  Breast-feeding trace amounts in milk  Side-effects see under Ampicillin  Dose   • By mouth, ADULT and CHILD over 5 years, 250 mg every  8 hours, dose doubled in severe infection; CHILD, 1  month- 1 year, 62.5 mg every 8 hours, dose doubled in  severe infection; 1-5 years, 125 mg every 8 hours,  dose doubled in severe infection   Otitis media, 500 mg every 8 hours; CHILD 40 mg/kg  daily in 3 divided doses (max. 1.5 g daily)   Lyme disease (see also notes above), ADULT and CHILD  over 5 years, 500 mg every 8 hours for 14-21 days (for  28 days in Lyme arthritis) [unlicensed indication];  CHILD 1 month-5 years see BNF for Children  Anthrax (treatment and post-exposure prophylaxis —  see also section 5.1.12), 500 mg every 8 hours; CHILD  body-weight under 20 kg, 80 mg/kg daily in 3 divided  doses, body-weight over 20 kg, adult dose   Dental abscess, ADULT over 18 years, 3 g repeated after  8 hours   Urinary-tract infections, ADULT over 18 years, 3 g  repeated after 10-12 hours   • By intravenous injection or infusion, 500 mg every 8  hours increased to 1 g every 6 hours in severe infec-  tion; CHILD 1 month-18 years, 20-30 mg/kg (max.  500 mg) every 8 hours; dose doubled in severe  infection (max. 4 g daily)   • Listerial meningitis (in combination with another  antibiotic, see Table 1, section 5.1), by intravenous  infusion, ADULT over 18 years, 2g every 4 hours for  10-14 days; CHILD under 18 years see BNF for Chil-  dren   • Endocarditis (in combination with another antibiotic if  necessary, see Table 1, section 5.1), by intravenous  infusion, ADULT over 18 years, 2g every 6 hours,  increased to 2 g every 4 hours e.g. in enterococcal  endocarditis or if amoxicillin used alone; CHILD under  18 years see BNF for Children   Note Amoxicillin doses in BNF may differ from those in  product literature    Amoxicillin (Non-proprietary) (Ml  Capsules, amoxicillin (as trihydrate) 250 mg, net price  21 = £1.07; 500 mg, 21 = £1.31. Label: 9   Brands include Amix ® , Amoram ®, Amoxident ®, Galenamox ® ,  Rimoxallin ®   Oral suspension, amoxicillin (as trihydrate) for  reconstitution with water, 125 mg/5 mL, net price  100 mL = £1.22; 250mg/5mL, 100 mL = £1.39.  Label: 9    Sachets, sugar-free, amoxicillin (as trihydrate) 3g/  sachet, net price 2-sachet pack = £8.34, 14-sachet  pack = £31.94. Label: 9, 13   Dental prescribing on NHS Amoxicillin Sachets may be  prescribed as Amoxicillin Oral Powder  Injection, powder for reconstitution, amoxicillin (as  sodium salt), net price 250-mg vial = 32p; 500-mg vial  = 66p; 1-g vial = £1.16   Capsules, both maroon/gold, amoxicillin (as trihy-  drate), 250 mg, net price 21-cap pack = £3.45; 500 mg,  21-cap pack = £6.91. Label: 9  Paediatric suspension, amoxicillin 125 mg (as trihy-  drate)/ 1.25 mL when reconstituted with water, net  price 20 mL (peach- strawberry- and lemon-fla-  voured) = £3.25. Label: 9, counselling , use of pipette   Sachets S£ powder, sugar-free, amoxicillin (as trihy-  drate) 3 g/sachet, 2-sachet pack (peach- strawberry-  and lemon-flavoured) = £2.99. Label: 9, 13  Injection, powder for reconstitution, amoxicillin (as  sodium salt), net price 500-mg vial = 56p; 1-g vial =  £ 1.12   Indications urinary-tract infections, otitis media,  sinusitis, oral infections (see notes above), bronchitis,  low or moderate-severity community-acquired pneu-  monia (Table 1, section 5.1), invasive salmonellosis;  listerial meningitis (Table 1, section 5.1)   Cautions history of allergy; erythematous rashes  common in glandular fever (see notes above);  increased risk of erythematous rashes in cyto-  megalovirus infection, and acute or chronic lympho-  cytic leukaemia (see notes above); interactions:  Appendix 1 (penicillins)   Contra-indications penicillin hypersensitivity  Renal impairment reduce dose if eGFR less than  10mL/minute/1.73m 2 ; rashes more common  Pregnancy not known to be harmful  Breast-feeding trace amounts in milk  Side-effects nausea, vomiting, diarrhoea; rashes (dis-  continue treatment); rarely, antibiotic-associated col-  itis; see also under Benzylpenicillin (section 5. 1.1.1)  Dose   • By mouth, 0.25-1 g every 6 hours, CHILD 1 month-1  year, 62.5 mg every 6 hours, dose doubled in severe  infection; 1-5 years, 125 mg every 6 hours, dose  doubled in severe infection; 5-12 years, 250 mg every  6 hours, dose doubled in severe infection  Urinary-tract infections, ADULT and CHILD over 10  years, 500 mg every 8 hours; CHILD under 10 years,  half adult dose   • By intramuscular injection or intravenous injection or  infusion, 500 mg every 4-6 hours; CHILD under 18  years see BNF for Children   • Endocarditis (in combination with another antibiotic if  necessary, see Table 1, section 5.1), by intravenous  infusion, ADULT over 18 years, 2 g every 6 hours,  increased to 2 g every 4 hours e.g. in enterococcal  endocarditis or if ampicillin used alone; CHILD under  18 years see BNF for Children   • Listerial meningitis (in combination with another  antibiotic, see Table 1, section 5.1), by intravenous  infusion, ADULT over 18 years, 2 g every 4 hours for   Note Ampicillin doses in BNF may differ from those in product  literature   Ampicillin (Non-proprietary) (Ml  Capsules, ampicillin 250 mg, net price 28 = £7.18;  500 mg, 28 = £32.93. Label: 9, 23  Brands include Rimacillin ®   Oral suspension, ampicillin 125 mg/5 mL when  reconstituted with water, net price 100 mL = £9.23;  250 mg/5 mL, 100 mL = £14.17. Label: 9, 23  Brands include Rimacillin ®   Injection, powder for reconstitution, ampicillin (as  sodium salt), net price 500-mg vial = £7.83   Penbritin® (Chemidex) (Ml  Capsules, grey/red, ampicillin (as trihydrate) 250 mg,  net price 28-cap pack = £2.10; 500 mg, 28-cap pack =  £5.28. Label: 9, 23   Syrup, apricot- caramel- and peppermint-flavoured,  ampicillin (as trihydrate) for reconstitution with water,  125 mg/5 mL, net price 100 mL = £3.78; 250 mg/  5mL, 100 mL = £7.39. Label: 9, 23   A mixture of amoxicillin (as the trihydrate or as the  sodium salt) and clavulanic acid (as potassium cla-  vulanate); the proportions are expressed in the form  x/y where x and y are the strengths in milligrams of  amoxicillin and clavulanic acid respectively   Indications infections due to beta-lactamase-produ-  cing strains (where amoxicillin alone not appropriate)  including respiratory-tract infections, bone and joint  infections, genito-urinary and abdominal infections,  cellulitis, animal bites, severe dental infection with  spreading cellulitis or dental infection not responding  to first-line antibacterial   Cautions see under Ampicillin and notes above;  maintain adequate hydration with high doses (parti-  cularly during parenteral therapy); interactions:  Appendix 1 (penicillins)   Cholestatic jaundice Cholestatic jaundice can occur either  during or shortly after the use of co-amoxiclav. An epide-  miological study has shown that the risk of acute liver  toxicity was about 6 times greater with co-amoxiclav than  with amoxicillin. Cholestatic jaundice is more common in  patients above the age of 65 years and in men; these  reactions have only rarely been reported in children. Jaun-  dice is usually self-limiting and very rarely fatal. The duration  of treatment should be appropriate to the indication and  should not usually exceed 14 days  Contra-indications penicillin hypersensitivity, history  of co-amoxiclav-associated or penicillin-associated  jaundice or hepatic dysfunction  Hepatic impairment monitor liver function in liver  disease; see also Cholestatic Jaundice above  Renal impairment risk of crystalluria with high doses  (particularly during parenteral therapy).   Co-amoxiclav 250/125 tablets or 500/125 tablets : if  eGFR 10-30 mL/minute/ 1.73m 2 , one 250/125  strength tablet every 12 hours or one 500/125  strength tablet every 12 hours; if eGFR less than    10mL/minute/1.73m 2 , one 250/125 strength tablet  every 24 hours or one 500/125 strength tablet every  24 hours.   Co-amoxiclav 400/57 suspension, avoid if eGFR less  than 30 mL/minute/ 1.73 m 2 .    Co-amoxiclav injection (expressed as co-amoxiclav):  if eGFR 10-30 mL/minute/ 1.73 m 2 , 1.2 g initially,  then 600 mg every 12 hours; if eGFR less than 10 mL/  minute/ 1.73m 2 , 1.2 g initially, then 600 mg every 24  hours   Pregnancy not known to be harmful  Breast-feeding trace amounts in milk  Side-effects see under Ampicillin; hepatitis, chole-  static jaundice (see above); Stevens- Johnson  syndrome, toxic epidermal necrolysis, exfoliative  dermatitis, vasculitis reported; rarely prolongation of  bleeding time, dizziness, headache, convulsions (par-  ticularly with high doses or in renal impairment);  superficial staining of teeth with suspension, phlebitis  at injection site   • By mouth, expressed as co-amoxiclav, one 250/125  strength tablet every 8 hours, increased in severe  infections to one 500/125 strength tablet every 8  hours; NEONATE 0.25mL/kg of 125/31 suspension  every 8 hours; CHILD 1 month-1 year, 0.25mL/kg of  125/31 suspension every 8 hours, dose doubled in  severe infection; 1-6 years, 5 mL of 125/31 suspen-  sion every 8 hours or 0.25mL/kg of 125/31 sus-  pension every 8 hours, dose doubled in severe infec-  tion; 6-12 years, 5mL of 250/62 suspension every 8  hours or 0.15 mL/kg of 250/62 suspension every 8  hours, dose doubled in severe infection    Severe dental infections (but not generally first-line,  see notes above), expressed as co-amoxiclav, ADULT  and CHILD over 12 years, one 250/125 strength tablet  every 8 hours for 5 days   • By intravenous injection over 3-4 minutes or by  intravenous infusion, expressed as co-amoxiclav,   1.2 g every 8 hours; INFANTS up to 3 months 30 mg/kg  every 8 hours (every 12 hours in the perinatal period  and in premature infants); CHILD 3 months-18 years,  30 mg/kg (max. 1.2 g) every 8 hours  Surgical prophylaxis, expressed as co-amoxiclav, 1.2 g  up to 30 minutes before the procedure; for high risk  procedures up to 2-3 further doses of 1.2 g may be  given every 8 hours    Co-amoxiclav (Non-proprietary) (Ml  Tablets, co-amoxiclav 250/125 (amoxicillin 250 mg  as trihydrate, clavulanic acid 125 mg as potassium  salt), net price 21-tab pack = £2.63. Label: 9  Dental prescribing on NHS Co-amoxiclav 250/125 Tablets may  be prescribed   Oral suspension, co-amoxiclav 250/62 (amoxicillin  250 mg as trihydrate, clavulanic acid 62.5 mg as   Injection 500/100, powder for reconstitution, co-  amoxiclav 500/100 (amoxicillin 500 mg as sodium  salt, clavulanic acid 100 mg as potassium salt), net  price per vial = £1.21   Injection 1000/200, powder for reconstitution, co-  amoxiclav 1000/200 (amoxicillin 1 g as sodium salt,  clavulanic acid 200 mg as potassium salt), net price  per vial = £2.63   Tablets 375 mg, f/c, co-amoxiclav 250/125 (amox-  icillin 250 mg as trihydrate, clavulanic acid 125 mg as  potassium salt), net price 2 1-tab pack = £4. 19. Label: 9  Tablets 625 mg, f/c, co-amoxiclav 500/125 (amox-  icillin 500 mg as trihydrate, clavulanic acid 125 mg as  potassium salt), net price 21-tab pack = £8.00. Label: 9  Suspension ‘125/31 SF’, sugar-free, co-amoxiclav  125/31 (amoxicillin 125 mg as trihydrate, clavulanic  acid 3 1.25 mg as potassium salt)/5mL when recon-  stituted with water, net price 100 mL (raspberry-and  orange-flavoured) = £4.08. Label: 9   Suspension ‘250/62 SF’, sugar-free, co-amoxiclav  250/62 (amoxicillin 250 mg as trihydrate, clavulanic  acid 62.5 mg as potassium salt)/ 5 mL when reconsti-  tuted with water, net price 100 mL (raspberry-and  orange-flavoured) = £5.74. Label: 9   Injection 600 mg, powder for reconstitution, co-  amoxiclav 500/100 (amoxicillin 500 mg as sodium  salt, clavulanic acid 100 mg as potassium salt), net  price per vial = £1.31   Injection 1.2 g, powder for reconstitution, co-amoxi-  clav 1000/200 (amoxicillin 1 g as sodium salt, clavu-  lanic acid 200 mg as potassium salt), net price per vial  = £2.61   Electrolytes Na + 2.7 mmol, K + 1 mmol/ 1.2-g vial   JITwice daily oral preparations  Co-amoxiclav (Non-proprietary) (Ml  Suspension ‘400/57’, co-amoxiclav 400/57 (amox-  icillin 400 mg as trihydrate, clavulanic acid 57 mg as  potassium salt)/ 5 mL when reconstituted with water,  net price 35 mL = £4.13, 70 mL = £5.79. Label: 9   Dose CHILD 2 months-2 years 0.15 mL/kg twice daily, 2-6 years  (13-21 kg) 2.5 mL twice daily, 7-12 years (22-40 kg) 5 mL twice  daily, doubled in severe infections   A mixture of equal parts by mass of flucloxacillin and  ampicillin   Indications mixed infections involving beta-lacta-  mase-producing staphylococci  Cautions see under Ampicillin and Flucloxacillin;   • By mouth, co-fluampicil, 250/250 every 6 hours, dose  doubled in severe infections; CHILD under 10 years half  adult dose, dose doubled in severe infections   • By intramuscular or slow intravenous injection or by  intravenous infusion, co-fluampicil 250/250 every 6  hours, dose doubled in severe infections; CHILD under  2 years quarter adult dose, 2-10 years half adult dose,  dose doubled in severe infections   Co-fluampicil (Non-proprietary) (S  Capsules, co-fluampicil 250/250 (flucloxacillin  250 mg as sodium salt, ampicillin 250 mg as trihy-  drate), net price 28-cap pack = £14.73. Label: 9, 22  Brands include Flu-Amp ®   Syrup, co-fluampicil 125/125 (flucloxacillin 125 mg  as magnesium salt, ampicillin 125 mg as trihydrate)/  5 mL when reconstituted with water, net price 100 mL  = £4.99. Label: 9, 22   Injection 500 mg, powder for reconstitution, co-flu-  ampicil 250/250 (flucloxacillin 250 mg as sodium salt,  ampicillin 250 mg as sodium salt), net price per vial =  £1.33    Piperacillin, a ureidopenicillin, is only available in com-  bination with the beta-lactamase inhibitor tazobactam.  Ticarcillin, a carboxypenicillin, is only available in  combination with the beta-lactamase inhibitor clavu-  lanic acid (section 5. 1.1. 3). Both preparations have a  broad spectrum of activity against a range of Gram-  positive and Gram-negative bacteria, and anaerobes.  Piperacillin with tazobactam has activity against a  wider range of Gram-negative organisms than ticarcillin  with clavulanic acid and it is more active against  Pseudomonas aeruginosa. These antibacterials are  not active against MRSA. They are used in the treatment  of septicaemia, peritonitis, hospital-acquired pneu-  monia, complicated urinary-tract infections, and skin  and soft-tissue infections.    For severe pseudomonas infections (especially in neu-  tropenia or endocarditis) these antipseudomonal peni-  cillins can be given with an aminoglycoside (e.g. genta-  micin section 5.1.4) since they have a synergistic effect.   Owing to the sodium content of many of these anti-  biotics, high doses may lead to hypematraemia.   Cautions see under Benzylpenicillin (section 5. 1.1.1);  interactions: Appendix 1 (penicillins)   Renal impairment max. 4.5 g every 8 hours if eGFR  20-80 mL/minute/1.73 m 2 ; max. 4.5 g every 12 hours  if eGFR less than 20 mL/minute/ 1.73 m 2   Breast-feeding present in milk — manufacturers  advise use only if potential benefit outweighs risk   Side-effects see under Benzylpenicillin (section  5. 1.1.1); also nausea, vomiting, diarrhoea; less com-  monly stomatitis, dyspepsia, constipation, jaundice,  hypotension, headache, insomnia, and injection-site  reactions; rarely abdominal pain, hepatitis, oedema,  fatigue, and eosinophilia; very rarely hypoglycaemia,  hypokalaemia, pancytopenia, Stevens-Johnson  syndrome, and toxic epidermal necrolysis  Dose   Note Expressed as a combination of piperacillin and tazo-  bactam (both as sodium salts) in a ratio of 8: 1   • Lower respiratory-tract, urinary-tract, intra-abdo-  minal and skin infections, and septicaemia, ADULT and  CHILD over 12 years, by intravenous injection over 3-5  minutes or by intravenous infusion, 2.25-4.5 g every  6-8 hours, usually 4.5 g every 8 hours   • Complicated appendicitis, by intravenous injection  over 3-5 minutes or by intravenous infusion, CHILD 2-  12 years, 112.5 mg/kg (max. 4.5 g) every 8 hours for  5-14 days; CHILD under 2 years, not recommended   • Infections in neutropenic patients (in combination  with an aminoglycoside), by intravenous injection  over 3-5 minutes or by intravenous infusion, ADULT  and CHILD over 50 kg, 4.5 g every 6 hours; CHILD less  than 50 kg, 90 mg/kg every 6 hours    Piperacillin with tazobactam (Non-proprietary) ®  Injection 2.25 g, powder for reconstitution, pipera-  cillin 2 g (as sodium salt), tazobactam 250 mg (as  sodium salt), net price 2.25-g vial = £7.16   Injection 4.5 g, powder for reconstitution, piperacillin  4 g (as sodium salt), tazobactam 500 mg (as sodium  salt), net price 4.5-g vial = £14.21   Injection 2.25 g, powder for reconstitution, pipera-  cillin 2 g (as sodium salt), tazobactam 250 mg (as  sodium salt), net price 2.25-g vial = £7.65   Injection 4.5 g, powder for reconstitution, piperacillin  4 g (as sodium salt), tazobactam 500 mg (as sodium  salt), net price 4.5-g vial = £15.17   Cautions see under Benzylpenicillin (section 5. 1.1.1);  interactions: Appendix 1 (penicillins)   Cholestatic jaundice For a warning on cholestatic jaundice  possibly associated with clavulanic acid, see under Co-  amoxiclav, p. 337.   Hepatic impairment manufacturer advises caution in  severe impairment; also cholestatic jaundice, see  under Co-amoxiclav, p. 337   Renal impairment reduce dose to 3.2 g every eight  hours if eGFR 30-60 mL/minute/1.73 m 2 ; 1.6 g every  eight hours if eGFR 10-30 mL/minute/1.73 m 2 ; 1.6 g  every twelve hours if eGFR less than 10 mL/minute/  1.73 m 2    Breast-feeding trace amounts in milk  Side-effects see under Benzylpenicillin (section  5. 1.1.1); also nausea, vomiting, coagulation disorders,  haemorrhagic cystitis (more frequent in children),  injection-site reactions, Stevens- Johnson syndrome,  toxic epidermal necrolysis, hypokalaemia, eosino-  philia  Dose   Note Expressed as a combination of ticarcillin (as sodium  salt) and clavulanic acid (as potassium salt) in a ratio of 15:1  • By intravenous infusion, 3.2 g every 6-8 hours  increased to every 4 hours in more severe infections;  CHILD 1 month-18 years, body-weight under 40 kg,   80 mg/kg every 8 hours, increased to every 6 hours in  more severe infections; body-weight over 40 kg, adult  dose   Injection 3.2 g, powder for reconstitution, ticarcillin  3 g (as sodium salt), clavulanic acid 200 mg (as  potassium salt). Net price per vial = £5.33   Electrolytes Na + 16 mmol, K + 1 mmol /3.2-g vial   Pivmecillinam has significant activity against many  Gram-negative bacteria including Escherichia coli, kleb-  siella, enterobacter, and salmonellae. It is not active  against Pseudomonas aeruginosa or enterococci.  Pivmecillinam is hydrolysed to mecillinam, which is  the active drug.   Cautions see under Benzylpenicillin (section 5. 1.1.1);  also liver and renal function tests required in long-  term use; avoid in acute porphyria (section 9.8.2);  interactions: Appendix 1 (penicillins)   Contra-indications see under Benzylpenicillin (sec-  tion 5. 1.1.1); also carnitine deficiency, oesophageal  strictures, gastro-intestinal obstruction, infants under  3 months   Side-effects see under Benzylpenicillin (section  5. 1.1.1); nausea, vomiting, dyspepsia; also reduced  serum and total body carnitine (especially with long-  term or repeated use)   • Acute uncomplicated cystitis, ADULT and CHILD over  40 kg, initially 400 mg then 200 mg every 8 hours for 3  days   • Chronic or recurrent bacteriuria, ADULT and CHILD over  40 kg, 400 mg every 6-8 hours   • Urinary-tract infections, CHILD under 40 kg, 20-  40 mg/kg daily in 3-4 divided doses   Counselling Tablets should be swallowed whole with plenty  of fluid during meals while sitting or standing   Tablets, f/c, pivmecillinam hydrochloride 200 mg, net  price 10-tab pack = £4.50. Label 9, 21, 27, counselling,  posture (see Dose above)   Antibiotics in this section include the cephalosporins,  such as cefotaxime, ceftazidime, cefuroxime, cefalexin  and cefradine, the monobactam, aztreonam, and the  carbapenems, imipenem (a thienamycin derivative),  meropenem, doripenem, and ertapenem.    The cephalosporins are broad-spectrum antibiotics  which are used for the treatment of septicaemia, pneu-  monia, meningitis, biliary-tract infections, peritonitis,  and urinary-tract infections. The pharmacology of the  cephalosporins is similar to that of the penicillins, excre-  tion being principally renal. Cephalosporins penetrate  the cerebrospinal fluid poorly unless the meninges are  inflamed; cefotaxime is a suitable cephalosporin for  infections of the CNS (e.g meningitis).    The principal side-effect of the cephalosporins is hyper-  sensitivity and about 0.5-6. 5% of penicillin-sensitive  patients will also be allergic to the cephalosporins.  Patients with a history of immediate hypersensitivity  to penicillin should not receive a cephalosporin. If a  cephalosporin is essential in these patients because a  suitable alternative antibacterial is not available, then  cefixime, cefotaxime, ceftazidime, ceftriaxone, or cefur-  oxime can be used with caution; cefaclor, cefadroxil,  cefalexin, and cefradine should be avoided.    Antibiotic-associated colitis may occur with the use of  broad-spectrum cephalosporins, particularly second-  and-third-generation cephalosporins.   Cefuroxime is a ‘second generation’ cephalosporin that  is less susceptible than the earlier cephalosporins to  inactivation by beta-lactamases. It is, therefore, active  against certain bacteria which are resistant to the other  drugs and has greater activity against Haemophilus  influenzae.   Cefotaxime, ceftazidime and ceftriaxone are ‘third  generation’ cephalosporins with greater activity than  the ‘second generation’ cephalosporins against certain  Gram-negative bacteria. However, they are less active  than cefuroxime against Gram-positive bacteria, most  notably Staphylococcus aureus. Their broad anti-  bacterial spectrum may encourage superinfection with  resistant bacteria or fungi.   Ceftazidime has good activity against pseudomonas. It  is also active against other Gram-negative bacteria.  Ceftriaxone has a longer half-life and therefore needs to  be given only once daily. Indications include serious  infections such as septicaemia, pneumonia, and  meningitis. The calcium salt of ceftriaxone forms a  precipitate in the gall bladder which may rarely cause  symptoms but these usually resolve when the antibiotic  is stopped.    Orally active cephalosporins The orally active ‘first  generation’ cephalosporins, cefalexin, cefradine, and  cefadroxil and the ‘second generation’ cephalosporin,  cefaclor, have a similar antimicrobial spectrum. They  are useful for urinary-tract infections which do not  respond to other drugs or which occur in pregnancy,    respiratory-tract infections, otitis media, sinusitis, and  skin and soft-tissue infections. Cefaclor has good activ-  ity against H. influenzae, but it is associated with  protracted skin reactions especially in children. Cefa-  droxil has a long duration of action and can be given  twice daily; it has poor activity against H. influenzae.  Cefuroxime axetil, an ester of the ‘second generation’  cephalosporin cefuroxime, has the same antibacterial  spectrum as the parent compound; it is poorly absorbed.   Cefixime and cefpodoxime proxetil are orally active  ‘third generation’ cephalosporins. Cefixime has a longer  duration of action than the other cephalosporins that are  active by mouth. It is only licensed for acute infections.  Cefpodoxime proxetil is more active than the other oral  cephalosporins against respiratory bacterial pathogens  and it is licensed for upper and lower respiratory-tract  infections.   Oral infections The cephalosporins offer little advan-  tage over the penicillins in dental infections, often being  less active against anaerobes. Infections due to oral  streptococci (often termed viridans streptococci)  which become resistant to penicillin are usually also  resistant to cephalosporins. This is of importance in the  case of patients who have had rheumatic fever and are  on long-term penicillin therapy. Cefalexin and cefradine  have been used in the treatment of oral infections.   Indications infections due to sensitive Gram-positive  and Gram-negative bacteria, but see notes above  Cautions sensitivity to beta-lactam antibacterials  (avoid if history of immediate hypersensitivity reac-  tion, see also notes above and p. 332); false positive  urinary glucose (if tested for reducing substances) and  false positive Coombs’ test; interactions: Appendix 1  (cephalosporins)   Side-effects diarrhoea (rarely antibiotic-associated  colitis), nausea and vomiting, abdominal discomfort,  headache; allergic reactions including rashes, pruritus,  urticaria, serum sickness-like reactions with rashes,  fever and arthralgia, and anaphylaxis; Stevens- John-  son syndrome, toxic epidermal necrolysis reported;  disturbances in liver enzymes, transient hepatitis and  cholestatic jaundice; other side-effects reported  include eosinophilia and blood disorders (including  thrombocytopenia, leucopenia, agranulocytosis,  aplastic anaemia and haemolytic anaemia); reversible  interstitial nephritis, hyperactivity, nervousness, sleep  disturbances, hallucinations, confusion, hypertonia,  and dizziness  Dose   • 250 mg every 8 hours, doubled for severe infections;  max. 4g daily; CHILD over 1 month, 20 mg/kg daily in  3 divided doses, doubled for severe infections, max.   1 g daily; or 1 month-1 year, 62.5 mg every 8 hours;  1-5 years, 125 mg; over 5 years, 250 mg; doses  doubled for severe infections    Cefaclor (Non-proprietary) (Ml  Capsules, cefaclor (as monohydrate) 250 mg, net  price 21-cap pack = £5.09; 500 mg, 50-cap pack =  £31.99. Label: 9  Brands include Keftid®   Suspension, cefaclor (as monohydrate) for reconsti-  tution with water, 125 mg/5 mL, net price 100 mL =  £8.33; 250 mg/5 mL, 100 mL = £6.97. Label: 9  Note Sugar-free versions are available and can be ordered by  specifying ‘sugar-free’ on the prescription  Brands include Keftid®   Capsules, cefaclor (as monohydrate) 500 mg (violet/  grey), net price 21-cap pack = £18.19. Label: 9  Suspension, both pink, cefaclor (as monohydrate) for  reconstitution with water, 125 mg/5 mL, net price  100 mL = £4.13; 250 mg/5 mL, 100 mL = £8.26.  Label: 9   Distaclor MR® (Flynn) (Ml  Tablets, m/r, both blue, cefaclor (as monohydrate)  375 mg. Net price 14-tab pack = £8.31. Label: 9, 21, 25  Dose 375 mg every 12 hours with food, dose doubled for pneu-  monia    Indications see under Cefaclor; see also notes above  Cautions see under Cefaclor; interactions: Appendix  1 (cephalosporins)   Contra-indications see under Cefaclor  Renal impairment 1 g initially, then 500 mg every 12  hours if eGFR 26-50 mL/minute/ 1.73 m 2 ; 1 g initially,  then 500 mg every 24 hours if eGFR ll-26mL/min-  ute/1.73m 2 ; 1 g initially, then 500 mg every 36 hours  if eGFR less than 11 mL/minute/ 1.73 m 2   Pregnancy see under Cefaclor  Breast-feeding see under Cefaclor  Side-effects see under Cefaclor    • 0.5-1 g twice daily; skin, soft-tissue, and uncompli-  cated urinary-tract infections, 1 g daily; CHILD 6-18  years, body-weight under 40 kg, 500 mg twice daily;  body-weight over 40 kg, adult dose   Capsules, cefadroxil (as monohydrate) 500 mg, net  price 20-cap pack = £4.83. Label: 9   Indications see under Cefaclor  Cautions see under Cefaclor; interactions: Appendix  1 (cephalosporins)   Contra-indications see under Cefaclor  Renal impairment max. 3 g daily if eGFR 40-50 mL/  minute/ 1.73 m 2 ; max. 1.5 g daily if eGFR 10-40 mL/  minute/1.73 m 2 ; max. 750 mg daily if eGFR less than  10 mL/minute/ 1.73 m 2  Pregnancy see under Cefaclor  Breast-feeding see under Cefaclor  Side-effects see under Cefaclor  Dose   • 250 mg every 6 hours or 500 mg every 8-12 hours  increased to 1-1.5 g every 6-8 hours for severe    infections; CHILD 25 mg/kg daily in divided doses,  doubled for severe infections, max. 100 mg/kg daily;  or under 1 year 125 mg every 12 hours, 1-5 years  125 mg every 8 hours, 5-12 years 250 mg every 8  hours   • Prophylaxis of recurrent urinary-tract infection, ADULT  125 mg at night   Cefalexin (Non-proprietary) (Ml  Capsules, cefalexin 250 mg, net price 28-cap pack =  £1.66; 500 mg, 21-cap pack = £2.09. Label: 9  Dental prescribing on NHS Cefalexin Capsules may be  prescribed   Tablets, cefalexin 250 mg, net price 28-tab pack =  £1.94; 500 mg, 21-tab pack = £2.39. Label: 9  Dental prescribing on NHS Cefalexin Tablets may be  prescribed   Oral suspension, cefalexin for reconstitution with  water, 125 mg/5 mL, net price 100 mL = £1.75;   Capsules, both caramel/grey, cefalexin 250 mg, net  price 28-cap pack = £4.02; 500 mg, 28-cap pack =  £7.85. Label: 9   Tablets, all pink, f/c, cefalexin 250 mg, net price 28-  tab pack = £4.02; 500 mg, 28-tab pack = £7.85.   Syrup, all orange, cefalexin for reconstitution with  water, 125 mg/5 mL, net price 100 mL = £1.43;   250 mg/5 mL, 100 mL = £2.87; 500 mg/5 mL, 100 mL  = £5.57. Label: 9   Capsules, cefalexin 250 mg (green/white), net price  28-cap pack = £1.46; 500 mg (pale green/dark green),  21-cap pack = £1.98. Label: 9  Tablets, both peach, cefalexin 250 mg, net price 28-  tab pack = £1.60; 500 mg (scored), 21-tab pack =  £2.08. Label: 9   Suspension, cefalexin for reconstitution with water,  125 mg/5 mL, net price 100 mL = 84p; 250 mg/5 mL,  100 mL = £1.40. Label: 9   Indications see under Cefaclor (acute infections only);  gonorrhoea [unlicensed indication] (Table 1, section   Contra-indications see under Cefaclor  Renal impairment reduce dose if eGFR less than  20 mL/minute/ 1.73 m 2 (max. 200 mg once daily)  Pregnancy see under Cefaclor  Breast-feeding manufacturer advises avoid — no  information available  Side-effects see under Cefaclor  Dose   • ADULT and CHILD over 10 years, 200-400 mg daily in 1-   2 divided doses; CHILD over 6 months 8 mg/kg daily in  1-2 divided doses or 6 months- 1 year 75 mg daily; 1-  4 years 100 mg daily; 5-10 years 200 mg daily   • Uncomplicated gonorrhoea [unlicensed indication],  400 mg as a single dose   Suprax® (Sanofi-Aventis) [Ml  Tablets, f/c, scored, cefixime 200 mg. Net price 7-tab  pack = £13.23. Label: 9    Paediatric oral suspension, cefixime 100 mg/5 mL  when reconstituted with water, net price 50 mL (with  double-ended spoon for measuring 3.75 mL or 5mL  since dilution not recommended) = £10.53, 100 mL =  £18.91. Label: 9   Indications see under Cefaclor; gonorrhoea; surgical  prophylaxis; Haemophilus epiglottitis and meningitis  (Table 1, section 5.1); see also notes above  Cautions see under Cefaclor; interactions: Appendix  1 (cephalosporins)   Contra-indications see under Cefaclor  Renal impairment if eGFR less than 5 mL/minute/  1.73 m 2 , initial dose of 1 g then use half normal dose  Pregnancy see under Cefaclor  Breast-feeding see under Cefaclor  Side-effects see under Cefaclor; rarely arrhythmias  following rapid injection reported  Dose   • By intramuscular or intravenous injection or by  intravenous infusion, 1 g every 12 hours increased in  severe infections (e.g. meningitis) to 8 g daily in 4  divided doses; higher doses (up to 12 g daily in 3-4  divided doses) may be required; NEONATE 50 mg/kg  daily in 2-4 divided doses increased to 150-200 mg/  kg daily in severe infections; CHILD 100-150 mg/kg  daily in 2-4 divided doses increased up to 200 mg/kg  daily in very severe infections   Uncomplicated gonorrhoea, 500 mg as a single dose  Important. If meningococcal disease (meningitis with non-  blanching rash or meningococcal septicaemia) is suspected,  and the patient cannot be given benzylpenicillin (e.g.  because of an allergy), a single dose of cefotaxime can be  given (if available) before urgent transfer to hospital, so long  as this does not delay the transfer. If a patient with suspected  bacterial meningitis without non-blanching rash cannot be  transferred to hospital urgently and cannot be given  benzylpenicillin, a single dose of cefotaxime can be given  before transfer. Suitable doses of cefotaxime by intravenous  injection (or by intramuscular injection) are ADULT and CHILD  over 12 years 1 g; CHILD under 12 years 50 mg/kg; chlor-  amphenicol (section 5.1.7) maybe used if there is a history of  anaphylaxis to penicillins or cephalosporins   Cefotaxime (Non-proprietary) (§MI  Injection, powder for reconstitution, cefotaxime (as  sodium salt), net price 500-mg vial = £2.14; 1-g vial =  £4.31; 2-g vial = £8.57   Contra-indications see under Cefaclor  Renal impairment increase dose interval to every 24  hours if eGFR 10-40 mL/minute/ 1.73m 2 ; increase  dose interval to every 48 hours if eGFR less than  10 mL/minute/ 1.73 m 2  Pregnancy see under Cefaclor  Breast-feeding see under Cefaclor  Side-effects see under Cefaclor  Dose   • Upper respiratory-tract infections (but in pharyngitis  and tonsillitis reserved for infections which are  recurrent, chronic, or resistant to other antibacterials),  100 mg twice daily (200 mg twice daily in sinusitis);  CHILD 15 days-6 months 4 mg/kg every 12 hours, 6    months-2 years 40 mg every 12 hours, 3-8 years  80 mg every 12 hours, over 9 years 100 mg every 12  hours   • Lower respiratory-tract infections (including bronch-  itis and pneumonia), 100-200 mg twice daily; CHILD 15  days-6 months 4 mg/kg every 12 hours, 6 months-2  years 40 mg every 12 hours, 3-8 years 80 mg every 12  hours, over 9 years 100 mg every 12 hours   • Skin and soft-tissue infections, 200 mg twice daily;  CHILD 15 days-6 months 4 mg/kg every 12 hours, 6  months-2 years 40 mg every 12 hours, 3-8 years   80 mg every 12 hours, over 9 years 100 mg every 12  hours   • Uncomplicated urinary-tract infections, 100 mg twice  daily (200 mg twice daily in uncomplicated upper  urinary-tract infections); CHILD 15 days-6 months   4 mg/kg every 12 hours, 6 months-2 years 40 mg  every 12 hours, 3-8 years 80 mg every 12 hours, over  9 years 100 mg every 12 hours   Orelox® (Sanofi-Aventis) (Ml  Tablets, f/c, cefpodoxime 100 mg (as proxetil), net  price 10-tab pack = £9.78. Label: 5, 9, 21  Oral suspension, cefpodoxime (as proxetil) for  reconstitution with water, 40 mg/ 5 mL, net price  100 mL = £11.50. Label: 5, 9, 21    route only; ELDERLY usual max. 3 g daily; CHILD, up to 2  months 25-60 mg/kg daily in 2 divided doses, over 2  months 30-100 mg/kg daily in 2-3 divided doses; up  to 150 mg/kg daily (max. 6 g daily) in 3 divided doses  if immunocompromised or meningitis; intravenous  route recommended for children  Urinary-tract and less serious infections, 0.5-1 g every  12 hours   Pseudomonal lung infection in cystic fibrosis, ADULT  100-150 mg/kg daily in 3 divided doses; CHILD up to  150 mg/kg daily (max. 6g daily) in 3 divided doses;  intravenous route recommended for children  Surgical prophylaxis, prostatic surgery, 1 g up to 30  minutes before the procedure, repeated if necessary  when catheter removed   Ceftazidime (Non-proprietary) (Ml  Injection, powder for reconstitution, ceftazidime (as  pentahydrate), with sodium carbonate, net price 1-g  vial = £8.50; 2-g vial = £17.90   Injection, powder for reconstitution, ceftazidime (as  pentahydrate), with sodium carbonate, net price 250-  mg vial = £2.20, 500-mg vial = £4.40, 1-g vial = £8.79,  2-g vial = £17.59, 3-g vial = £25.76; Monovial, 2 g vial  (with transfer needle) = £17.59   Injection, powder for reconstitution, ceftazidime (as  pentahydrate), with sodium carbonate, net price 1-g  vial = £7.92; 2-g vial = £15.84   Indications see under Cefaclor; surgical prophylaxis  Cautions see under Cefaclor; interactions: Appendix  1 (cephalosporins)   Contra-indications see under Cefaclor  Renal impairment use half normal dose if eGFR 5-  20mL/minute/1.73m 2 ; use one-quarter normal dose  if eGFR less than 5 mL/minute/1.73 m 2  Pregnancy see under Cefaclor  Breast-feeding see under Cefaclor  Side-effects see under Cefaclor  Dose   • 250-500 mg every 6 hours or 0.5-1 g every 12 hours;  up to 1 g every 6 hours in severe infections; CHILD 7-  12 years, 25-50 mg/kg daily in 2-4 divided doses   Cefradine (Non-proprietary) (Ml  Capsules, cefradine 250 mg, net price 20-cap pack =  £2.86; 500 mg, 20-cap pack = £4.50. Label: 9  Brands include Nice]®   Indications see under Cefaclor; see also notes above  Cautions see under Cefaclor; interactions: Appendix  1 (cephalosporins)   Contra-indications see under Cefaclor  Renal impairment reduce dose if eGFR less than  50 mL/minute/1.73 m 2 — consult product literature  Pregnancy see under Cefaclor  Breast-feeding see under Cefaclor  Side-effects see under Cefaclor  Dose   • By deep intramuscular injection or intravenous  injection or infusion, 1 g every 8 hours or 2 g every 12  hours; 2 g every 8-12 hours or 3 g every 12 hours in  severe infections; single doses over 1 g intravenous    Indications see under Cefaclor and notes above; sur-  gical prophylaxis; prophylaxis of meningococcal  meningitis [unlicensed indication] (Table 2, section  5.1)   Cautions see under Cefaclor; may displace bilirubin  from serum albumin, administer over 60 minutes in  neonates (see also Contra-indications); treatment  longer than 14 days, renal failure, dehydration — risk of  ceftriaxone precipitation in gall bladder; interactions:  Appendix 1 (cephalosporins)   Contra-indications see under Cefaclor; neonates less  than 41 weeks postmenstrual age; neonates over 41  weeks postmenstrual age with jaundice, hypoalbumi-  naemia, or acidosis; concomitant treatment with  intravenous calcium (including total parenteral nutri-  tion containing calcium) in neonates over 41 weeks  postmenstrual age — risk of precipitation in urine and  lungs   Hepatic impairment reduce dose and monitor plasma  concentration if both hepatic and severe renal  impairment   Renal impairment reduce dose if eGFR less than  10 mL/minute/ 1.73m 2 (max. 2g daily); monitor  plasma concentration if both hepatic and severe renal  impairment   Side-effects see under Cefaclor; calcium ceftriaxone  precipitates in urine (particularly in very young,  dehydrated or those who are immobilised) or in gall  bladder — consider discontinuation if symptomatic;  rarely prolongation of prothrombin time, pancreatitis   • By deep intramuscular injection, or by intravenous  injection over at least 2-4 minutes, or by intravenous  infusion, 1 g daily; 2-4 g daily in severe infections;  intramuscular doses over 1 g divided between more  than one site; single intravenous doses above 1 g by  intravenous infusion only   NEONATE, by intravenous infusion over 60 minutes,  20-50 mg/kg daily (max. 50 mg/kg daily); INFANT and  CHILD under 50 kg, by deep intramuscular injection, or  by intravenous injection over 2-4 minutes, or by  intravenous infusion, 20-50 mg/kg daily; up to  80 mg/kg daily in severe infections; doses of 50 mg/  kg and over by intravenous infusion only; 50 kg and  over, adult dose   • Endocarditis caused by haemophilus, actinobacillus,  cardiobacterium, eikenella, and kingella species  (‘HACEK organisms’) (in combination with another  antibacterial, see Table 1, section 5.1; [unlicensed  indication]), by intravenous infusion, 2-4 g daily   • Early syphilis [unlicensed indication], by deep intra-  muscular injection, 500 mg daily for 10 days   • Uncomplicated gonorrhoea, pelvic inflammatory  disease (see also Table 1, section 5.1) by deep intra-  muscular injection, 250 mg as a single dose   • Surgical prophylaxis, by deep intramuscular injection  or by intravenous injection over at least 2-4 minutes,  1 g up to 30 minutes before the procedure; colorectal  surgery, by deep intramuscular injection or by intra-  venous infusion, 2 g up to 30 minutes before the  procedure; intramuscular doses over 1 g divided  between more than one site   Ceftriaxone (Non-proprietary) (Ml  Injection, powder for reconstitution, ceftriaxone (as  sodium salt), net price 1-g vial = £10.17; 2-g vial =  £20.36   Injection, powder for reconstitution, ceftriaxone (as  sodium salt), net price 250-mg vial = £2.40; 1-g vial =  £9.58; 2-g vial = £19.18   Indications see under Cefaclor; surgical prophylaxis;  more active against Haemophilus influenzae ; Lyme  disease   Renal impairment use parenteral dose of 750 mg  twice daily if eGFR 10-20 mL/minute/ 1.73 m 2 ; use  parenteral dose of 750 mg once daily if eGFR less than  10 mL/minute/ 1.73 m 2   • By mouth (as cefuroxime axetil), 250 mg twice daily in  most infections including mild to moderate lower  respiratory-tract infections (e.g. bronchitis); doubled  for more severe lower respiratory-tract infections or if  pneumonia suspected   CHILD over 3 months, 125 mg twice daily, if necessary  doubled in child over 2 years with otitis media    Lyme disease (see also section 5. 1.1.3), ADULT and  CHILD over 12 years, 500 mg twice daily for 14-2 1 days  (for 28 days in Lyme arthritis) [unlicensed duration]   • By intramuscular injection or intravenous injection or  infusion, 750 mg every 6-8 hours; 1.5 g every 6-8  hours in severe infections; single doses over 750 mg  intravenous route only   CHILD usual dose 60 mg/kg daily (range 30-100 mg/  kg daily) in 3-4 divided doses (2-3 divided doses in  neonates)   • Surgical prophylaxis, 1.5 g by intravenous injection up  to 30 minutes before the procedure; up to 3 further  doses of 750 mg may be given by intramuscular or  intravenous injection every 8 hours for high-risk  procedures   Cefuroxime (Non-proprietary) LmD  Tablets, cefuroxime (as axetil) 250 mg, net price 14-  tab pack = £10.39. Label: 9, 21, 25  Injection, powder for reconstitution, cefuroxime (as  sodium salt), net price 750-mg vial =£2.52; 1.5-g vial =  £5.05   Injection, powder for reconstitution, cefuroxime (as  sodium salt). Net price 250-mg vial = 94p; 750-mg vial  = £2.34; 1.5-g vial = £4.70   Tablets, both f/c, cefuroxime (as axetil) 125 mg, net  price 14-tab pack = £4.56; 250 mg, 14-tab pack =  £9.11. Label: 9, 21, 25   Suspension, cefuroxime (as axetil) 125 mg/5 mL  when reconstituted with water, net price 70 mL (tutti-  frutti-flavoured) = £5.20. Label: 9, 21   The carbapenems are beta-lactam antibacterials with a  broad-spectrum of activity which includes many Gram-  positive and Gram-negative bacteria, and anaerobes;  imipenem, meropenem, and doripenem have good  activity against Pseudomonas aeruginosa. The carba-  penems are not active against meticillin-resistant Sta-  phylococcus aureus and Enterococcus faecium.   Imipenem and meropenem are used for the treatment of  severe hospital-acquired infections and polymicrobial  infections including septicaemia, hospital-acquired  pneumonia, intra-abdominal infections, skin and soft-  tissue infections, and complicated urinary-tract infec-  tions. Doripenem is an alternative for hospital-acquired  pneumonia, complicated intra-abdominal infections,  and complicated urinary-tract infections.   Ertapenem is licensed for treating abdominal and  gynaecological infections and for community-acquired  pneumonia, but it is not active against atypical respir-  atory pathogens and it has limited activity against peni-  cillin-resistant pneumococci. It is also licensed for treat-  ing foot infections of the skin and soft tissue in patients  with diabetes. Unlike the other carbapenems, ertape-  nem is not active against Pseudomonas or against  Acinetobacter spp.   Imipenem is partially inactivated in the kidney by enzy-  matic activity and is therefore administered in combina-  tion with cilastatin, a specific enzyme inhibitor, which  blocks its renal metabolism. Meropenem, doripenem,    and ertapenem are stable to the renal enzyme which  inactivates imipenem and therefore can be given with-  out cilastatin.   Side-effects of imipenem with cilastatin are similar to  those of other beta-lactam antibiotics; neurotoxicity has  been observed at very high dosage, in renal failure, or in  patients with CNS disease. Ertapenem has been asso-  ciated with seizures uncommonly. Meropenem has less  seizure-inducing potential and can be used to treat  central nervous system infection.   Cautions sensitivity to beta-lactam antibacterials  (avoid if history of immediate hypersensitivity reac-  tion, see also p. 332); interactions: Appendix 1 (dor-  ipenem)   Renal impairment 250 mg every 8 hours if eGFR 30-  50mL/minute/1.73m 2 ; 250 mg every 12 hours if  eGFR less than 30 mL/minute/ 1.73 m 2  Pregnancy manufacturer advises avoid unless essen-  tial — no information available  Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — present in milk in  animal studies   Side-effects nausea, diarrhoea; headache; phlebitis,  pruritus, rash; less commonly antibiotic-associated  colitis, thrombocytopenia, neutropenia; also reported,  toxic epidermal necrolysis, and Stevens- Johnson  syndrome  Dose   • By intravenous infusion, ADULT over 18 years, 500 mg  every 8 hours; max. duration of treatment 14 days   Doribax® Oanssen-Cilag) ▼ (Ml  Intravenous infusion, powder for reconstitution,  doripenem (as monohydrate), net price 500-mg vial =  £14.52   The Scottish Medicines Consortium (p. 4) has advised (February  2009) that doripenem ( Doribax JS ) is not recommended for use  within NHS Scotland for the treatment of complicated urinary-  tract infections.   Indications abdominal infections; acute gynaecologi-  cal infections; community-acquired pneumonia; dia-  betic foot infections of the skin and soft-tissue;  prophylaxis for colorectal surgery  Cautions sensitivity to beta-lactam antibacterials  (avoid if history of immediate hypersensitivity reac-  tion, see also p. 332); elderly, CNS disorders — risk of  seizures; interactions: Appendix 1 (ertapenem)  Renal impairment risk of seizures; max. 500 mg daily  if eGFR less than 30 mL/minute/ 1.73 m 2  Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk  Breast-feeding present in milk — manufacturer  advises avoid   Side-effects diarrhoea, nausea, vomiting, headache,  injection-site reactions, rash (also reported with  eosinophilia and systemic symptoms), pruritus, raised  platelet count; less commonly dry mouth, taste dis-  turbances, dyspepsia, abdominal pain, anorexia, con-  stipation, melaena, antibiotic-associated colitis,  bradycardia, hypotension, chest pain, oedema, phar-  yngeal discomfort, dyspnoea, dizziness, sleep distur-    bances, confusion, asthenia, seizures, raised glucose,  petechiae; rarely dysphagia, cholecystitis, liver disor-  der (including jaundice), arrhythmia, increase in blood  pressure, syncope, nasal congestion, cough, wheez-  ing, anxiety, depression, agitation, tremor, pelvic  peritonitis, renal impairment, muscle cramp, scleral  disorder, blood disorders (including neutropenia,  thrombocytopenia, haemorrhage), hypoglycaemia,  electrolyte disturbances; also reported hallucinations,  dyskinesia  Dose   • By intravenous infusion, ADULT and ADOLESCENT over  13 years, 1 g once daily; CHILD 3 months-13 years,   Surgical prophylaxis, colorectal surgery, ADULT over 18  years, 1 g completed within 1 hour before surgery   Intravenous infusion, powder for reconstitution,  ertapenem (as sodium salt), net price 1-g vial = £31.65    Indications aerobic and anaerobic Gram-positive and  Gram-negative infections; surgical prophylaxis; hos-  pital-acquired septicaemia (Table 1, section 5.1); not  indicated for CNS infections  Cautions sensitivity to beta-lactam antibacterials  (avoid if history of immediate hypersensitivity reac-  tion, see also p. 332); CNS disorders (e.g. epilepsy);  interactions: Appendix 1 (imipenem with cilastatin)  Renal impairment risk of CNS side-effects; reduce  dose if eGFR less than 70 mL/minute/ 1.73 m 2 —  consult product literature   Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk (toxicity in animal studies)  Breast-feeding present in milk but unlikely to be  absorbed (however, manufacturer advises avoid)  Side-effects nausea, vomiting, diarrhoea (antibiotic-  associated colitis reported), taste disturbances, tooth  or tongue discoloration, hearing loss; blood disorders,  positive Coombs’ test; allergic reactions (with rash,  pruritus, urticaria, Stevens- Johnson syndrome, fever,  anaphylactic reactions, rarely toxic epidermal necro-  lysis, exfoliative dermatitis); myoclonic activity, con-  vulsions, confusion and mental disturbances reported;  slight increases in liver enzymes and bilirubin  reported, rarely hepatitis; increases in serum creat-  inine and blood urea; red coloration of urine in chil-  dren reported; local reactions: erythema, pain and  induration, and thrombophlebitis   • By intravenous infusion, in terms of imipenem, 1-2 g  daily (in 3-4 divided doses); less sensitive organisms,  up to 50 mg/kg daily (max. 4 g daily) in 3-4 divided  doses; CHILD 3 months and older, 60 mg/kg (max. 2 g)  daily in 4 divided doses; over 40 kg, adult dose  Surgical prophylaxis, 1 g up to 30 minutes before the  procedure, repeated after 3 hours, supplemented in  high risk (e.g. colorectal) surgery by doses of 500 mg 8  and 16 hours after initial dose   Intravenous infusion, powder for reconstitution,  imipenem (as monohydrate) 500 mg with cilastatin (as  sodium salt) 500 mg, net price per vial = £12.00   Indications aerobic and anaerobic Gram-positive and  Gram-negative infections (see notes above); hospital-  acquired septicaemia (Table 1, section 5.1)   Cautions sensitivity to beta-lactam antibacterials  (avoid if history of immediate hypersensitivity reac-  tion, see also p. 332); interactions: Appendix 1  (meropenem)   Hepatic impairment monitor liver function  Renal impairment use normal dose every 12 hours if  eGFR 26-50 mL/minute/ 1.73 m 2 ; use half normal  dose every 12 hours if eGFR 10-25 mL/minute/   1.73 m 2 ; use half normal dose every 24 hours if eGFR  less than 10 mL/minute/ 1.73 m 2  Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding unlikely to be absorbed (however,  manufacturer advises avoid unless potential benefit  justifies potential risk)   Side-effects nausea, vomiting, diarrhoea (antibiotic-  associated colitis reported), abdominal pain, distur-  bances in liver function tests, headache, thrombo-  cythaemia, rash, pruritus; less commonly paraes-  thesia, eosinophilia, thrombocytopenia, leucopenia;  rarely convulsions; also reported haemolytic anaemia,  positive Coombs’ test, Stevens- Johnson syndrome,  toxic epidermal necrolysis  Dose   • By intravenous injection over 5 minutes or by intra-  venous infusion, 0.5-1 g every 8 hours; CHILD 3   B months- 12 years 10-20 mg/kg every 8 hours, body-  weight over 50 kg, adult dose  • Exacerbations of chronic lower respiratory-tract  infection in cystic fibrosis, meningitis, by intravenous  infusion, 2g every 8 hours; CHILD 3 months-12 years  40 mg/kg every 8 hours, body-weight over 50 kg,  adult dose   Meronem® (AstraZeneca) (Ml  Injection, powder for reconstitution, meropenem (as  trihydrate), net price 500-mg vial = £8.60; 1-g vial =  £17.19    Aztreonam is a monocyclic beta-lactam (‘monobac-  tam’) antibiotic with an antibacterial spectrum limited  to Gram-negative aerobic bacteria including Pseudo-  monas aeruginosa. Neisseria meningitidis, and Haemo-  philus influenzae ; it should not be used alone for ‘blind’  treatment since it is not active against Gram-positive  organisms. Aztreonam is also effective against Neisseria  gonorrhoeae (but not against concurrent chlamydial  infection). Side-effects are similar to those of the other  beta-lactams although aztreonam may be less likely to  cause hypersensitivity in penicillin-sensitive patients.    Aztreonam may be administered by nebuliser for the  treatment of chronic Ps. aeruginosa infection in cystic  fibrosis.   Indications Gram-negative infections including  Pseudomonas aeruginosa, Haemophilus influenzae,  and Neisseria meningitidis   Specific cautions for inhaled treatment Other inhaled  drugs should be administered before aztreonam; a bronch-  odilator should be administered before each dose   1.73 m 2 , usual initial dose of injection, then half nor-  mal dose; if eGFR less than 10 mL/minute/ 1.73 m 2 ,  usual initial dose of injection, then one-quarter normal  dose   Specific side-effects for parenteral treatment Nausea,  vomiting, diarrhoea, abdominal cramps; mouth ulcers,  altered taste; jaundice and hepatitis; flushing; hypersensi-  tivity reactions; blood disorders (including thrombocytope-  nia and neutropenia); rashes, injection-site reactions; rarely  hypotension, seizures, asthenia, confusion, dizziness, head-  ache, halitosis, and breast tenderness; very rarely antibiotic-  associated colitis, gastro-intestinal bleeding, and toxic epi-  dermal necrolysis   Specific side-effects for inhaled treatment Wheezing,  bronchospasm, cough; pyrexia; rash; rhinorrhoea, pharyn-  golaryngeal pain   • By deep intramuscular injection or by intravenous  injection over 3-5 minutes or by intravenous infusion,  1 g every 8 hours or 2 g every 12 hours; 2 g every 6-8  hours for severe infections (including systemic  Pseudomonas aeruginosa and lung infections in  cystic fibrosis); single doses over 1 g intravenous route  only   • CHILD over 1 week, by intravenous injection or infu-  sion, 30 mg/kg every 6-8 hours increased in severe  infections for child of 2 years or older to 50 mg/kg  every 6-8 hours; max. 8 g daily   • Gonorrhoea, cystitis, by intramuscular injection, 1 g  as a single dose   • Chronic pulmonary Pseudomonas aeruginosa infec-  tion in patients with cystic fibrosis, by inhalation of  nebulised solution, ADULT over 18 years, 75 mg 3  times daily (at least 4 hours apart) for 28 days; if  additional courses required, a minimum of 28 days  without aztreonam nebuliser solution recommended  between courses   Injection, powder for reconstitution, aztreonam, net  price 1-g vial = £9.40; 2-g vial = £18.82   Powder for nebuliser solution, aztreonam (as lysine),  net price 84 x 75 mg vials (with solvent and nebuliser  handset) = £2566.50   The tetracyclines are broad-spectrum antibiotics whose  value has decreased owing to increasing bacterial resis-  tance. They remain, however, the treatment of choice    for infections caused by chlamydia (trachoma, psitta-  cosis, salpingitis, urethritis, and lymphogranuloma  venereum), rickettsia (including Q-fever), brucella (dox-  ycycline with either streptomycin or rifampicin), and the  spirochaete, Borrelia burgdorferi (Lyme disease — see  section 5. 1.1.3). They are also used in respiratory and  genital mycoplasma infections, in acne, in destructive  (refractory) periodontal disease, in exacerbations of  chronic bronchitis (because of their activity against  Haemophilus influenzae), and for leptospirosis in peni-  cillin hypersensitivity (as an alternative to erythro-  mycin).   For the role of tetracyclines in the management of  meticillin-resistant Staphylococcus aureus (MRSA)  infection, see p. 334.   Microbiologically, there is little to choose between the  various tetracyclines, the only exception being mino-  cycline which has a broader spectrum; it is active  against Neisseria meningitidis and has been used for  meningococcal prophylaxis but is no longer recom-  mended because of side-effects including dizziness  and vertigo (see section 5.1, table 2 for current recom-  mendations). Compared to other tetracyclines, mino-  cycline is associated with a greater risk of lupus-erythe-  matosus-like syndrome. Minocycline sometimes causes  irreversible pigmentation.   Oral infections In adults, tetracyclines can be effec-  tive against oral anaerobes but the development of  resistance (especially by oral streptococci) has reduced  their usefulness for the treatment of acute oral infec-  tions; they may still have a role in the treatment of  destructive (refractory) forms of periodontal disease.  Doxycycline has a longer duration of action than tetra-  cycline or oxytetracycline and need only be given once  daily; it is reported to be more active against anaerobes  than some other tetracyclines.   For the use of doxycycline in the treatment of recurrent  aphthous ulceration, oral herpes, or as an adjunct to  gingival scaling and root planing for periodontitis, see  section 12.3.1 and section 12.3.2.   Cautions Tetracyclines may increase muscle weakness  in patients with myasthenia gravis, and exacerbate sys-  temic lupus erythematosus. Antacids, and aluminium,  calcium, iron, magnesium and zinc salts decrease the  absorption of tetracyclines; milk also reduces the  absorption of demeclocycline, oxytetracycline, and  tetracycline. Other interactions: Appendix 1 (tetracy-  clines).   Contra-indications Deposition of tetracyclines in  growing bone and teeth (by binding to calcium) causes  staining and occasionally dental hypoplasia, and they  should not be given to children under 12 years, or to  pregnant or breast-feeding women. However, doxycy-  cline may be used in children for treatment and post-  exposure prophylaxis of anthrax when an alternative  antibacterial cannot be given [unlicensed indication], Te-  tracyclines should not be given to patients with acute  porphyria (section 9.8.2).   Hepatic impairment Tetracyclines should be avoided  or used with caution in patients with hepatic impair-  ment. Tetracyclines should also be used with caution in  those receiving potentially hepatotoxic drugs.   Renal impairment With the exception of doxycycline  and minocycline, the tetracyclines may exacerbate    renal failure and should not be given to patients with  renal impairment.   Pregnancy Tetracyclines should not be given to  pregnant women. Effects on skeletal development  have been documented when tetracyclines have been  used in the first trimester of pregnancy in animal  studies. Administration during the second or third tri-  mester may cause discoloration of the child’s teeth, and  maternal hepatotoxicity has been reported with large  parenteral doses.   Breast-feeding Tetracyclines should not be given to  women who are breast-feeding (although absorption  and therefore discoloration of teeth in the infant is  probably usually prevented by chelation with calcium  in milk).   Side-effects Side-effects of the tetracyclines include  nausea, vomiting, diarrhoea (antibiotic-associated col-  itis reported occasionally), dysphagia, and oesophageal  irritation. Other rare side-effects include hepatotoxicity,  pancreatitis, blood disorders, photosensitivity (particu-  larly with demeclocycline), and hypersensitivity reac-  tions (including rash, exfoliative dermatitis, Stevens-  Johnson syndrome, urticaria, angioedema, anaphylaxis,  pericarditis). Headache and visual disturbances may  indicate benign intracranial hypertension (discontinue  treatment); bulging fontanelles have been reported in  infants.   • 250 mg every 6 hours, increased in severe infections  to 500 mg every 6-8 hours   • Non-gonococcal urethritis, 500 mg every 6 hours for  7-14 days (21 days if failure or relapse after first  course)    Tetracycline (Non-proprietary) (Ml  Tablets, coated, tetracycline hydrochloride 250 mg,  net price 28-tab pack = £13.67. Label: 7, 9, 23,  counselling, posture   Cautions see notes above, but photosensitivity more  common (avoid exposure to sunlight or sun lamps)    Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also reversible nephro-  genic diabetes insipidus, acute renal failure   • 150 mg every 6 hours or 300 mg every 12 hours   Ledermycin® (Goldshield) (Ml  Capsules, red, demeclocycline hydrochloride 150 mg,  net price 28-cap pack = £16.02. Label: 7, 9, 11, 23    Indications see notes above; chronic prostatitis;  sinusitis, syphilis, pelvic inflammatory disease (Table  1, section 5.1); treatment and prophylaxis of anthrax  [unlicensed indication]; malaria treatment and  prophylaxis (section 5.4.1); recurrent aphthous ulcer-  ation, adjunct to gingival scaling and root planing for  periodontitis (section 12.3.1); oral herpes simplex  (section 12.3.2); rosacea, acne vulgaris (section 13.6)  Cautions see notes above; alcohol dependence;  photosensitivity reported (avoid exposure to sunlight  or sun lamps)   Breast-feeding see notes above  Side-effects see notes above; also anorexia, dry  mouth, flushing, anxiety, and tinnitus    • 200 mg on first day, then 100 mg daily; severe infec-  tions (including refractory urinary-tract infections),  200 mg daily   • Early syphilis, 100 mg twice daily for 14 days; late  latent syphilis, 100 mg twice daily for 28 days; neu-  rosyphilis, 200 mg twice daily for 28 days   • Uncomplicated genital chlamydia, non-gonococcal  urethritis, 100 mg twice daily for 7 days (14 days in  pelvic inflammatory disease, see also Table 1, section  5.1)   • Lyme disease (see also section 5. 1.1.3), 100 mg twice  daily for 10-14 days (28 days in Lyme arthritis)   • Anthrax (treatment or post-exposure prophylaxis; see  also section 5.1.12), 100 mg twice daily; CHILD (only if  alternative antibacterial cannot be given) [unlicensed  dose] 5 mg/kg daily in 2 divided doses (max. 200 mg  daily)   Counselling Capsules should be swallowed whole with plenty  of fluid during meals while sitting or standing  Note Doxycycline doses in BNF may differ from those in  product literature    Doxycycline (Non-proprietary) (Ml  Capsules, doxycycline (as hyclate) 50 mg, net price  28-cap pack = £1.79; 100 mg, 8-cap pack = £1.16.  Label: 6, 9, 11, 27, counselling, posture  Brands include Doxylar ®   Dental prescribing on NHS Doxycycline Capsules 100 mg may  be prescribed    Vibramycin-D® (Pfizer) (Ml  Dispersible tablets, yellow, scored, doxycycline  100 mg, net price 8-tab pack = £4.91. Label: 6, 9, 11,  13   Capsules, m/r, beige, doxycycline (as monohydrate)  40 mg, net price 56-cap pack = £29.78. Label: 6, 11,  27, counselling, posture   Dose papulopustular, facial rosacea (without ocular involve-  ment), 40 mg daily in the morning for 16 weeks; consider dis-  continuing treatment if no response after 6 weeks   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • 408 mg every 12 hours, increased to 1.224-1.632 g  daily in severe infections   Capsules, red/yellow, lymecycline 408 mg (= tetra-  cycline 300 mg), net price 28-cap pack = £7.77, 56-cap  pack = £14.97. Label: 6, 9   Cautions see notes above; if treatment continued for  longer than 6 months, monitor every 3 months for  hepatotoxicity, pigmentation and for systemic lupus  erythematosus — discontinue if these develop or if  pre-existing systemic lupus erythematosus worsens  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment use with caution (avoid excessive  doses)   Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also dizziness and  vertigo (more common in women); rarely anorexia,  tinnitus, impaired hearing, hyperaesthesia, paraes-  thesia, acute renal failure, pigmentation (sometimes  irreversible), and alopecia; very rarely systemic lupus  erythematosus, discoloration of conjunctiva, tears,  and sweat  Dose   • Prophylaxis of asymptomatic meningococcal carrier  state (but no longer recommended, see notes above),  100 mg twice daily for 5 days usually followed by  rifampicin   Counselling Tablets or capsules should be swallowed whole  with plenty of fluid while sitting or standing   Capsules, minocycline (as hydrochloride) 50 mg, net  price 56-cap pack = £15.27; 100 mg, 28-cap pack =  £13.09. Label: 6, 9, counselling, posture  Brands include Aknemin ®    Tablets, minocycline (as hydrochloride) 50 mg, net  price 28-tab pack = £4.93, 100 mg, 28-tab pack =  £9.52. Label: 6, 9, counselling, posture   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   Oxytetracycline (Non-proprietary) (Ml  Tablets, coated, oxytetracycline dihydrate 250 mg,  net price 28-tab pack = £1.28. Label: 7, 9, 23  Brands include Oxymycin®   Tigecycline is a glycylcycline antibacterial structurally  related to the tetracyclines; side-effects similar to those  of the tetracyclines can potentially occur. Tigecycline is  active against Gram-positive and Gram-negative bacter-  ia, including tetracycline-resistant organisms, and some  anaerobes. It is also active against meticillin-resistant  Staphylococcus aureus and vancomycin-resistant enter-  ococci, but Pseudomonas aeruginosa and many strains  of Proteus spp are resistant to tigecycline. Tigecycline  should be reserved for the treatment of complicated  skin and soft-tissue infections and complicated abdo-  minal infections caused by multiple-antibacterial resis-  tant organisms; however, it is not recommended for the  treatment of foot infections in patients with diabetes.   Indications complicated intra-abdominal infections;  complicated skin and soft-tissue infections, but not  diabetic foot infections   Contra-indications hypersensitivity to tetracyclines  Hepatic impairment initially 100 mg then 25 mg  every 12 hours in severe impairment  Pregnancy see under Tetracyclines, p. 347  Breast-feeding manufacturer advises caution — pre-  sent in milk in animal studies  Side-effects see notes above; also nausea, vomiting,  abdominal pain, dyspepsia, diarrhoea, anorexia,  bilirubinaemia, dizziness, headache, prolonged  prothrombin time, prolonged activated partial    thromboplastin time, rash, pruritus, and injection-site  reactions; less commonly pancreatitis, cholestatic  jaundice, and hypoproteinaemia; also reported, anti-  biotic-associated colitis, hepatic failure, and throm-  bocytopenia   • By intravenous infusion, ADULT over 18 years, initially  100 mg, then 50 mg every 12 hours for 5-14 days   Intravenous infusion, powder for reconstitution,  tigecycline, net price 50-mg vial = £32.31   These include amikacin, gentamicin, neomycin, strepto-  mycin, and tobramycin. All are bactericidal and active  against some Gram-positive and many Gram-negative  organisms. Amikacin, gentamicin, and tobramycin are  also active against Pseudomonas aeruginosa', strepto-  mycin is active against Mycobacterium tuberculosis and  is now almost entirely reserved for tuberculosis (section  5.1.9).   The aminoglycosides are not absorbed from the gut  (although there is a risk of absorption in inflammatory  bowel disease and liver failure) and must therefore be  given by injection for systemic infections.   Most side-effects of this group of antibiotics are dose-  related therefore care must be taken with dosage and  whenever possible treatment should not exceed 7 days.  The important side-effects are ototoxicity, and nephro-  toxicity; they occur most commonly in the elderly and in  patients with renal failure.   Aminoglycosides may impair neuromuscular transmis-  sion and should not be given to patients with myas-  thenia gravis; large doses given during surgery have  been responsible for a transient myasthenic syndrome  in patients with normal neuromuscular function.  Aminoglycosides should preferably not be given with  potentially ototoxic diuretics (e.g. furosemide); if con-  current use is unavoidable administration of the amino-  glycoside and of the diuretic should be separated by as  long a period as practicable.   Renal impairment Excretion of aminoglycosides is  principally via the kidney and accumulation occurs in  renal impairment. Ototoxicity and nephrotoxicity occur  commonly in patients with renal failure. If there is  impairment of renal function, the interval between  doses must be increased; if the renal impairment is  severe, the dose itself should be reduced as well.  Serum-aminoglycoside concentrations must be moni-  tored in patients with renal impairment, see Serum  Concentrations below; renal, auditory, and vestibular  function should also be monitored. A once-daily, high-  dose regimen of an aminoglycoside should be avoided  in patients with a creatinine clearance less than 20 mL/  minute.   Once daily dosage Once daily administration of  aminoglycosides is more convenient, provides adequate  serum concentrations, and in many cases has largely  superseded multiple daily dose regimens (given in 2-3  divided doses during the 24 hours). Local guidelines on  dosage and serum concentrations should be consulted.  A once-daily, high-dose regimen of an aminoglycoside    should be avoided in patients with endocarditis, burns of  more than 20% of the total body surface area, or creat-  inine clearance less than 20 mL/minute.   Serum concentrations Serum concentration moni-  toring avoids both excessive and subtherapeutic con-  centrations thus preventing toxicity and ensuring effi-  cacy. In patients with normal renal function,  aminoglycoside concentrations should be measured  after 3 or 4 doses of a multiple daily dose regimen;  patients with renal impairment may require earlier and  more frequent measurement of aminoglycoside concen-  tration.   For multiple daily dose regimens, blood samples should  be taken approximately 1 hour after intramuscular or  intravenous administration (‘peak’ concentration) and  also just before the next dose (‘trough’ concentration). If  the pre-dose (‘trough’) concentration is high, the interval  between doses must be increased. If the post-dose  (‘peak’) concentration is high, the dose must be  decreased. For once daily dose regimens, consult local  guidelines on serum concentration monitoring.   Serum-aminoglycoside concentrations should be mea-  sured in all patients and must be determined in infants,  in the elderly, in obesity, and in cystic fibrosis, or if high  doses are being given, or if there is renal impairment.   Endocarditis Gentamicin is used in combination with  other antibiotics for the treatment of bacterial endo-  carditis (Table 1, section 5.1). Serum-gentamicin con-  centration should be determined twice each week (more  often in renal impairment). Streptomycin may be used  as an alternative in gentamicin-resistant enterococcal  endocarditis.    Gentamicin is the aminoglycoside of choice in the UK  and is used widely for the treatment of serious infec-  tions. It has a broad spectrum but is inactive against  anaerobes and has poor activity against haemolytic  streptococci and pneumococci. When used for the  ‘blind’ therapy of undiagnosed serious infections it is  usually given in conjunction with a penicillin or metro-  nidazole (or both). Gentamicin is used together with  another antibiotic for the treatment of endocarditis (see  above and Table 1, section 5.1).   Loading and maintenance doses of gentamicin may be  calculated on the basis of the patient’s weight and renal  function (e.g. using a nomogram); adjustments are then  made according to serum-gentamicin concentrations.  High doses are occasionally indicated for serious infec-  tions, especially in the neonate, in the patient with cystic  fibrosis, or in the immunocompromised patient. When-  ever possible treatment should not exceed 7 days.  Amikacin is more stable than gentamicin to enzyme  inactivation. Amikacin is used in the treatment of ser-  ious infections caused by gentamicin-resistant Gram-  negative bacilli.   Tobramycin has similar activity to gentamicin. It is  slightly more active against Ps. aeruginosa but shows  less activity against certain other Gram-negative bacter-  ia. Tobramycin may be administered by nebuliser on a  cyclical basis (28 days of tobramycin followed by a 28-  day tobramycin-free interval) for the treatment of  chronic pulmonary Ps. aeruginosa infection in cystic  fibrosis; however, resistance may develop and some  patients do not respond to treatment.    Neomycin is too toxic for parenteral administration and  can only be used for infections of the skin or mucous  membranes or to reduce the bacterial population of the  colon prior to bowel surgery or in hepatic failure. Oral  administration may lead to malabsorption. Small  amounts of neomycin may be absorbed from the gut  in patients with hepatic failure and, as these patients  may also be uraemic, cumulation may occur with resul-  tant ototoxicity.   Pregnancy There is a risk of auditory or vestibular  nerve damage when aminoglycosides are used in the  second and third trimesters of pregnancy. The risk is  greatest with streptomycin (section 5.1.9). The risk is  probably very small with gentamicin and tobramycin,  but their use should be avoided unless essential (if given,  serum-aminoglycoside concentration monitoring is  essential).   Indications septicaemia and neonatal sepsis;  meningitis and other CNS infections; biliary-tract  infection, acute pyelonephritis or prostatitis, endo-  carditis (see notes above); pneumonia in hospital  patients, adjunct in listerial meningitis (Table 1, sec-  tion 5.1); eye (section 11.3.1); ear (section 12.1.1)  Cautions neonates, infants and elderly (adjust dose  and monitor renal, auditory and vestibular function  together with serum gentamicin concentrations);  avoid prolonged use; conditions characterised by  muscular weakness; see also notes above; interac-  tions: Appendix 1 (aminoglycosides)  Contra-indications myasthenia gravis  Renal impairment see notes above  Pregnancy see notes above  Side-effects vestibular and auditory damage,  nephrotoxicity; rarely, hypomagnesaemia on pro-  longed therapy, antibiotic-associated colitis, stomat-  itis; also reported, nausea, vomiting, rash, blood dis-  orders; see also notes above  Dose   ^To avoid excessive dosage in obese patients, use ideal  weight for height to calculate dose and monitor  serum-gentamicin concentration closely   • Multiple daily dose regimen, by intramuscular or by  slow intravenous injection over at least 3 minutes or  by intravenous infusion, 3-5 mg/kg daily (in divided  doses every 8 hours), see also notes above; CHILD  under 18 years see BNF for Children  Endocarditis (in combination with other antibac-  terials, see Table 1, section 5.1), ADULT 1 mg/kg every  8 hours; CHILD under 18 years see BNF for Children   • Once daily dose regimen (see notes above and also  consult local guidelines), by intravenous infusion,  initially 5-7 mg/kg, then adjust according to serum-  gentamicin concentration; CHILD under 18 years see  BNF for Children   • By intrathecal injection, seek specialist advice, lmg  daily (increased if necessary to 5 mg daily); only  preservative-free, intrathecal preparation should be  used; CHILD under 18 years see BNF for Children   Note For multiple daily dose regimen, one-hour (‘peak’) serum  concentration should be 5-10 mg/litre (3-5 mg/litre for endo-  carditis); pre-dose (‘trough’) concentration should be less than  2 mg/litre (less than 1 mg/litre for endocarditis). For once-daily  dose regimen, consult local guidelines on monitoring serum-  gentamicin concentration    Gentamicin (Non-proprietary) (5°M1  Injection, gentamicin (as sulphate), net price 40 mg/  mL, 1-mL amp = £1.40, 2-mL amp = £1.54, 2-mL vial  = £1.48   Paediatric injection, gentamicin (as sulphate) 10 mg/  mL, net price 2-mL vial = £1.80  Intrathecal injection, gentamicin (as sulphate) 5 mg/  mL, net price 1-mL amp = 74p  Intravenous infusion, gentamicin (as sulphate) 1 mg/  mL in sodium chloride intravenous infusion 0.9%, net  price 80-mL (80 mg) bottle = £1.95; 3mg/mL, 80-mL  (240 mg) bottle = £5.95, 120-mL (360 mg) bottle =  £8.45    Hepatic impairment absorbed from gastro-intestinal  tract in liver disease — increased risk of ototoxicity  Renal impairment avoid; ototoxic; nephrotoxic  Pregnancy see notes above  Side-effects see under Gentamicin but poorly  absorbed on oral administration; increased salivation,  stomatitis, impaired intestinal absorption with stea-  torrhoea and diarrhoea  Dose   • By mouth, pre-operative bowel sterilisation, 1 g every  hour for 4 hours, then 1 g every 4 hours for 2-3 days  Hepatic coma, up to 4 g daily in divided doses usually  for 5-7 days    Cidomycin® (Sanofi-Aventis) (mD  Injection, gentamicin (as sulphate) 40mg/mL. Net  price 2-mL amp or vial = £1.48  Genticin® (Amdipharm) (Ml  Injection, gentamicin (as sulphate) 40mg/mL. Net  price 2-mL amp = £1.40   800 micrograms/mL in sodium chloride intravenous  infusion 0.9%. Net price 100-mL (80-mg) Viaflex®  bag = £1.61   Contra-indications see under Gentamicin  Renal impairment see notes above  Pregnancy see notes above  Side-effects see under Gentamicin  Dose   To avoid excessive dosage in obese patients, use ideal  weight for height to calculate dose and monitor  serum-amikacin concentration closely    • By intramuscular or by slow intravenous injection or  by infusion, 15 mg/kg daily in 2 divided doses,  increased to 22.5 mg/kg daily in 3 divided doses in  severe infections; max. 1.5 g daily for up to 10 days  (max. cumulative dose 15 g); CHILD under 18 years see  BNF for Children   Note One-hour (‘peak’) serum concentration should not  exceed 30 mg/litre; pre-dose (‘trough’) concentration  should be less than 10 mg/litre   Amikacin (Non-proprietary) [Ml  Injection, amikacin (as sulphate) 250mg/mL. Net  price 2-mL vial = £10.14   Amikin® (Bristol-Myers Squibb) (Ml  Injection, amikacin (as sulphate) 50mg/mL. Net  price 2-mL vial = £2.07    Indications see under Gentamicin and notes above  Cautions see under Gentamicin; interactions:  Appendix 1 (aminoglycosides)   Specific cautions for inhaled treatment Other inhaled  drugs should be administered before tobramycin; monitor for  bronchospasm with initial dose, measure peak flow before  and after nebulisation — if bronchospasm occurs, repeat test  using bronchodilator; monitor renal function before treat-  ment and then annually; severe haemoptysis  Contra-indications see under Gentamicin    Renal impairment see notes above  Pregnancy see notes above  Side-effects see under Gentamicin; on inhalation,  mouth ulcers, taste disturbances, voice alteration,  cough, bronchospasm (see Cautions)   To avoid excessive dosage in obese patients, use ideal  weight for height to calculate parenteral dose and  monitor serum-tobramycin concentration closely    • By intramuscular injection or by slow intravenous  injection or by intravenous infusion, 3 mg/kg daily in  divided doses every 8 hours, see also notes above; in  severe infections up to 5 mg/kg daily in divided doses  every 6-8 hours (reduced to 3 mg/kg as soon as  clinically indicated); CHILD under 18 years see BNF for  Children   • Urinary-tract infection, by intramuscular injection, 2-  3 mg/kg daily as a single dose   • Chronic pulmonary Pseudomonas aeruginosa infec-  tion in patients with cystic fibrosis, by inhalation of  nebulised solution, ADULT and CHILD over 6 years,   300 mg every 12 hours for 28 days, subsequent  courses repeated after 28-day interval without tobra-  mycin nebuliser solution   Tobramycin (Non-proprietary) tMl  Injection, tobramycin (as sulphate) 40mg/mL, net  price 1-mL (40-mg) vial = £4.00, 2-mL (80-mg) vial =  £4.16, 6-mL (240-mg) vial = £19.20   Nebuliser solution, tobramycin 75 mg/mL, net price  56 x 4-mL (300-mg) unit = £1187.00   Nebuliser solution, tobramycin 60 mg/mL, net price  56 x 5-mL (300-mg) unit = £1187.20    Erythromycin has an antibacterial spectrum that is  similar but not identical to that of penicillin; it is thus  an alternative in penicillin-allergic patients.    Indications for erythromycin include respiratory infec-  tions, whooping cough, legionnaires’ disease, and  Campylobacter enteritis. It is active against many peni-  cillin-resistant staphylococci but some are now also  resistant to erythromycin; it has poor activity against  Haemophilus influenzae. Erythromycin is also active  against chlamydia and mycoplasmas.    Erythromycin causes nausea, vomiting, and diarrhoea in  some patients; in mild to moderate infections this can be  avoided by giving a lower dose (250 mg 4 times daily)  but if a more serious infection, such as Legionella pneu-  monia, is suspected higher doses are needed.   Azithromycin is a macrolide with slightly less activity  than erythromycin against Gram-positive bacteria but  enhanced activity against some Gram-negative organ-  isms including H. influenzae. Plasma concentrations are  very low but tissue concentrations are much higher. It  has a long tissue half-life and once daily dosage is  recommended. Azithromycin is also used in the treat-  ment of trachoma [unlicensed indication] (section  11.3.1).   Clarithromycin is an erythromycin derivative with  slightly greater activity than the parent compound.  Tissue concentrations are higher than with erythro-  mycin. It is given twice daily.    For the role of erythromycin, azithromycin, and  clarithromycin in the treatment of Lyme disease, see  section 5. 1.1.3    Oral infections Clarithromycin or erythromycin is an  alternative for oral infections in penicillin-allergic  patients or where a beta-lactamase producing organism  is involved. However, many organisms are now resistant  to macrolides or rapidly develop resistance; their use  should therefore be limited to short courses. Metronid-  azole (section 5.1.1 1) may be preferred as an alternative  to a penicillin.    Cautions Macrolides should be used with caution in  patients with a predisposition to QT interval prolonga-  tion (including electrolyte disturbances and concomi-  tant use of drugs that prolong the QT interval).    Side-effects Nausea, vomiting, abdominal discomfort,  and diarrhoea are the most common side-effects of the  macrolides, but they are mild and less frequent with  azithromycin and clarithromycin than with erythro-  mycin. Hepatotoxicity (including cholestatic jaundice)  and rash occur less frequently. Other side-effects  reported rarely or very rarely include pancreatitis, anti-  biotic-associated colitis, QT interval prolongation,  arrhythmias, generally reversible hearing loss (some-  times with tinnitus) after large doses, Stevens- Johnson  syndrome, and toxic epidermal necrolysis. Intravenous  infusion may cause local tenderness and phlebitis.   Indications respiratory-tract infections; otitis media;  skin and soft-tissue infections; uncomplicated genital  chlamydial infections and non-gonococcal urethritis  (Table 1, section 5.1); mild or moderate typhoid due to  multiple-antibacterial-resistant organisms [unlicensed  indication]; Lyme disease (see also section 5. 1.1.3  [unlicensed indication]); prophylaxis of group A  streptococcal infection (Table 2, section 5.1)   Renal impairment use with caution if eGFR less than  1 0 mL/minute/ 1.73 m 2   Side-effects see notes above; also anorexia, dys-  pepsia, flatulence, dizziness, headache, drowsiness,  convulsions, arthralgia, and disturbances in taste and  smell; rarely constipation, syncope, insomnia, agita-  tion, anxiety, asthenia, paraesthesia, hyperactivity,  thrombocytopenia, haemolytic anaemia, interstitial  nephritis, acute renal failure, photosensitivity, tooth  and tongue discoloration  Dose   • 500 mg once daily for 3 days or 500 mg on first day  then 250 mg once daily for 4 days; CHILD over 6  months 10 mg/kg once daily for 3 days; or body-  weight 15-25 kg, 200 mg once daily for 3 days; body-  weight 26-35 kg, 300 mg once daily for 3 days; body-  weight 36-45 kg, 400 mg once daily for 3 days   • Uncomplicated genital chlamydial infections and non-  gonococcal urethritis, 1 g as a single dose   • Lyme disease (see also section 5. 1.1.3), typhoid  [unlicensed indications], 500 mg once daily for 7-10  days (7 days in typhoid)   Capsules, azithromycin (as dihydrate) 250 mg, net  price 4-cap pack = £9.82, 6-cap pack = £14.73.   Tablets, azithromycin (as monohydrate hemi-etha-  nolate) 250 mg, net price 4-tab pack = £9.83; 500 mg,  3-tab pack = £6.75. Label: 5, 9  Note Azithromycin tablets can be sold to the public for the  treatment of confirmed, asymptomatic Chlamydia tracho-  matis genital infection in those over 16 years of age, and for  the epidemiological treatment of their sexual partners, sub-  ject to max. single dose of 1 g, max. daily dose 1 g, and a pack  size of 1 g   200 mg/ 5 mL when reconstituted with water, net  price 15-mL pack = £5.86, 30-mL pack = £11.04.  Label: 5, 9   Capsules, azithromycin (as dihydrate) 250 mg, net  price 4-cap pack = £7.16, 6-cap pack = £10.74.   Oral suspension, cherry /banana-flavoured, azithro-  mycin (as dihydrate) 200 mg/ 5 mL when reconsti-  tuted with water. Net price 15-mL pack = £4.06, 22.5-  mL pack = £6.10, 30-mL pack = £11.04. Label: 5, 9   Indications respiratory-tract infections, mild to mod-  erate skin and soft-tissue infections, otitis media;  Lyme disease (see also section 5. 1.1.3); Helicobacter  pylori eradication (section 1.3)   Renal impairment use half normal dose if eGFR less  than 30 mL/minute/ 1.73 m 2 ; avoid Klaricid XL® if  eGFR less than 30 mL/minute/ 1.73 m 2   Side-effects see notes above; also tooth and tongue  discoloration, smell and taste disturbances, stomatitis,  glossitis, and headache; less commonly arthralgia and  myalgia; rarely tinnitus; very rarely dizziness, insom-  nia, nightmares, anxiety, confusion, psychosis,  paraesthesia, convulsions, hypoglycaemia, renal fail-  ure, interstitial nephritis, leucopenia, and thrombocy-  topenia   • By mouth, ADULT and CHILD over 12 years, 250 mg  every 12 hours for 7 days, increased in pneumonia or  severe infections to 500 mg every 12 hours for up to  14 days (see also Table 1, section 5.1); CHILD body-  weight under 8 kg, 7.5 mg/kg twice daily; 8-1 1 kg,  62.5 mg twice daily; 12-19 kg, 125 mg twice daily; 20-  29 kg, 187.5 mg twice daily; 30-40 kg, 250 mg twice  daily   Lyme disease (see also section 5. 1.1. 3), ADULT and  CHILD over 12 years, 500 mg every 12 hours for 14-21  days [unlicensed duration]; CHILD 1 month-12 years  see BNF for Children   • By intravenous infusion into larger proximal vein,  ADULT and CHILD over 12 years, 500 mg twice daily;  CHILD 1 month-12 years see BNF for Children   Clarithromycin (Non-proprietary) (Ml  Tablets, clarithromycin 250 mg, net price 14-tab pack  = £3.17; 500 mg, 14-tab pack = £4.10. Label: 9  Dental prescribing on NHS Clarithromycin Tablets maybe  prescribed   Oral suspension, clarithromycin for reconstitution  with water 125 mg/5 mL, net price 70 mL = £6.18;  250 mg/5 mL, 70 mL = £12.36. Label: 9  Dental prescribing on NHS Clarithromycin Oral Suspen-  sion may be prescribed   Tablets, both yellow, f/c, clarithromycin 250 mg, net  price 14-tab pack = £6.30; 500 mg, 14-tab pack =  £10.17, 20-tab pack = £14.54. Label: 9  Paediatric suspension, clarithromycin for reconsti-  tution with water 125 mg/ 5 mL, net price 70 mL =  £4.73, 100 mL = £8.14; 250 mg/5 mL, 70 mL = £9.46.  Label: 9   Granules, clarithromycin 250 mg/sachet, net price  14-sachet pack = £11.68. Label: 9, 13  Intravenous infusion, powder for reconstitution,  clarithromycin. Net price 500-mg vial = £9.45   Tablets, m/r, yellow, clarithromycin 500 mg, net price  7-tab pack = £6.46, 14-tab pack = £12.71. Label: 9, 21,  25   Dose 500 mg once daily (doubled in severe infections) for 7-14  days    Indications susceptible infections in patients with  penicillin hypersensitivity; oral infections (see notes  above); Campylobacter enteritis, syphilis, non-gono-  coccal urethritis, respiratory-tract infections (includ-  ing Legionella infection), skin infections (Table 1,  section 5.1); chronic prostatitis; prophylaxis of diph-  theria, group A streptococcal infection, and whooping  cough (Table 2, section 5.1); acne vulgaris and rosa-  cea (section 13.6)   Cautions see notes above; neonate under 2 weeks (risk  of hypertrophic pyloric stenosis); avoid in acute por-  phyria (section 9.8.2); interactions: Appendix 1  (macrolides)   Renal impairment max. 1.5 g daily in severe renal  impairment (ototoxicity)   Breast-feeding only small amounts in milk — not  known to be harmful   • By mouth, ADULT and CHILD over 8 years, 250-500 mg  every 6 hours or 0.5-1 g every 12 hours (see notes  above); up to 4 g daily in divided doses in severe  infections; NEONATE 12.5 mg/kg every 6 hours; CHILD 1  month-2 years 125 mg every 6 hours, 2-8 years  250 mg every 6 hours, doses doubled for severe  infections   Early syphilis, 500 mg 4 times daily for 14 days  Uncomplicated genital chlamydia, non-gonococcal  urethritis, 500 mg twice daily for 14 days  Lyme disease (see also section 5. 1.1.3), 500 mg 4  times daily for 14-21 days  • By intravenous infusion, ADULT and CHILD severe  infections, 12.5 mg/kg every 6 hours; mild infections  (when oral treatment not possible), 6.25 mg/kg every  6 hours; NEONATE see BNF for Children    Erythromycin (Non-proprietary) (Ml  Capsules, enclosing e/c microgranules, erythromycin  250 mg, net price 28-cap pack = £1 5.00. Label: 5, 9, 25  Brands include Tiloryth ®    Erythromycin Ethyl Succinate (Non-proprietary) (Ml  Oral suspension, erythromycin (as ethyl succinate)  for reconstitution with water 125 mg/ 5 mL, net price  100 mL = £1.99; 250 mg/5 mL, 100 mL = £2.64;   Dental prescribing on NHS Erythromycin Ethyl Succinate  Oral Suspension may be prescribed    Erythromycin Lactobionate (Non-proprietary) ®  Intravenous infusion, powder for reconstitution,  erythromycin (as lactobionate), net price 1-g vial =  £9.98   Capsules, opaque orange/clear orange, enclosing  orange and white e/c pellets, erythromycin 250 mg,  net price 28-cap pack = £5.61, 112-cap pack = £22.44.  Label: 5, 9, 25   Dose 1 capsule every 6 hours or 2 capsules every 12 hours; acne,  1 capsule twice daily for 1 month then 1 capsule daily   Erythrocin® (Amdipharm) (Ml  Tablets, both f/c, erythromycin (as stearate), 250 mg,  net price 100 =£18.20; 500 mg, 100 = £36.40. Label: 9  Dental prescribing on NHS Maybe prescribed as Erythro-  mycin Stearate Tablets   Erythroped® (Amdipharm) (Ml  Suspension SF, sugar-free, banana-flavoured,  erythromycin (as ethyl succinate) for reconstitution  with water, 125 mg/5 mL ( Suspension PI SF), net  price 140 mL = £3.06; 250 mg/5 mL, 140 mL = £5.95;  500 mg/ 5 mL ( Suspension SF Forte), 140 mL =  £10.56. Label: 9   The ketolide telithromycin is a derivative of erythro-  mycin. The antibacterial spectrum of telithromycin is  similar to that of macrolides and it is also active against  penicillin- and erythromycin-resistant Streptococcus  pneumoniae. Telithromycin should only be used to  treat beta-haemolytic streptococcal pharyngitis and  tonsillitis, sinusitis, community-acquired pneumonia,  and exacerbations of chronic bronchitis if caused by  organisms resistant to beta-lactam antibacterials and  other macrolides, or if conventional treatment is con-  tra-indicated.   Indications see notes above  Cautions coronary heart disease, ventricular arrhyth-  mias, bradycardia, hypokalaemia, hypomagnes-  aemia — risk of QT interval prolongation; concomitant  administration of drugs that prolong QT-interval;  avoid in acute porphyria (section 9.8.2); interactions:  Appendix 1 (telithromycin)   Hepatic disorders Patients should be told how to recognise  signs of liver disorder, and advised to discontinue treatment  and seek prompt medical attention if symptoms such as  anorexia, nausea, vomiting, abdominal pain, jaundice, or  dark urine develop   Driving Visual disturbances or transient loss of conscious-  ness may affect performance of skilled tasks (e.g. driving);  effects may occur after the first dose. Administration at  bedtime may reduce these side-effects. Patients should be  advised not to drive or operate machinery if affected  Contra-indications myasthenia gravis; history of teli-  thromycin-associated hepatitis or jaundice; prolon-  gation of QT interval; congenital or family history of  QT interval prolongation (if not excluded by ECG)  Hepatic impairment manufacturer advises caution;  see also Hepatic Disorders above    Renal impairment manufacturer advises avoid if  possible if eGFR less than 30 mL/minute/1.73 m 2 — if  no alternative, use alternating daily doses of 800 mg  and 400 mg, starting with 800 mg dose   Pregnancy toxicity in animal studies — manufacturer  advises use only if potential benefit outweighs risk   Side-effects diarrhoea, nausea, vomiting, flatulence,  abdominal pain, taste disturbances; dizziness, head-  ache; less commonly constipation, stomatitis, ano-  rexia, hepatitis, flushing, palpitations, drowsiness,  insomnia, nervousness, eosinophilia, blurred vision,  rash, urticaria, and pruritus; rarely cholestatic jaun-  dice, arrhythmias, hypotension, transient loss of con-  sciousness, paraesthesia, and diplopia; very rarely  antibiotic-associated colitis, altered sense of smell,  muscle cramp, erythema multiforme; also reported  pancreatitis, confusion, hallucinations and arthralgia  Dose   • 800 mg once daily for 5 days for sinusitis or exacer-  bation of chronic bronchitis or for 7-10 days in  community-acquired pneumonia; CHILD under 18  years safety and efficacy not established   • Tonsillitis or pharyngitis caused by Streptococcus  pyogenes, ADULT and CHILD over 12 years, 800 mg once  daily for 5 days   Ketek® (Sanofi-Aventis) ▼ [Ml  Tablets, orange, f/c, telithromycin 400 mg, net price  10-tab pack = £18.56. Label: 9, counselling , driving,  hepatic disorders    Clindamycin is active against Gram-positive cocci,  including streptococci and penicillin-resistant staphylo-  cocci, and also against many anaerobes, especially Bac-  teroides fragilis. It is well concentrated in bone and  excreted in bile and urine.    Clindamycin is recommended for staphylococcal joint  and bone infections such as osteomyelitis, and intra-  abdominal sepsis; it is an alternative to macrolides for  erysipelas or cellulitis in penicillin-allergic patients.  Clindamycin can also be used for infections associated  with meticillin-resistant Staphylococcus aureus (MRSA)  in bronchiectasis, bone and joint infections, and skin and  soft-tissue infections.    Clindamycin has been associated with antibiotic-asso-  ciated colitis (section 1.5), which may be fatal; it is most  common in middle-aged and elderly women, especially  following an operation. Although antibiotic-associated  colitis can occur with most antibacterials, it occurs more  frequently with clindamycin. Patients should therefore  discontinue treatment immediately if diarrhoea devel-  ops.    Oral infections Clindamycin should not be used  routinely for the treatment of oral infections because it  may be no more effective than penicillins against anae-  robes and there may be cross-resistance with erythro-  mycin-resistant bacteria. Clindamycin can be used for  the treatment of dentoalveolar abscess that has not  responded to penicillin or to metronidazole.   Cautions discontinue immediately if diarrhoea or col-  itis develops; monitor liver and renal function if  treatment exceeds 10 days, and in neonates and  infants; avoid rapid intravenous administration; avoid  in acute porphyria (section 9.8.2); interactions:  Appendix 1 (clindamycin)   Contra-indications diarrhoeal states; avoid injections  containing benzyl alcohol in neonates (see under  preparations below)   Breast-feeding amount probably too small to be  harmful but bloody diarrhoea reported in 1 infant   Side-effects diarrhoea (discontinue treatment),  abdominal discomfort, oesophagitis, oesophageal  ulcers, taste disturbances, nausea, vomiting, antibio-  tic-associated colitis; jaundice; leucopenia, eosino-  philia, and thrombocytopenia reported; polyarthritis  reported; rash, pruritus, urticaria, anaphylactoid  reactions, Stevens-Johnson syndrome, toxic epider-  mal necrolysis, exfoliative and vesiculobullous  dermatitis reported; pain, induration, and abscess  after intramuscular injection; thrombophlebitis after  intravenous injection   • By mouth, 150-300 mg every 6 hours; up to 450 mg  every 6 hours in severe infections; CHILD, 3-6 mg/kg  every 6 hours   Counselling Patients should discontinue immediately and  contact doctor if diarrhoea develops; capsules should be  swallowed with a glass of water.   • By deep intramuscular injection or by intravenous  infusion, 0.6-2. 7 g daily (in 2-4 divided doses); life-  threatening infection, up to 4.8 g daily; single doses  above 600 mg by intravenous infusion only; single  doses by intravenous infusion not to exceed 1.2 g;  CHILD over 1 month, 15-40 mg/kg daily in 3-4 divided  doses; severe infections, at least 300 mg daily  regardless of weight   Clindamycin (Non-proprietary) (Ml  Capsules, clindamycin (as hydrochloride) 150 mg, net  price 24-cap pack = £11.75. Label: 9, 27, counselling,  see above (diarrhoea)   Dalacin C® (Pharmacia) (Ml  Capsules, clindamycin (as hydrochloride) 75 mg  (green/ white), net price 24-cap pack = £7.45; 150 mg,  (white), 24-cap pack = £13.72. Label: 9, 27, counsel-  ling, see above (diarrhoea)   Injection, clindamycin (as phosphate) 150mg/mL,  net price 2-mL amp = £6.20; 4-mL amp = £12.35   discussed in this section include chlor-  amphenicol, fusidic acid, glycopeptide antibiotics  (vancomycin and teicoplanin), linezolid, and the poly-  myxin, colistin.   Chloramphenicol is a potent broad-spectrum antibio-  tic; however, it is associated with serious haematological  side-effects when given systemically and should there-  fore be reserved for the treatment of life-threatening  infections, particularly those caused by Haemophilus  influenzae, and also for typhoid fever.   Chloramphenicol eye drops (section 11.3.1) and chlor-  amphenicol ear drops (section 12.1.1) are also available.    Cautions avoid repeated courses and prolonged  treatment; blood counts required before and periodi-  cally during treatment; monitor plasma-chloram-  phenicol concentration in neonates (see below);  interactions: Appendix 1 (chloramphenicol)  Contra-indications acute porphyria (section 9.8.2)  Hepatic impairment avoid if possible — increased risk  of bone-marrow depression; reduce dose and monitor  plasma-chloramphenicol concentration  Renal impairment avoid in severe renal impairment  unless no alternative; dose-related depression of  haematopoiesis   Side-effects blood disorders including reversible and  irreversible aplastic anaemia (with reports of resulting  leukaemia), peripheral neuritis, optic neuritis, head-  ache, depression, urticaria, erythema multiforme,  nausea, vomiting, diarrhoea, stomatitis, glossitis, dry  mouth; nocturnal haemoglobinuria reported; grey  syndrome (abdominal distension, pallid cyanosis, cir-  culatory collapse) may follow excessive doses in  neonates with immature hepatic metabolism    • By mouth or by intravenous injection or infusion,  12.5 mg/kg every 6 hours (exceptionally, can be  doubled for severe infections such as septicaemia and  meningitis, providing high doses reduced as soon as  clinically indicated); CHILD over 1 month, haemophilus  epiglottitis and pyogenic meningitis, 12.5-25 mg/kg  every 6 hours (high dosages decreased as soon as  clinically indicated); NEONATE under 2 weeks, 12.5 mg/  kg twice daily; 2 weeks-1 month, 12.5 mg/kg 2-4  times daily   Note Plasma concentration monitoring required in neonates  and preferred in those under 4 years of age, in the elderly,  and in hepatic impairment; recommended peak plasma  concentration (approx. 2 hours after administration by  mouth, intravenous injection or infusion) 10-25 mg/litre;  pre-dose (‘trough’) concentration should not exceed 15 mg/  litre   Fusidic acid and its salts are narrow-spectrum anti-  biotics. The only indication for their use is in infections  caused by penicillin-resistant staphylococci, especially  osteomyelitis, as they are well concentrated in bone;  they are also used for staphylococcal endocarditis. A  second antistaphylococcal antibiotic is usually required  to prevent emergence of resistance.    Indications penicillin-resistant staphylococcal infec-  tion including osteomyelitis; staphylococcal endo-  carditis in combination with other antibacterials  (Table 1, section 5.1)   Cautions monitor liver function with high doses or on  prolonged therapy; elimination may be reduced in  biliary disease or biliary obstruction; interactions:  Appendix 1 (fusidic acid)   Hepatic impairment impaired biliary excretion; pos-  sibly increased risk of hepatotoxicity; avoid or reduce  dose; monitor liver function  Pregnancy not known to be harmful; manufacturer  advises use only if potential benefit outweighs risk  Breast-feeding present in milk — manufacturer  advises caution   Side-effects nausea, vomiting, reversible jaundice,  especially after high dosage or rapid infusion (with-  draw therapy if persistent); rarely hypersensitivity  reactions, acute renal failure (usually with jaundice),  blood disorders  Dose    Sodium fusidate (LEO) iMl  Intravenous infusion, powder for reconstitution,  sodium fusidate 500 mg (= fusidic acid 480 mg), with  buffer, net price per vial (with diluent) = £70.04   Electrolytes Na 3.1 mmol/vial when reconstituted with buffer  Dose as sodium fusidate, by intravenous infusion, ADULT over  50kg, 500 mg 3 times daily; ADULT under 50kg and CHILD, 6-  7 mg/kg 3 times daily   Dose as sodium fusidate, 500 mg every 8 hours, doubled for  severe infections   Skin infection, as sodium fusidate, 250 mg every 12 hours for 5-10  days   Suspension, off-white, banana- and orange-fla-  voured, fusidic acid 250 mg/5 mL, net price 50 mL =  £6.73. Label: 9, 21   Dose as fusidic acid, ADULT 750 mg every 8 hours; CHILD up to 1  year 50 mg/kg daily (in 3 divided doses), 1-5 years 250 mg every  8 hours, 5-12 years 500 mg every 8 hours  Note Fusidic acid is incompletely absorbed and doses recom-  mended for suspension are proportionately higher than those for  sodium fusidate tablets   The glycopeptide antibiotics vancomycin and teico-  planin have bactericidal activity against aerobic and  anaerobic Gram-positive bacteria including multi-resis-  tant staphylococci. However, there are reports of Sta-  phylococcus aureus with reduced susceptibility to gly-  copeptides. There are increasing reports of  glycopeptide-resistant enterococci.    Vancomycin is used by the intravenous route in the  treatment of endocarditis and other serious infections  caused by Gram-positive cocci. It has a long duration of  action and can therefore be given every 12 hours.  Vancomycin (added to dialysis fluid) is also used in  the treatment of peritonitis associated with peritoneal  dialysis [unlicensed route] (Table 1 section 5.1).   Vancomycin given by mouth for 10-14 days is effective  in the treatment of Clostridium difficile infection (see  also section 1.5); low doses are considered adequate  (higher dose may be considered if the infection fails to  respond or it is life threatening). Vancomycin should not  be given by mouth for systemic infections since it is not  significantly absorbed.   Teicoplanin is similar to vancomycin but has a signifi-  cantly longer duration of action allowing once-daily  administration. Unlike vancomycin, teicoplanin can be  given by intramuscular as well as by intravenous injec-  tion; it is not given by mouth.   Indications see notes above  Cautions avoid rapid infusion (risk of anaphylactoid  reactions, see Side-effects); rotate infusion sites;  elderly; avoid if history of deafness; all patients require  plasma-vancomycin measurement (after 3 or 4 doses  if renal function normal, earlier if renal impairment),  blood counts, urinalysis, and renal function tests;  monitor auditory function in elderly or if renal  impairment; teicoplanin sensitivity; systemic absorp-  tion may follow oral administration especially in  inflammatory bowel disorders or following multiple  doses; interactions: Appendix 1 (vancomycin)   Renal impairment reduce dose — monitor plasma-  vancomycin concentration and renal function regu-  larly; see also Cautions above  Pregnancy manufacturer advises use only if potential  benefit outweighs risk — plasma-vancomycin concen-  tration monitoring essential to reduce risk of fetal  toxicity   Breast-feeding present in milk — significant absorp-  tion following oral administration unlikely  Side-effects after parenteral administration: nephro-  toxicity including renal failure and interstitial nephri-  tis; ototoxicity (discontinue if tinnitus occurs); blood  disorders including neutropenia (usually after 1 week  or cumulative dose of 25 g), rarely agranulocytosis  and thrombocytopenia; nausea; chills, fever; eosino-  philia, anaphylaxis, rashes (including exfoliative  dermatitis, Stevens- Johnson syndrome, toxic epider-  mal necrolysis, and vasculitis); phlebitis (irritant to  tissue); on rapid infusion, severe hypotension  (including shock and cardiac arrest), wheezing, dys-  pnoea, urticaria, pruritus, flushing of the upper body  (‘red man’ syndrome), pain and muscle spasm of back  and chest  Dose   • By mouth, Clostridium difficile infection, (see also  notes above), ADULT and CHILD over 12 years, 125 mg  every 6 hours for 10-14 days (increased up to 500 mg  every 6 hours if infection fails to respond or is life-  threatening); CHILD 1 month-5 years, 5 mg/kg every 6  hours for 10-14 days (increased up to 10 mg/kg every  6 hours if infection fails to respond or is life-threa-  tening); 5-12 years, half adult dose    • CHILD over 2 months by intravenous injection or  infusion, initially 10 mg/kg (max. 400 mg) every 12  hours for 3 doses, subsequently 6 mg/kg (max.   200 mg) once daily (severe infections or in neutrope-  nia, 10 mg/kg (max. 400 mg) once daily); subsequent  doses can be given by intramuscular injection (but  intravenous administration preferred in children);  NEONATE by intravenous infusion, initially a single  dose of 16 mg/kg, subsequently 8 mg/kg once daily   • Streptococcal endocarditis (in combination with  another antibacterial if necessary, see Table 1, section  5.1), by intravenous injection or infusion, ADULT initi-  ally 6 mg/kg every 12 hours for 3 doses, then 6 mg/kg  once daily   • Enterococcal endocarditis (in combination with  another antibacterial, see Table 1, section 5.1), by  intravenous injection or infusion, ADULT initially   10 mg/kg every 12 hours for 3 doses, then 10 mg/kg  once daily   • Surgical prophylaxis, ADULT, by intravenous injection,  400 mg up to 30 minutes before the procedure; open  fractures, by intravenous infusion, 800 mg up to 30  minutes before skeletal stabilisation and definitive  soft-tissue closure   Note Plasma-teicoplanin concentration is not measured routi-  nely because a relationship between plasma concentration and  toxicity has not been established. However, the plasma-teico-  planin concentration can be used to optimise treatment in  some patients (see Cautions). Pre-dose (‘trough’) concentra-  tions should be greater than 10 mg/litre (greater than 15-  20 mg/litre in endocarditis; greater than 20 mg/litre in deep-  seated infection such as bone and joint infection), but less than  60 mg/litre. Teicoplanin doses in BNF may differ from those in  product literature   Injection, powder for reconstitution, teicoplanin, net  price 200-mg vial (with diluent) = £3.57; 400-mg vial  (with diluent) = £6.10   Daptomycin is a lipopeptide antibacterial with a spec-  trum of activity similar to vancomycin but its efficacy  against enterococci has not been established. Daptomy-  cin should be reserved for complicated skin and soft-  tissue infections caused by resistant Gram-positive bac-  teria including meticillin-resistant Staphylococcus aur-  eus (MRSA). It needs to be given with other antibac-  terials for mixed infections involving Gram-negative  bacteria and some anaerobes.   The Scottish Medicines Consortium (p. 4) has advised  (February 2008) that daptomycin ( Cubicin ®) is accepted  for restricted use within NHS Scotland for the treatment  of MRSA bacteraemia associated with right-sided  endocarditis or with complicated skin and soft-tissue  infections.    • By intravenous infusion, 1-1.5 g every 12 hours;  ELDERLY over 65 years, 500 mg every 12 hours or 1 g  once daily; CHILD over 1 month, 15 mg/kg every 8  hours (max. 2 g daily)   Note Plasma concentration monitoring required (see Cau-  tions above); pre-dose (‘trough’) concentration should be 10-  15 mg/litre (15—20 mg/litre for less sensitive strains of  meticillin-resistant Staphylococcus aureus)   • Surgical prophylaxis, by intravenous infusion, ADULT  over 18 years, 1 g   Note Vancomycin doses in BNF may differ from those in  product literature   Vancomycin (Non-proprietary) CMC  Capsules, vancomycin (as hydrochloride) 125 mg, net  price 28-cap pack = £132.47; 250 mg, 28-cap pack =  £132.47. Label: 9   Injection, powder for reconstitution, vancomycin (as  hydrochloride), for use as an infusion, net price 500-  mg vial = £7.25; 1-g vial = £14.50  Note Can be used to prepare solution for oral administration   Matrigel capsules, vancomycin (as hydrochloride)  125 mg, net price 28-cap pack = £88.31. Label: 9  Injection, powder for reconstitution, vancomycin (as  hydrochloride), for use as an infusion, net price 500-  mg vial = £8.05; 1-g vial = £16.11  Note Can be used to prepare solution for oral administration   Indications potentially serious Gram-positive infec-  tions including endocarditis, dialysis-associated peri-  tonitis, and serious infections due to Staphylococcus  aureus ; prophylaxis in orthopaedic surgery at risk of  infection with Gram-positive organisms  Cautions vancomycin sensitivity; blood counts and  liver and kidney function tests required; monitor  plasma-teicoplanin concentration if severe sepsis or  burns, deep-seated staphylococcal infection (includ-  ing bone and joint infection), endocarditis, renal  impairment, in elderly, and in intravenous drug abu-  sers; monitor renal and auditory function during  prolonged treatment in renal impairment or if other  nephrotoxic or neurotoxic drugs given; interactions:  Appendix 1 (teicoplanin)   Renal impairment on day 4 use half normal dose if  eGFR is 40-60 mL/minute/1.73 m 2 and use one-third  normal dose if eGFR is less than 40 mL/minute/   1.73 m 2 ; see also Cautions above  Pregnancy manufacturer advises use only if potential  benefit outweighs risk  Breast-feeding no information available  Side-effects rash, pruritus; less commonly nausea,  vomiting, diarrhoea, bronchospasm, dizziness, head-  ache, fever, leucopenia, thrombocytopenia, eosino-  philia, tinnitus, mild hearing loss, vestibular disorders,  thrombophlebitis; also reported renal failure, exfol-  iative dermatitis, Stevens-Johnson syndrome, toxic  epidermal necrolysis  Dose   • By intravenous injection or infusion, ADULT body-  weight under 70 kg, initially 400 mg every 12 hours for  3 doses, subsequently 400 mg once daily (subsequent  doses can alternatively be given by intramuscular  injection); body-weight over 70 kg, initially 6 mg/kg  every 12 hours for 3 doses, then 6 mg/kg once daily;  higher doses may be required in severe infection  (including burns, septicaemia, septic arthritis, and  osteomyelitis), consult product literature   Muscle effects Myalgia, muscle weakness, and myositis  may occur uncommonly; rhabdomyolysis is very rare.  Monitor creatine kinase before treatment and then weekly  during treatment (more frequently if creatine kinase elevated  more than 5 times upper limit of normal before treatment, or  if receiving another drug known to cause myopathy (pre-  ferably avoid concomitant use), or if eGFR less than 30 mL/    minute/ 1.73m 2 ). If unexplained muscle pain, tenderness,  weakness, or cramps develop during treatment, measure  creatine kinase every 2 days; discontinue if unexplained  muscular symptoms and creatine kinase elevated markedly  Hepatic impairment manufacturer advises caution in  severe hepatic impairment — no information available  Renal impairment see Muscle Effects above; also  monitor renal function if eGFR less than 80 mL/  minute/ 1.73 m 2 ; use normal dose every 48 hours if  eGFR less than 30 mL/minute/ 1.73 m 2    Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding manufacturer advises avoid  Side-effects nausea, vomiting, abdominal pain, flatu-  lence, diarrhoea (antibiotic-associated colitis  reported), constipation, hypertension, hypotension,  headache, anxiety, insomnia, dizziness, asthenia,  anaemia, arthralgia, rash, pruritus, injection-site  reactions; less commonly dyspepsia, anorexia, taste  disturbance, glossitis, flushing, arrhythmias, tremor,  paraesthesia, hyperglycaemia, renal failure, eosino-  philia, thrombocythaemia, electrolyte disturbances,  muscle effects (see Cautions); rarely jaundice; also  reported syncope, wheezing, pulmonary eosinophilia,  peripheral neuropathy   • By slow intravenous injection over 2 minutes or by  intravenous infusion, complicated skin and soft-tissue  infections caused by Gram-positive bacteria, ADULT  over 18 years, 4 mg/kg once daily; increased to 6 mg/  kg once daily if associated with Staphylococcus aur-  eus bacteraemia   Right-sided endocarditis caused by Staphylococcus  aureus, ADULT over 18 years, 6 mg/kg once daily    Cubicin® (Novartis) ▼ (Ml  Intravenous infusion, powder for reconstitution,  daptomycin, net price 350-mg vial = £62.00; 500-mg  vial = £88.57   Linezolid, an oxazolidinone antibacterial, is active  against Gram-positive bacteria including meticillin-  resistant Staphylococcus aureus (MRS A), and vanco-  mycin-resistant enterococci. Resistance to linezolid can  develop with prolonged treatment or if the dose is less  than that recommended. Linezolid is an option if a  glycopeptide, such as vancomycin, cannot be used to  treat pneumonia or severe skin and soft-tissue infections  caused by MRSA. Linezolid is not active against Gram-  negative organisms and must be given with other anti-  bacterials if the infection also involves Gram-negative  organisms (the combination should be used for mixed  skin and soft tissue infections only when other treat-  ments are not available). A higher incidence of blood  disorders and optic neuropathy have been reported in  patients receiving linezolid for more than the maximum  recommended duration of 28 days.   Indications pneumonia, complicated skin and soft-  tissue infections caused by Gram-positive bacteria  (initiated under expert supervision)   Cautions monitor full blood count (including platelet  count) weekly (see also Blood disorders below); his-  tory of seizures; unless close observation and blood-    pressure monitoring possible, avoid in uncontrolled  hypertension, phaeochromocytoma, carcinoid  tumour, thyrotoxicosis, bipolar depression, schizo-  phrenia, or acute confusional states; interactions:  Appendix 1 (MAOIs)   Haematopoietic disorders (including thrombocytope-  nia, anaemia, leucopenia, and pancytopenia) have  been reported in patients receiving linezolid. It is  recommended that full blood counts are monitored  weekly. Close monitoring is recommended in patients  who:   • are receiving drugs that may have adverse effects on  haemoglobin, blood counts, or platelet function;   If significant myelosuppression occurs, treatment  should be stopped unless it is considered essential,  in which case intensive monitoring of blood counts  and appropriate management should be implemented.   Severe optic neuropathy may occur rarely, particularly  if linezolid is used for longer than 28 days. The CHM  recommends that:   • patients should be warned to report symptoms of visual  impairment (including blurred vision, visual field defect,  changes in visual acuity and colour vision) immediately;   • patients experiencing new visual symptoms (regardless of  treatment duration) should be evaluated promptly, and  referred to an ophthalmologist if necessary;   • visual function should be monitored regularly if treatment  is required for longer than 28 days.   Monoamine oxidase inhibition Linezolid is a reversible,  non-selective monoamine oxidase inhibitor (MAOI). Patients  should avoid consuming large amounts of tyramine-rich  foods (such as mature cheese, yeast extracts, undistilled  alcoholic beverages, and fermented soya bean products). In  addition, linezolid should not be given with another MAOI or  within 2 weeks of stopping another MAOI. Unless close  observation and blood-pressure monitoring is possible, avoid  in those receiving SSRIs, 5HT! agonists (‘triptans’), tricyclic  antidepressants, sympathomimetics, dopaminergics, buspir-  one, pethidine and possibly other opioid analgesics. For other  interactions see Appendix 1 (MAOIs)   Hepatic impairment in severe hepatic impairment  manufacturer advises use only if potential benefit  outweighs risk   Renal impairment manufacturer advises metabolites  may accumulate if eGFR less than 30 mL/minute/  1.73m 2 ; see also Blood Disorders, above  Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding manufacturer advises avoid — present  in milk in animal studies   Side-effects diarrhoea (antibiotic-associated colitis  reported), nausea, vomiting, taste disturbances,  headache; less commonly thirst, dry mouth, glossitis,  stomatitis, tongue discoloration, abdominal pain,  dyspepsia, gastritis, constipation, pancreatitis, hyper-  tension, fever, fatigue, dizziness, insomnia,  hypoaesthesia, paraesthesia, tinnitus, polyuria, leuco-  penia, thrombocytopenia, eosinophilia, electrolyte  disturbances, blurred vision, rash, pruritus, diaphor-  esis, injection-site reactions; rarely tachycardia, tran-  sient ischaemic attacks, renal failure; also reported  tooth discoloration, convulsions, lactic acidosis, pan-  cytopenia, anaemia, Stevens-Johnson syndrome,    toxic epidermal necrolysis; peripheral and optic  neuropathy reported on prolonged therapy (see also  CHM advice above)   • By mouth, 600 mg every 12 hours usually for 10-14  days (max. duration of treatment 28 days); CHILD  [unlicensed] 1 week-12 years, 10 mg/kg every 8  hours; 12-18 years, adult dose   • By intravenous infusion over 30-120 minutes, 600 mg  every 12 hours; CHILD [unlicensed] 1 week-12 years,  10 mg/kg every 8 hours; 12-18 years, adult dose   Zyvox® (Pharmacia) T (Ml  Tablets, f/c, linezolid 600 mg, net price 10-tab pack =  £445.00. Label: 9, 10, patient information leaflet  Suspension, yellow, linezolid 100 mg/5 mL when  reconstituted with water, net price 150 mL (orange-  flavoured) = £222.50. Label: 9, 10 patient information  leaflet   Excipients include Na + 5 mmol/300-mL bag, glucose 13.71 g/300-mL  bag   The polymyxin antibiotic, colistin, is active against  Gram-negative organisms including Pseudomonas  aeruginosa, Acinetobacter baumanii, and Klebsiella  pneumoniae. It is not absorbed by mouth and thus  needs to be given by injection for a systemic effect.  Intravenous administration of colistin should be  reserved for Gram-negative infections resistant to  other antibacterials; its major adverse effects are dose-  related neurotoxicity and nephrotoxicity.   Colistin is used by mouth in bowel sterilisation regimens  in neutropenic patients (usually with nystatin); it is not  recommended for gastro-intestinal infections. It is also  given by inhalation of a nebulised solution as an adjunct  to standard antibacterial therapy in patients with cystic  fibrosis.   Both colistin and polymyxin B are included in some  preparations for topical application.   Cautions acute porphyria (section 9.8.2); risk of bron-  chospasm on inhalation — may be prevented or trea-  ted with a selective beta 2 agonist; interactions:  Appendix 1 (polymyxins)   Pregnancy avoid — possible risk of fetal toxicity espe-  cially in second and third trimesters  Breast-feeding present in milk but poorly absorbed  from gut; manufacturers advise avoid (or use only if  potential benefit outweighs risk)   Side-effects neurotoxicity reported especially with  excessive doses (including apnoea, perioral and per-  ipheral paraesthesia, vertigo, headache, muscle  weakness; rarely vasomotor instability, slurred  speech, confusion, psychosis, visual disturbances);  nephrotoxicity; hypersensitivity reactions including  rash; injection-site reactions; inhalation may cause  sore throat, sore mouth, cough, bronchospasm   • By mouth, bowel sterilisation, 1.5-3 million units  every 8 hours   • By slow intravenous injection into a totally implan-  table venous access device, or by intravenous infu-  sion (but see notes above), ADULT and CHILD body-  weight under 60 kg, 50 000-75 000 units/kg daily in 3  divided doses; body-weight over 60 kg, 1-2 million  units every 8 hours   Note Plasma concentration monitoring required in renal  impairment; recommended ‘peak’ plasma-colistin concen-  tration (approx. 30 minutes after intravenous injection or  infusion) 10-15 mg/litre (125-200 units/mL)   • By inhalation of nebulised solution, ADULT and CHILD  over 2 years, 1-2 million units every 12 hours; CHILD  under 2 years, 0.5-1 million units every 12 hours   Syrup, colistin sulphate 250 000 units/5 mL when  reconstituted with water. Net price 80 mL = £3.48  Injection, powder for reconstitution, colistimethate  sodium (colistin sulphomethate sodium). Net price 1  million-unit vial = £1.68; 2 million-unit vial = £3.09   Electrolytes (before reconstitution) Na + < 0.5 mmol/1 million-unit and 2  million-unit vial   Note Colomycin ® Injection (dissolved in physiological  saline) may be used for nebulisation   Powder for nebuliser solution, colistimethate sod-  ium (colistin sulphomethate sodium), net price 1  million-unit vial = £4.60   Injection, powder for reconstitution, colistimethate  sodium (colistin sulphomethate sodium), net price 1  million unit- vial = £2.30   The importance of the sulfonamides has decreased as a  result of increasing bacterial resistance and their repla-  cement by antibacterials which are generally more  active and less toxic.   Sulfamethoxazole and trimethoprim are used in combi-  nation (as co-trimoxazole) because of their synergistic  activity. However, co-trimoxazole is associated with rare  but serious side-effects (e.g. Stevens- Johnson syndrome  and blood dyscrasias, notably bone marrow depression  and agranulocytosis) especially in the elderly (see  Restrictions on the use of Co-trimoxazole below)    Restrictions on the use of co-trimoxazole  Co-trimoxazole should be limited to the role of drug  of choice in Pneumocystis jirovecii [Pneumocystis  carinii) pneumonia; it is also indicated for toxo-  plasmosis and nocardiasis. It should now only be  considered for use in acute exacerbations of chronic  bronchitis and infections of the urinary tract when  there is good bacteriological evidence of sensitivity  to co-trimoxazole and good reason to prefer this  combination to a single antibacterial; similarly it  should only be used in acute otitis media in children  when there is good reason to prefer it.   Trimethoprim can be used alone for urinary- and resp-  iratory-tract infections and for prostatitis, shigellosis,    and invasive salmonella infections. Trimethoprim has  side-effects similar to co-trimoxazole but they are less  severe and occur less frequently.   For topical preparations of sulfonamides used in the  treatment of burns see section 13.10.1.1.   A mixture of trimethoprim and sulfamethoxazole  (sulphamethoxazole) in the proportions of 1 part to 5  parts   Indications see restrictions above  Cautions maintain adequate fluid intake; avoid in  blood disorders (unless under specialist supervision);  monitor blood counts on prolonged treatment; dis-  continue immediately if blood disorders or rash  develop; predisposition to folate deficiency or hyper-  kalaemia; elderly (see Restrictions on the use of Co-  trimoxazole above); asthma; G6PD deficiency (section  9.1.5); avoid in infants under 6 weeks (except for  treatment or prophylaxis of pneumocystis pneu-  monia); interactions: Appendix 1 (trimethoprim, sul-  famethoxazole)   Renal impairment use half normal dose if eGFR 15-  30 mL/minute/ 1.73 m 2 ; avoid if eGFR less than  15 mL/minute/ 1.73 m 2 and if plasma-sulfamethoxa-  zole concentration cannot be monitored  Pregnancy teratogenic risk in first trimester (tri-  methoprim a folate antagonist). Neonatal haemolysis  and methaemoglobinaemia in third trimester; fear of  increased risk of kemicterus in neonates appears to  be unfounded   Breast-feeding small risk of kemicterus in jaundiced  infants and of haemolysis in G6PD-deficient infants  (due to sulfamethoxazole)   Side-effects nausea, diarrhoea; headache; hyperkal-  aemia; rash (very rarely including Stevens-Johnson  syndrome, toxic epidermal necrolysis, photosensit-  ivity) — discontinue immediately; less commonly  vomiting; very rarely glossitis, stomatitis, anorexia,  liver damage (including jaundice and hepatic necro-  sis), pancreatitis, antibiotic-associated colitis, myo-  carditis, cough and shortness of breath, pulmonary  infiltrates, aseptic meningitis, depression, convulsions,  peripheral neuropathy, ataxia, tinnitus, vertigo, hallu-  cinations, hypoglycaemia, blood disorders (including  leucopenia, thrombocytopenia, megaloblastic anae-  mia, eosinophilia), hyponatraemia, renal disorders  including interstitial nephritis, arthralgia, myalgia,  vasculitis, systemic lupus erythematosus and uveitis;  rhabdomyolysis reported in HIV-infected patients  Dose   • By mouth, 960 mg every 12 hours; CHILD, every 12  hours, 6 weeks-5 months, 120 mg; 6 months-5 years,  240 mg; 6-12 years, 480 mg   • By intravenous infusion, 960 mg every 12 hours  increased to 1.44 g every 12 hours in severe infec-  tions; CHILD 36 mg/kg daily in 2 divided doses  increased to 54 mg/kg daily in severe infections   • Treatment of Pneumocystis jirovecii [Pneumocystis  carinii) infections (undertaken where facilities for  appropriate monitoring available — consult microbiol-  ogist and product literature), by mouth or by intra-  venous infusion, ADULT and CHILD over 4 weeks,    • Prophylaxis of Pneumocystis jirovecii [Pneumocystis  carinii ) infections, by mouth, 960 mg once daily (may  be reduced to 480 mg once daily to improve toler-  ance) or 960 mg on alternate days (3 times a week) or  960 mg twice daily on alternate days (3 times a week);  CHILD 6 weeks-5 months, 120 mg twice daily on 3  consecutive or alternate days per week or on 7 days  per week; 6 months-5 years, 240 mg; 6-12 years,   Note 480 mg of co-trimoxazole consists of sulfamethoxazole  400 mg and trimethoprim 80 mg   Forte tablets, scored, co-trimoxazole 960 mg, net  price 100-tab pack = £23.46. Label: 9  Adult suspension, co-trimoxazole 480 mg/5 mL, net  price 100 mL (vanilla-flavoured) = £4.41. Label: 9  Paediatric suspension, sugar-free, co-trimoxazole  240 mg/5 mL, net price 100 mL (banana- and vanilla-  flavoured) = £2.45. Label: 9  Intravenous infusion, co-trimoxazole 96mg/mL. To  be diluted before use. Net price 5-mL amp = £1.78   Contra-indications see under Co-trimoxazole  Hepatic impairment use with caution in mild to  moderate impairment; avoid in severe impairment  Renal impairment use with caution in mild to mod-  erate impairment; avoid in severe impairment; high  risk of crystalluria   Pregnancy neonatal haemolysis and methaemo-  globinaemia in third trimester; fear of increased risk of  kemicterus in neonates appears to be unfounded  Breast-feeding small risk of kemicterus in jaundiced  infants and of haemolysis in G6PD-deficient infants  Side-effects see under Co-trimoxazole; also hypo-  thyroidism, benign intracranial hypertension, optic  neuropathy  Dose   • Prevention of rheumatic fever, by mouth, 1 g daily  (500 mg daily for patients less than 30 kg)   Tablets, sulfadiazine 500 mg, net price 56-tab pack =  £37.50. Label: 9, 27   Indications urinary-tract infections, acute and chronic  bronchitis; pneumocystis pneumonia (section 5.4.8)  Cautions predisposition to folate deficiency; elderly;  manufacturer recommends blood counts on long-   Blood disorders On long-term treatment, patients and their  carers should be told how to recognise signs of blood  disorders and advised to seek immediate medical attention if  symptoms such as fever, sore throat, rash, mouth ulcers,  purpura, bruising or bleeding develop  Contra-indications blood dyscrasias  Renal impairment use half normal dose after 3 days if  eGFR 15-30 mL/minute/1. 73 m 2 ; use half normal  dose if eGFR less than 15 mL/minute/1.73 m 2  (monitor plasma-trimethoprim concentration if eGFR  less than 10 mL/minute/ 1.73 m 2 )   Pregnancy teratogenic risk in first trimester (folate  antagonist); manufacturers advise avoid  Breast-feeding present in milk — short-term use not  known to be harmful   Side-effects gastro-intestinal disturbances including  nausea and vomiting, pruritus, rashes, hyperkalaemia,  depression of haematopoiesis; rarely erythema mul-  tiforme, toxic epidermal necrolysis, photosensitivity  and other allergic reactions including angioedema  and anaphylaxis; aseptic meningitis and uveitis  reported  Dose   • Acute infections, 200 mg every 12 hours; CHILD 1  month-12 years, 4 mg/kg (max. 200 mg) every 12  hours; or 6 weeks-6 months 25 mg every 12 hours, 6  months-6 years 50 mg every 12 hours, 6-12 years  100 mg every 12 hours   Trimethoprim (Non-proprietary) (Ml  Tablets, trimethoprim 100 mg, net price 28 = 94p;  200 mg, 14-tab pack = 91p. Label: 9  Brands include Trimopan ®   Tuberculosis is treated in two phases — an initial phase  using 4 drugs and a continuation phase using 2 drugs in  fully sensitive cases. Treatment requires specialised  knowledge, particularly where the disease involves  resistant organisms or non-respiratory organs.   The regimens given below are recommended for the  treatment of tuberculosis in the UK; variations occur in  other countries. Either the unsupervised regimen or the  supervised regimen described below should be used; the  two regimens should not be used concurrently.   obtained, but susceptibility results are not available after  2 months, treatment with rifampicin, isoniazid, pyrazin-  amide and ethambutol should be continued until full  susceptibility is confirmed, even if this is for longer than  2 months.   Streptomycin is rarely used in the UK but it may be used  in the initial phase of treatment if resistance to isoniazid  has been established before therapy is commenced.   Continuation phase After the initial phase, treatment  is continued for a further 4 months with isoniazid and  rifampicin (preferably given as a combination prepara-  tion). Longer treatment is necessary for meningitis,  direct spinal cord involvement, and for resistant organ-  isms which may also require modification of the regi-  men.    Unsupervised treatment The following regimen  should be used for patients who are likely to take anti-  tuberculous drugs reliably without supervision.  Patients who are unlikely to comply with daily admin-  istration of antituberculous drugs should be treated with  the regimen described under Supervised Treatment.  Recommended dosage for standard unsupervised 6-  month treatment    Rifater® [rifampicin, isoniazid, and pyrazinamide] (for 2-  month initial phase only)   ADULT body- weight under 40 kg 3 tablets daily; body- weight  40-49 kg 4 tablets daily; body-weight 50-64 kg 5 tablets  daily; body-weight over 65 kg 6 tablets daily   ADULT AND CHILD 15 mg/kg daily  Rifinah® [rifampicin and isoniazid] (for 4-month con-  tinuation phase following initial treatment with  Rifater®)   ADULT body-weight under 50 kg 3 tablets daily of Rifinah ®  150/100\ body-weight 50 kg and over, 2 tablets daily of  Rifinah ® 300/150   or (if combination preparations not appropriate):  Isoniazid (for 2-month initial and 4-month continuation  phases)   ADULT 300 mg daily; CHILD 10 mg/kg (max. 300 mg) daily   ADULT body-weight under 50 kg 450 mg daily; body-weight  50kg and over, 600 mg daily; CHILD 10 mg/kg daily (max.  450 mg daily if body-weight under 50 kg; max. 600 mg daily if  body-weight 50 kg and over)   ADULT body-weight under 50 kg 1.5 g daily; body-weight  50 kg and over, 2g daily; CHILD 35 mg/kg daily (max. 1.5 g  daily if body-weight under 50 kg; max. 2 g daily if body-  weight 50 kg and over)    Ethambutol (for 2-month initial phase only)  ADULT AND CHILD 15 mg/kg daily    Initial phase The concurrent use of 4 drugs during the  initial phase is designed to reduce the bacterial popula-  tion as rapidly as possible and to prevent the emergence  of drug-resistant bacteria. The drugs are best given as  combination preparations unless one of the components  cannot be given because of resistance or intolerance.  The treatment of choice for the initial phase is the daily  use of isoniazid, rifampicin, pyrazinamide and etham-  butol. Treatment should be started without waiting for  culture results if clinical features or histology results are  consistent with tuberculosis; treatment should be con-  tinued even if initial culture results are negative. The  initial phase drugs should be continued for 2 months.  Where a positive culture for M. tuberculosis has been    Pregnancy The standard regimen (above) may be  used during pregnancy. Streptomycin should not be  given in pregnancy.   Children Children are given isoniazid, rifampicin,  pyrazinamide, and ethambutol for the first 2 months  followed by isoniazid and rifampicin during the next 4  months. However, care is needed in young children  receiving ethambutol because of the difficulty in testing  eyesight and in obtaining reports of visual symptoms  (see below).    Supervised treatment Drug administration needs to  be fully supervised (directly observed therapy, DOT) in  patients who cannot comply reliably with the treatment  regimen. These patients are given isoniazid, rifampicin,  pyrazinamide and ethambutol (or streptomycin) 3 times  a week under supervision for the first 2 months followed  by isoniazid and rifampicin 3 times a week for a further 4  months.   ADULT AND CHILD 15 mg/kg (max. 900 mg) 3 times a week   ADULT 600-900 mg 3 times a week; CHILD 15 mg/kg (max.  900 mg) 3 times a week   ADULT body-weight under 50 kg 2 g 3 times a week; body-  weight 50 kg and over, 2.5 g 3 times a week; CHILD 50 mg/kg  3 times a week (max. 2 g 3 times a week if body-weight under  50 kg; max. 2.5 g 3 times a week if body-weight 50 kg and  over)   Immunocompromised patients Multi-resistant  Mycobacterium tuberculosis may be present in immu-  nocompromised patients. The organism should always  be cultured to confirm its type and drug sensitivity.  Confirmed M. tuberculosis infection sensitive to first-  line drugs should be treated with a standard 6-month  regimen; after completing treatment, patients should be  closely monitored. The regimen may need to be mod-  ified if infection is caused by resistant organisms, and  specialist advice is needed.    Specialist advice should be sought about tuberculosis  treatment or chemoprophylaxis in a HIV-positive indi-  vidual; care is required in choosing the regimen and in  avoiding potentially serious interactions. Starting anti-  retroviral treatment in the first 2 months of anti-  tuberculosis treatment increases the risk of immune  reconstitution syndrome.    Infection may also be caused by other mycobacteria e.g.  M. avium complex in which case specialist advice on  management is needed.    Corticosteroids In meningeal or pericardial tuber-  culosis, a corticosteroid should be started at the same  time as antituberculosis therapy.    Prevention of tuberculosis Some individuals may  develop tuberculosis owing to reactivation of previously  latent disease. Chemoprophylaxis may be required in  those who have evidence of latent tuberculosis and are  receiving treatment with immunosuppressants (includ-  ing cytotoxics and possibly long-term treatment with  systemic corticosteroids). In these cases, chemoprophy-  laxis involves use of either isoniazid alone for 6 months  or of isoniazid and rifampicin for 3 months, see Table 2,  section 5.1; longer chemoprophylaxis is not recom-  mended.   For prevention of tuberculosis in susceptible close con-  tacts or those who have become tuberculin-positive, see  Table 2, section 5.1. For advice on immunisation against  tuberculosis, see section 14.4    Monitoring Since isoniazid, rifampicin and pyrazin-  amide are associated with liver toxicity, hepatic function  should be checked before treatment with these drugs.  Those with pre-existing liver disease or alcohol depend-  ence should have frequent checks particularly in the first  2 months. If there is no evidence of liver disease (and  pre-treatment liver function is normal), further checks  are only necessary if the patient develops fever, malaise,  vomiting, jaundice or unexplained deterioration during  treatment. In view of the need to comply fully with  antituberculous treatment on the one hand and to  guard against serious liver damage on the other, patients  and their carers should be informed carefully how to  recognise signs of liver disorders and advised to dis-  continue treatment and seek immediate medical atten-  tion should symptoms of liver disease occur.   Renal function should be checked before treatment with  antituberculous drugs and appropriate dosage adjust-  ments made. Streptomycin or ethambutol should pre-  ferably be avoided in patients with renal impairment,  but if used, the dose should be reduced and the plasma-  drug concentration monitored.   Visual acuity should be tested before ethambutol is  used (see below).    Major causes of treatment failure are incorrect pre-  scribing by the physician and inadequate compli-  ance by the patient. Monthly tablet counts and urine  examination (rifampicin imparts an orange-red col-  oration) may be useful indicators of compliance with  treatment. Avoid both excessive and inadequate  dosage. Treatment should be supervised by a spe-  cialist physician.    Isoniazid is cheap and highly effective. Like rifampicin  it should always be included in any antituberculous  regimen unless there is a specific contra-indication. Its  only common side-effect is peripheral neuropathy which  is more likely to occur where there are pre-existing risk  factors such as diabetes, alcohol dependence, chronic  renal failure, malnutrition and HIV infection. In these  circumstances pyridoxine 10 mg daily (or 20 mg daily if  suitable product not available) (section 9.6.2) should be  given prophylactically from the start of treatment. Other  side-effects such as hepatitis (important: see Monitoring  above) and psychosis are rare.   Rifampicin, a rifamycin, is a key component of any  antituberculous regimen. Like isoniazid it should always  be included unless there is a specific contra-indication.   During the first two months (‘initial phase’) of rifampicin  administration transient disturbance of liver function  with elevated serum transaminases is common but  generally does not require interruption of treatment.  Occasionally more serious liver toxicity requires a  change of treatment particularly in those with pre-exist-  ing liver disease (important: see Monitoring above).   On intermittent treatment six toxicity syndromes have  been recognised — influenza-like, abdominal, and resp-  iratory symptoms, shock, renal failure, and thrombo-  cytopenic purpura — and can occur in 20 to 30% of  patients.   Rifampicin induces hepatic enzymes which accelerate  the metabolism of several drugs including oestrogens,  corticosteroids, phenytoin, sulfonylureas, and anticoa-  gulants; interactions: Appendix 1 (rifamycins). Impor-  tant: the effectiveness of hormonal contraceptives is    reduced and alternative family planning advice should  be offered (section 7.3.1).   Rifabutin, another rifamycin, is indicated for prophy-  laxis against M. avium complex infections in patients  with a low CD4 count; it is also licensed for the treat-  ment of non-tuberculous mycobacterial disease and  pulmonary tuberculosis. Important: as with rifampicin  it induces hepatic enzymes and the effectiveness of  hormonal contraceptives is reduced requiring alterna-  tive family planning methods.   Pyrazinamide [unlicensed] is a bactericidal drug only  active against intracellular dividing forms of Mycobac-  terium tuberculosis', it exerts its main effect only in the  first two or three months. It is particularly useful in  tuberculous meningitis because of good meningeal  penetration. It is not active against M. bovis. Serious  liver toxicity may occasionally occur (important: see  Monitoring above).   Ethambutol is included in a treatment regimen if iso-  niazid resistance is suspected; it can be omitted if the  risk of resistance is low.   Side-effects of ethambutol are largely confined to visual  disturbances in the form of loss of acuity, colour blind-  ness, and restriction of visual fields. These toxic effects  are more common where excessive dosage is used or if  the patient’s renal function is impaired. The earliest  features of ocular toxicity are subjective and patients  should be advised to discontinue therapy immediately if  they develop deterioration in vision and promptly seek  further advice. Early discontinuation of the drug is  almost always followed by recovery of eyesight. Patients  who cannot understand warnings about visual side-  effects should, if possible, be given an alternative  drug. In particular, ethambutol should be used with  caution in children until they are at least 5 years old  and capable of reporting symptomatic visual changes  accurately.   Visual acuity should be tested by Snellen chart before  treatment with ethambutol.   Streptomycin [unlicensed] is now rarely used in the UK  except for resistant organisms. It is given intramuscu-  larly in a dose of 15 mg/kg (max. 1 g) daily; the dose is  reduced in those under 50 kg, those over 40 years or  those with renal impairment. Plasma-drug concentra-  tion should be measured in patients with impaired renal  function in whom streptomycin must be used with great  care. Side-effects increase after a cumulative dose of  100 g, which should only be exceeded in exceptional  circumstances.   Drug-resistant tuberculosis should be treated by a spe-  cialist physician with experience in such cases, and  where appropriate facilities for infection-control exist.  Second-line drugs available for infections caused by  resistant organisms, or when first-line drugs cause unac-  ceptable side-effects, include amikacin, capreomycin,  cycloserine, newer macrolides (e.g. azithromycin and  clarithromycin), moxifloxacin and protionamide (pro-  thionamide; no longer on UK market).   Indications in combination with other drugs, tuber-  culosis resistant to first-line drugs  Cautions auditory impairment; monitor renal, hepatic,  auditory, and vestibular function and electrolytes;  interactions: Appendix 1 (capreomycin)   Side-effects hypersensitivity reactions including urti-  caria and rashes; leucocytosis or leucopenia, rarely  thrombocytopenia; changes in liver function tests;  nephrotoxicity, electrolyte disturbances; hearing loss  with tinnitus and vertigo; neuromuscular block after  large doses, pain and induration at injection site  Dose   • By deep intramuscular injection, 1 g daily (not more  than 20 mg/kg) for 2-4 months, then 1 g 2-3 times  each week   injection, powder for reconstitution, capreomycin  sulphate 1 million units (= capreomycin approx, lg).  Net price per vial = £25.18    Indications in combination with other drugs, tuber-  culosis resistant to first-line drugs  Cautions monitor haematological, renal, and hepatic  function; interactions: Appendix 1 (cycloserine)  Contra-indications epilepsy, depression, severe  anxiety, psychotic states, alcohol dependence, acute  porphyria (section 9.8.2)   Pregnancy manufacturer advises use only if potential  benefit outweighs risk — crosses the placenta  Breast-feeding amount too small to be harmful  Side-effects mainly neurological, including headache,  dizziness, vertigo, drowsiness, tremor, convulsions,  confusion, psychosis, depression (discontinue or  reduce dose if symptoms of CNS toxicity); rashes,  allergic dermatitis (discontinue or reduce dose);  megaloblastic anaemia; changes in liver function  tests; heart failure at high doses reported  Dose    • Initially 250 mg every 12 hours for 2 weeks increased  according to blood concentration and response to  max. 500 mg every 12 hours; CHILD 2-18 years see  BNF for Children   Note Blood concentration monitoring required especially in  renal impairment or if dose exceeds 500 mg daily or if signs  of toxicity; blood concentration should not exceed 30 mg/  litre   Renal impairment reduce dose; if creatinine clear-  ance less than 30mL/minute, monitor plasma-  ethambutol concentration; optic nerve damage   Side-effects optic neuritis, red/green colour blind-  ness, peripheral neuritis, rarely rash, pruritus, urti-  caria, thrombocytopenia   Note ‘Peak’ concentration (2-2.5 hours after dose) should be  2-6 mg/litre (7-22 micromol/litre); ‘trough’ (pre-dose) con-  centration should be less than 1 mg/litre (4 micromol/litre);  see Cautions above; for advice on laboratory assay of  ethambutol contact the Poisons Unit at New Cross Hospital  (Tel (020) 7771 5360)   Ethambutol (Non-proprietary) (MO  Tablets, ethambutol hydrochloride 100 mg, net price  56-tab pack = £12.00; 400 mg, 56-tab pack = £44.18.  Label: 8   Indications tuberculosis, in combination with other  drugs; prophylaxis — Table 2, section 5.1  Cautions see Monitoring in notes above; also slow  acetylator status (increased risk of side-effects); epi-  lepsy; history of psychosis; alcohol dependence,  malnutrition, diabetes mellitus, HIV infection (risk of  peripheral neuritis); acute porphyria (section 9.8.2);  interactions: Appendix 1 (isoniazid)   Hepatic disorders Patients or their carers should be told  how to recognise signs of liver disorder, and advised to  discontinue treatment and seek immediate medical attention  if symptoms such as persistent nausea, vomiting, malaise or  jaundice develop    Contra-indications drug-induced liver disease  Hepatic impairment use with caution; monitor liver  function regularly and particularly frequently in first 2  months; see also Hepatic Disorders above  Renal impairment max. 200 mg daily if eGFR less  than 10 mL/minute/ 1.73 m 2 ; peripheral neuropathy  Pregnancy not known to be harmful; see also p. 361  Breast-feeding monitor infant for possible toxicity;  theoretical risk of convulsions and neuropathy; pro-  phylactic pyridoxine advisable in mother and infant;  see also p. 361   Side-effects nausea, vomiting, constipation, dry  mouth; peripheral neuritis with high doses (pyridoxine  prophylaxis, see notes above), optic neuritis, con-  vulsions, psychotic episodes, vertigo; hypersensitivity  reactions including fever, Stevens-Johnson syndrome,  purpura; blood disorders including agranulocytosis,  haemolytic anaemia, aplastic anaemia; hepatitis  (especially over age of 35 years); pancreatitis; inter-  stitial pneumonitis; systemic lupus erythematosus-like  syndrome, pellagra, hyperreflexia, difficulty with  micturition, hyperglycaemia, and gynaecomastia  reported; hearing loss and tinnitus (in patients with  end-stage renal impairment); when used with tyra-  mine or histamine rich foods, tachycardia, palpitation,  hypotension, flushing, headache, dizziness, and  sweating also reported    • By mouth or by intramuscular or intravenous injec-  tion, see notes above    Isoniazid (Non-proprietary) (Ml  Tablets, isoniazid 50 mg, net price 56-tab pack =  £11.10; 100 mg, 28-tab pack = £11.30. Label: 8, 22  Elixir (BPC), isoniazid 50 mg, citric acid monohydrate  12.5 mg, sodium citrate 60 mg, concentrated anise  water 0.05 mL, compound tartrazine solution 0.05 mL,  glycerol 1 mL, double-strength chloroform water  2 mL, water to 5 mL. Label: 8, 22  Available from ‘special-order’ manufacturers or specialist  importing companies, see p. 988   Cautions see Monitoring in notes above; also diabetes;  gout (avoid in acute attack); interactions: Appendix 1  (pyrazinamide)   Hepatic disorders Patients or their carers should be told  how to recognise signs of liver disorder, and advised to  discontinue treatment and seek immediate medical attention  if symptoms such as persistent nausea, vomiting, malaise or  jaundice develop   Pregnancy manufacturer advises use only if potential  benefit outweighs risk; see also p. 361   Side-effects hepatotoxicity including fever, anorexia,  hepatomegaly, splenomegaly, jaundice, liver failure;  nausea, vomiting, flushing, dysuria, arthralgia,  sideroblastic anaemia, thrombocytopenia, rash and  occasionally photosensitivity  Dose   Renal impairment use half normal dose if eGFR less  than 30 mL/minute/ 1.73 m 2   Side-effects nausea, vomiting; leucopenia, thrombo-  cytopenia, anaemia, rarely haemolysis; raised liver  enzymes, jaundice, rarely hepatitis; uveitis following  high doses or administration with drugs which raise  plasma concentration — see also interactions:  Appendix 1 (rifamycins); arthralgia, myalgia, influ-  enza-like syndrome, dyspnoea; also hypersensitivity  reactions including fever, rash, eosinophilia, bron-    chospasm, shock; skin, urine, saliva and other body  secretions coloured orange-red; asymptomatic  comeal opacities reported with long-term use   • Prophylaxis of Mycobacterium avium complex  infections in immunosuppressed patients with low  CD4 count (see product literature), 300 mg daily as a  single dose   • Treatment of non-tuberculous mycobacterial disease,  in combination with other drugs, 450-600 mg daily as  a single dose for up to 6 months after cultures nega-  tive   • Treatment of pulmonary tuberculosis, in combination  with other drugs, 150-450 mg daily as a single dose  for at least 6 months   Mycobutin® (Pharmacia) (Ml  Capsules, red-brown, rifabutin 150 mg. Net price 30-  cap pack = £90.38. Label: 8, 14, counselling, lenses,  see under Rifampicin   Cautions see Monitoring in notes above; also liver  function tests and blood counts in hepatic disorders,  alcohol dependence, and on prolonged therapy, see  also below); acute porphyria (section 9.8.2); impor-  tant: advise patients on hormonal contraceptives to  use additional means (see also section 7.3.1); disco-  lours soft contact lenses; see also notes above;  interactions: Appendix 1 (rifamycins)   Note If treatment interrupted re-introduce with low dosage  and increase gradually; discontinue permanently if serious  side-effects develop   Hepatic disorders Patients or their carers should be told  how to recognise signs of liver disorder, and advised to  discontinue treatment and seek immediate medical attention  if symptoms such as persistent nausea, vomiting, malaise or  jaundice develop   Hepatic impairment impaired elimination; monitor  liver function; avoid or do not exceed 8 mg/kg daily;  see also Cautions above   Pregnancy manufacturers advise very high doses ter-  atogenic in animal studies in first trimester; risk of  neonatal bleeding may be increased in third trimester;  see also p. 361   Side-effects gastro-intestinal symptoms including  anorexia, nausea, vomiting, diarrhoea (antibiotic-  associated colitis reported); headache, drowsiness;  those occurring mainly on intermittent therapy  include influenza-like symptoms (with chills, fever,  dizziness, bone pain), respiratory symptoms (includ-  ing shortness of breath), collapse and shock, haemo-  lytic anaemia, thrombocytopenic purpura, dissemi-  nated intravascular coagulation, and acute renal  failure; alterations of liver function, jaundice; flushing,  urticaria, and rashes; other side-effects reported  include oedema, psychoses, adrenal insufficiency,  muscular weakness and myopathy, exfoliative  dermatitis, toxic epidermal necrolysis, Stevens- John-  son syndrome, pemphigoid reactions, leucopenia,  eosinophilia, menstrual disturbances; urine, saliva,   • Brucellosis, legionnaires’ disease, endocarditis and  serious staphylococcal infections, in combination with  other drugs, by mouth or by intravenous infusion,  0.6-1. 2 g daily (in 2-4 divided doses)   • Prophylaxis of meningococcal meningitis and  Haemophilus influenzae (type b) infection, section  5.1, table 2   Rifampicin (Non-proprietary) iMl  Capsules, rifampicin 150 mg, net price 100 = £20.82;  300 mg, 100 = £46.21. Label: 8, 14, 22, counselling,  see lenses above    Rifadin® (Sanofi-Aventis) £mD  Capsules, rifampicin 150 mg (blue/red), net price  100-cap pack= £18.32; 300 mg (red), 100-cap pack=  £36.63. Label: 8, 14, 22, counselling, see lenses above  Syrup, red, rifampicin 100 mg/5 mL (raspberry-fla-  voured), net price 120 mL = £3.56. Label: 8, 14, 22,  counselling, see lenses above  Intravenous infusion, powder for reconstitution, rif-  ampicin, net price 600-mg vial (with solvent) = £7.67    Rimactane® (Sandoz) (Ml  Capsules, rifampicin 150 mg (red), net price 60-cap  pack = £11.35; 300 mg (red/brown), 60-cap pack =  £22.69. Label: 8, 14, 22, counselling, see lenses above   Rifater® (Sanofi-Aventis) (Ml  Tablets, pink, s/c, rifampicin 120 mg, isoniazid 50 mg,  pyrazinamide 300 mg, net price 100-tab pack= £21.95.  Label: 8, 14, 22, counselling, see lenses above  Dose initial treatment of pulmonary tuberculosis, patients up to  40 kg 3 tablets daily preferably before breakfast, 40-49 kg 4 tablets  daily, 50-64 kg 5 tablets daily, 65 kg or more, 6 tablets daily; not  suitable for use in children   Rifinah® 150/100 (Sanofi-Aventis) IMl  Tablets, pink, s/c, rifampicin 150 mg, isoniazid  100 mg, net price 84-tab pack = £15.91. Label: 8, 14,  22, counselling, see lenses above  Dose ADULT under 50kg, 3 tablets daily, preferably before  breakfast   Rifinah® 300/150 (Sanofi-Aventis) (Ml  Tablets, orange, s/c, rifampicin 300 mg, isoniazid  150 mg, net price 56-tab pack = £21.02. Label: 8, 14,  22, counselling, see lenses above  Dose ADULT 50kg and over, 2 tablets daily, preferably before  breakfast   Indications tuberculosis, in combination with other  drugs; adjunct to doxycycline in brucellosis; entero-  coccal endocarditis (Table 1, section 5.1)   Note One-hour (‘peak’) concentration should be 15-40 mg/  litre; pre-dose (‘trough’) concentration should be less than  5 mg/litre (less than 1 mg/litre in renal impairment or in  those over 50 years)   Streptomycin Sulphate (Non-proprietary) (M\  Injection, powder for reconstitution, streptomycin (as  sulphate), net price 1-g vial = £8.25  Available as an unlicensed preparation from UCB Pharma    and it should never be used in women of child-bearing  potential (significant teratogenic risk — for CSM gui-  dance on prescribing, see Current Problems in Pharma-  covigilance 1994; 20, 8). Increased doses of clofazimine  100 mg 3 times daily for the first month with subsequent  reductions, are also useful but may take 4-6 weeks to  attain full effect.   Rifampicin 600 mg once-monthly, supervised (450 mg  for those weighing less than 35 kg)   daily or 1-2 mg/kg daily for adults weigh-  ing less than 35 kg)   Paucibacillary leprosy should be treated for 6 months. If  treatment is interrupted the regimen should be recom-  menced where it was left off to complete the full course.   Neither the multibacillary nor the paucibacillary anti-  leprosy regimen is sufficient to treat tuberculosis.   Advice from a member of the Panel of Leprosy Opinion  is essential for the treatment of leprosy (Hansen’s dis-  ease). Details of the Panel can be obtained from the  Department of Health telephone (020) 7972 4480.    The World Health Organization has made recommen-  dations to overcome the problem of dapsone resistance  and to prevent the emergence of resistance to other  antileprotic drugs. Drugs recommended are dapsone,  rifampicin (section 5.1.9), and clofazimine. Other  drugs with significant activity against Mycobacterium  leprae include ofloxacin, minocycline and clarithro-  mycin, but none of these are as active as rifampicin; at  present they should be reserved as second-line drugs for  leprosy.    A three-drug regimen is recommended for multibacil-  lary leprosy (lepromatous, borderline-lepromatous, and  borderline leprosy) and a two-drug regimen for pauci-  bacillary leprosy (borderline-tuberculoid, tuberculoid,  and indeterminate). The following regimens are widely  used throughout the world (with minor local variations):  Multibacillary leprosy (3-drug regimen)   Rifampicin 600 mg once-monthly, supervised (450 mg  for adults weighing less than 35 kg)   daily or 1-2 mg/kg daily for adults weigh-  ing less than 35 kg)   Indications leprosy, dermatitis herpetiformis;  Pneumocystis jirovecii (. Pneumocystis carinii) pneu-  monia (section 5.4.8)   Cautions cardiac or pulmonary disease; anaemia  (treat severe anaemia before starting); susceptibility  to haemolysis including G6PD deficiency (section  9.1.5); avoid in acute porphyria (section 9.8.2); inter-  actions: Appendix 1 (dapsone)   Blood disorders On long-term treatment, patients and their  carers should be told how to recognise signs of blood  disorders and advised to seek immediate medical attention if  symptoms such as fever, sore throat, rash, mouth ulcers,  purpura, bruising or bleeding develop   Pregnancy folic acid 5 mg daily should be given to  mother throughout pregnancy; neonatal haemolysis  and methaemoglobinaemia reported in third trimester   Breast-feeding haemolytic anaemia; although signifi-  cant amount in milk, risk to infant very small unless  infant is G6PD deficient   Side-effects (dose-related and uncommon at doses  used for leprosy), haemolysis, methaemoglobinaemia,  neuropathy, allergic dermatitis (rarely including toxic  epidermal necrolysis and Stevens- Johnson  syndrome), anorexia, nausea, vomiting, tachycardia,  headache, insomnia, psychosis, hepatitis, agranulo-  cytosis; dapsone syndrome (rash with fever and  eosinophilia) — discontinue immediately (may  progress to exfoliative dermatitis, hepatitis, hypoal-  buminaemia, psychosis and death)    Multibacillary leprosy should be treated for at least 2  years. Treatment should be continued unchanged dur-  ing both type I (reversal) or type II (erythema nodosum  leprosum) reactions. During reversal reactions neuritic  pain or weakness can herald the rapid onset of perma-  nent nerve damage. Treatment with prednisolone (initi-  ally 40-60 mg daily) should be instituted at once. Mild  type II reactions may respond to aspirin. Severe type II  reactions may require corticosteroids; thalidomide [unli-  censed] is also useful in men and post-menopausal  women who have become corticosteroid dependent,  but it should be used under specialist supervision    Dapsone (Non-proprietary) (Ml  Tablets, dapsone 50 mg, net price 28-tab pack =  £32.53; 100 mg, 28-tab pack = £47.44 Label: 8   Breast-feeding may alter colour of milk; skin disco-  loration of infant   Side-effects nausea, vomiting (hospitalise if persis-  tent), abdominal pain; headache, tiredness; brownish-  black discoloration of lesions and skin including areas  exposed to light; reversible hair discoloration; dry  skin; red discoloration of faeces, urine and other body  fluids; also rash, pruritus, photosensitivity, acne-like  eruptions, anorexia, eosinophilic enteropathy, bowel  obstruction, dry eyes, dimmed vision, macular and  subepithelial corneal pigmentation; elevation of blood  sugar, weight loss, splenic infarction, lymphadenopa-  thy  Dose   • Lepromatous lepra reactions, dosage increased to  300 mg daily for max. of 3 months   Clofazimine (Non-proprietary) (Ml  Capsules, clofazimine 100 mg. Label: 8, 14, 21  Available on named-patient basis   Metronidazole is an antimicrobial drug with high activ-  ity against anaerobic bacteria and protozoa; indications  include trichomonal vaginitis (section 5.4.3), bacterial  vaginosis (notably Gardnerella vaginalis infections),  and Entamoeba histolytica and Giardia lamblia infec-  tions (section 5.4.2). It is also used for surgical and  gynaecological sepsis in which its activity against colo-  nic anaerobes, especially Bacteroides fragilis, is impor-  tant. Metronidazole by the rectal route is an effective  alternative to the intravenous route when oral adminis-  tration is not possible. Intravenous metronidazole is  used for the treatment of established cases of tetanus;  diazepam (section 10.2.2) and tetanus immunoglobulin  (section 14.5.2) are also used.   Metronidazole by mouth is effective for the treatment of  Clostridium difficile infection , see also section 1.5; it  can be given by intravenous infusion if oral treatment is  inappropriate.   Topical metronidazole (section 13.10.1.2) reduces the  odour produced by anaerobic bacteria in fungating  tumours; it is also used in the management of rosacea  (section 13.6).   Tinidazole is similar to metronidazole but has a longer  duration of action.   Oral infections Metronidazole is an alternative to a  penicillin for the treatment of many oral infections  where the patient is allergic to penicillin or the infection  is due to beta-lactamase-producing anaerobes (Table 1,  section 5.1). It is the drug of first choice for the treat-  ment of acute necrotising ulcerative gingivitis (Vincent’s  infection) and pericoronitis; suitable alternatives are  amoxicillin (section 5. 1.1.3) and erythromycin (section  5.1.5). For these purposes metronidazole in a dose of  200 mg 3 times daily for 3 days is sufficient, but the  duration of treatment may need to be longer in pericor-  onitis. Tinidazole is licensed for the treatment of acute  ulcerative gingivitis.    Indications anaerobic infections (including dental),  see under Dose below; protozoal infections (section  5.4.2); Helicobacter pylori eradication (section 1.3);  skin (section 13.10.1.2)   Cautions disulfiram-like reaction with alcohol; avoid in  acute porphyria (section 9.8.2); clinical and laboratory  monitoring advised if treatment exceeds 10 days;  interactions: Appendix 1 (metronidazole)   Hepatic impairment in severe liver disease reduce  total daily dose to one-third, and give once daily; use  with caution in hepatic encephalopathy  Pregnancy manufacturer advises avoidance of high-  dose regimens   Breast-feeding significant amount in milk; manufac-  turer advises avoid large single doses  Side-effects gastro-intestinal disturbances (including  nausea and vomiting), taste disturbances, furred ton-  gue, oral mucositis, anorexia; very rarely hepatitis,  jaundice, pancreatitis, drowsiness, dizziness, head-  ache, ataxia, psychotic disorders, darkening of urine,  thrombocytopenia, pancytopenia, myalgia, arthralgia,  visual disturbances, rash, pruritus, and erythema  multiforme; on prolonged or intensive therapy per-  ipheral neuropathy, transient epileptiform seizures,  and leucopenia  Dose    • Anaerobic infections (usually treated for 7 days and  for 10-14 days in Clostridium difficile infection), by  mouth, either 400 mg every 8 hours or 500 mg every 8  hours, CHILD 1 month-12 years 7.5 mg/kg (max.   400 mg) every 8 hours; by rectum, 1 g every 8 hours  for 3 days, then 1 g every 12 hours, CHILD every 8  hours for 3 days, then every 12 hours, 1 month-1 year  125 mg, 1-5 years 250 mg, 5-10 years 500 mg, over 10  years, adult dose; by intravenous infusion over 20  minutes, 500 mg every 8 hours; CHILD 7.5 mg/kg  (max. 500 mg) every 8 hours   • Leg ulcers and pressure sores, by mouth, 400 mg  every 8 hours for 7 days   • Bacterial vaginosis, by mouth, 400-500 mg twice daily  for 5-7 days or 2 g as a single dose   • Pelvic inflammatory disease (see also Table 1, section  5.1), by mouth, 400 mg twice daily for 14 days   • Acute ulcerative gingivitis, by mouth, 200-250 mg  every 8 hours for 3 days; CHILD 1-3 years 50 mg every  8 hours for 3 days; 3-7 years 100 mg every 12 hours;  7-10 years 100 mg every 8 hours   • Acute oral infections, by mouth, 200 mg every 8 hours  for 3-7 days (see also notes above); CHILD 1-3 years  50 mg every 8 hours for 3-7 days; 3-7 years 100 mg  every 12 hours; 7-10 years 100 mg every 8 hours   • Surgical prophylaxis, by mouth, 400-500 mg 2 hours  before surgery; up to 3 further doses of 400-500 mg  may be given every 8 hours for high-risk procedures;  CHILD 1 month-12 years 7.5 mg/kg (max. 400 mg) 2  hours before surgery; up to 3 further doses of 7.5 mg/  kg may be given every 8 hours for high-risk proce-  dures    By rectum, 1 g 2 hours before surgery; up to 3 further  doses of 1 g may be given every 8 hours for high-risk  procedures; CHILD 5-10 years 500 mg 2 hours before  surgery; up to 3 further doses of 500 mg may be given  every 8 hours for high-risk procedures  By intravenous infusion (if rectal administration  inappropriate), 500 mg up to 30 minutes before the    procedure; up to 3 further doses of 500 mg may be  given every 8 hours for high-risk procedures; CHILD  7.5 mg/kg (max. 500 mg) up to 30 minutes before the  procedure; up to 3 further doses of 7.5 mg/kg may be  given every 8 hours for high-risk procedures  Note Metronidazole doses in BNF may differ from those in  product literature   Metronidazole (Non-proprietary) (Ml  Tablets, metronidazole 200 mg, net price 21-tab pack  = £1.36; 400 mg, 21-tab pack = £1.35. Label: 4, 9, 21,  25, 27   Tablets, both f/c, ivory, metronidazole 200 mg, net  price 21-tab pack = £4.49; 400 mg, 14-tab pack =  £6.34. Label: 4, 9, 21, 25, 27  Suppositories, metronidazole 500 mg, net price 10 =  £15.18; 1 g, 10 = £23.06. Label: 4, 9   Suspension, orange- and lemon-flavoured, metro-  nidazole (as benzoate) 200 mg/5 mL. Net price  lOOmL = £11.18. Label: 4, 9   Suppositories, metronidazole 500 mg, net price 10 =  £12.34; 1 g, 10 = £18.34. Label: 4, 9   Cautions see under Metronidazole; avoid in acute  porphyria (section 9.8.2); interactions: Appendix 1  (tinidazole)   • Anaerobic infections, 2 g initially, followed by 1 g daily  or 500 mg twice daily, usually for 5-6 days   • Bacterial vaginosis and acute ulcerative gingivitis, a  single 2-g dose   • Abdominal surgery prophylaxis, a single 2-g dose  approximately 12 hours before surgery   Tablets, f/c, tinidazole 500 mg. Net price 16-tab pack  = £11.04. Label: 4, 9, 21, 25   Nalidixic acid and norfloxacin are effective in uncom-  plicated urinary-tract infections.   Ciprofloxacin is active against both Gram-positive and  Gram-negative bacteria. It is particularly active against  Gram-negative bacteria, including salmonella, shigella,  Campylobacter, neisseria, and pseudomonas. Ciproflox-  acin has only moderate activity against Gram-positive  bacteria such as Streptococcus pneumoniae and Enter-  ococcus faecalis\ it should not be used for pneumo-  coccal pneumonia. It is active against chlamydia and  some mycobacteria. Most anaerobic organisms are not  susceptible. Ciprofloxacin can be used for respiratory  tract infections (but not for pneumococcal pneumonia),  urinary-tract infections, infections of the gastrointes-  tinal system (including typhoid fever), bone and joint  infections, gonorrhoea and septicaemia caused by sen-  sitive organisms.   Ofloxacin is used for urinary-tract infections, lower  respiratory-tract infections, gonorrhoea, and non-gono-  coccal urethritis and cervicitis.   Levofloxacin is active against Gram-positive and Gram-  negative organisms. It has greater activity against pneu-  mococci than ciprofloxacin. Levofloxacin is licensed for  community-acquired pneumonia but it is considered to  be second-line treatment for this indication.   Although ciprofloxacin, levofloxacin, moxifloxacin, and  ofloxacin are licensed for skin and soft-tissue infections,  many staphylococci are resistant to the quinolones and  their use should be avoided in MRSA infections.  Moxifloxacin should be reserved for the treatment of  sinusitis, community-acquired pneumonia, exacerba-  tions of chronic bronchitis, or complicated skin and  soft-tissue infections which have failed to respond to  other antibacterials or for patients who cannot be trea-  ted with other antibacterials. It has been associated with  life-threatening hepatotoxicity. Moxifloxacin is active  against Gram-positive and Gram-negative organisms.  It has greater activity against Gram-positive organisms,  including pneumococci, than ciprofloxacin. Moxifloxa-  cin is not active against Pseudomonas aeruginosa or  meticillin-resistant Staphylococcus aureus (MRSA).   Anthrax Inhalation or gastro-intestinal anthrax  should be treated initially with either ciprofloxacin  [not licensed for gastro-intestinal anthrax] or doxycy-  cline [unlicensed indication] (section 5.1.3) combined  with one or two other antibacterials (such as amoxicillin,  benzylpenicillin, chloramphenicol, clarithromycin,  clindamycin, imipenem with cilastatin, rifampicin [unli-  censed indication], and vancomycin). When the condi-  tion improves and the sensitivity of the Bacillus anthra-  cis strain is known, treatment may be switched to a  single antibacterial. Treatment should continue for 60  days because germination may be delayed.   Cutaneous anthrax should be treated with either cipro-  floxacin [unlicensed indication] or doxycycline [unli-  censed indication] (section 5.1.3) for 7 days. Treatment  may be switched to amoxicillin (section 5. 1.1.3) if the  infecting strain is susceptible. Treatment may need to be  extended to 60 days if exposure is due to aerosol. A  combination of antibacterials for 14 days is recom-  mended for cutaneous anthrax with systemic features,  extensive oedema, or lesions of the head or neck.  Ciprofloxacin or doxycycline may be given for post-  exposure prophylaxis. If exposure is confirmed, anti-    bacterial prophylaxis should continue for 60 days. Anti-  bacterial prophylaxis may be switched to amoxicillin  after 10-14 days if the strain of B. anthracis is suscep-  tible. Vaccination against anthrax (section 14.4) may  allow the duration of antibacterial prophylaxis to be  shortened.   Cautions Quinolones should be used with caution in  patients with a history of epilepsy or conditions that  predispose to seizures, in G6PD deficiency (section  9.1.5), myasthenia gravis (risk of exacerbation), and in  children or adolescents (arthropathy has developed in  weight-bearing joints in young animals — see below).  Exposure to excessive sunlight should be avoided (dis-  continue if photosensitivity occurs). The CSM has  warned that quinolones may induce convulsions in  patients with or without a history of convulsions; taking  NSAIDs at the same time may also induce them. Other  interactions: Appendix 1 (quinolones).   Use in children Quinolones cause arthropathy in the weight-  bearing joints of immature animals and are therefore generally  not recommended in children and growing adolescents. How-  ever, the significance of this effect in humans is uncertain and  in some specific circumstances short-term use of either cipro-  floxacin or nalidixic acid may be justified in children. For  further details see BNF for Children.   Tendon damage (including rupture) has been  reported rarely in patients receiving quinolones.  Tendon rupture may occur within 48 hours of start-  ing treatment; cases have also been reported several  months after stopping a quinolone. Healthcare pro-  fessionals are reminded that:   • quinolones are contra-indicated in patients with  a history of tendon disorders related to quino-  lone use;   • patients over 60 years of age are more prone to  tendon damage;   • the risk of tendon damage is increased by the  concomitant use of corticosteroids;   • if tendinitis is suspected, the quinolone should  be discontinued immediately.   Pregnancy Quinolones should be avoided in  pregnancy because they have been shown to cause  arthropathy in animal studies; safer alternatives are  available   Side-effects Side-effects of the quinolones include  nausea, vomiting, dyspepsia, abdominal pain, diarrhoea  (rarely antibiotic-associated colitis), headache, dizzi-  ness, rash (very rarely Stevens- Johnson syndrome and  toxic epidermal necrolysis). Less frequent side-effects  include anorexia, sleep disturbances, asthenia, confu-  sion, anxiety, depression, hallucinations, tremor, blood  disorders (including eosinophilia, leucopenia, thrombo-  cytopenia), arthralgia, myalgia, disturbances in vision  and taste. Other side-effects reported rarely or very  rarely include hepatic dysfunction (including jaundice  and hepatitis), hypotension, vasculitis, dyspnoea (more  frequent with moxifloxacin), convulsions, psychoses,  paraesthesia, renal failure, interstitial nephritis, tendon  inflammation and damage (see also Tendon Damage  above), photosensitivity, disturbances in hearing and  smell. The drug should be discontinued if psychiatric,  neurological or hypersensitivity reactions (including  severe rash) occur.   Cautions see notes above; avoid excessive alkalinity of  urine and ensure adequate fluid intake (risk of crys-  talluria); interactions: Appendix 1 (quinolones)  Driving May impair performance of skilled tasks (e.g. driv-  ing); effects enhanced by alcohol   Contra-indications see notes above  Renal impairment by mouth, 250-500 mg every 12  hours if eGFR 30-60 mL/minute/ 1.73 m 2 (every 24  hours if eGFR less than 30 mL/minute/ 1.73 m 2 ); by  intravenous infusion (200 mg over 30 minutes), 200-  400 mg every 12 hours if eGFR 30-60 mL/minute/  1.73 m 2 (every 24 hours if eGFR less than 30 mL/  minute/ 1.73 m 2 )    Side-effects see notes above; also flatulence, pain and  phlebitis at injection site; rarely dysphagia, pancreat-  itis, chest pain, tachycardia, syncope, oedema, hot  flushes, abnormal dreams, sweating, hyperglycaemia,  and erythema nodosum; very rarely movement dis-  orders, tinnitus, and tenosynovitis   • By mouth, respiratory-tract infections, 500-750 mg  twice daily (750 mg twice daily in pseudomonal lower  respiratory-tract infection in cystic fibrosis)  Urinary-tract infections, 250-750 mg twice daily  (250 mg twice daily for 3 days usually adequate for  acute uncomplicated cystitis in women)   Acute or chronic prostatitis, 500 mg twice daily for 28  days   Gonorrhoea, 500 mg as a single dose  Most other infections, 500 mg twice daily (increased  to 750 mg twice daily in severe or deep-seated infec-  tion)   • By intravenous infusion over 60 minutes, 400 mg  every 8-12 hours   • Anthrax (treatment and post-exposure prophylaxis,  see notes above), by mouth, 500 mg twice daily   By intravenous infusion over 60 minutes, 400 mg  every 12 hours    Ciprofloxacin (Non-proprietary) (Ml  Tablets, ciprofloxacin (as hydrochloride) 100 mg, net  price 6-tab pack = £1.42; 250 mg, 10-tab pack = 96p,  20-tab pack = £1.09; 500 mg, 10-tab pack = £1.06, 20-  tab pack = £1.22; 750 mg, 10-tab pack = £6.15.   Label: 7, 9, 25, counselling, driving  Intravenous infusion, ciprofloxacin (as lactate)  2mg/mL, net price 50-mL bottle = £8.00, 100-mL  bottle = £15.00, 200-mL bottle = £22.00   250 mg (scored), 10-tab pack = £6.59; 500 mg  (scored), 10-tab pack = £12.49; 750 mg, 10-tab pack =  £17.78. Label: 7, 9, 25, counselling, driving  Suspension, strawberry-flavoured, ciprofloxacin for  reconstitution with diluent provided, 250 mg/5 mL,   2 mg/mL, in sodium chloride 0.9%, net price 50-mL  bottle = £7.61, 100-mL bottle = £15.02, 200-mL bottle  = £22.85   Indications see under Dose  Cautions see notes above; predisposition to QT  interval prolongation (including cardiac disease, con-  genital long QT syndrome, electrolyte disturbances,  concomitant use with other drugs known to prolong  QT interval); history of psychiatric illness; interac-  tions: Appendix 1 (quinolones)   Contra-indications see notes above  Renal impairment usual initial dose then use half  normal dose if eGFR 20-50 mL/minute/ 1.73 m 2 ;  consult product literature if eGFR less than 20 mL/  minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding manufacturer advises avoid  Side-effects see notes above; also flatulence, consti-  pation; rarely tachycardia; very rarely pneumonitis,  peripheral neuropathy, and hypoglycaemia; also  reported, rhabdomyolysis and potentially life-threa-  tening hepatic failure; local reactions and transient  hypotension reported with infusion  Dose   • By mouth, acute sinusitis, 500 mg daily for 10-14 days  Exacerbation of chronic bronchitis, 250-500 mg daily  for 7-10 days   Community-acquired pneumonia, 500 mg once or  twice daily for 7-14 days   Urinary-tract infections, 250 mg daily for 7-10 days  (for 3 days in uncomplicated infection)   Chronic prostatitis, 500 mg once daily for 28 days  Skin and soft tissue infections, 250 mg daily or 500 mg  once or twice daily for 7-14 days   • By intravenous infusion (over at least 60 minutes for  500 mg), community-acquired pneumonia, 500 mg  once or twice daily   Complicated urinary-tract infections, 250 mg daily,  increased in severe infections  Skin and soft tissue infections, 500 mg twice daily  Tavanic® (Sanofi-Aventis) (Ml  Tablets, yellow-red, f/c, scored, levofloxacin 250 mg,  net price 5-tab pack = £7.23, 10-tab pack = £14.45;  500 mg, 5-tab pack = £12.93, 10-tab pack = £25.85.  Label: 6, 9, 25, counselling, driving  Intravenous infusion, levofloxacin 5 mg/mL, net  price 100-mL bottle = £26.40   Indications sinusitis, community-acquired pneu-  monia, exacerbations of chronic bronchitis, or com-  plicated skin and soft-tissue infections which have  failed to respond to other antibacterials or for patients  who cannot be treated with other antibacterials  Cautions see notes above; conditions pre-disposing to  arrhythmias, including myocardial ischaemia; inter-  actions: Appendix 1 (quinolones)    Contra-indications see notes above; history of QT-  interval prolongation, bradycardia, history of symp-  tomatic arrhythmias, heart failure with reduced left  ventricular ejection fraction, electrolyte disturbances,  concomitant use with other drugs known to prolong  QT-interval   Side-effects see notes above; also gastritis, flatulence,  constipation, arrhythmias, palpitation, angina, vaso-  dilatation, hyperlipidaemia, and sweating; rarely  oedema, hypertension, syncope, dysphagia, abnormal  dreams, incoordination, amnesia, hyperglycaemia,  hyperuricaemia, and stomatitis; very rarely rhabdo-  myolysis and potentially life-threatening hepatic fail-  ure; on intravenous infusion, pain and phlebitis at  injection site  Dose   • By intravenous infusion over 60 minutes, community-  acquired pneumonia, complicated skin and soft-tissue  infections, 400 mg once daily   Note Recommended duration of treatment is 7-14 days for  community-acquired pneumonia, 5-10 days in exacerbations  of chronic bronchitis, 7 days in sinusitis, 7-2 1 days for com-  plicated skin and soft-tissue infections   Avelox® (Bayer Schering) T [Ml  Tablets, red, f/c, moxifloxacin (as hydrochloride)   Intravenous infusion, moxifloxacin (as hydro-  chloride) 1.6 mg/mL, net price 250-mL bottle  (400 mg) =£39.95   Indications urinary-tract infections  Cautions see notes above; avoid in acute porphyria  (section 9.8.2); false positive urinary glucose (if tested  for reducing substances); monitor blood counts, renal  and liver function if treatment exceeds 2 weeks;  interactions: Appendix 1 (quinolones)  Contra-indications see notes above  Hepatic impairment manufacturer advises caution in  liver disease   Renal impairment use with caution; avoid if eGFR  less than 20 mL/minute/ 1.73 m 2  Pregnancy see notes above   Breast-feeding risk to infant very small but one case  of haemolytic anaemia reported  Side-effects see notes above; also reported toxic  psychosis, increased intracranial pressure, cranial  nerve palsy, peripheral neuropathy, and metabolic  acidosis  Dose   • 900 mg every 6 hours for 7 days, reduced in chronic  infections to 600 mg every 6 hours; CHILD 3 months-  18 years see BNF for Children   Nalidixic Acid (Rosemont) (Ml  Suspension, pink, nalidixic acid 300 mg/5 mL, net  price 150 mL (raspberry- and strawberry-flavoured) =  £12.50. Label: 9, 11   Contra-indications see notes above  Renal impairment use 400 mg once daily if eGFR less  than 30 mL/minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding no information available — manufac-  turer advises avoid   Side-effects see notes above; also tinnitus, epiphora;  rarely pancreatitis; very rarely arrhythmias; also  reported, polyneuropathy and exfoliative dermatitis   • ‘Lower’ urinary-tract infections, 400 mg twice daily for  7-10 days (for 3 days for uncomplicated infections in  women)   400 mg twice daily for up to 12 weeks; may be  reduced to 400 mg once daily if adequate suppression  within first 4 weeks   Tablets, norfloxacin 400 mg, net price 6-tab pack =  £2.30, 14-tab pack = £6.20. Label: 7, 9, 23, counselling,  driving   Tablets, scored, norfloxacin 400 mg. Net price 7-tab  pack = £2.56, 14-tab pack = £5.11. Label: 7, 9, 23,  counselling, driving   Driving May affect performance of skilled tasks (e.g. driv-  ing); effects enhanced by alcohol  Contra-indications see notes above  Hepatic impairment use with caution; elimination  may be reduced in severe impairment  Renal impairment usual initial dose, then use half  normal dose if eGFR 20-50 mL/minute/ 1.73 m 2 ;   100 mg every 24 hours if eGFR less than 20 mL/  minute/ 1.73 m 2  Pregnancy see notes above  Breast-feeding amount probably too small to be  harmful but manufacturer advises avoid  Side-effects see notes above; also eye irritation;  rarely arrhythmias, abnormal dreams, hot flushes,  hyperhidrosis; very rarely neuropathy, extrapyramidal  symptoms; also reported pneumonitis, changes in  blood sugar, myopathy, rhabdomyolysis; on intra-  venous infusion, hypotension and local reactions  (including thrombophlebitis)   • By mouth, urinary-tract infections, 200-400 mg daily  preferably in the morning, increased if necessary in  upper urinary-tract infections to 400 mg twice daily  Acute or chronic prostatitis, 200 mg twice daily for 28  days   Lower respiratory-tract infections, 400 mg daily pre-  ferably in the morning, increased if necessary to  400 mg twice daily    Uncomplicated gonorrhoea, 400 mg as a single dose  Uncomplicated genital chlamydial infection, non-  gonococcal urethritis, 400 mg daily in single or  divided doses for 7 days   Pelvic inflammatory disease (see also section 5.1,  table 1), 400 mg twice daily for 14 days   • By intravenous infusion (over at least 30 minutes for  each 200 mg), complicated urinary-tract infection,  200 mg daily   Lower respiratory-tract infection, 200 mg twice daily  Septicaemia, 200 mg twice daily  Skin and soft-tissue infections, 400 mg twice daily  Severe or complicated infections, dose may be  increased to 400 mg twice daily   Ofloxacin (Non-proprietary) fMl  Tablets, ofloxacin 200 mg, net price 10-tab pack =  £8.29; 400 mg, 5-tab pack = £5.71, 10-tab pack =  £5.52. Label: 6, 9, 11, counselling, driving   Tarivid® (Sanofi-Aventis) [MI  Tablets, f/c, scored, ofloxacin 200 mg, net price 10-  tab pack = £7.53, 20-tab pack = £15.05; 400 mg  (yellow), 5-tab pack = £7.52, 10-tab pack = £14.99.  Label: 6, 9, 11, counselling, driving  Intravenous infusion, ofloxacin (as hydrochloride)  2mg/mL, net price 100-mL bottle = £16.16 (hosp.  only)   Urinary-tract infection is more common in women than  in men; when it occurs in men there is frequently an  underlying abnormality of the renal tract. Recurrent  episodes of infection are an indication for radiological  investigation especially in children in whom untreated  pyelonephritis may lead to permanent kidney damage.  Escherichia coli is the most common cause of urinary-  tract infection; Staphylococcus saprophyticus is also  common in sexually active young women. Less com-  mon causes include Proteus and Klebsiella spp. Pseudo-  monas aeruginosa infections usually occur in the hos-  pital setting and may be associated with functional or  anatomical abnormalities of the renal tract. Staphylo-  coccus epidermidis and Enterococcus faecalis infection  may complicate catheterisation or instrumentation.   A specimen of urine should be collected for culture  and sensitivity testing before starting antibacterial  therapy;   • in patients with suspected upper urinary-tract  infection, complicated infection, or recurrent  infection;   • if urine dipstick testing gives a single positive  result for leucocyte esterase or nitrite;   • if clinical symptoms are not consistent with  results of dipstick testing.   Treatment should not be delayed while waiting for  results. The antibacterial chosen should reflect cur-  rent local bacterial sensitivity to antibacterials.    Uncomplicated lower urinary-tract infections often  respond to trimethoprim, nitrofurantoin, amoxicillin,  or nalidixic acid given for 7 days (3 days may be    adequate for infections in women; see also Table 1,  section 5.1); those caused by fully sensitive bacteria  respond to two 3-g doses of amoxicillin (section  5. 1.1.3). Widespread bacterial resistance to ampicillin,  amoxicillin, and trimethoprim has been reported. Alter-  natives for resistant organisms include co-amoxiclav  (amoxicillin with clavulanic acid), an oral cephalosporin,  pivmecillinam, or a quinolone.   Long-term low dose therapy may be required in  selected patients to prevent recurrence of infection',  indications include frequent relapses and significant  kidney damage. Trimethoprim, nitrofurantoin and cefa-  lexin have been recommended for long-term therapy.   Methenamine (hexamine) should not generally be used  because it requires an acidic urine for its antimicrobial  activity and it is ineffective for upper urinary-tract infec-  tions; it may, however, have a role in the prophylaxis and  treatment of chronic or recurrent uncomplicated lower  urinary-tract infections.   Acute pyelonephritis can lead to septicaemia and is  treated initially by injection of a broad-spectrum anti-  bacterial such as cefuroxime or a quinolone if the  patient is severely ill; gentamicin can also be used.   Prostatitis can be difficult to cure and requires treat-  ment for several weeks with an antibacterial which  penetrates prostatic tissue such as trimethoprim, or  some quinolones.   Where infection is localised and associated with an  indwelling catheter a bladder instillation is often effec-  tive (section 7.4.4).   Pregnancy Urinary-tract infection in pregnancy may  be asymptomatic and requires prompt treatment to  prevent progression to acute pyelonephritis. Penicillins  and cephalosporins are suitable for treating urinary-  tract infection during pregnancy. Nitrofurantoin may  also be used but it should be avoided at term. Sulfona-  mides, quinolones, and tetracyclines should be avoided  during pregnancy; trimethoprim should also preferably  be avoided particularly in the first trimester.    Renal impairment In renal failure antibacterials nor-  mally excreted by the kidney accumulate with resultant  toxicity unless the dose is reduced. This applies espe-  cially to the aminoglycosides which should be used with  great caution; tetracyclines, methenamine, and nitro-  furantoin should be avoided altogether.    Children Urinary-tract infections in children require  prompt antibacterial treatment to minimise the risk of  renal scarring. Uncomplicated ‘lower’ urinary-tract  infections in children over 3 months of age can be  treated with trimethoprim, nitrofurantoin, a first genera-  tion cephalosporin (e.g. cefalexin), or amoxicillin for 3  days; children should be reassessed if they continue to  be unwell 24-48 hours after the initial assessment.  Amoxicillin should only be used if the organism causing  the infection is sensitive to it.   Acute pyelonephritis in children over 3 months of age  can be treated with a first generation cephalosporin or  co-amoxiclav for 7-10 days. If the patient is severely ill,  then the infection is best treated initially by injection of a  broad-spectrum antibacterial such as cefotaxime or co-  amoxiclav; gentamicin is an alternative.   Children under 3 months of age should be transferred to  hospital and treated initially with intravenous anti-    bacterial drugs such as ampicillin with gentamicin, or  cefotaxime alone, until the infection responds; full doses  of oral antibacterials are then given for a further period.  Recurrent episodes of infection are an indication for  imaging tests. Antibacterial prophylaxis with low doses  of trimethoprim or nitrofurantoin may be considered for  children with recurrent infection, significant urinary-  tract anomalies, or significant kidney damage.   Cautions anaemia; diabetes mellitus; electrolyte  imbalance; vitamin B and folate deficiency; pulm-  onary disease; on long-term therapy, monitor liver  function and monitor for pulmonary symptoms,  especially in the elderly (discontinue if deterioration in  lung function); susceptibility to peripheral neuropathy;  false positive urinary glucose (if tested for reducing  substances); urine may be coloured yellow or brown;  interactions: Appendix 1 (nitrofurantoin)   Contra-indications infants less than 3 months old,  G6PD deficiency (section 9.1.5); acute porphyria  (section 9.8.2)   Hepatic impairment use with caution; cholestatic  jaundice and chronic active hepatitis reported   Renal impairment avoid if eGFR less than 60 mL/  minute/ 1.73 m 2 ; risk of peripheral neuropathy; inef-  fective because of inadequate urine concentrations   Breast-feeding avoid; only small amounts in milk but  could be enough to produce haemolysis in G6PD-  deficient infants (section 9.1.5)   Side-effects anorexia, nausea, vomiting, and diarr-  hoea; acute and chronic pulmonary reactions (pulm-  onary fibrosis reported; possible association with  lupus erythematosus-like syndrome); peripheral  neuropathy; also reported, hypersensitivity reactions  (including angioedema, anaphylaxis, sialadenitis,  urticaria, rash and pruritus); rarely, cholestatic jaun-  dice, hepatitis, exfoliative dermatitis, erythema mul-  tiforme, pancreatitis, arthralgia, blood disorders  (including agranulocytosis, thrombocytopenia, and  aplastic anaemia), benign intracranial hypertension,  and transient alopecia  Dose   • Acute uncomplicated infection, 50 mg every 6 hours  with food for 7 days (3 days usually adequate in  women); CHILD over 3 months, 3 mg/kg daily in 4  divided doses   • Severe chronic recurrent infection, 100 mg every 6  hours with food for 7 days (dose reduced or discon-  tinued if severe nausea)   • Prophylaxis (but see Cautions), 50-100 mg at night;  CHILD over 3 months, 1 mg/kg at night   Nitrofurantoin (Non-proprietary) iMl  Tablets, nitrofurantoin 50 mg, net price 28-tab pack =  £1.84; 100 mg, 28-tab pack = £4.43. Label: 9, 14, 21  Oral suspension, nitrofurantoin 25 mg/5 mL, net  price 300 mL = £99.05. Label: 9, 14, 21  Note Sugar-free versions are available and can be ordered by  specifying ‘sugar-free’ on the prescription   Tablets, all yellow, scored, nitrofurantoin 50 mg, net  price 100-tab pack = £9.79; 100 mg, 100-tab pack =  £18.11. Label: 9, 14, 21   Capsules, yellow/white, nitrofurantoin 50 mg (as  macrocrystals), net price 30-cap pack = £2.49; 100 mg  (yellow/ white), 30-cap pack = £4.81. Label: 9, 14, 21   Macrobid® (Goldshield) [Ml  Capsules, m/r, blue/yellow, nitrofurantoin 100 mg  (as nitrofurantoin macrocrystals and nitrofurantoin  monohydrate), net price 14-cap pack = £4.89.   Genito-urinary surgical prophylaxis, 1 capsule twice daily on day  of procedure and for 3 days after   Indications prophylaxis and long-term treatment of  chronic or recurrent lower urinary-tract infections  Cautions avoid concurrent administration with sulfo-  namides (risk of crystalluria) or urinary alkalinising  agents; interactions: Appendix 1 (methenamine)  Contra-indications severe dehydration, gout, metab-  olic acidosis   Hepatic impairment avoid  Renal impairment avoid if eGFR less than 10 mL/  minute/1.73 m 2 — risk of hippurate crystalluria  Pregnancy use with caution  Breast-feeding amount too small to be harmful  Side-effects gastro-intestinal disturbances, bladder  irritation, rash  Dose   • 1 g every 12 hours (may be increased in patients with  catheters to 1 g every 8 hours); CHILD 6-12 years  500 mg every 12 hours   Tablets, scored, methenamine hippurate 1 g, net price  60-tab pack = £6.58. Label: 9   The systemic treatment of common fungal infections is  outlined below; specialist treatment is required in most  forms of systemic or disseminated fungal infections. For  local treatment of fungal infections, see section 7.2.2  (genital), section 7.4.4 (bladder), section 11.3.2 (eye),  section 12.1.1 (ear), section 12.3.2 (oropharynx), and  section 13.10.2 (skin).   Aspergillosis Aspergillosis most commonly affects  the respiratory tract but in severely immunocompro-  mised patients, invasive forms can affect the heart,  brain, and skin. Voriconazole (section 5.2.1) is the  treatment of choice for aspergillosis; liposomal  amphotericin (section 5.2.3) is an alternative first-line  treatment when voriconazole cannot be used. Caspo-    fungin (section 5.2.4), itraconazole (section 5.2.1), or  posaconazole (section 5.2.1) can be used in patients  who are refractory to, or intolerant of voriconazole and  liposomal amphotericin. Itraconazole is also used for  the treatment of chronic pulmonary aspergillosis or as  an adjunct in the treatment of allergic bronchopulmon-  ary aspergillosis [unlicensed indication].   Candidiasis Many superficial candidal infections  including infections of the skin (section 13.10.2) are  treated locally; widespread or intractable infection  requires systemic antifungal treatment. Vaginal candi-  diasis (section 7.2.2) may be treated with locally acting  antifungals or with fluconazole (section 5.2.1) given by  mouth; for resistant organisms, itraconazole (section  5.2.1) can be given by mouth.   Oropharyngeal candidiasis generally responds to topi-  cal therapy (section 12.3.2); fluconazole is given by  mouth for unresponsive infections; it is effective and is  reliably absorbed. Itraconazole may be used for flucon-  azole-resistant infections. Topical therapy may not be  adequate in immunocompromised patients and an oral  triazole antifungal is preferred.   For invasive or disseminated candidiasis, an echino-  candin (section 5.2.4) can be used. Fluconazole (sec-  tion 5.2.1) is an alternative for Candida albicans infec-  tion in clinically stable patients who have not received  an azole antifungal recently. Amphotericin (section  5.2.3) is an alternative when an echinocandin or flucon-  azole cannot be used, however, amphotericin should be  considered for the initial treatment of CNS candidiasis,  Voriconazole (section 5.2.1) can be used for infections  caused by fluconazole-resistant Candida spp. when oral  therapy is required, or in patients intolerant of amphot-  ericin or an echinocandin. In refractory cases, flucyto-  sine (section 5.2.5) can be used with intravenous  amphotericin.   Cryptococcosis Cryptococcosis is uncommon but  infection in the immunocompromised, especially in  HIV-positive patients, can be life-threatening; crypto-  coccal meningitis is the most common form of fungal  meningitis. The treatment of choice in cryptococcal  meningitis is amphotericin (section 5.2.3) by intra-  venous infusion and flucytosine (section 5.2.5) by intra-  venous infusion for 2 weeks, followed by fluconazole  (section 5.2.1) by mouth for 8 weeks or until cultures are  negative. In cryptococcosis, fluconazole is sometimes  given alone as an alternative in HIV-positive patients  with mild, localised infections or in those who cannot  tolerate amphotericin. Following successful treatment,  fluconazole can be used for prophylaxis against relapse  until immunity recovers.   Histoplasmosis Histoplasmosis is rare in temperate  climates; it can be life-threatening, particularly in HIV-  infected persons. Itraconazole (section 5.2.1) can be  used for the treatment of immunocompetent patients  with indolent non-meningeal infection, including  chronic pulmonary histoplasmosis. Amphotericin (sec-  tion 5.2.3) by intravenous infusion is preferred in  patients with fulminant or severe infections. Following  successful treatment, itraconazole can be used for  prophylaxis against relapse until immunity recovers.   Skin and nail infections Mild localised fungal infec-  tions of the skin (including tinea corporis, tinea cruris,  and tinea pedis) respond to topical therapy (section    13.10.2). Systemic therapy is appropriate if topical ther-  apy fails, if many areas are affected, or if the site of  infection is difficult to treat such as in infections of the  nails (onychomycosis) and of the scalp (tinea capitis).  Oral imidazole or triazole antifungals (particularly itra-  conazole) and terbinafine are used more frequently  than griseofulvin because they have a broader spectrum  of activity and require a shorter duration of treatment.  Tinea capitis is treated systemically; additional topical  application of an antifungal (section 13.10.2) may  reduce transmission. Griseofulvin (section 5.2.5) is  used for tinea capitis in adults and children; it is effective  against infections caused by Trichophyton tonsurans  and Microsporum spp. Terbinafine (section 5.2.5) is  used for tinea capitis caused by T. tonsurans [unli-  censed indication]. The role of terbinafine in the man-  agement of Microsporum infections is uncertain.   Pityriasis versicolor (section 13.10.2) may be treated  with itraconazole (section 5.2.1) by mouth if topical  therapy is ineffective; fluconazole (section 5.2.1) by  mouth is an alternative. Oral terbinafine is not effective  for pityriasis versicolor.   Antifungal treatment may not be necessary in asympto-  matic patients with tinea infection of the nails. If treat-  ment is necessary, a systemic antifungal is more effec-  tive than topical therapy. Terbinafine (section 5.2.5) and  itraconazole (section 5.2.1) have largely replaced  griseofulvin for the systemic treatment of onycho-  mycosis, particularly of the toenail; terbinafine is con-  sidered to be the drug of choice. Itraconazole can be  administered as intermittent ‘pulse’ therapy. For the role  of topical antifungals in the treatment of onycho-  mycosis, see section 13.10.2.    Immunocompromised patients Immunocompro-  mised patients are at particular risk of fungal infections  and may receive antifungal drugs prophylactically; oral  triazole antifungals are the drugs of choice for prophy-  laxis. Fluconazole (section 5.2.1) is more reliably  absorbed than itraconazole (section 5.2.1), but flucon-  azole is not effective against Aspergillus spp. Itracon-  azole is preferred in patients at risk of invasive asper-  gillosis. Posaconazole (section 5.2.1) can be used for  prophylaxis in patients who are undergoing haemato-  poietic stem cell transplantation or receiving chemo-  therapy for acute myeloid leukaemia and myelodysplas-  tic syndrome, if they are intolerant of fluconazole or  itraconazole. Micafungin (section 5.2.4) can be used for  prophylaxis of candidiasis in patients undergoing hae-  matopoietic stem cell transplantation when fluconazole,  itraconazole or posaconazole cannot be used.   Amphotericin (section 5.2.3) by intravenous infusion or  caspofungin (section 5.2.4) is used for the empirical  treatment of serious fungal infections; caspofungin is not  effective against fungal infections of the CNS.   For the role of triazole antifungal drugs in the prevention  and systemic treatment of fungal infections, see p. 373.  Fluconazole is very well absorbed after oral adminis-  tration. It also achieves good penetration into the cere-  brospinal fluid to treat fungal meningitis. Fluconazole is  excreted largely unchanged in the urine and can be used  to treat candiduria.   Itraconazole is active against a wide range of derma-  tophytes. Itraconazole capsules require an acid environ-  ment in the stomach for optimal absorption.  Itraconazole has been associated with liver damage and  should be avoided or used with caution in patients with  liver disease; fluconazole is less frequently associated  with hepatotoxicity.   Posaconazole is licensed for the treatment of invasive  fungal infections unresponsive to conventional treat-  ment.   Voriconazole is a broad-spectrum antifungal drug  which is licensed for use in life-threatening infections.   Cautions concomitant use with hepatotoxic drugs,  monitor liver function with high doses or extended  courses — discontinue if signs or symptoms of hepatic  disease (risk of hepatic necrosis); susceptibility to QT  interval prolongation; interactions: Appendix 1  (antifungals, triazole)   Renal impairment usual initial dose then halve sub-  sequent doses if eGFR less than 50 mL/minute/   Breast-feeding present in milk but amount probably  too small to be harmful   Side-effects nausea, abdominal discomfort, diarr-  hoea, flatulence, headache, rash (discontinue treat-  ment or monitor closely if infection invasive or sys-  temic); less frequently dyspepsia, vomiting, taste  disturbance, hepatic disorders, hypersensitivity reac-  tions, anaphylaxis, dizziness, seizures, alopecia, pru-  ritus, toxic epidermal necrolysis, Stevens- Johnson  syndrome (severe cutaneous reactions more likely in  AIDS patients), hyperlipidaemia, leucopenia, throm-  bocytopenia, and hypokalaemia reported   • Vaginal candidiasis (see also Recurrent Vulvovaginal  Candidiasis, section 7.2.2) and candidal balanitis,  ADULT and CHILD over 16 years, by mouth, a single dose  of 150 mg   • Mucosal candidiasis (except genital), by mouth, 50 mg  daily (100 mg daily in unusually difficult infections)  given for 7-14 days in oropharyngeal candidiasis  (max. 14 days except in severely immunocompro-  mised patients); for 14 days in atrophic oral candi-  diasis associated with dentures; for 14-30 days in  other mucosal infections (e.g. oesophagitis, candi-  duria, non-invasive bronchopulmonary infections);  CHILD by mouth or by intravenous infusion, 3-6 mg/  kg on first day then 3 mg/kg daily (every 72 hours in  NEONATE up to 2 weeks old, every 48 hours in neonate  2-4 weeks old)   • Tinea pedis, corporis, cruris, pityriasis versicolor, and  dermal candidiasis, by mouth, 50 mg daily for 2-4  weeks (for up to 6 weeks in tinea pedis); max. duration  of treatment 6 weeks   • Invasive candidal infections (including candidaemia  and disseminated candidiasis) and cryptococcal    infections (including meningitis), by mouth or intra-  venous infusion, 400 mg on first day then 200-400 mg  daily; max. 800 mg daily in severe infections [unli-  censed dose]; treatment continued according to  response (at least 8 weeks for cryptococcal mening-  itis); CHILD 6-12 mg/kg daily (every 72 hours in NEO-  NATE up to 2 weeks old, every 48 hours in NEONATE 2-4  weeks old); max. 800 mg daily [unlicensed dose]   • Prevention of relapse of cryptococcal meningitis in  HIV-infected patients after completion of primary  therapy, by mouth or by intravenous infusion, 200 mg  daily   • Prevention of fungal infections in immunocompro-  mised patients, by mouth or by intravenous infusion,  50-400 mg daily adjusted according to risk; 400 mg  daily if high risk of systemic infections e.g. following  bone-marrow transplantation; commence treatment  before anticipated onset of neutropenia and continue  for 7 days after neutrophil count in desirable range;  CHILD according to extent and duration of neutrope-  nia, 3-12 mg/kg daily (every 72 hours in NEONATE up  to 2 weeks old, every 48 hours in NEONATE 2-4 weeks  old); max. 400 mg daily   Fluconazole (Non-proprietary) (Ml  1 Capsules, fluconazole 50 mg, net price 7-cap pack =  £1.14; 150 mg, single-capsule pack = 98p; 200 mg, 7-  cap pack = £5.04. Label: 9, (50 and 200 mg)   Intravenous infusion, fluconazole 2mg/mL, net  price 25-mL bottle = £7.31; 100-mL bottle = £29.27;  100-mL infusion bag = £27.82   1 Capsules, fluconazole 50 mg (blue/white), net price  7-cap pack = £16.61; 150 mg (blue), single-capsule  pack = £7.12; 200 mg (purple /white), 7-cap pack =  £66.42. Label: 9, (50 and 200 mg)   Oral suspension, orange-flavoured, fluconazole for  reconstitution with water, 50 mg/ 5 mL, net price  35 mL = £16.61; 200 mg/5 mL, 35 mL =£66.42.  Label: 9   Intravenous infusion, fluconazole 2mg/mL in sod-  ium chloride intravenous infusion 0.9%, net price 25-  mL bottle = £7.32; 100-mL bottle = £29.28   Cautions absorption reduced in AIDS and neutropenia  (monitor plasma-itraconazole concentration and  increase dose if necessary); susceptibility to conges-  tive heart failure (see also Heart Failure, below);  interactions: Appendix 1 (antifungals, triazole)  Hepatotoxicity Potentially life-threatening hepatotoxicity  reported very rarely — discontinue if signs of hepatitis  develop. Avoid or use with caution if history of hepatotoxi-  city with other drugs or in active liver disease. Monitor liver  function if treatment continues for longer than one month, if  receiving other hepatotoxic drugs, if history of hepatotoxicity  with other drugs, or in hepatic impairment  Counselling Patients should be told how to recognise signs  of liver disorder and advised to seek prompt medical atten-    1. Capsules can be sold to the public for vaginal candidiasis  and associated candidal balanitis in those aged 16-60   years, in a container or packaging containing not more  than 150 mg and labelled to show a max. dose of 150 mg    tion if symptoms such as anorexia, nausea, vomiting, fatigue,  abdominal pain or dark urine develop   Following reports of heart failure, caution is advised  when prescribing itraconazole to patients at high risk  of heart failure. Those at risk include:   • patients receiving treatment with negative inotropic drugs,  e.g. calcium channel blockers.   Itraconazole should be avoided in patients with  ventricular dysfunction or a history of heart failure  unless the infection is serious.   Contra-indications acute porphyria (section 9.8.2)  Hepatic impairment use only if potential benefit out-  weighs risk of hepatotoxicity (see Hepatotoxicity  above); dose reduction may be necessary  Renal impairment risk of congestive heart failure;  bioavailability of oral formulations possibly reduced;  use intravenous infusion with caution if eGFR 30-  80mL/minute/1.73m 1 2 ; avoid intravenous infusion if  eGFR less than 30 mL/minute/ 1.73m 2    Pregnancy manufacturer advises use only in life-  threatening situations (toxicity at high doses in ani-  mal studies); ensure effective contraception during  treatment and until the next menstrual period fol-  lowing end of treatment   Side-effects nausea, abdominal pain, rash; less com-  monly vomiting, dyspepsia, taste disturbances, flatu-  lence, diarrhoea, constipation, oedema, headache,  dizziness, paraesthesia (discontinue treatment if  neuropathy), menstrual disorder, and alopecia; rarely  pancreatitis, hypoaesthesia, urinary frequency, leuco-  penia, visual disturbances, and tinnitus; also reported,  heart failure (see Cautions above), hypertriglyceri-  daemia, hepatitis (see Hepatotoxicity above), erectile  dysfunction, thrombocytopenia, hypokalaemia, myal-  gia, arthralgia, photosensitivity, toxic epidermal  necrolysis, and Stevens-Johnson syndrome; with  intravenous injection hypertension and hyperglyc-  aemia   • By mouth, oropharyngeal candidiasis, see under  Sporanox® oral liquid below  Vulvovaginal candidiasis, (see also Recurrent Vulvo-  vaginal Candidiasis, section 7.2.2) 200 mg twice daily  for 1 day   Pityriasis versicolor, 200 mg once daily for 7 days  Tinea corporis and tinea cruris, either 100 mg once  daily for 15 days or 200 mg once daily for 7 days  Tinea pedis and tinea manuum, either 100 mg once  daily for 30 days or 200 mg twice daily for 7 days  Onychomycosis, either 200 mg once daily for 3  months or course (‘pulse’) of 200 mg twice daily for 7  days, subsequent courses repeated after 21-day  interval; fingernails 2 courses, toenails 3 courses  Histoplasmosis, 200 mg 3 times daily for 3 days, then  200 mg once or twice daily  Systemic aspergillosis, candidiasis and crypto-  coccosis including cryptococcal meningitis where  other antifungal drugs inappropriate or ineffective,  200 mg once daily (candidiasis 100-200 mg once  daily) increased in invasive or disseminated disease  and in cryptococcal meningitis to 200 mg twice daily    Maintenance in HIV-infected patients to prevent  relapse of underlying fungal infection and prophylaxis  in neutropenia when standard therapy inappropriate,  200 mg once daily, increased to 200 mg twice daily if  low plasma-itraconazole concentration (see Cautions)  Prophylaxis in patients with haematological malig-  nancy or undergoing bone-marrow transplant, see  under Sporanox® oral liquid below   • By intravenous infusion, systemic aspergillosis,  candidiasis and cryptococcosis including crypto-  coccal meningitis where other antifungal drugs inap-  propriate or ineffective, histoplasmosis, 200 mg every  12 hours for 2 days, then 200 mg once daily for max.  12 days    Itraconazole (Non-proprietary) (Ml  Capsules, enclosing coated beads, itraconazole  100 mg, net price 15-cap pack = £7.21. Label: 5, 9, 21,  25, counselling, hepatotoxicity    Sporanox® Qanssen-Cilag) [Ml  Capsules, blue/pink, enclosing coated beads, itra-  conazole 100 mg, net price 4-cap pack = £3.67; 15-cap  pack = £13.77; 28-cap pack (Sporanox® -Pulse) =  £25.72; 60-cap pack = £55.10. Label: 5, 9, 21, 25,  counselling, hepatotoxicity   Oral liquid, sugar-free, cherry-flavoured, itraconazole  lOmg/mL, net price 150mL (with 10-mL measuring  cup) = £45.80. Label: 9, 23, counselling, administra-  tion, hepatotoxicity   Dose oral or oesophageal candidiasis in HIV-positive or other  immunocompromised patients, 20 mL (2 measuring cups) daily in  1-2 divided doses for 1 week (continue for another week if no  response)   Fluconazole-resistant oral or oesophageal candidiasis, 10-20 mL  ( 1-2 measuring cups) twice daily for 2 weeks (continue for another  2 weeks if no response; the higher dose should not be used for  longer than 2 weeks if no signs of improvement)   Prophylaxis of deep fungal infections (when standard therapy is  inappropriate) in patients with haematological malignancy or  undergoing bone-marrow transplantation who are expected to  become neutropenic, 5 mg/kg daily in 2 divided doses; starting  before transplantation or before chemotherapy (taking care to  avoid interaction with cytotoxic drugs) and continued until neu-  trophil count recovers; CHILD and ELDERLY safety and efficacy not  established    Concentrate for intravenous infusion, itraconazole  lOmg/mL. For dilution before use. Net price 25-mL  amp (with infusion bag and filter) = £62.58   Indications invasive aspergillosis (see notes above);  fusariosis either unresponsive to, or in patients intol-  erant of, amphotericin; chromoblastomycosis and  mycetoma either unresponsive to, or in patients  intolerant of, itraconazole; coccidioidomycosis either  unresponsive to, or in patients intolerant of, amphot-  ericin, itraconazole, or fluconazole; see also under  Dose   Cautions cardiomyopathy, bradycardia, symptomatic  arrhythmias, history of QT interval prolongation,  concomitant use with other drugs known to cause QT-  interval prolongation; monitor electrolytes (including  potassium, magnesium, and calcium) before and   Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk and recommends effective  contraception during treatment; toxicity in animal  studies   Side-effects gastro-intestinal disturbances (including  nausea, vomiting, abdominal pain, diarrhoea, dys-  pepsia, and flatulence); dizziness, headache, paraes-  thesia, drowsiness, fatigue, fever, anorexia; blood  disorders (including anaemia, neutropenia, and  thrombocytopenia), electrolyte disturbances; dry  mouth; rash; less commonly pancreatitis, hepatic dis-  orders, arrhythmias, palpitation, changes in blood  pressure, oedema, convulsions, neuropathy, tremor,  hyperglycaemia, menstrual disorders, renal failure,  musculoskeletal pain, visual disturbances, mouth  ulcers, and alopecia; rarely ileus, cardiac failure,  myocardial infarction, stroke, thrombosis, syncope,  pneumonitis, psychosis, depression, encephalopathy,  adrenal insufficiency, breast pain, hearing impair-  ment, and Stevens-Johnson syndrome  Dose   • 400 mg twice daily with food or if food not tolerated,  200 mg 4 times daily   • Oropharyngeal candidiasis (severe infection or in  immunocompromised patients only), 200 mg with  food on first day, then 100 mg once daily with food for  13 days   • Prophylaxis of invasive fungal infections in patients  undergoing bone-marrow transplantation or receiving  chemotherapy for acute myeloid leukaemia and  myelodysplastic syndrome who are expected to  become neutropenic, and who are intolerant of flu-  conazole or itraconazole, 200 mg 3 times daily with  food, starting before transplantation or before  chemotherapy and continued until neutrophil count  recovers   Noxafil® (Schering-Plough) ▼ (Ml  Suspension, posaconazole 200 mg/5 mL, net price  105 mL (cherry-flavoured) = £491.20. Label: 3, 9, 21   Indications invasive aspergillosis; serious infections  caused by Scedosporium spp., Fusarium spp., or  invasive fluconazole-resistant Candida spp. (includ-  ing C. krusei)   Cautions electrolyte disturbances, cardiomyopathy,  bradycardia, symptomatic arrhythmias, history of QT  interval prolongation, concomitant use with other  drugs that prolong QT interval; avoid exposure to  sunlight; patients at risk of pancreatitis; monitor liver  function before treatment and during treatment; hae-  matological malignancy (increased risk of hepatic  reactions); monitor renal function; interactions:  Appendix 1 (antifungals, triazole)    doses; no information available for severe hepatic  cirrhosis — manufacturer advises use only if potential  benefit outweighs risk   Renal impairment intravenous vehicle may accumu-  late if eGFR less than 50 mL/minute/ 1.73 m 2 — use  intravenous infusion only if potential benefit out-  weighs risk, and monitor renal function; alternatively,  use tablets or oral suspension (no dose adjustment  required)   Side-effects nausea, vomiting, abdominal pain, diarr-  hoea, jaundice, oedema, hypotension, chest pain,  respiratory distress syndrome, sinusitis, headache,  dizziness, asthenia, anxiety, depression, confusion,  agitation, hallucinations, paraesthesia, tremor, influ-  enza-like symptoms, hypoglycaemia, haematuria,  blood disorders (including anaemia, thrombocytope-  nia, leucopenia, pancytopenia), acute renal failure,  hypokalaemia, visual disturbances (including altered  perception, blurred vision, and photophobia), rash,  pruritus, photosensitivity, alopecia, cheilitis, injection-  site reactions; less commonly dyspepsia, duodenitis,  cholecystitis, pancreatitis, hepatitis, constipation,  arrhythmias (including QT interval prolongation),  syncope, raised serum cholesterol, hypersensitivity  reactions (including flushing), ataxia, nystagmus,  hypoaesthesia, adrenocortical insufficiency, arthritis,  blepharitis, optic neuritis, scleritis, glossitis, gingivitis,  psoriasis, Stevens- Johnson syndrome; rarely  pseudomembranous colitis, taste disturbances (more  common with oral suspension), convulsions, insom-  nia, tinnitus, hearing disturbances, extrapyramidal  effects, hypertonia, hypothyroidism, hyperthyroidism,  discoid lupus erythematosus, toxic epidermal necro-  lysis, pseudoporphyria, retinal haemorrhage, optic  atrophy; also reported squamous cell carcinoma of  skin (particularly in presence of phototoxicity or in the  immunosuppressed)   • By mouth, ADULT and CHILD over 12 years, body-weight  over 40 kg, 400 mg every 12 hours for 2 doses then  200 mg every 12 hours, increased if necessary to  300 mg every 12 hours; body-weight under 40 kg,   200 mg every 12 hours for 2 doses then 100 mg every  12 hours, increased if necessary to 150 mg every 12  hours; CHILD 2-12 years, (oral suspension recom-  mended) 200 mg every 12 hours   • By intravenous infusion, 6 mg/kg every 12 hours for 2  doses, then 4 mg/kg every 12 hours (reduced to   3 mg/kg every 12 hours if not tolerated) for max. 6  months; CHILD 2-18 years see BNF for Children   Tablets, f/c, voriconazole 50 mg, net price 28-tablet  pack = £275.68; 200 mg, 28-tab pack = £1102.74.  Label: 9, 11, 23   Oral suspension, voriconazole 200 mg/5 mL when  reconstituted with water, net price 75 mL (orange-  flavoured) = £551.37. Label: 9, 11, 23  Intravenous infusion, powder for reconstitution,  voriconazole, net price 200-mg vial = £77.14   Excipients include sulphobutylether beta cyclodextrin sodium (risk of  accumulation in renal impairment)   The imidazole antifungals include clotrimazole, econ-  azole, ketoconazole, and tioconazole. They are used for  the local treatment of vaginal candidiasis (section 7.2.2)  and for dermatophyte infections (section 13.10.2).  Ketoconazole is better absorbed by mouth than other  imidazoles. However, its use is restricted because it is  associated with fatal hepatotoxicity (see below).  Miconazole (section 12.3.2) can be used locally for oral  infections; it is also effective in intestinal infections.  Systemic absorption may follow use of miconazole  oral gel and may result in significant drug interactions.    Indications dermatophytoses and Malassezia follicu-  litis either resistant to fluconazole, terbinafine, or  itraconazole or in patients intolerant of these anti-  fungals; chronic mucocutaneous, cutaneous, and  oropharyngeal candidiasis either resistant to flucon-  azole or itraconazole or in patients intolerant of these  antifungals   Cautions predisposition to adrenocortical insuffi-  ciency; interactions: Appendix 1 (antifungals, imid-  azole)   Hepatotoxicity Potentially life-threatening hepatotoxicity  reported very rarely; risk of hepatotoxicity greater if given  for longer than 10 days. Monitor liver function before treat-  ment, then on weeks 2 and 4 of treatment, then every month.  Avoid or use with caution if abnormal liver function tests  (avoid in active liver disease) or if history of hepatotoxicity  with other drugs.   Counselling Patients should be told how to recognise signs  of liver disorder and advised to seek prompt medical atten-  tion if symptoms such as anorexia, nausea, vomiting, fatigue,  abdominal pain, jaundice, or dark urine develop    Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk (teratogenicity in animal  studies)   Breast-feeding manufacturer advises avoid  Side-effects nausea, vomiting, abdominal pain; pru-  ritus; less commonly diarrhoea, headache, dizziness,  drowsiness, and rash; also reported fatal liver damage  (see Hepatotoxicity above), dyspepsia, raised intra-  cranial pressure, paraesthesia, adrenocortical insuffi-  ciency, erectile dysfunction, menstrual disorders,  azoospermia (with high doses), gynaecomastia,  thrombocytopenia, photophobia, photosensitivity,  and alopecia  Dose   • 200 mg once daily, increased if response inadequate  to 400 mg once daily; continued until symptoms have  cleared and cultures negative, but see Cautions (max.  duration of treatment 4 weeks for Malassezia infec-  tion); CHILD body-weight 15-30 kg, 100 mg once daily;  body-weight over 30 kg, adult dose    Nizoral® Oanssen-Cilag) (M\C*4  Tablets, scored, ketoconazole 200 mg. Net price 30-  tab pack = £14.02. Label: 5, 9, 21, counselling,  hepatotoxicity   The polyene antifungals include amphotericin and nys-  tatin; neither drug is absorbed when given by mouth.  Nystatin is used for oral, oropharyngeal, and perioral  infections by local application in the mouth (section  12.3.2). Nystatin is also used for Candida albicans  infection of the skin (section 13.10.2).   Amphotericin by intravenous infusion is used for the  treatment of systemic fungal infections and is active  against most fungi and yeasts. It is highly protein bound  and penetrates poorly into body fluids and tissues.  When given parenterally amphotericin is toxic and  side-effects are common. Lipid formulations of amphot-  ericin (Abelcet® and AmBisome ®) are significantly less  toxic and are recommended when the conventional  formulation of amphotericin is contra-indicated because  of toxicity, especially nephrotoxicity or when response  to conventional amphotericin is inadequate; lipid  formulations are more expensive. For the role of  amphotericin in the systemic treatment of fungal  infections, see p. 373.   Cautions when given parenterally, toxicity common  (close supervision necessary and test dose required;  see Anaphylaxis below); hepatic and renal function  tests, blood counts, and plasma electrolyte (including  plasma-potassium and magnesium concentration)  monitoring required; corticosteroids (avoid except to  control reactions); avoid rapid infusion (risk of arrhy-  thmias); interactions: Appendix 1 (amphotericin)  Anaphylaxis Anaphylaxis occurs rarely with any intra-  venous amphotericin product and a test dose is advisable  before the first infusion; the patient should be carefully  observed for at least 30 minutes after the test dose. Pro-  phylactic antipyretics or hydrocortisone should only be used  in patients who have previously experienced acute adverse  reactions (in whom continued treatment with amphotericin  is essential)    Renal impairment use only if no alternative; nephro-  toxicity may be reduced with use of lipid formulation    Pregnancy not known to be harmful but manufac-  turers advise avoid unless potential benefit outweighs  risk    Breast-feeding no information available  Side-effects when given parenterally, anorexia,  nausea and vomiting, diarrhoea, epigastric pain; feb-  rile reactions, headache, muscle and joint pain;  anaemia; disturbances in renal function (including  hypokalaemia and hypomagnesaemia) and renal  toxicity; also cardiovascular toxicity (including  arrhythmias, blood pressure changes), blood disor-  ders, neurological disorders (including hearing loss,  diplopia, convulsions, peripheral neuropathy,  encephalopathy), abnormal liver function (discon-  tinue treatment), rash, anaphylactoid reactions (see  Anaphylaxis, above); pain and thrombophlebitis at  injection site  Dose   • By intravenous infusion, see preparations  Note Different preparations of intravenous amphotericin  vary in their pharmacodynamics, pharmacokinetics,  dosage, and administration; these preparations should not be  considered interchangeable. To avoid confusion, prescribers  should specify the brand to be dispensed.    Fungizone® (Squibb) (Ml  Intravenous infusion, powder for reconstitution,  amphotericin (as sodium deoxycholate complex), net  price 50-mg vial = £3.88   Dose by intravenous infusion, systemic fungal infections, initial  test dose of 1 mg over 20-30 minutes then 250 micrograms/kg  daily, gradually increased over 2-4 days, if tolerated, to 1 mg/kg  daily; max. (severe infection) 1.5 mg/kg daily or on alternate days;  CHILD under 18 years see BNF for Children  Note Prolonged treatment usually necessary; if interrupted for  longer than 7 days recommence at 250 micrograms/kg daily and  increase gradually   Intravenous infusion, amphotericin 5 mg/mL as lipid  complex with L-a-dimyristoylphosphatidylcholine and  L-a-dimyristoylphosphatidylglycerol, net price 20-mL  vial = £77.43 (hosp. only)   Dose by intravenous infusion, severe invasive candidiasis;  severe systemic fungal infections in patients not responding to  conventional amphotericin or to other antifungal drugs or where  toxicity or renal impairment precludes conventional amphot-  ericin, including invasive aspergillosis, cryptococcal meningitis  and disseminated cryptococcosis in HIV patients, initial test dose  1 mg over 15 minutes then 5 mg/kg once daily for at least 14 days;  CHILD under 18 years see BNF for Children   AmBisome® (Gilead) (Ml  Intravenous infusion, powder for reconstitution,  amphotericin 50 mg encapsulated in liposomes, net  price 50-mg vial = £96.69   Electrolytes Na + < 0.5 mmol/vial  Excipients include sucrose 900 mg/vial   Dose by intravenous infusion, severe systemic or deep mycoses  where toxicity (particularly nephrotoxicity) precludes use of  conventional amphotericin, aspergillosis, initial test dose 1 mg  over 10 minutes then 3 mg/kg once daily; max. 5 mg/kg once  daily [unlicensed dose]; CHILD under 18 years see BNF for  Children   Suspected or proven infection in febrile neutropenic patients  unresponsive to broad-spectrum antibacterials, initial test dose  1 mg over 10 minutes then 3 mg/kg once daily until afebrile for 3  consecutive days; max. period of treatment 42 days; max. 5 mg/  kg once daily [unlicensed dose]; CHILD under 18 years see BNF for  Children   The echinocandin antifungals include anidulafungin,  caspofungin and micafungin. They are only active  against Aspergillus spp. and Candida spp.; however,  anidulafungin and micafungin are not used for the  treatment of aspergillosis. Echinocandins are not effec-  tive against fungal infections of the CNS. For the role of  echinocandin antifungals in the prevention and systemic  treatment of fungal infections, see p. 373.   Side-effects diarrhoea, nausea, vomiting, flushing,  convulsion, headache, coagulopathy, hypokalaemia,  raised serum creatinine, rash, pruritus; less commonly  abdominal pain, cholestasis, hypertension, hyper-    Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — present in milk in  animal studies   • By intravenous infusion, ADULT over 18 years, 200 mg  on first day then 100 mg once daily   Intravenous infusion, powder for reconstitution,  anidulafungin, net-price 100-mg vial = £299.99   Indications invasive aspergillosis (see notes above);  invasive candidiasis (see notes above); empirical  treatment of systemic fungal infections in patients  with neutropenia   Cautions interactions: Appendix 1 (caspofungin)  Hepatic impairment 70 mg on first day then 35 mg  once daily in moderate impairment; no information  available for severe impairment  Pregnancy manufacturer advises avoid unless essen-  tial — toxicity in animal studies  Breast-feeding present in milk in animal studies —  manufacturer advises avoid  Side-effects nausea, diarrhoea, vomiting; dyspnoea;  headache; hypokalaemia; arthralgia; rash, pruritus,  sweating, injection-site reactions; less commonly  abdominal pain, dyspepsia, dry mouth, dysphagia,  taste disturbances, anorexia, constipation, flatulence,  cholestasis, hepatic dysfunction, ascites, palpitation,  arrhythmia, chest pain, heart failure, thrombophleb-  itis, flushing, hypotension, hypertension, broncho-  spasm, cough, dizziness, fatigue, paraesthesia,  hypoaesthesia, sleep disturbances, tremor, anxiety,  disorientation, hyperglycaemia, renal failure, hypo-  magnesaemia, hypocalcaemia, metabolic acidosis,  anaemia, thrombocytopenia, leucopenia, myalgia,  muscular weakness, blurred vision, and erythema  multiforme; also reported, adult respiratory distress  syndrome and anaphylaxis  Dose   • By intravenous infusion, 70 mg on first day then  50 mg once daily (70 mg once daily if body-weight  over 80 kg); CHILD under 18 years see BNF for Chil-  dren   Cancidas® (MSD) ▼ (Ml  Intravenous infusion, powder for reconstitution,  caspofungin (as acetate), net price 50-mg vial =  £327.67; 70-mg vial = £416.78   Indications see under Dose  Cautions monitor renal function; interactions:  Appendix 1 (micafungin)   Hepatotoxicity Potentially life-threatening hepatotoxicity  reported. Monitor liver function — discontinue if significant  and persistent abnormalities in liver function tests develop.  Use with caution in hepatic impairment (avoid if severe) or if  receiving other hepatotoxic drugs. Risk of hepatic side-  effects greater in children under 1 year of age  Hepatic impairment use with caution in mild to  moderate impairment; avoid in severe impairment;  see also Hepatotoxicity above  Renal impairment use with caution; renal function  may deteriorate    Side-effects nausea, vomiting, diarrhoea, abdominal  pain; headache, fever; hypokalaemia, hypomagnes-  aemia, hypocalcaemia, leucopenia, anaemia; rash,  phlebitis; less commonly dyspepsia, constipation,  hepatomegaly, hepatitis and cholestasis (see also  Hepatotoxicity above), taste disturbances, anorexia,  tachycardia, palpitation, bradycardia, blood pressure  changes, flushing, dyspnoea, sleep disturbances,  anxiety, confusion, dizziness, tremor, pancytopenia,  thrombocytopenia, eosinophilia, hyponatraemia,  hypophosphataemia, hyperkalaemia, hyperhidrosis,  and pruritus; rarely haemolytic anaemia; also  reported renal failure (more frequent in children)    • By intravenous infusion, invasive candidiasis, ADULT  body-weight over 40 kg, 100 mg once daily (increased  to 200 mg daily if inadequate response) for at least 14  days; body-weight under 40 kg, 2 mg/kg once daily  (increased to 4 mg/kg daily if inadequate response)  for at least 14 days; CHILD under 18 years see BNF for  Children   Oesophageal candidiasis, ADULT body-weight over  40 kg, 150 mg once daily; body-weight under 40 kg,   3 mg/kg once daily; CHILD 16-18 years see BNF for  Children    Flucytosine is used with amphotericin in a synergistic  combination. Bone marrow depression can occur which  limits its use, particularly in AIDS patients; weekly blood  counts are necessary during prolonged therapy. Resis-  tance to flucytosine can develop during therapy and  sensitivity testing is essential before and during treat-  ment. For the role of flucytosine in the treatment of  systemic candidiasis and cryptococcal meningitis, see  p. 373.   Griseofulvin is effective for widespread or intractable  dermatophyte infections but has been superseded by  newer antifungals, particularly for nail infections. It is  the drug of choice for trichophyton infections in chil-  dren. Duration of therapy is dependent on the site of the  infection and may extend to a number of months. For  the role of griseofulvin in the treatment of tinea capitis,  see p. 373.   Terbinafine is the drug of choice for fungal nail infec-  tions and is also used for ringworm infections where  oral treatment is considered appropriate (see p. 373).    Prophylaxis of candidiasis in patients undergoing  bone-marrow transplantation or who are expected to  become neutropenic for over 10 days, ADULT body-  weight over 40 kg, 50 mg once daily; body-weight  under 40 kg, 1 mg/kg once daily; continue for at least  7 days after neutrophil count in desirable range; CHILD  under 18 years see BNF for Children    Mycamine® (Astellas) ▼ Ml  Intravenous infusion, powder for reconstitution,  micafungin (as sodium), net price 50-mg vial =  £196.08; 100-mg vial = £341.00   Indications systemic yeast and fungal infections;  adjunct to amphotericin in cryptococcal meningitis  (see Cryptococcosis, p. 373), adjunct to amphotericin  in severe systemic candidiasis and in other severe or  long-standing infections   Cautions elderly; blood disorders; liver- and kidney-  function tests and blood counts required (weekly in  blood disorders); interactions: Appendix 1 (flucyto-  sine)   Renal impairment liver- and kidney-function tests  and blood counts required weekly; use 50 mg/kg  every 12 hours if creatinine clearance 20-40 mL/  minute; use 50 mg/kg every 24 hours if creatinine  clearance 10-20 mL/minute; use initial dose of  50 mg/kg if creatinine clearance less than 10 mL/  minute and then adjust dose according to plasma-  flucytosine concentration   Pregnancy teratogenic in animal studies; manufac-  turer advises use only if potential benefit outweighs  risk   Breast-feeding manufacturer advises avoid  Side-effects nausea, vomiting, diarrhoea, rashes; less  frequently cardiotoxicity, confusion, hallucinations,  convulsions, headache, sedation, vertigo, alterations  in liver function tests (hepatitis and hepatic necrosis  reported), and toxic epidermal necrolysis; blood dis-  orders including thrombocytopenia, leucopenia, and  aplastic anaemia reported  Dose   • By intravenous infusion over 20-40 minutes, 200 mg/  kg daily in 4 divided doses usually for not more than 7  days; extremely sensitive organisms, 100-150 mg/kg  daily may be sufficient; CHILD under 18 years see BNF  for Children   Cryptococcal meningitis (adjunct to amphotericin,  see Cryptococcosis, p. 373) 100 mg/kg daily in 4  divided doses for 2 weeks [unlicensed duration]; CHILD  under 18 years see BNF for Children  Note For plasma concentration monitoring, blood should be  taken shortly before starting the next infusion; plasma con-  centration for optimum response 25-50 mg/litre (200-  400 micromol/litre) — should not be allowed to exceed  80 mg/litre (620 micromol/litre)   Indications dermatophyte infections of the skin, scalp,  hair and nails where topical therapy has failed or is  inappropriate   Cautions interactions: Appendix 1 (griseofulvin)  Driving May impair performance of skilled tasks (e.g. driv-  ing); effects of alcohol enhanced  Contra-indications severe liver disease; systemic  lupus erythematosus (risk of exacerbation); acute  porphyria (section 9.8.2)   Hepatic impairment avoid in severe liver disease  Pregnancy avoid (fetotoxicity and teratogenicity in  animals)-, effective contraception required during and  for at least 1 month after administration to women  (important: effectiveness of oral contraceptives may    be reduced, additional contraceptive precautions e.g.  barrier method, required); also men should avoid  fathering a child during and for at least 6 months after  administration   Breast-feeding avoid — no information available  Side-effects nausea, vomiting, diarrhoea; headache;  also reported, abdominal pain, dyspepsia, hepato-  toxicity, glossitis, taste disturbances, sleep distur-  bances, dizziness, fatigue, confusion, agitation,  depression, impaired coordination and hearing, per-  ipheral neuropathy, menstrual disturbances, renal  failure, leucopenia, systemic lupus erythematosus,  rash (including rarely erythema multiforme, toxic  epidermal necrolysis), and photosensitivity  Dose   • Dermatophyte infections, 500 mg once daily or in  divided doses; in severe infection dose may be  doubled, reducing when response occurs; CHILD under  50 kg, 10 mg/kg once daily or in divided doses   • Tinea capitis caused by Trichophyton tonsurans, 1 g  once daily or in divided doses; CHILD under 50 kg, 15-  20 mg/kg once daily or in divided doses   Note Griseofulvin doses in BNF may differ from those in  product literature   Griseofulvin (Non-proprietary) (Ml  Tablets, griseofulvin 125 mg, net price 100 = £34.86;  500 mg, 100= £90.34. Label: 9, 21, counselling, driving   Oral suspension, griseofulvin 125 mg/5 mL, net  price 100 mL (peppermint-flavoured) = £59.90.   Indications dermatophyte infections of the nails,  ringworm infections (including tinea pedis, cruris, and  corporis) where oral therapy appropriate (due to site,  severity or extent)   Cautions psoriasis (risk of exacerbation); autoimmune  disease (risk of lupus-erythematosus-like effect);  interactions: Appendix 1 (terbinafine)   Renal impairment use half normal dose if eGFR less  than 50 mL/minute/ 1.73 m 2 and no suitable alterna-  tive available   Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding avoid — present in milk  Side-effects abdominal discomfort, anorexia, nausea,  diarrhoea; headache; rash and urticaria occasionally  with arthralgia or myalgia; less commonly taste dis-  turbance; rarely liver toxicity (including jaundice,  cholestasis and hepatitis) — discontinue treatment,  angioedema, dizziness, malaise, paraesthesia,  hypoaesthesia, photosensitivity, serious skin reactions  (including Stevens- Johnson syndrome and toxic epi-  dermal necrolysis) — discontinue treatment if pro-  gressive skin rash; very rarely psychiatric distur-  bances, blood disorders (including leucopenia and  thrombocytopenia), lupus erythematosus-like effect,  and exacerbation of psoriasis  Dose   • By mouth, 250 mg daily usually for 2-6 weeks in tinea  pedis, 2-4 weeks in tinea cruris, 4 weeks in tinea  corporis, 6 weeks-3 months in nail infections (occa-    sionally longer in toenail infections); CHILD [unli-  censed] usually for 4 weeks, tinea capitis, over 1 year,  body-weight 10-2 Okg, 62.5 mg once daily; body-  weight 20-40 kg, 125 mg once daily; body-weight over  40 kg, 250 mg once daily   Tablets, terbinafine (as hydrochloride) 250 mg, net  price 14-tab pack = £2.33, 28-tab pack = £3.02.  Label: 9   Tablets, off-white, scored, terbinafine (as hydro-  chloride) 250 mg, net price 14-tab pack = £21.30, 28-  tab pack = £41.09. Label: 9   The majority of virus infections resolve spontaneously  in immunocompetent subjects. A number of specific  treatments for viral infections are available, particularly  for the immunocompromised. This section includes  notes on herpes simplex and varicella-zoster, human  immunodeficiency virus, cytomegalovirus, respiratory  syncytial virus, viral hepatitis and influenza.   There is no cure for infection caused by the human  immunodeficiency virus (HIV) but a number of drugs  slow or halt disease progression. Drugs for HIV infec-  tion (antiretrovirals) may be associated with serious  side-effects. Although antiretrovirals increase life expec-  tancy considerably and decrease the risk of complica-  tions associated with premature ageing, mortality and  morbidity remain slightly higher than in uninfected  individuals. Treatment should be undertaken only by  those experienced in their use.   Principles of treatment Treatment is aimed at redu-  cing the plasma viral load as much as possible and for as  long as possible; it should be started before the immune  system is irreversibly damaged. The need for early drug  treatment should, however, be balanced against the risk  of toxicity. Commitment to treatment and strict adher-  ence over many years are required; the regimen chosen  should take into account convenience and patient tol-  erance. The development of drug resistance is reduced  by using a combination of drugs; such combinations  should have synergistic or additive activity while ensur-  ing that their toxicity is not additive. It is recommended  that viral sensitivity to antiretroviral drugs is established  before starting treatment or before switching drugs if  the infection is not responding.   Initiation of treatment The optimum time for initiat-  ing antiretroviral treatment depends primarily on the   CD4 cell count; the plasma viral load and clinical  symptoms may also help. The timing and choice of  treatment should also take account of the possible  effects of antiretroviral drugs on factors such as the  risk of cardiovascular events. Treatment includes a  combination of drugs known as ‘highly active anti-  retroviral therapy’. Treatment is initiated with 2 nucleo-  side reverse transcriptase inhibitors and a non-nucleo-  side reverse transcriptase inhibitor; the regimens of  choice contain either tenofovir, emtricitabine, and efa-  virenz or abacavir, lamivudine, and efavirenz. Regimens  containing 2 nucleoside reverse transcriptase inhibitors  and a boosted protease inhibitor are reserved for  patients with resistance to first-line regimens, women  wishing to become pregnant, or patients with psychia-  tric illness. Patients who require treatment for both HIV  and chronic hepatitis B should be treated with antivirals  active against both diseases (section 5.3.3).   Switching therapy Deterioration of the condition  (including clinical and virological changes) may require  a change in therapy. The choice of an alternative regi-  men depends on factors such as the response to pre-  vious treatment, tolerance and the possibility of cross-  resistance.    Pregnancy Treatment of HIV infection in pregnancy  aims to reduce the risk of toxicity to the fetus (although  the teratogenic potential of most antiretroviral drugs is  unknown), to minimise the viral load and disease pro-  gression in the mother, and to prevent transmission of  infection to the neonate. All treatment options require  careful assessment by a specialist. Zidovudine mono-  therapy reduces transmission of infection to the neo-  nate. However, combination antiretroviral therapy max-  imises the chance of preventing transmission and  represents optimal therapy for the mother. Combination  antiretroviral therapy may be associated with a greater  risk of preterm delivery.   Breast-feeding Breast-feeding by HIV-positive  mothers may cause HIV infection in the infant and  should be avoided.    Children HIV disease in children has a different natural  progression to adults. Children infected with HIV should  be managed within a formal paediatric HIV clinical  network by specialists with access to guidelines and  information on antiretroviral drugs for children.   Post-exposure prophylaxis Prophylaxis with anti-  retroviral drugs [unlicensed indication] may be appro-  priate following exposure to HIV-contaminated materi-  al. Immediate expert advice should be sought in such  cases; national guidelines on post-exposure prophylaxis  for healthcare workers have been developed (by the  Chief Medical Officer’s Expert Advisory Group on  AIDS, www.dh.gov.uk) and local ones may also be  available. Antiretrovirals for prophylaxis are chosen on  the basis of efficacy and potential for toxicity. Prompt  prophylaxis with antiretroviral drugs [unlicensed indica-  tion] is also appropriate following potential sexual expo-  sure to HIV; recommendations have been developed by  the British Association for Sexual Health and HIV,  www.bashh.org   Drugs for HIV infection Zidovudine, a nucleoside  reverse transcriptase inhibitor (or ‘nucleoside analo-  gue’), was the first anti-HIV drug to be introduced.    Other nucleoside reverse transcriptase inhibitors  include abacavir, didanosine, emtricitabine, lamivu-  dine, stavudine, and tenofovir.    The protease inhibitors include atazanavir, darunavir,  fosamprenavir (a pro-drug of amprenavir), indinavir,  lopinavir, nelfinavir, ritonavir, saquinavir, and tipra-  navir. Ritonavir in low doses boosts the activity of  atazanavir, darunavir, fosamprenavir, indinavir, lopina-  vir, saquinavir, and tipranavir increasing the persistence  of plasma concentrations of these drugs; at such a low  dose, ritonavir has no intrinsic antiviral activity. A com-  bination of lopinavir with low-dose ritonavir is available.  The protease inhibitors are metabolised by cytochrome  P450 enzyme systems and therefore have a significant  potential for drug interactions. Protease inhibitors are  associated with lipodystrophy and metabolic effects  (see below).   The non-nucleoside reverse transcriptase inhibitors efa-  virenz, etravirine, and nevirapine are active against  the subtype HIV-1 but not HIV-2, a subtype that is rare  in the UK. These drugs may interact with a number of  drugs metabolised in the liver. Nevirapine is associated  with a high incidence of rash (including Stevens- John-  son syndrome) and occasionally fatal hepatitis. Rash is  also associated with efavirenz and etravirine but it is  usually milder. Psychiatric or CNS disturbances are  common with efavirenz. CNS disturbances are often  self-limiting and can be reduced by taking the dose at  bedtime (especially in the first 2-4 weeks of treatment).  Efavirenz has also been associated with an increased  plasma cholesterol concentration. Etravirine is used in  regimens containing a boosted protease inhibitor for  HIV infection resistant to other non-nucleoside reverse  transcriptase inhibitors and protease inhibitors.    Enfuvirtide, which inhibits the fusion of HIV to the host  cell, is licensed for managing infection that has failed to  respond to a regimen of other antiretroviral drugs;  enfuvirtide should be combined with other potentially  active antiretroviral drugs.    Maraviroc is an antagonist of the CCR5 chemokine  receptor. It is licensed for patients exclusively infected  with CCR5-tropic HIV. The Scottish Medicines Consor-  tium (p. 4) has advised (March 2008) that maraviroc  ( Celsentri ®) is not recommended for use within NHS  Scotland.    Raltegravir is an inhibitor of HIV integrase. It is  licensed for the treatment of HIV infection in combina-  tion with other antiretroviral drugs. The Scottish Med-  icines Consortium (p. 4) has advised (April 2010) that  raltegravir ( Isentress ®) is accepted for restricted use  within NHS Scotland for the treatment of HIV infection  when non-nucleoside reverse transcriptase inhibitors or  protease inhibitors cannot be used because of intoler-  ance, drug interactions, or resistance.    antiretroviral therapy and patients should be advised  about lifestyle changes to reduce their cardiovascular  risk. Plasma lipids and blood glucose should be mea-  sured before starting antiretroviral therapy, after 3-6  months of treatment, and then annually.   Fat redistribution (with loss of subcutaneous fat,  increased abdominal fat, ‘buffalo hump’ and breast  enlargement) is associated with regimens containing  protease inhibitors and nucleoside reverse transcriptase  inhibitors. Stavudine (especially in combination with  didanosine), and to a lesser extent zidovudine, are  associated with a higher risk of lipoatrophy and should  be used only if alternative regimens are not suitable.   Dyslipidaemia is associated with antiretroviral treat-  ment, particularly with protease inhibitors. Protease  inhibitors and some nucleoside reverse transcriptase  inhibitors are associated with insulin resistance and  hyperglycaemia. Of the protease inhibitors, atazanavir  and darunavir may be less likely to cause dyslipidaemia,  while saquinavir and atazanavir may be less likely to  impair glucose tolerance.   Osteonecrosis Osteonecrosis has been reported in  patients with advanced HIV disease or following long-  term exposure to combination antiretroviral therapy.   Lactic acidosis Life-threatening lactic acidosis asso-  ciated with hepatomegaly and hepatic steatosis has  been reported with nucleoside reverse transcriptase  inhibitors. They should be used with caution in patients  (particularly obese women) with hepatomegaly, hepat-  itis (especially hepatitis C treated with interferon alfa  and ribavirin), liver-enzyme abnormalities and with  other risk factors for liver disease and hepatic steatosis  (including alcohol abuse). Treatment with the nucleo-  side reverse transcriptase inhibitor should be discon-  tinued in case of symptomatic hyperlactataemia, lactic  acidosis, progressive hepatomegaly or rapid deteriora-  tion of liver function. Stavudine, especially with didano-  sine, is associated with a higher risk of lactic acidosis  and should be used only if alternative regimens are not  suitable.   Hepatic impairment Nucleoside reverse transcrip-  tase inhibitors should be used with caution in patients  with chronic hepatitis B or C (greater risk of hepatic  side-effects); see also Lactic acidosis above.    Immune reconstitution syndrome Improvement in  immune function as a result of antiretroviral treatment  may provoke a marked inflammatory reaction against  residual opportunistic organisms.   Lipodystrophy syndrome Metabolic effects asso-  ciated with antiretroviral treatment include fat redistri-  bution, insulin resistance, and dyslipidaemia', collec-  tively these have been termed lipodystrophy  syndrome. The usual risk factors for cardiovascular  disease should be taken into account before starting   Side-effects Side-effects of the nucleoside reverse  transcriptase inhibitors include gastro-intestinal distur-  bances (such as nausea, vomiting, abdominal pain,  flatulence and diarrhoea), anorexia, pancreatitis, liver  damage (see also Lactic Acidosis, above), dyspnoea,  cough, headache, insomnia, dizziness, fatigue, blood  disorders (including anaemia, neutropenia, and throm-  bocytopenia), myalgia, arthralgia, rash, urticaria, and  fever. See notes above for metabolic effects and lipody-  strophy (Lipodystrophy Syndrome), and Osteonecrosis.   Cautions see notes above; also test for HLA-B*5701  allele before treatment or if restarting treatment and  HLA-B*5701 status not known — increased risk of  hypersensitivity reaction in presence of HLA-B*5701  allele; HIV load greater than 100 000 copies/mL;  patients at high risk of cardiovascular disease (espe-  cially if 10-year cardiovascular risk greater than 20%);  interactions: Appendix 1 (abacavir)   Hypersensitivity reactions Life-threatening hypersensi-  tivity reactions reported — characterised by fever or rash  and possibly nausea, vomiting, diarrhoea, abdominal pain,  dyspnoea, cough, lethargy, malaise, headache, and myalgia;  less frequently mouth ulceration, oedema, hypotension, sore  throat, acute respiratory distress syndrome, anaphylaxis,  paraesthesia, arthralgia, conjunctivitis, lymphadenopathy,  lymphocytopenia and renal failure; rarely myolysis; labora-  tory abnormalities may include raised liver function tests  (see Lactic Acidosis p. 382) and creatine kinase; symptoms  usually appear in the first 6 weeks, but may occur at any  time; monitor for symptoms every 2 weeks for 2 months;  discontinue immediately if any symptom of hypersensitivity  develops and do not rechallenge (risk of more severe  hypersensitivity reaction); discontinue if hypersensitivity  cannot be ruled out, even when other diagnoses possible — if  rechallenge necessary it must be carried out in hospital  setting; if abacavir is stopped for any reason other than  hypersensitivity, exclude hypersensitivity reaction as the  cause and rechallenge only if medical assistance is readily  available; care needed with concomitant use of drugs which  cause skin toxicity   Counselling Patients should be told the importance of  regular dosing (intermittent therapy may increase the risk  of sensitisation), how to recognise signs of hypersensitivity,  and advised to seek immediate medical attention if symp-  toms develop or before re-starting treatment; patients should  be advised to keep Alert Card with them at all times   Renal impairment manufacturer advises avoid in  end-stage renal disease; avoid Kivexa® or Trizivir ® if  eGFR less than 50 mL/minute/ 1.73 m 2 (consult  product literature)   Side-effects see notes above; also hypersensitivity  reactions (see above); very rarely Stevens-Johnson  syndrome and toxic epidermal necrolysis; rash and  gastro-intestinal disturbances more common in chil-  dren   • 600 mg daily in 1-2 divided doses; CHILD 3 months-12  years, 8 mg/kg every 12 hours (max. 600 mg daily) or  body-weight 14-21 kg, 150 mg every 12 hours; body-  weight 2 1-30 kg, 150 mg in the morning and 300 mg  in the evening; body-weight over 30 kg, 300 mg every  12 hours   Tablets, yellow, f/c, scored, abacavir (as sulphate)  300 mg, net price 60-tab pack = £208.95. Counselling,  hypersensitivity reactions  Oral solution, sugar-free, banana and strawberry  flavoured, abacavir (as sulphate) 20 mg/mL, net price  240-mL = £55.72. Counselling, hypersensitivity reac-  tions   Tablets, orange, f/c, abacavir (as sulphate) 600 mg,  lamivudine 300 mg, net price 30-tab pack = £352.25.  Counselling, hypersensitivity reactions  Dose ADULT and CHILD over 12 years, body-weight over 40 kg, 1  tablet once daily    JlWith lamivudine and zidovudine  Note For patients stabilised (for 6-8 weeks) on the individual  components in the same proportions. For cautions, contra-  indications and side-effects see under individual drugs   300 mg, lamivudine 150 mg, zidovudine 300 mg, net  price 60-tab pack = £509.06. Counselling, hyper-  sensitivity reactions  Dose ADULT over 18 years, 1 tablet twice daily   Cautions see notes above; also history of pancreatitis  (preferably avoid, otherwise extreme caution, see also  below); peripheral neuropathy or hyperuricaemia (see  under Side-effects); ophthalmological examination  (including visual acuity, colour vision, and dilated  fundus examination) recommended annually or if  visual changes occur; interactions: Appendix 1  (didanosine)   Pancreatitis Suspend treatment if serum lipase raised (even  if asymptomatic) or if symptoms of pancreatitis develop;  discontinue if pancreatitis confirmed. Whenever possible  avoid concomitant treatment with other drugs known to  cause pancreatic toxicity (e.g. intravenous pentamidine ise-  tionate); monitor closely if concomitant therapy unavoidable.  Since significant elevations of triglycerides cause pancreatitis  monitor closely if elevated   Hepatic impairment see notes above; also insufficient  information but monitor for toxicity  Renal impairment reduce dose if eGFR less than  60mL/minute/1.73m 2 ; consult product literature  Pregnancy manufacturer advises use only if potential  benefit outweighs risk  Breast-feeding see p. 381   Side-effects see notes above; also pancreatitis (see  also under Cautions), liver failure, anaphylactic reac-  tions, peripheral neuropathy (switch to another anti-  retroviral if peripheral neuropathy develops), diabetes  mellitus, hypoglycaemia, acute renal failure, rhabdo-  myolysis, dry eyes, retinal and optic nerve changes,  dry mouth, parotid gland enlargement, sialadenitis,  alopecia, hyperuricaemia (suspend if raised signifi-  cantly)    • ADULT under 60 kg 250 mg daily in 1-2 divided doses,  60 kg and over 400 mg daily in 1-2 divided doses;  CHILD over 3 months (under 6 years Videx® tablets  only), 240 mg/m 2 daily (180 mg/m 2 daily in combi-  nation with zidovudine) in 1-2 divided doses    Videx® (Bristol-Myers Squibb) (Ml  Tablets, with calcium and magnesium antacids,  didanosine 25 mg, net price 60-tab pack = £25.06.  Label: 23, counselling, administration, see below   Excipients include aspartame equivalent to phenylalanine 36.5 mg per  tablet (section 9.4.1)   Note Antacids in formulation may affect absorption of other  drugs — see interactions: Appendix 1 (antacids)   Counselling To ensure sufficient antacid, each dose to be taken as  at least 2 tablets (CHILD under 1 year 1 tablet) chewed thoroughly,  crushed or dispersed in water; clear apple juice may be added for  flavouring; tablets to be taken 2 hours after lopinavir with ritonavir  capsules and oral solution or atazanavir with ritonavir   200 mg, 30-cap pack = £77.09; 250 mg, 30-cap pack =  £96.37; 400 mg, 30-cap pack = £154.19. Label: 25,  counselling, administration, see below  Counselling Capsules to be taken at least 2 hours before or 2  hours after food   Cautions see notes above; also on discontinuation,  monitor patients with hepatitis B (risk of exacerbation  of hepatitis); interactions: Appendix 1 (emtricitabine)  Hepatic impairment see notes above and Cautions  above   Capsules, white/blue, emtricitabine 200 mg, net price  30-cap pack = £163.50   Dose ADULT and CHILD body-weight over 33 kg, 200 mg once  daily   Oral solution, orange, emtricitabine lOmg/mL, net  price 170-mL pack (candy-flavoured) = £46.50  Dose ADULT and CHILD body-weight over 33 kg, 240 mg once  daily; CHILD 4 months-18 years, body-weight under 33 kg, 6 mg/  kg once daily   Note 240 mg oral solution = 200 mg capsule; where appropriate the  capsule may be used instead of the oral solution    vudine. When treating chronic hepatitis B with lamivudine,  monitor liver function tests every 3 months, and viral and  serological markers of hepatitis B every 3-6 months, more  frequently in patients with advanced liver disease or follow-  ing transplantation (monitoring to continue for at least 1 year  after discontinuation)   Renal impairment reduce dose if eGFR less than  50 mL/minute/ 1.73 m 2 ; consult product literature   Breast-feeding can be used with caution in women  infected with chronic hepatitis B alone, providing  adequate measures are taken to prevent hepatitis B  infection in infants; for women infected with HIV, see  p. 381   Side-effects see notes above; also peripheral neuro-  pathy, muscle disorders including rhabdomyolysis,  nasal symptoms, alopecia   Tablets, f/c, lamivudine 150 mg (scored, white), net  price 60-tab pack = £143.32; 300 mg (grey), 30-tab  pack = £157.51   Oral solution, banana- and strawberry-flavoured,  lamivudine 50 mg/5 mL, net price 240-mL pack =  £39.01   Dose HIV infection in combination with other antiretroviral  drugs, 150 mg every 12 hours or 300 mg once daily; CHILD 3  months-12 years, 4 mg/kg (max. 150 mg) every 12 hours or body-  weight 14-21 kg, 75 mg twice daily; body-weight 21-30 kg, 75 mg  in the morning and 150 mg in the evening; body- weight over  30 kg, 150 mg twice daily   Oral solution, banana and strawberry flavoured,  lamivudine 25 mg/5 mL, net price 240-mL pack =  £22.79   Dose chronic hepatitis B infection either with compensated liver  disease (with evidence of viral replication and histology of active  liver inflammation or fibrosis) when first-line treatments cannot  be used, or (in combination with another antiviral drug without  cross-resistance to lamivudine) with decompensated liver disease,  100 mg daily; CHILD [unlicensed indication] 2-11 years, 3 mg/kg  once daily (max. 100 mg daily); 12-17 years, adult dose  Note Patients receiving lamivudine for concomitant HIV infection  should continue to receive lamivudine in a dose appropriate for  HIV infection   Chronic Hepatitis B Recurrent hepatitis in patients with  chronic hepatitis B may occur on discontinuation of lami-   Cautions see notes above; also history of peripheral  neuropathy (see under Side-effects); history of pan-    creatitis or concomitant use with other drugs asso-  ciated with pancreatitis; interactions: Appendix 1  (stavudine)   Renal impairment use half normal dose every 12  hours if eGFR 25-50 mL/minute/ 1.73 m 2 ; use half  normal dose every 24 hours if eGFR less than 25 mL/  minute /1.73m 2   Side-effects see notes above; also peripheral neuro-  pathy (switch to another antiretroviral if peripheral  neuropathy develops), abnormal dreams, cognitive  dysfunction, drowsiness, depression, pruritus; less  commonly anxiety, gynaecomastia   • ADULT under 60 kg, 30 mg every 12 hours preferably at  least 1 hour before food; 60 kg and over, 40 mg every  12 hours; NEONATE under 2 weeks, 500 micrograms/kg  every 12 hours; CHILD over 2 weeks, body-weight  under 30 kg, 1 mg/kg every 12 hours; body-weight  30 kg and over, adult dose   Zerit® (Bristol-Myers Squibb) (Ml  Capsules, stavudine 20 mg (brown), net price 56-cap  pack = £139.46; 30 mg (light orange/dark orange), 56-  cap pack = £146.25; 40 mg (dark orange), 56-cap pack  = £150.66 (all hosp. only)   Oral solution, cherry-flavoured, stavudine for recon-  stitution with water, 1 mg/mL, net price 200 mL =  £22.94   Tablets, f/c, blue, tenofovir disoproxil (as fumarate)  245 mg, net price 30-tab pack = £255.00. Label; 21,  counselling, administration   Counselling Patients with swallowing difficulties may disperse  tablet in half a glass of water, orange juice, or grape juice (but  bitter taste)   Tablets, blue, f/c, tenofovir disoproxil (as fumarate)  245 mg, emtricitabine 200 mg, net price 30-tab pack =  £418.50. Label: 21, counselling, administration  Counselling Patients with swallowing difficulties may disperse  tablet in half a glass of water, orange juice, or grape juice (but  bitter taste)   Dose HIV infection in combination with other antiretroviral  drugs, ADULT over 18 years, 1 tablet once daily    ^With efavirenz and emtricitabine  For cautions, contra-indications, and side-effects  see under individual drugs   Tablets, pink, f/c, efavirenz 600 mg, emtricitabine  200 mg, tenofovir disoproxil (as fumarate) 245 mg, net  price 30-tab pack = £626.90. Label: 23, 25  Dose HIV infection stabilised on antiretroviral therapy for more  than 3 months, ADULT over 18 years, 1 tablet once daily   Indications HIV infection in combination with other  antiretroviral drugs; chronic hepatitis B infection with  either compensated liver disease (with evidence of  viral replication, and histologically documented active  liver inflammation or fibrosis) or decompensated liver  disease   Cautions see notes above; also test renal function and  serum phosphate before treatment, then every 4  weeks (more frequently if at increased risk of renal  impairment) for 1 year and then every 3 months,  interrupt treatment if renal function deteriorates or  serum phosphate decreases; concomitant or recent  use of nephrotoxic drugs; on discontinuation, monitor  patients with hepatitis B (risk of exacerbation of  hepatitis); interactions: Appendix 1 (tenofovir)   Renal impairment monitor renal function — interrupt  treatment if further deterioration; 245 mg every 2  days if eGFR 30-50 mL/minute/ 1.73 m 2 ; 245 mg  every 3-4 days if eGFR 10-30mL/minute/1.73m 2 ;  avoid Atripla® if eGFR less than 50 mL/minute/   1.73 m 2 ; use normal dose of Truvuda® every 2 days if  eGFR 30-50 mL/minute/ 1. 73 m 2 ; avoid Truvada® if  eGFR less than 30 mL/minute/ 1.73 m 2   Side-effects see notes above; hypophosphataemia;  rarely renal failure, proximal renal tubulopathy,  nephrogenic diabetes insipidus; also reported reduced  bone density   Note The abbreviation AZT which is sometimes used for  zidovudine has also been used for another drug   Indications HIV infection in combination with other  antiretroviral drugs; prevention of maternal-fetal HIV  transmission (see notes above under Pregnancy and  Breast-feeding)   Cautions see notes above; also haematological toxi-  city particularly with high dose and advanced dis-  ease — monitor full blood count after 4 weeks of  treatment, then every 3 months; vitamin B 12 defi-  ciency (increased risk of neutropenia); if anaemia or  myelosuppression occur, reduce dose or interrupt  treatment according to product literature, or consider  other treatment; elderly; interactions: Appendix 1  (zidovudine)   Contra-indications abnormally low neutrophil counts  or haemoglobin concentration (consult product lit-  erature); neonates with hyperbilirubinaemia requiring  treatment other than phototherapy, or with raised  transaminase (consult product literature); acute por-  phyria (section 9.8.2)   Renal impairment reduce oral dose to 300-400 mg  daily in divided doses or intravenous dose to 1 mg/kg  3-4 times daily if eGFR is less than 10 mL/minute/  1.73 m 2 ; avoid Combivir ® if eGFR less than 50 mL/  minute/ 1.73m 2 (consult product literature)    Breast-feeding see p. 381  Side-effects see notes above; also anaemia (may  require transfusion), taste disturbance, chest pain,  influenza-like symptoms, paraesthesia, neuropathy,  convulsions, dizziness, drowsiness, anxiety, depres-  sion, loss of mental acuity, myopathy, gynaecomastia,  urinary frequency, sweating, pruritus, pigmentation of  nails, skin and oral mucosa  Dose   • By mouth, ADULT and CHILD body-weight over 30 kg,  250-300 mg twice daily; CHILD body-weight 4-9 kg,   12 mg/kg twice daily; body-weight 9-30 kg, 9 mg/kg  twice daily or body-weight 8-14 kg, 100 mg twice  daily; body-weight 14-21 kg, 100 mg in the morning  and 200 mg in the evening; body-weight 2 1-28 kg,  200 mg twice daily; body-weight 28-30 kg, 200-  250 mg twice daily   • Prevention of maternal-fetal HIV transmission, seek  specialist advice (combination therapy preferred)   • Patients temporarily unable to take zidovudine by  mouth, by intravenous infusion over 1 hour, 0.8-   1 mg/kg every 4 hours (approximating to 1.2-1. 5 mg/  kg every 4 hours by mouth) usually for not more than   2 weeks; CHILD 3 months-12 years, 60-80 mg/m 2  every 6 hours (approximating to 9-12 mg/kg twice  daily by mouth)   Zidovudine (Non-proprietary) [Ml  Capsules, zidovudine 100 mg, net price 60-cap pack  = £50.17; 250 mg, 60-cap pack = £125.44   Capsules, zidovudine 100 mg (white/blue band), net  price 100-cap pack = £104.54; 250 mg (blue/white/  dark blue band), 40-cap pack = £104.54  Oral solution, sugar-free, strawberry-flavoured,  zidovudine 50 mg/5 mL, net price 200-mL pack with  10-mL oral syringe = £20.91   Injection, zidovudine 10 mg/mL. For dilution and use  as an intravenous infusion. Net price 20-mL vial =  £10.50   Tablets, f/c, scored, zidovudine 300 mg, lamivudine  150 mg, net price 60-tab pack = £300.12  Dose ADULT and CHILD body-weight over 30 kg, 1 tablet twice  daily; CHILD body-weight 14-21 kg, half a tablet twice daily; body-  weight 2 1-30 kg, half a tablet in the morning and one tablet in the  evening   Note Tablets may be crushed and mixed with semi-solid food or  liquid just before administration    Hepatic impairment Protease inhibitors should be  used with caution in patients with chronic hepatitis B or  C (increased risk of hepatic side-effects)   Side-effects Side-effects of the protease inhibitors  include gastro-intestinal disturbances (including diarr-  hoea, nausea, vomiting, abdominal pain, flatulence),  anorexia, hepatic dysfunction, pancreatitis; blood dis-  orders including anaemia, neutropenia, and thrombocy-  topenia; sleep disturbances, fatigue, headache, dizzi-  ness, paraesthesia, myalgia, myositis, rhabdomyolysis;  taste disturbances; rash, pruritus, Stevens- Johnson  syndrome, hypersensitivity reactions including anaphy-  laxis; see also notes above for lipodystrophy and metab-  olic effects (Lipodystrophy Syndrome), and Osteonecro-  sis.   Cautions see notes above; also concomitant use with  drugs that prolong PR interval; cardiac conduction  disorders; predisposition to QT interval prolongation  (including electrolyte disturbances, concomitant use  of drugs that prolong QT interval); interactions:  Appendix 1 (atazanavir)   Contra-indications see notes above  Hepatic impairment see notes above; also manufac-  turer advises caution in mild impairment; avoid in  moderate to severe impairment  Pregnancy manufacturer advises use only if potential  benefit outweighs risk; theoretical risk of hyperbilir-  ubinaemia in neonate if used at term  Breast-feeding see p. 381   Side-effects see notes above; also AV block (in chil-  dren); less commonly mouth ulcers, dry mouth,  hypertension, syncope, chest pain, dyspnoea, per-  ipheral neuropathy, abnormal dreams, amnesia, dis-  orientation, depression, anxiety, weight changes,  increased appetite, gynaecomastia, nephrolithiasis,  urinary frequency, haematuria, proteinuria, arthralgia,  and alopecia; rarely hepatosplenomegaly, oedema,  palpitation, and abnormal gait; also reported, chole-  lithiasis, cholecystitis, and torsade de pointes  Dose   • With low-dose ritonavir, 300 mg once daily; CHILD  over 6 years, body-weight 15-20 kg, 150 mg once  daily; body-weight 20-40 kg, 200 mg once daily; body-  weight over 40 kg, adult dose   Capsules, atazanavir (as sulphate) 150 mg (dark blue/  light blue), net price 60-cap pack = £303.38; 200 mg  (dark blue), 60-cap pack = £303.38; 300 mg (red/  blue), 30-cap pack = £303.38. Label: 5, 21    Cautions Protease inhibitors are associated with  hyperglycaemia and should be used with caution in  diabetes (see Lipodystrophy Syndrome, p. 382). Caution  is also needed in patients with haemophilia who may be  at increased risk of bleeding.   Contra-indications Protease inhibitors should not be  given to patients with acute porphyria (but see section  9.8.2).   Cautions see notes above; also sulfonamide sensitiv-  ity; monitor liver function before and during treat-  ment; interactions: Appendix 1 (darunavir)   Rash Mild to moderate rash occurs commonly, usually  within the first 4 weeks of therapy and resolves without    stopping treatment. Severe skin rash (including Stevens-  Johnson syndrome and toxic epidermal necrolysis) occurs  less frequently and may be accompanied by fever, malaise,  arthralgia, myalgia, oral lesions, conjunctivitis, hepatitis, or  eosinophilia; treatment should be stopped if severe rash  develops   Contra-indications see notes above  Hepatic impairment see notes above; also manufac-  turer advises caution in mild to moderate impairment;  avoid in severe impairment — no information available  Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding see p. 381  Side-effects see notes above; also haematemesis,  myocardial infarction, angina, QT interval prolonga-  tion, syncope, bradycardia, tachycardia, palpitation,  hypertension, flushing, peripheral oedema, dyspnoea,  cough, peripheral neuropathy, anxiety, confusion,  memory impairment, depression, abnormal dreams,  convulsions, increased appetite, weight changes,  pyrexia, hypothyroidism, osteoporosis, gynaecomas-  tia, erectile dysfunction, reduced libido, dysuria,  polyuria, nephrolithiasis, renal failure, arthralgia,  visual disturbances, dry eyes, conjunctival hyperae-  mia, rhinorrheoa, throat irritation, dry mouth, sto-  matisis, nail discoloration, acne, seborrhoeic  dermatitis, eczema, increased sweating, alopecia  Dose   • With low-dose ritonavir, ADULT and CHILD over 6 years,  body-weight over 40 kg, previously treated with anti-  retroviral therapy, 600 mg twice daily; CHILD over 6  years, previously treated with antiretroviral therapy,  body-weight 20-30 kg, 375 mg twice daily; body-  weight 30-40 kg, 450 mg twice daily   • With low-dose ritonavir, ADULT over 18 years not  previously treated with antiretroviral therapy, 800 mg  once daily   Missed dose If a dose is more than 6 hours late on the twice  daily regimen (or more than 12 hours late on the once daily  regimen), the missed dose should not be taken and the next  dose should be taken at the normal time   Prezista® (Janssen-Cilag) Y (Ml  Tablets, f/c, darunavir (as ethanolate) 75 mg (white),  net price 480-tab pack = £446.70; 150 mg (white),  240-tab pack = £446.70; 400 mg (light orange), 60-tab  pack = £297.80; 600 mg (orange), 60-tab pack =  £446.70. Label: 21   Rash Rash may occur, usually in the second week of therapy;  discontinue permanently if severe rash with systemic or  allergic symptoms or, mucosal involvement; if rash mild or  moderate, may continue without interruption — usually  resolves within 2 weeks and may respond to antihistamines   Hepatic impairment see notes above; also manufac-  turer advises caution in mild impairment; reduce dose  to 450 mg twice daily in moderate impairment; reduce  dose to 300 mg twice daily in severe impairment   Pregnancy toxicity in animal studies; manufacturer  advises use only if potential benefit outweighs risk    Side-effects see notes above; also reported, rash  including rarely Stevens- Johnson syndrome (see also  Rash above)   • With low-dose ritonavir, ADULT and CHILD over 6 years,  body-weight over 39 kg, 700 mg twice daily; CHILD  over 6 years, body-weight 25-39 kg, 18 mg/kg twice  daily   Note 700 mg fosamprenavir is equivalent to approx. 600 mg  amprenavir   Tablets, f/c, pink, fosamprenavir (as calcium) 700 mg,  net price 60-tab pack = £258.97  Oral suspension, fosamprenavir (as calcium) 50 mg/  mL, net price 225-mL pack (grape-bubblegum-and  peppermint-flavoured) (with 10-mL oral syringe) =  £69.06. Counselling, administration  Counselling In adults, oral suspension should be taken on  an empty stomach; in children under 18 years, oral suspen-  sion should be taken with food    Indications HIV infection in combination with  nucleoside reverse transcriptase inhibitors  Cautions see notes above; also ensure adequate  hydration (risk of nephrolithiasis especially in chil-  dren); patients at risk of nephrolithiasis (monitor for  nephrolithiasis); patients at high risk of cardiovascular  disease (especially if 10-year cardiovascular risk  greater than 20%); interactions: Appendix 1 (indina-  vir)   Contra-indications see notes above  Hepatic impairment see notes above; also increased  risk of nephrolithiasis; reduce dose in mild to mod-  erate impairment; not studied in severe impairment  Renal impairment use with caution; monitor for  nephrolithiasis   Pregnancy toxicity in animal studies; manufacturer  advises use only if potential benefit outweighs risk;  theoretical risk of hyperbilirubinaemia and renal  stones in neonate if used at term  Breast-feeding see p. 381  Side-effects see notes above; also reported, dry  mouth, hypoaesthesia, dry skin, hyperpigmentation,  alopecia, paronychia, interstitial nephritis (with  medullary calcification and cortical atrophy in  asymptomatic severe leucocyturia), nephrolithiasis  (may require interruption or discontinuation; more  frequent in children), dysuria, haematuria, crystalluria,  proteinuria, pyuria (in children), pyelonephritis;  haemolytic anaemia  Dose   Capsules, indinavir (as sulphate), 200 mg, net price  360-cap pack = £226.28; 400 mg, 180-cap pack =  £226.28. Label: 27, counselling, administration  Counselling Administer 1 hour before or 2 hours after a meal;  may be administered with a low-fat light meal; in combination  with didanosine tablets, allow 1 hour between each drug (antacids  in didanosine tablets reduce absorption of indinavir); in combi-  nation with low-dose ritonavir, give with food  Note Dispense in original container (contains desiccant)   Cautions see notes above; concomitant use with drugs  that prolong QT or PR interval; cardiac conduction  disorders, structural heart disease; patients at high  risk of cardiovascular disease (especially if 10-year  cardiovascular risk greater than 20%); pancreatitis  (see below); interactions: Appendix 1 (lopinavir,  ritonavir)   Pancreatitis Signs and symptoms suggestive of pancreatitis  (including raised serum lipase) should be evaluated — dis-  continue if pancreatitis diagnosed   Hepatic impairment see notes above; also avoid oral  solution due to propylene glycol content; manufac-  turer advises avoid capsules and tablets in severe  impairment   Renal impairment avoid oral solution due to propy-  lene glycol content; use tablets with caution in severe  impairment   Pregnancy avoid oral solution due to high propylene  glycol content; manufacturer advises use capsules  and tablets only if potential benefit outweighs risk  (toxicity in animal studies)   Side-effects see notes above; also electrolyte distur-  bances in children; less commonly haemorrhagic  colitis, weight changes, chest pain, oedema, anxiety,  depression, abnormal dreams, peripheral neuropathy,  pyrexia, Cushing’s syndrome, sexual dysfunction,  dehydration, arthralgia, tinnitus, dry mouth, acne,  alopecia, and sweating; rarely cholecystitis, gastric  ulcer, rectal bleeding, myocardial infarction, hyper-  tension, palpitation, AV block, deep vein thrombosis,  thromobophlebitis, vasculitis, dyspnoea, cough,  appetite changes, agitation, confusion, amnesia,  ataxia, hypertonia, extrapyramidal effects, influenza-  like symptoms, hypothyroidism, amenorrhoea,  menorrhagia, gynaecomastia, nephrolithiasis, nephri-  tis, albuminuria, haematuria, hypercalciuria, hypo-  phosphataemia, lactic acidosis, hyperuricaemia,  visual disturbances, otitis media, dysphagia, mouth  ulceration, stomatitis, periodontitis, sialadenitis, ecz-  ema, skin discoloration, and nail disorders   Tablets, pale yellow, f/c, lopinavir 100 mg, ritonavir  25 mg, net price 60-tab pack = £76.85. Label: 25  Dose CHILD over 2 years with body-weight under 40 kg and body  surface area 0.5-0.9m 2 , 2 tablets twice daily; body surface area  0.9-1.4m 2 , 3 tablets twice daily   Tablets, yellow, f/c, lopinavir 200 mg, ritonavir 50 mg,  net price 120-tab pack = £307.39. Label: 25  Dose ADULT and CHILD with body surface area greater than  1.4 m 2 or body-weight 40 kg and over, 2 tablets twice daily  Note Alternatively, in adults with a HIV strain that has less than 3  mutations to protease inhibitors, 4 tablets may be taken once daily  Oral solution, lopinavir 400 mg, ritonavir 100 mg/  5mL, net price 5x60-mL packs = £307.39. Label: 21   Excipients include propylene glycol 153mg/mL (see Excipients, p. 2),  alcohol 42%   Dose 5 mL twice daily with food; CHILD 2-12 years 2.9mL/m 2  twice daily with food, max. 5 mL twice daily   • 1.25 g twice daily or 750 mg 3 times daily; CHILD 3-13  years, initially 50-55 mg/kg twice daily (max. 1.25 g  twice daily) or 25-30 mg/kg 3 times daily (max.   Tablets, blue, f/c, nelfinavir (as mesilate) 250 mg, net  price 300-tab pack = £257.32. Label: 21   Indications HIV infection in combination with other  antiretroviral drugs; low doses used to increase effect  of some protease inhibitors   Cautions see notes above; concomitant use with drugs  that prolong PR interval; cardiac conduction disor-  ders, structural heart disease; pancreatitis (see below);  interactions: Appendix 1 (ritonavir)   Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding see p. 381  Side-effects see notes and Cautions above; also  diarrhoea (may impair absorption — close monitoring  required), vasodilatation, cough, throat irritation,  anxiety, perioral and peripheral paraesthesia, hyper-  aesthesia, fever, decreased blood thyroxine concen-  tration, electrolyte disturbances, raised uric acid, dry  mouth, mouth ulcers, and sweating; less commonly  increased prothrombin time and dehydration; syn-  cope, postural hypotension, seizures, menorrhagia,  and renal failure also reported  Dose   • Initially 300 mg every 12 hours for 3 days, increased  in steps of 100 mg every 12 hours over not longer than  14 days to 600 mg every 12 hours; CHILD over 2 years  initially 250 mg/m 2 every 12 hours, increased by   50 mg/m 2 at intervals of 2-3 days to 350 mg/m 2  every 12 hours (max. 600 mg every 12 hours)   • Low-dose booster to increase effect of other protease  inhibitors, 100-200 mg once or twice daily   Oral solution, sugar-free, ritonavir 400 mg/5 mL, net  price 5 x 90-mL packs (with measuring cup) =  £403.20. Label: 21, counselling, administration  Counselling Oral solution contains 43% alcohol; bitter taste can  be masked by mixing with chocolate milk; do not mix with water,  measuring cup must be dry    Aptivus® (Boehringer Ingelheim) ▼ (S  Capsules, pink, tipranavir 250 mg, net price 120-cap  pack = £441.00. Label: 5, 21   Oral Solution, toffee-and mint-flavoured, tipranavir  lOOmg/mL, net price 95-mL pack = £129.65.   Note The bioavailability of Aptivus ® oral solution is higher than  that of the capsules; the oral solution is not interchangeable with  the capsules on a milligram-for-milligram basis  Counselling Patients should be told to observe the oral solution  for crystallisation; the bottle should be replaced if more than a thin  layer of crystals form (doses should continue to be taken at the  normal time until the bottle is replaced)   Cautions elderly; history of mental illness or seizures;  monitor liver function if receiving other hepatotoxic  drugs; interactions: Appendix 1 (efavirenz)   Rash Rash, usually in the first 2 weeks, is the most common  side-effect; discontinue if severe rash with blistering, des-  quamation, mucosal involvement or fever; if rash mild or  moderate, may continue without interruption — usually  resolves within 1 month   Psychiatric disorders Patients or their carers should be  advised to seek immediate medical attention if symptoms  such as severe depression, psychosis or suicidal ideation  occur   Cautions see notes above; monitor ECG before start-  ing treatment and then on day 3 or 4 of treatment —  discontinue if QT interval over 480 milliseconds, if QT  interval more than 20 milliseconds above baseline, or  if prolongation of PR interval; concomitant use of  garlic (avoid garlic capsules — reduces plasma-saqui-  navir concentration); interactions: Appendix 1  (saquinavir)   Counselling Patients should be told how to recognise signs  of arrhythmia and advised to seek medical attention if  symptoms such as palpitation or syncope develop   Contra-indications see notes above; predisposition to  cardiac arrhythmias (including congenital QT pro-  longation, bradycardia, history of symptomatic  arrhythmias, heart failure with reduced left ventricular  ejection fraction, electrolyte disturbances, concomi-  tant use of drugs that prolong QT or PR interval);  concomitant use of drugs that increase plasma-  saquinavir concentration (avoid unless no alternative  treatment available)   Renal impairment use with caution if eGFR less than  30 mL/minute/ 1.73 m 2   Side-effects see notes above; also dyspnoea,  increased appetite, peripheral neuropathy, con-  vulsions, changes in libido, renal impairment, dry  mouth, and alopecia  Dose   • With low-dose ritonavir, ADULT and ADOLESCENT over  16 years previously treated with antiretroviral therapy,  1 g every 12 hours   • With low-dose ritonavir, ADULT and ADOLESCENT over  16 years not previously treated with antiretroviral  therapy, 500 mg every 12 hours for 7 days then 1 g  every 12 hours   Indications HIV infection resistant to other protease  inhibitors, in combination with other antiretroviral  drugs in patients previously treated with anti-  retrovirals   Cautions see notes above; also patients at risk of  increased bleeding from trauma, surgery or other  pathological conditions; concomitant use of drugs  that increase risk of bleeding; interactions: Appendix  1 (tipranavir)   Hepatotoxicity Potentially life-threatening hepatotoxicity  reported; monitor liver function before treatment then  every 2 weeks for 1 month, then every 3 months. Discon-  tinue if signs or symptoms of hepatitis develop or if liver-  function abnormality develops (consult product literature)   Hepatic impairment in mild liver disease, monitor for  dose related side-effects (e.g. CNS effects) and  monitor liver function; avoid in moderate to severe  impairment; greater risk of hepatic side-effects in  chronic hepatitis B or C    Pregnancy manufacturer advises avoid (effective  contraception required during treatment and for 12  weeks after treatment); use efavirenz only if no alter-  native available    Side-effects rash including Stevens- Johnson  syndrome (see Rash above); abdominal pain, diarr-  hoea, nausea, vomiting; anxiety, depression, sleep  disturbances, abnormal dreams, dizziness, headache,  fatigue, impaired concentration (administration at  bedtime especially in first 2-4 weeks reduces CNS  effects); pruritus; less commonly pancreatitis, hepat-  itis, flushing, psychosis, mania, suicidal ideation,  amnesia, ataxia, tremor, convulsions, gynaecomastia,  blurred vision, tinnitus; rarely hepatic failure, photo-  sensitivity; also reported raised serum cholesterol (see  Lipodystrophy Syndrome, p. 382); see also Osteone-  crosis, p. 382  Dose   Sustiva® (Bristol-Myers Squibb) tMl  Capsules, efavirenz 50 mg (yellow/white), net price  30-cap pack = £16.73; 100 mg (white), 30-cap pack =  £33.41; 200 mg (yellow), 90-cap pack = £200.27.  Label: 23   200 mg once daily; body-weight 15-20 kg, 250 mg once daily;  body-weight 20-25 kg, 300 mg once daily; body-weight 25-  32.5 kg, 350 mg once daily; body-weight 32.5-40 kg, 400 mg once  daily; body-weight 40 kg and over, 600 mg once daily    Hepatic impairment manufacturer advises caution in  moderate impairment; avoid in severe impairment —  no information available; greater risk of hepatic side-  effects in chronic hepatitis B or C  Pregnancy manufacturer advises use only if potential  benefit outweighs risk  Breast-feeding see p. 381  Side-effects rash (including Stevens- Johnson  syndrome rarely and toxic epidermal necrolysis very  rarely; see also Hypersensitivity Reactions above);  gastro-oesophageal reflux, nausea, abdominal pain,  flatulence, gastritis; myocardial infarction, hyper-  tension; peripheral neuropathy; diabetes, hyperlipid-  aemia (see also Lipodystrophy Syndrome, p. 382);  renal failure; anaemia; less commonly pancreatitis,  haematemesis, hepatitis, angina, bronchospasm,  drowsiness, malaise, gynaecomastia, blurred vision,  dry mouth, and sweating; also reported, haemorrha-  gic stroke and hypersensitivity reactions; see also  Osteonecrosis, p. 382  Dose   • ADULT over 18 years, 200 mg twice daily after food  Missed dose If a dose is more than 6 hours late, the missed  dose should not be taken and the next dose should be taken  at the normal time   Dose ADULT and CHILD, body-weight over 40kg, 600 mg once  daily   Oral solution, sugar-free, strawberry and mint fla-  vour, efavirenz 30mg/mL, net price 180-mL pack =  £53.84   270 mg once daily; body-weight 15-20 kg, 300 mg once daily;  body-weight 20-25 kg, 360 mg once daily; body-weight 25-  32.5 kg, 450 mg once daily; body-weight 32.5-40 kg, 510 mg once  daily; body-weight 40kg and over, 720 mg once daily; CHILD 3-5  years, body-weight 13-15 kg, 360 mg once daily; body-weight 15-  20 kg, 390 mg once daily; body-weight 20-25 kg, 450 mg once  daily; body-weight 25-32.5 kg, 5 10 mg once daily  Note The bioavailability of Sustiva ® oral solution is lower than  that of the capsules and tablets; the oral solution is not  interchangeable with either capsules or tablets on a milligram-for-  milligram basis   Indications in combination with other antiretroviral  drugs (including a boosted protease inhibitor) for HIV  infection resistant to other non-nucleoside reverse  transcriptase inhibitors and protease inhibitors  Cautions interactions: Appendix 1 (etravirine)  Hypersensitivity reactions Rash, usually in the second  week, is the most common side-effect and appears more  frequently in women. Life-threatening hypersensitivity  reactions reported usually during week 3-6 of treatment and  characterised by rash, eosinophilia, and systemic symptoms  (including fever, general malaise, myalgia, arthralgia, blis-  tering, oral lesions, conjunctivitis, and hepatitis). Discontinue  permanently if hypersensitivity reaction or severe rash  develop. If rash mild or moderate (without signs of hyper-  sensitivity reaction), may continue without interruption —  usually resolves within 2 weeks   Counselling Patients should be told how to recognise hyper-  sensitivity reactions and advised to seek immediate medical  attention if hypersensitivity reaction or severe rash develop  Contra-indications acute porphyria (but see section  9.8.2)    Intelence® (Janssen-Cilag) Y (Ml  Tablets, etravirine 100 mg, net price 120-tab pack =  £301.27. Label: 21, counselling, rash and hypersensi-  tivity reactions   Note Dispense in original container (contains desiccant).  Patients with swallowing difficulties may disperse tablets in  a glass of water just before administration   Cautions chronic hepatitis B or C, high CD4 cell count,  and women (all at greater risk of hepatic side-  effects — if plasma HIV-1 RNA detectable, manufac-  turer advises avoid in women with CD4 cell count  greater than 250 cells/mm 3 or in men with CD4 cell  count greater than 400 cells/mm 3 unless potential  benefit outweighs risk); interactions: Appendix 1  (nevirapine)   Hepatic disease Potentially life-threatening hepatotoxicity  including fatal fulminant hepatitis reported usually in first 6  weeks; close monitoring required during first 18 weeks;  monitor liver function before treatment then every 2 weeks  for 2 months then after 1 month and then regularly; dis-  continue permanently if abnormalities in liver function tests  accompanied by hypersensitivity reaction (rash, fever,  arthralgia, myalgia, lymphadenopathy, hepatitis, renal  impairment, eosinophilia, granulocytopenia); suspend if  severe abnormalities in liver function tests but no hyper-  sensitivity reaction — discontinue permanently if significant  liver function abnormalities recur; monitor patient closely if  mild to moderate abnormalities in liver function tests with no  hypersensitivity reaction   Rash Rash, usually in first 6 weeks, is most common side-  effect; incidence reduced if introduced at low dose and dose  increased after 14 days; monitor closely for skin reactions  during first 18 weeks; discontinue permanently if severe rash  or if rash accompanied by blistering, oral lesions, con-  junctivitis, facial oedema, general malaise or hypersensitivity  reactions; if rash mild or moderate may continue without  interruption but dose should not be increased until rash  resolves   Counselling Patients should be told how to recognise hyper-  sensitivity reactions and advised to discontinue treatment  and seek immediate medical attention if severe skin reaction,  hypersensitivity reactions, or symptoms of hepatitis develop    Contra-indications acute porphyria (but see section  9.8.2); post-exposure prophylaxis  Hepatic impairment manufacturer advises caution in  moderate impairment; avoid in severe impairment;  see also Hepatic Disease, above  Pregnancy although manufacturer advises caution,  may be appropriate to use if clearly indicated; see also  p. 381   Breast-feeding see p. 381  Side-effects rash including Stevens- Johnson  syndrome and rarely, toxic epidermal necrolysis (see  also Cautions above); nausea, hepatitis (see also  Hepatic Disease above), headache; less commonly  vomiting, abdominal pain, fatigue, fever, and myalgia;  rarely diarrhoea, angioedema, anaphylaxis, hyper-  sensitivity reactions (may involve hepatic reactions  and rash, see Hepatic Disease above), arthralgia,  anaemia, and granulocytopenia (more frequent in  children); see also Osteonecrosis, p. 382  Dose   • ADULT and CHILD over 16 years, 200 mg once daily for  first 14 days then (if no rash present) 200 mg twice  daily; NEONATE and CHILD under 8 years, 150 mg/m 2  (max. 200 mg) once daily for first 14 days, then (if no  rash present) 150 mg/m 2 (max. 200 mg) twice daily or  4 mg/kg (max. 200 mg) once daily for first 14 days  then (if no rash present) 7 mg/kg (max. 200 mg) twice  daily; CHILD 8-16 years, 150 mg/m 2 (max. 200 mg)  once daily for first 14 days then (if no rash present)  150 mg/m 2 (max. 200 mg) twice daily or 4 mg/kg  (max. 200 mg) once daily for first 14 days then (if no  rash present) 4 mg/kg (max. 200 mg) twice daily  Note Duration of once daily dose regimen should not exceed  28 days; if rash not resolved within 28 days, alternative  treatment should be sought. If treatment interrupted for  more than 7 days, restart using the lower dose for the first 14  days as for new treatment   Tablets, nevirapine 200 mg, net price 14-tab pack =  £39.67, 60-tab pack = £170.00. Counselling, hyper-  sensitivity reactions   Suspension, nevirapine 50 mg/5 mL, net price 240-  mL pack = £50.40. Counselling, hypersensitivity  reactions   Indications HIV infection in combination with other  antiretroviral drugs for resistant infection or for  patients intolerant to other antiretroviral regimens   Hypersensitivity reactions Hypersensitivity reactions  including rash, fever, nausea, vomiting, chills, rigors, low  blood pressure, respiratory distress, glomerulonephritis, and  raised liver enzymes reported; discontinue immediately if  any signs or symptoms of systemic hypersensitivity develop  and do not rechallenge   Counselling Patients should be told how to recognise signs  of hypersensitivity, and advised to discontinue treatment and  seek immediate medical attention if symptoms develop  Hepatic impairment manufacturer advises caution —  no information available; chronic hepatitis B or C  (possibly greater risk of hepatic side-effects)  Pregnancy manufacturer advises use only if potential  benefit outweighs risk    Breast-feeding see p. 381  Side-effects injection-site reactions; pancreatitis,  gastro-oesophageal reflux disease, anorexia, weight  loss; hypertriglyceridaemia; peripheral neuropathy,  asthenia, tremor, anxiety, nightmares, irritability,  impaired concentration, vertigo; pneumonia, sinusitis,  influenza-like illness; diabetes mellitus; haematuria;  renal calculi, lymphadenopathy; myalgia; conjunctiv-  itis; dry skin, acne, erythema, skin papilloma; less  commonly hypersensitivity reactions (see Cautions);  see also Osteonecrosis, p. 382  Dose   • By subcutaneous injection, ADULT and ADOLESCENT  over 16 years, 90 mg twice daily; CHILD 6-15 years,   Injection, powder for reconstitution, enfuvirtide  108 mg (= enfuvirtide 90mg/mL when reconstituted  with 1.1 mL Water for Injections), net price 108-mg  vial = £18.03 (with solvent, syringe, and alcohol  swabs). Counselling, hypersensitivity reactions    Indications CCR5-tropic HIV infection in combination  with other antiretroviral drugs in patients previously  treated with antiretrovirals    Cautions cardiovascular disease; chronic hepatitis B  or C; interactions: Appendix 1 (maraviroc)   Hepatic impairment manufacturer advises caution  Renal impairment if eGFR less than 80 mL/minute/  1.73m 2 , consult product literature  Pregnancy manufacturer advises use only if potential  benefit outweighs risk — toxicity in animal studies  Breast-feeding see p. 381   Side-effects nausea, vomiting, abdominal pain, dys-  pepsia, constipation, diarrhoea; cough; dizziness,  paraesthesia, asthenia, sleep disturbances, headache,  weight loss; muscle spasms, back pain; taste distur-  bances; rash, pruritus; less commonly pancreatitis,  hepatic cirrhosis, rectal bleeding, myocardial infarc-  tion, myocardial ischaemia, bronchospasm, seizures,  hallucinations, loss of consciousness, polyneuropathy,  pancytopenia, neutropenia, lymphadenopathy, renal  failure, polyuria, and myositis; see also Osteonecrosis,  p. 382   Tablets, blue, f/c, maraviroc, 150 mg, net-price 60-tab  pack = £519.14; 300 mg, 60-tab pack = £519.14   Cautions risk factors for myopathy or rhabdomyolysis;  chronic hepatitis B or C (greater risk of hepatic side-  effects); interactions: Appendix 1 (raltegravir)  Hepatic impairment manufacturer advises caution in  severe impairment — no information available  Pregnancy manufacturer advises avoid — toxicity in  animal studies  Breast-feeding see p. 381    headache, insomnia, abnormal dreams, asthenia, rash  (Stevens- Johnson syndrome reported); less com-  monly gastritis, hepatitis, pancreatitis, dry mouth,  gastro-oesophageal reflux, taste disturbances, pain on  swallowing, peptic ulcer, constipation, rectal bleeding,  lipodystrophy (see Lipodystrophy Syndrome, p. 382),  palpitation, ventricular extrasystoles, bradycardia,  hypertension, flushing, chest pain, oedema, dyspho-  nia, epistaxis, nasal congestion, drowsiness, anxiety,  appetite changes, confusion, impaired memory and  attention, depression, pyrexia, chills, carpal tunnel  syndrome, tremor, peripheral neuropathy, erectile  dysfunction, gynaecomastia, menopausal symptoms,  osteopenia, renal failure, nocturia, polydipsia, anae-  mia, thrombocytopenia, neutropenia, arthralgia,  myalgia, rhabdomyolysis, visual disturbances, tinni-  tus, gingivitis, glossitis, acne, pruritus, hyperhidrosis,  dry skin, skin papilloma, and alopecia; also reported  suicidal ideation; see also Osteonecrosis, p. 382   • ADULT and CHILD over 16 years, 400 mg twice daily   The two most important herpesvirus pathogens are  herpes simplex virus (herpesvirus hominis) and vari-  cella-zoster virus.   Herpes simplex infections Herpes infection of the  mouth and lips and in the eye is generally associated  with herpes simplex virus serotype 1 (HSV-1); other  areas of the skin may also be infected, especially in  immunodeficiency. Genital infection is most often asso-  ciated with HSV-2 and also HSV-1. Treatment of herpes  simplex infection should start as early as possible and  usually within 5 days of the appearance of the infection.   In individuals with good immune function, mild infec-  tion of the eye (ocular herpes, section 1 1.3.3) and of the  lips (herpes labialis or cold sores, section 13.10.3) is  treated with a topical antiviral drug. Primary herpetic  gingivostomatitis is managed by changes to diet and  with analgesics (section 12.3.2). Severe infection, neo-  natal herpes infection or infection in immunocompro-  mised individuals requires treatment with a systemic  antiviral drug. Primary or recurrent genital herpes sim-  plex infection is treated with an antiviral drug given by  mouth. Persistence of a lesion or recurrence in an  immunocompromised patient may signal the develop-  ment of resistance.   Specialist advice should be sought for systemic treat-  ment of herpes simplex infection in pregnancy.   Varicella-zoster infections Regardless of immune  function and the use of any immunoglobulins, neonates  with chickenpox should be treated with a parenteral  antiviral to reduce the risk of severe disease. Chicken-  pox in otherwise healthy children between 1 month and   12 years is usually mild and antiviral treatment is not  usually required.   Chickenpox is more severe in adolescents and adults  than in children; antiviral treatment started within 24  hours of the onset of rash may reduce the duration and  severity of symptoms in otherwise healthy adults and  adolescents. Antiviral treatment is generally recom-  mended in immunocompromised patients and those at  special risk (e.g. because of severe cardiovascular or  respiratory disease or chronic skin disorder); in such  cases, an antiviral is given for 10 days with at least 7  days of parenteral treatment.   Pregnant women who develop severe chickenpox may  be at risk of complications, especially varicella pneu-  monia. Specialist advice should be sought for the treat-  ment of chickenpox during pregnancy.   Those who have been exposed to chickenpox and are at  special risk of complications may require prophylaxis  with varicella-zoster immunoglobulin (see under Dis-  ease Specific Immunoglobulins, section 14.5.2).   In herpes zoster (shingles) systemic antiviral treatment  can reduce the severity and duration of pain, reduce  complications, and reduce viral shedding. Treatment  with the antiviral should be started within 72 hours of  the onset of rash and is usually continued for 7-10 days.  Immunocompromised patients at high risk of dissemi-  nated or severe infection should be treated with a par-  enteral antiviral drug.   Chronic pain which persists after the rash has healed  (postherpetic neuralgia) requires specific management  (section 4.7.3).   Choice Aciclovir is active against herpesviruses but  does not eradicate them. Uses of aciclovir include sys-  temic treatment of varicella-zoster and the systemic  and topical treatment of herpes simplex infections of  the skin (section 13.10.3) and mucous membranes (sec-  tion 7.2.2). It is used by mouth for severe herpetic  stomatitis (see also p. 696). Aciclovir eye ointment (sec-  tion 11.3.3) is used for herpes simplex infections of the  eye; it is combined with systemic treatment for  ophthalmic zoster.   Famciclovir, a prodrug of penciclovir, is similar to  aciclovir and is licensed for use in herpes zoster and  genital herpes. Penciclovir itself is used as a cream for  herpes simplex labialis (section 13.10.3).   Valaciclovir is an ester of aciclovir, licensed for herpes  zoster and herpes simplex infections of the skin and  mucous membranes (including genital herpes); it is also  licensed for preventing cytomegalovirus disease follow-  ing renal transplantation. Famciclovir or valaciclovir are  suitable alternatives to aciclovir for oral lesions asso-  ciated with herpes zoster. Valaciclovir once daily may  reduce the risk of transmitting genital herpes to hetero-  sexual partners — specialist advice should be sought.   Idoxuridine (section 13.10.3) has been used topically  for treating herpes simplex infections of the skin and  external genitalia with variable results. Its value in the  treatment of shingles is unclear.   Foscarnet (section 5. 3.2. 2) is used for mucocutaneous  herpes simplex virus infection unresponsive to aciclovir  in immunocompromised patients; it is toxic and can  cause renal impairment.   Inosine pranobex has been used by mouth for herpes  simplex infections; its effectiveness remains unproven.   Cautions maintain adequate hydration (especially with  infusion or high doses, or during renal impairment);  elderly (risk of neurological reactions); interactions:  Appendix 1 (aciclovir)   Renal impairment see Cautions above; also risk of  neurological reactions increased; use normal intra-  venous dose every 12 hours if eGFR 25-50 mL/min-  ute/ 1.73 m 2 (every 24 hours if eGFR 10-25 mL/min-  ute/1.73 m 2 ); consult product literature for  intravenous dose if eGFR less than 10mL/minute/  1.73 m 2 ; for herpes zoster, use normal oral dose every  8 hours if eGFR 10-25 mL/minute/ 1.73 m 2 (every  12 hours if eGFR less than 10mL/minute/1.73m 2 );  for herpes simplex, use normal oral dose every  12 hours if eGFR less than 10mL/minute/1.73m 2  Pregnancy not known to be harmful — manufacturers  advise use only when potential benefit outweighs risk  Breast-feeding significant amount in milk after sys-  temic administration — not known to be harmful but  manufacturer advises caution  Side-effects nausea, vomiting, abdominal pain, diarr-  hoea, headache, fatigue, rash, urticaria, pruritus,  photosensitivity; very rarely hepatitis, jaundice, dys-  pnoea, neurological reactions (including dizziness,  confusion, hallucinations, convulsions, ataxia, dysar-  thria, and drowsiness), acute renal failure, anaemia,  thrombocytopenia and leucopenia; on intravenous  infusion, severe local inflammation (sometimes lead-  ing to ulceration), and very rarely agitation, tremors,  psychosis and fever  Dose   200 mg (400 mg in the immunocompromised or if  absorption impaired) 5 times daily, usually for 5 days  (longer if new lesions appear during treatment or if  healing incomplete); CHILD 1 month-2 years, half adult  dose, over 2 years, adult dose  Genital herpes simplex, treatment of first episode,  200 mg 5 times daily or 400 mg 3 times daily usually  for 5 days, longer if new lesions appear during treat-  ment or if healing is incomplete (400 mg 5 times daily  for 7-10 days in immunocompromised or HIV-posi-  tive patients); treatment of recurrent infection, 800 mg  3 times daily for 2 days or 200 mg 5 times daily for 5  days or 400 mg 3 times daily for 3-5 days (400 mg 3  times daily for 5-10 days in immunocompromised or  HIV-positive patients)   Herpes simplex, suppression, 400 mg twice daily or  200 mg 4 times daily; increased to 400 mg 3 times  daily if recurrences occur on standard suppressive  therapy or for suppression of genital herpes during  late pregnancy (from 36 weeks gestation); therapy  interrupted every 6-12 months to reassess recurrence  frequency — consider restarting after two or more  recurrences   Herpes simplex, prophylaxis in the immunocompro-  mised, 200-400 mg 4 times daily; CHILD 1 month-2  years, half adult dose, over 2 years, adult dose  Varicella and herpes zoster, treatment, 800 mg 5 times  daily for 7 days; CHILD, varicella, 1 month-2 years  200 mg 4 times daily for 5 days; 2-6 years 400 mg 4  times daily for 5 days; 6-12 years 800 mg 4 times daily  for 5 days    Attenuation of chickenpox (if varicella-zoster  immunoglobulin not indicated) [unlicensed use],  ADULT and CHILD 40 mg/kg daily in 4 divided doses for  7 days starting 1 week after exposure   • By intravenous infusion, treatment of herpes simplex  in the immunocompromised, severe initial genital  herpes, and varicella-zoster, 5 mg/kg every 8 hours  usually for 5 days, doubled to 10 mg/kg every 8 hours  in varicella-zoster in the immunocompromised and in  simplex encephalitis (usually given for at least 10 days  in encephalitis, possibly for 14-21 days); prophylaxis  of herpes simplex in the immunocompromised, 5 mg/  kg every 8 hours   Note To avoid excessive dosage in obese patients, parenteral  dose should be calculated on the basis of ideal weight for  height   NEONATE and INFANT up to 3 months, herpes simplex,  20 mg/kg every 8 hours for 14 days (21 days if CNS  involvement); varicella-zoster [unlicensed use] 10-  20 mg/kg every 8 hours for at least 7 days; CHILD 3  months-12 years, herpes simplex or varicella-zoster,  250 mg/m 2 every 8 hours usually for 5 days, doubled  to 500 mg/m 2 every 8 hours for varicella-zoster in the  immunocompromised and in simplex encephalitis  (usually given for at least 10 days in encephalitis,  possibly for 14-21 days)   • By topical application, see section 13.10.3 (skin) and  section 11.3.3 (eye)    Aciclovir (Non-proprietary) 2°M1  Tablets, aciclovir 200 mg, net price 25-tab pack =  £4.45; 400 mg, 56-tab pack = £8.10; 800 mg, 35-tab  pack = £10.21. Label: 9  Brands include Virovir ®   Dental prescribing on NHS Aciclovir Tablets 200 mg or 800 mg  may be prescribed    Dispersible tablets, aciclovir 200 mg, net price 25-  tab pack = £2.05; 400 mg, 56-tab pack = £7.24;   800 mg, 35-tab pack = £7.02. Label: 9  Suspension, aciclovir 200 mg/5 mL, net price  125 mL = £38.22; 400 mg/5 mL, 100 mL = £41.55.  Label: 9   Intravenous infusion, powder for reconstitution,  aciclovir (as sodium salt), net price 250-mg vial =  £9.13; 500-mg vial = £20.22    Intravenous infusion, aciclovir (as sodium salt),  25mg/mL, net price 10-mL (250-mg) vial = £10.37;  20-mL (500-mg) vial = £19.21; 40-mL (1-g) vial =  £40.44   Tablets, all dispersible, f/c, aciclovir 200 mg, net price  25-tab pack = £17.71; 800 mg (scored, Shingles  Treatment Pack), 35-tab pack = £65.80. Label: 9  Suspension, both off-white, sugar-free, aciclovir  200 mg/5 mL (banana-flavoured), net price 125 mL =  £29.53; 400 mg/5 mL (Double Strength Suspension,  orange-flavoured) 100 mL = £33.01. Label: 9  Intravenous infusion, powder for reconstitution,  aciclovir (as sodium salt), net price 250-mg vial =  £9.96; 500-mg vial = £17.72   Hepatic impairment usual dose in well compensated  liver disease (information not available on decom-  pensated)   Side-effects nausea, vomiting, abdominal pain, diarr-  hoea; headache, fatigue; sweating, pruritus; rarely  confusion; very rarely jaundice, dizziness, drowsiness,  hallucinations, thrombocytopenia, rash (including  Stevens- Johnson syndrome); also reported, constipa-  tion and fever   • Herpes zoster, treatment, 500 mg 3 times daily for 7  days or 750 mg 1-2 times daily for 7 days (in immu-  nocompromised, 500 mg 3 times daily for 10 days)   • Genital herpes, treatment of first episode, 250 mg 3  times daily for 5 days, longer if new lesions appear  during treatment or if healing incomplete (500 mg  twice daily for 5-10 days in immunocompromised or  HIV-positive patients); treatment of recurrent infec-  tion, 125 mg twice daily for 5 days or 1 g twice daily  for 1 day (500 mg twice daily for 5-10 days in  immunocompromised or HIV-positive patients)   • Genital herpes, suppression, 250 mg twice daily  (500 mg twice daily in immunocompromised or HIV-  positive patients); therapy interrupted every 6-12  months to reassess recurrence frequency — consider  restarting after two or more recurrences   • Non-genital herpes simplex, treatment in the immu-  nocompromised, 500 mg twice daily for 7 days   Note Famciclovir doses in BNF may differ from those in  product literature    Famciclovir (Non-proprietary) (Ml  Tablets, famciclovir 125 mg, net price 10-tab pack =  £34.98; 250 mg, 15-tab pack = £109.49, 21-tab pack =  £152.34, 56-tab pack = £408.74; 500 mg, 14-tab pack  = £199.57, 30-tab pack = £433.69, 56-tab pack =  £831.46; 750 mg, 7-tab pack = £143.05. Label: 9   Tablets, all f/c, famciclovir 125 mg, net price 10-tab  pack = £37.12; 250 mg, 15-tab pack = £111.35, 21-tab  pack = £155.87; 56-tab pack = £415.67; 500 mg, 14-  tab pack = £207.86, 30-tab pack = £445.28, 56-tab  pack = £831.46; 750 mg, 7-tab pack = £148.79.    Side-effects reversible increase in serum and urinary  uric acid; less commonly nausea, vomiting, epigastric  discomfort, headache, vertigo, fatigue, arthralgia,  rashes and itching; rarely diarrhoea, constipation,  anxiety, sleep disturbances, and polyuria  Dose   • Mucocutaneous herpes simplex, 1 g 4 times daily for  7-14 days   • Adjunctive treatment of genital warts, 1 g 3 times daily  for 14-28 days   • Subacute sclerosing panencephalitis, 50-100 mg/kg  daily in 6 divided doses   Tablets, scored, inosine pranobex 500 mg, net price  100-tab pack = £39.50. Label: 9   Indications treatment of herpes zoster; treatment of  initial and suppression of recurrent herpes simplex  infections of skin and mucous membranes including  initial and recurrent genital herpes; reduction of  transmission of genital herpes; prevention of cyto-  megalovirus disease following solid organ transplan-  tation when valganciclovir or ganciclovir cannot be  used   Renal impairment maintain adequate hydration; for  herpes zoster, 1 g every 12 hours if eGFR 30-50 mL/  minute/1.73 m 2 (1 g every 24 hours if eGFR 10-  30 mL/minute/ 1.73 m 2 ; 500 mg every 24 hours if  eGFR less than 10 mL/minute/ 1.73 m 2 ); for treatment  of herpes simplex, 500 mg (1 g in immunocompro-  mised or HIV-positive patients) every 24 hours if  eGFR less than 30 mL/minute/ 1.73 m 2 ; for treatment  of herpes labialis, if eGFR 30-50 mL/minute/ 1.73 m 2 ,  initially 1 g, then 1 g 12 hours after initial dose (if eGFR  10-30 mL/minute/ 1. 73 m 2 , initally 500 mg, then  500 mg 12 hours after initial dose; if eGFR less than  10 mL/minute/ 1.73 m 2 , 500 mg as a single dose); for  suppression of herpes simplex, 250 mg (500 mg in  immunocompromised or HIV-positive patients) every  24 hours if eGFR less than 30 mL/minute/ 1.73 m 2 ; for  reduction of genital herpes transmission, 250 mg  every 24 hours if eGFR less than 1 5 mL/minute/   Pregnancy see under Aciclovir  Breast-feeding see under Aciclovir  Side-effects see under Aciclovir but neurological  reactions more frequent with high doses  Dose   • Herpes simplex, treatment of first episode, 500 mg  twice daily for 5 days, longer if new lesions appear  during treatment or if healing incomplete (1 g twice  daily for 10 days in immunocompromised or HIV-    positive patients); treatment of recurrent infection,  500 mg twice daily for 3-5 days (1 g twice daily for 5-  10 days in immunocompromised or HIV-positive  patients); CHILD 12-18 years see BNF for Children   • Herpes labialis, treatment, ADULT and CHILD over 12  years, initially 2g, then 2 g 12 hours after initial dose   • Herpes simplex, suppression, 500 mg daily in 1-2  divided doses (in immunocompromised or HIV posi-  tive patients, 500 mg twice daily); therapy interrupted  every 6-12 months to reassess recurrence fre-  quency — consider restarting after two or more  recurrences; CHILD 12-18 years see BNF for Children   • Reduction of transmission of genital herpes, seek  specialist advice, 500 mg once daily to be taken by the  infected partner   • Prevention of cytomegalovirus disease following solid  organ transplantation (preferably starting within 72  hours of transplantation), 2 g 4 times daily usually for  90 days; CHILD 12-18 years see BNF for Children   Valaciclovir (Non-proprietary) [Ml  Tablets, valaciclovir 500 mg, net price 10-tab pack =  £19.48, 42 tab-pack = £81.64. Label: 9   Tablets, f/c, valaciclovir (as hydrochloride) 250 mg,  net price 60-tab pack = £123.28; 500 mg, 10-tab pack  = £20.59, 42-tab pack = £86.30. Label: 9   Recommendations for the optimum maintenance ther-  apy of cytomegalovirus (CMV) infections and the dura-  tion of treatment are subject to rapid change.   Ganciclovir is related to aciclovir but it is more active  against cytomegalovirus; it is also much more toxic than  aciclovir and should therefore be prescribed only when  the potential benefit outweighs the risks. Ganciclovir is  administered by intravenous infusion for the initial  treatment of CMV infection. Ganciclovir causes pro-  found myelosuppression when given with zidovudine;  the two should not normally be given together particu-  larly during initial ganciclovir therapy. The likelihood of  ganciclovir resistance increases in patients with a high  viral load or in those who receive the drug over a long  duration; cross-resistance to cidofovir is common.   Valaciclovir (see p. 394) is licensed for prevention of  cytomegalovirus disease following renal transplanta-  tion.   Valganciclovir is an ester of ganciclovir which is  licensed for the initial treatment and maintenance treat-  ment of CMV retinitis in AIDS patients. Valganciclovir is  also licensed for preventing CMV disease following  solid organ transplantation from a cytomegalovirus-  positive donor.   Foscarnet is also active against cytomegalovirus; it is  toxic and can cause renal impairment.   Cidofovir is given in combination with probenecid for  CMV retinitis in AIDS patients when ganciclovir and  foscarnet are contra-indicated. Cidofovir is nephrotoxic.    Indications cytomegalovirus retinitis in AIDS patients  for whom other drugs are inappropriate  Cautions monitor renal function (serum creatinine and  urinary protein) and neutrophil count within 24 hours  before each dose; co-treatment with probenecid and  prior hydration with intravenous fluids necessary to  minimise potential nephrotoxicity (see below); dia-  betes mellitus (increased risk of ocular hypotony);  interactions: Appendix 1 (cidofovir)   Nephrotoxicity Do not initiate treatment in renal impair-  ment (assess creatinine clearance and proteinuria — consult  product literature); discontinue treatment and give intra-  venous fluids if renal function deteriorates — consult product  literature   Ocular disorders Regular ophthalmological examinations  recommended; iritis and uveitis have been reported which  may respond to a topical corticosteroid with or without a  cycloplegic drug — discontinue cidofovir if no response to  topical corticosteroid or if condition worsens, or if iritis or  uveitis recurs after successful treatment    Contra-indications concomitant administration of  potentially nephrotoxic drugs (discontinue potentially  nephrotoxic drugs at least 7 days before starting  cidofovir)   Renal impairment avoid if creatinine clearance less  than 55 mL/minute; nephrotoxic    Pregnancy avoid (toxicity in animal studies); effective  contraception required during and for 1 month after  treatment; also men should avoid fathering a child  during and for 3 months after treatment  Breast-feeding manufacturer advises avoid   Side-effects nephrotoxicity (see Cautions above);  nausea, vomiting, diarrhoea; dyspnoea; headache,  fever, asthenia; neutropenia; decreased intra-ocular  pressure, iritis, uveitis (see Cautions above); alopecia,  rash; less commonly Fanconi syndrome; also  reported, hearing impairment and pancreatitis   • Initial (induction) treatment, ADULT over 18 years, by  intravenous infusion over 1 hour, 5 mg/kg once  weekly for 2 weeks (give probenecid and intravenous  fluids with each dose, see below)   • Maintenance treatment, beginning 2 weeks after  completion of induction, ADULT over 18 years, by  intravenous infusion over 1 hour, 5 mg/kg once every  2 weeks (give probenecid and intravenous fluids with  each dose, see below)   Probenecid co-treatment By mouth (preferably after food),  probenecid 2 g 3 hours before cidofovir infusion followed by  probenecid 1 g at 2 hours and 1 g at 8 hours after the end of  cidofovir infusion (total probenecid 4 g); for cautions, contra-  indications and side-effects of probenecid see section 10.1.4  Prior hydration Sodium chloride 0.9%, by intravenous  infusion, 1 litre over 1 hour immediately before cidofovir  infusion (if tolerated an additional 1 litre may be given over  1-3 hours, starting at the same time as the cidofovir infusion  or immediately afterwards)   Caution in handling Cidofovir is toxic and personnel should be  adequately protected during handling and administration; if  solution comes into contact with skin or mucosa, wash off  immediately with water   Indications life-threatening or sight-threatening cyto-  megalovirus infections in immunocompromised  patients only; prevention of cytomegalovirus disease  during immunosuppressive therapy following organ  transplantation; local treatment of CMV retinitis  (section 11.3.3)   Cautions close monitoring of full blood count (severe  deterioration may require correction and possibly  treatment interruption); history of cytopenia; poten-  tial carcinogen and teratogen; radiotherapy; ensure  adequate hydration during intravenous administra-  tion; vesicant — infuse into vein with adequate flow  preferably using plastic cannula; children (possible  risk of long-term carcinogenic or reproductive toxi-  city); interactions: Appendix 1 (ganciclovir)  Contra-indications hypersensitivity to valganciclovir,  ganciclovir, aciclovir, or valaciclovir; abnormally low  haemoglobin, neutrophil, or platelet counts (consult  product literature)   Renal impairment reduce dose if eGFR less than  70mL/minute/1.73m 2 ; consult product literature  Pregnancy avoid — teratogenic risk; ensure effective  contraception during treatment and barrier contra-  ception for men during and for at least 90 days after  treatment   Breast-feeding avoid — no information available  Side-effects diarrhoea, nausea, vomiting, dyspepsia,  abdominal pain, constipation, flatulence, dysphagia,  taste disturbance, hepatic dysfunction; dyspnoea,  chest pain, cough; headache, insomnia, convulsions,  dizziness, peripheral neuropathy, depression, anxiety,  confusion, abnormal thinking, fatigue, weight loss,  anorexia; infection, pyrexia, night sweats; anaemia,  leucopenia, thrombocytopenia, pancytopenia, renal  impairment; myalgia, arthralgia; macular oedema,  retinal detachment, vitreous floaters, eye pain; ear  pain; dermatitis, pruritus; injection-site reactions; less  commonly mouth ulcers, pancreatitis, arrhythmias,  hypotension, anaphylactic reactions, psychosis, tre-  mor, male infertility, haematuria, disturbances in  hearing and vision, and alopecia  Dose   • By intravenous infusion, initially (induction) 5 mg/kg  every 12 hours for 14-21 days for treatment or for 7-  14 days for prevention; maintenance (for patients at  risk of relapse of retinitis) 6 mg/kg daily on 5 days per  week or 5 mg/kg daily until adequate recovery of  immunity; if retinitis progresses initial induction  treatment may be repeated; CHILD under 18 years, see  BNF for Children    Cymevene® (Roche) (Mi  Intravenous infusion, powder for reconstitution,  ganciclovir (as sodium salt). Net price 500-mg vial =  £29.77   Caution in handling Ganciclovir is toxic and personnel should be  adequately protected during handling and administration; if  solution comes into contact with skin or mucosa, wash off  immediately with soap and water   Indications cytomegalovirus disease [licensed for  cytomegalovirus retinitis in AIDS patients only];  mucocutaneous herpes simplex virus infections   Cautions monitor electrolytes, particularly calcium  and magnesium; monitor serum creatinine every  second day during induction and every week during  maintenance; ensure adequate hydration; avoid rapid  infusion; interactions: Appendix 1 (foscamet)   Side-effects nausea, vomiting, diarrhoea (occasion-  ally constipation and dyspepsia), abdominal pain,  anorexia; changes in blood pressure and ECG; head-  ache, fatigue, mood disturbances (including psycho-  sis), asthenia, paraesthesia, convulsions, tremor, diz-  ziness, and other neurological disorders; rash;  impairment of renal function including acute renal  failure; hypocalcaemia (sometimes symptomatic) and  other electrolyte disturbances; abnormal liver func-  tion tests; decreased haemoglobin concentration,  leucopenia, granulocytopenia, thrombocytopenia;  thrombophlebitis if given undiluted by peripheral vein;  genital irritation and ulceration (due to high concen-  trations excreted in urine); isolated reports of pan-  creatitis   • CMV disease [licensed for CMV retinitis only], by  intravenous infusion, initially (induction) 60 mg/kg  every 8 hours or 90 mg/kg every 12 hours, for 2-3  weeks; maintenance 60 mg/kg daily, increased to 90-  120 mg/kg if tolerated; if disease progresses on  maintenance dose, repeat induction regimen   • Mucocutaneous herpes simplex infection, by intra-  venous infusion, 40 mg/kg every 8 hours for 2-3  weeks or until lesions heal   Note Foscamet doses in BNF may differ from those in  product literature   Indications induction and maintenance treatment of  cytomegalovirus retinitis in AIDS patients; prevention  of cytomegalovirus disease following solid organ  transplantation from a cytomegalovirus-positive  donor.   • CMV retinitis, induction, ADULT over 18 years, 900 mg  twice daily for 2 1 days then 900 mg once daily;  induction regimen may be repeated if retinitis pro-  gresses   • Prevention of cytomegalovirus disease following solid  organ transplantation (starting within 10 days of    reduced susceptibility to lamivudine have emerged fol-  lowing extended therapy. Adefovir or tenofovir can be  given with lamivudine in lamivudine-resistant chronic  hepatitis B; telbivudine or entecavir should not be used  because cross-resistance can occur.    transplantation), ADULT over 18 years, 900 mg once  daily for 100 days (for 100-200 days following kidney  transplantation)   Note Oral valganciclovir 900 mg twice daily is equivalent to  intravenous ganciclovir 5 mg/kg twice daily   Tablets, pink, f/c, valganciclovir (as hydrochloride)  450 mg, net price 60-tab pack = £1081.46. Label: 21  Oral solution, tutti-frutti flavoured, valganciclovir (as  hydrochloride) 250 mg/ 5 mL when reconstituted with  water, net price 100 mL = £230.32. Label: 21  Caution in handling Valganciclovir is a potential teratogen  and carcinogen and caution is advised when handling the  powder, reconstituted solution, or broken tablets; if these come  into contact with skin or mucosa, wash off immediately with  water; avoid inhalation of powder   Treatment for viral hepatitis should be initiated by a  specialist. The management of uncomplicated acute  viral hepatitis is largely symptomatic. Early treatment  of acute hepatitis C with interferon alfa [unlicensed  indication] may reduce the risk of chronic infection.  Hepatitis B and hepatitis C viruses are major causes  of chronic hepatitis. For details on immunisation against  hepatitis A and B infections, see section 14.4 (active  immunisation), section 14.5.1 (passive immunisation  against hepatitis A), and section 14.5.2 (passive immuni-  sation against hepatitis B).    Chronic Hepatitis B Peginterferon alfa (section  8.2.4) is an option for the initial treatment of chronic  hepatitis B and may be preferable to interferon alfa.  The use of peginterferon alfa and interferon alfa is  limited by a response rate of 30-40% and relapse is  frequent. Treatment should be discontinued if no  improvement occurs after 4 months. The manufacturers  of peginterferon alfa-2a and interferon alfa contraindi-  cate use in decompensated liver disease, but low doses  can be used with great caution in these patients.  Although interferon alfa is contra-indicated in patients  receiving immunosuppressant treatment (or who have  received it recently), cautious use of peginterferon alfa-  2a may be justified in some cases.   Entecavir or tenofovir disoproxil (see p. 385) are  options for the initial treatment of chronic hepatitis B.  If the response is inadequate after 6-9 months of treat-  ment, a change in treatment should be considered.  Other drugs that are licensed for the treatment of  chronic hepatitis B include adefovir dipivoxil, lamivu-  dine (see p. 384), or telbivudine (but see NICE gui-  dance below).   Entecavir alone, tenofovir disoproxil alone, or a combi-  nation of lamivudine with either adefovir dipivoxil or  tenofovir disoproxil can be used in patients with decom-  pensated liver disease; entecavir is not licensed for these  patients.   If drug-resistant hepatitis B virus emerges during treat-  ment, another antiviral drug with a different resistance  profile should be added. Hepatitis B viruses with    If there is no toxicity or loss in efficacy, treatment with  adefovir, entecavir, lamivudine, telbivudine, or tenofovir  is usually continued until 6 months after adequate  seroconversion has occurred. Treatment is usually con-  tinued long-term in patients with decompensated liver  disease.   Tenofovir, or a combination of tenofovir with either  emtricitabine or lamivudine may be used with other  antiretrovirals, as part of ‘highly active antiretroviral  therapy’ (section 5.3.1) in patients who require treat-  ment for both HIV and chronic hepatitis B. If patients  infected with both HIV and chronic hepatitis B only  require treatment for chronic hepatitis B, they should  receive antivirals that are not active against HIV, such as  peginterferon alfa or adefovir. Treatment may be con-  tinued long-term, even if adequate seroconversion  occurs. Management of these patients should be coor-  dinated between HIV and hepatology specialists.    Chronic Hepatitis C Before starting treatment, the  genotype of the infecting hepatitis C virus should be  determined and the viral load measured as this may  affect the choice and duration of treatment. A combina-  tion of ribavirin (see p. 400) and peginterferon alfa  (section 8.2.4) is used for the treatment of chronic  hepatitis C (see NICE guidance, below). The combina-  tion of ribavirin and interferon alfa is less effective than  the combination of peginterferon alfa and ribavirin.  Peginterferon alfa alone should be used if ribavirin is  contra-indicated or not tolerated. Ribavirin monother-  apy is ineffective.   Peginterferon alfa and ribavirin for mild  chronic hepatitis C (August 2006 and  September 2010)   The combination of peginterferon alfa and ribavirin  can be used for treating mild chronic hepatitis C in  patients over 18 years. Alternatively, treatment can  be delayed until the disease has reached a moderate  stage (‘watchful waiting’). Peginterferon alfa alone  can be used if ribavirin is contra-indicated or not  tolerated.   Entecavir is an option for the treatment of chronic  hepatitis B.   Telbivudine is not recommended for the treatment  of chronic hepatitis B. Patients currently receiving  telbivudine can continue treatment until they and  their clinician consider it appropriate to stop.   Tenofovir disoproxil for the treatment of  chronic hepatitis B (July 2009)   Tenofovir is an option for the treatment of chronic  hepatitis B.   Peginterferon alfa, interferon alfa, and  ribavirin for moderate to severe chronic  hepatitis C (January 2004 and September  2010)   The combination of peginterferon alfa and ribavirin  should be used for treating moderate to severe  chronic hepatitis C in patients aged over 18 years:   • treated previously with interferon alfa alone or  in combination with ribavirin;   • whose condition did not respond to peginterfer-  on alfa alone or to a combination of peginterfer-  on alfa and ribavirin, or responded but subse-  quently relapsed;   Peginterferon alfa alone should be used if ribavirin is  contra-indicated or not tolerated. Interferon alfa for  either monotherapy or combined therapy should be  used only if neutropenia and thrombocytopenia are  a particular risk. Patients receiving interferon alfa  may be switched to peginterferon alfa.   Indications chronic hepatitis B infection with either  compensated liver disease with evidence of viral  replication, and histologically documented active liver  inflammation and fibrosis or decompensated liver  disease   Cautions monitor liver function tests every 3 months,  and viral and serological markers for hepatitis B every  3-6 months during treatment (continue monitoring  for at least 1 year after discontinuation — recurrent  hepatitis may occur on discontinuation); monitor  renal function before treatment then every 3 months,  more frequently in renal impairment or in patients  receiving nephrotoxic drugs; elderly; discontinue if  deterioration in liver function, hepatic steatosis, pro-  gressive hepatomegaly or unexplained lactic acidosis  Renal impairment 10 mg every 48 hours if eGFR 30-  50mL/minute/1.73m 2 ; 10 mg every 72 hours if  eGFR 10-30 mL/minute/1. 73 m 2 ; no information  available if eGFR less than 10 mL/minute/1. 73 m 2 ;  see also Cautions above    Side-effects nausea, vomiting, dyspepsia, abdominal  pain, flatulence, diarrhoea; asthenia, headache; renal  failure; hypophosphataemia; rash and pruritus; also  reported pancreatitis   Tablets, adefovir dipivoxil 10 mg, net price 30-tab  pack = £296.73   Indications chronic hepatitis B infection with com-  pensated liver disease, evidence of viral replication,   Cautions monitor liver function tests every 3 months,  and viral and serological markers for hepatitis B every  3-6 months during treatment (continue monitoring  for at least 1 year after discontinuation — recurrent  hepatitis may occur on discontinuation); HIV infec-  tion — risk of HIV resistance in patients not receiving  ‘highly active antiretroviral therapy’; lamivudine-  resistant chronic hepatitis B — risk of entecavir resis-  tance; discontinue if deterioration in liver function,  hepatic steatosis, progressive hepatomegaly or unex-  plained lactic acidosis   Pregnancy toxicity in animal studies — manufacturer  advises use only if potential benefit outweighs risk;  effective contraception required during treatment   Side-effects nausea, vomiting, dyspepsia, diarrhoea,  raised serum amylase and lipase, headache, fatigue,  dizziness, sleep disturbances; less commonly throm-  bocytopenia, rash, alopecia   • ADULT over 18 years, not previously treated with  nucleoside analogues, 500 micrograms once daily   • ADULT over 18 years with lamivudine-resistant chronic  hepatitis B (but see notes above), 1 mg once daily;  consider other treatment if inadequate response after  6 months   Counselling To be taken at least 2 hours before or 2 hours  after food   Baraclude® (Bristol-Myers Squibb) T (Ml  Tablets, f/c, entecavir (as monohydrate) 500 micr-  ograms (white), net price 30-tab pack = £363.26; 1 mg  (pink), 30-tab pack = £363.26. Counselling, adminis-  tration   Indications chronic hepatitis B infection with com-  pensated liver disease, evidence of viral replication,  and histologically documented active liver inflam-  mation or fibrosis   Cautions monitor liver function tests every 3 months  and viral and serological markers of hepatitis B every  3-6 months during treatment (continue monitoring  for at least 1 year after discontinuation — recurrent  hepatitis may occur on discontinuation); lamivudine-  resistant chronic hepatitis B — risk of telbivudine  resistance; discontinue if deterioration in liver func-  tion, hepatic steatosis, progressive hepatomegaly or  unexplained lactic acidosis; interactions: Appendix 1  (telbivudine)   Counselling Patients should be advised to promptly report  unexplained muscle pain, tenderness, or weakness, or  numbness, tingling or burning sensations   Renal impairment 600 mg every 48 hours if eGFR  30-49 mL/minute/1. 73m 2 ; 600 mg every 72 hours if  eGFR less than 30 mL/minute/ 1.73 m 2    Side-effects nausea, diarrhoea, abdominal pain,  raised serum amylase and lipase; cough; dizziness,  headache, fatigue; rash; less commonly, taste distur-  bance, arthralgia, myalgia, myopathy (discontinue  treatment), and peripheral neuropathy; also reported,  lactic acidosis and rhabdomyolysis  Dose   • ADULT and CHILD over 16 years, 600 mg once daily  Sebivo® (Novartis) ▼ (Ml   Tablets, f/c, telbivudine 600 mg, net price 28-tab pack  = £290.33. Counselling, muscle effects, peripheral  neuropathy   Oseltamivir and zanamivir reduce replication of influ-  enza A and B viruses by inhibiting viral neuraminidase.  They are most effective for the treatment of influenza if  started within a few hours of the onset of symptoms;  they are licensed for use within 48 hours (within 36  hours for zanamivir in children) of the first symptoms. In  otherwise healthy individuals they reduce the duration  of symptoms by about 1-1.5 days. Oseltamivir or zana-  mivir can reduce the risk of complications from influ-  enza in the elderly and in patients with chronic disease  (see also NICE guidance, below).   Oseltamivir and zanamivir are licensed for post-expo-  sure prophylaxis of influenza when influenza is circulat-  ing in the community. Oseltamivir should be given  within 48 hours of exposure to influenza while zanami-  vir should be given within 36 hours of exposure to  influenza (see also NICE guidance, below). Oseltamivir  and zanamivir are also licensed for use in exceptional  circumstances (e.g. when vaccination does not cover the  infecting strain) to prevent influenza in an epidemic.  There is evidence that some strains of influenza A virus  have reduced susceptibility to oseltamivir, but may  retain susceptibility to zanamivir.   Amantadine is licensed for prophylaxis and treatment  of influenza A but it is no longer recommended (see  NICE guidance).   Information on pandemic influenza, avian influenza,  and swine influenza may be found at www.hpa.org.uk   Oseltamivir in children under 1 year of age Data  on the use of oseltamivir in children under 1 year of age  is limited. Furthermore oseltamivir may be ineffective in  neonates because they may not be able to metabolise  oseltamivir to its active form. In exceptional circum-  stances, oseltamivir can be used (under specialist super-  vision) for the treatment or post-exposure prophylaxis  of influenza in children under 1 year of age. The Depart-  ment of Health has advised (May 2009) that during a  pandemic, treatment with oseltamivir can be overseen  by healthcare professionals experienced in assessing  children.   Oseltamivir, zanamivir, and amantadine for  prophylaxis and treatment of influenza  (September 2008 and February 2009)   The drugs described here are not a substitute for  vaccination, which remains the most effective way of  preventing illness from influenza.   • Amantadine is not recommended for prophy-  laxis or treatment of influenza.   • Oseltamivir or zanamivir are not recommended  for seasonal prophylaxis against influenza.   • When influenza is circulating in the commu-  nity 1 , either oseltamivir or zanamivir is recom-  mended (in accordance with UK licensing) for  post-exposure prophylaxis in at-risk patients  who are not effectively protected by influenza  vaccine, and who have been in close contact  with someone suffering from influenza-like ill-  ness in the same household or residential set-  ting. Oseltamivir should be given within 48  hours of exposure to influenza while zanamivir  should be given within 36 hours of exposure to  influenza.   • When influenza is circulating in the commu-  nity 1 , either oseltamivir or zanamivir is recom-  mended (in accordance with UK licensing) for  the treatment of influenza in at-risk patients who  can start treatment within 48 hours (within 36  hours for zanamivir in children) of the onset of  symptoms.   • During local outbreaks of influenza-like illness,  when there is a high level of certainty that influ-  enza is present, either oseltamivir or zanamivir  may be used for post-exposure prophylaxis or  treatment in at-risk patients (regardless of influ-  enza vaccination) living in long-term residential  or nursing homes.   At risk 2 patients include those aged over 65 years or  those who have one or more of the following con-  ditions:   • chronic respiratory disease (including asthma  and chronic obstructive pulmonary disease);   This guidance does not cover the circumstances of a  pandemic, an impending pandemic, or a widespread  epidemic of a new strain of influenza to which there  is little or no immunity in the community.    Pregnancy and breast-feeding Although safety  data are limited, either oseltamivir or zanamivir can be  used in women who are pregnant or breast-feeding  when the potential benefit outweighs the risk (e.g. dur-  ing a pandemic). Zanamivir is the preferred drug during  pregnancy; however, oseltamivir is recommended dur-  ing severe infection or when zanamivir cannot be used.    1. National surveillance schemes, including those run by the  Health Protection Agency, should be used to indicate when  influenza is circulating in the community.   2. The Department of Health in England has advised  (November 2010) that ‘at risk patients’ also includes  women who are pregnant.    Renal impairment section 4.9.1  Pregnancy section 4.9.1  Breast-feeding section 4.9.1  Si de-effects section 4.9.1   • Influenza A (see also notes above), ADULT and CHILD  over 10 years, treatment, 100 mg daily for 4-5 days;  prophylaxis, 100 mg daily usually for 6 weeks or with  influenza vaccination for 2-3 weeks after vaccination   Capsules, red-brown, amantadine hydrochloride  100 mg, net price 5-cap pack = £2.40, 14-cap pack =  £5.76. Counselling, driving   Capsules, oseltamivir (as phosphate) 30 mg (yellow),  net price 10-cap pack = £7.71; 45 mg (grey), 10-cap  pack = £15.41; 75 mg (grey-yellow), 10-cap pack =  £15.41. Label: 9   Note If suspension not available, capsules can be opened  and the contents mixed with a small amount of sweetened  food, such as sugar water or chocolate syrup, just before  administration   Suspension, sugar-free, tutti-frutti-flavoured, oselta-  mivir (as phosphate) for reconstitution with water,   Indications see notes above  Renal impairment for treatment, use 75 mg once  daily or 30 mg twice daily if eGFR 10-30 mL/minute/  1.73 m 2 ; for prevention, use 75 mg every 48 hours or  30 mg once daily if eGFR 10-30 mL/minute/ 1.73 m 2 ;  avoid for treatment and prevention if eGFR less than  10 mL/minute/ 1.73 m 2   Pregnancy use only if potential benefit outweighs risk  (e.g. during a pandemic); see also p. 399  Breast-feeding amount probably too small to be  harmful; use only if potential benefit outweighs risk  (e.g. during a pandemic); see also p. 399  Side-effects nausea, vomiting, abdominal pain, diarr-  hoea; headache; conjunctivitis; less commonly ecz-  ema; also reported hepatitis, gastro-intestinal bleed-  ing, arrhythmias, neuropsychiatric disorders (more  frequent in children and adolescents), visual distur-  bances, Stevens- Johnson syndrome, and toxic epi-  dermal necrolysis  Dose   • Prevention of influenza, ADULT and CHILD over 13  years, 75 mg once daily for 10 days for post-exposure  prophylaxis; for up to 6 weeks during an epidemic;  CHILD under 1 month (see notes above), 2 mg/kg once  daily for 10 days for post-exposure prophylaxis; 1-3  months (see notes above), 2.5 mg/kg once daily for 10  days for post-exposure prophylaxis; 3 months-1 year  (see notes above), 3 mg/kg once daily for 10 days for  post-exposure prophylaxis; 1-13 years, body-weight  under 15 kg, 30 mg once daily for 10 days for post-  exposure prophylaxis (for up to 6 weeks during an  epidemic); body-weight 15-23 kg, 45 mg once daily  for 10 days for post-exposure prophylaxis (for up to 6  weeks during an epidemic); body-weight 23-40 kg,   60 mg once daily for 10 days for post-exposure  prophylaxis (for up to 6 weeks during an epidemic);  body-weight over 40 kg, adult dose   • Treatment of influenza, ADULT and CHILD over 13 years,  75 mg every 12 hours for 5 days; CHILD under 1 month  (see notes above), 2 mg/kg every 12 hours for 5 days;  1-3 months (see notes above), 2.5 mg/kg every 12  hours for 5 days; 3 months-1 year (see notes above),  3 mg/kg every 12 hours for 5 days; 1-13 years, body-  weight under 15 kg, 30 mg every 12 hours for 5 days,  body-weight 15-2 3 kg, 45 mg every 12 hours for 5  days, body- weight 23-40 kg, 60 mg every 12 hours for  5 days, body-weight over 40 kg, adult dose   Note Not licensed for use in children under 1 year of age  unless there is a pandemic   Cautions asthma and chronic pulmonary disease (risk  of bronchospasm — short-acting bronchodilator  should be available; avoid in severe asthma unless  close monitoring possible and appropriate facilities  available to treat bronchospasm); uncontrolled  chronic illness; other inhaled drugs should be admi-  nistered before zanamivir)   Pregnancy use only if potential benefit outweighs risk  (e.g. during a pandemic); see also p. 399  Breast-feeding amount probably too small to be  harmful; use only if potential benefit outweighs risk  (e.g. during a pandemic); see also p. 399  Side-effects very rarely, bronchospasm, respiratory  impairment, angioedema, urticaria, and rash; also  reported, neuropsychiatric disorders (especially in  children and adolescents), Stevens- Johnson  syndrome, toxic epidermal necrolysis  Dose   • By inhalation of powder, post-exposure prophylaxis of  influenza, ADULT and CHILD over 5 years, 10 mg once  daily for 10 days   Prevention of influenza during an epidemic, ADULT and  CHILD over 5 years, 10 mg once daily for up to 28 days  Treatment of influenza, ADULT and CHILD over 5 years,  10 mg twice daily for 5 days  ^elenza® (GSK) (Ml   Dry powder for inhalation disks containing 4 blisters  of zanamivir 5 mg/blister, net price 5 disks with Dis-  khaler® device = £16.36   Ribavirin inhibits a wide range of DNA and RNA  viruses. It is licensed for administration by inhalation  for the treatment of severe bronchiolitis caused by the  respiratory syncytial virus (RSV) in infants, especially  when they have other serious diseases. However, there  is no evidence that ribavirin produces clinically relevant  benefit in RSV bronchiolitis. Ribavirin is given by mouth  with peginterferon alfa or interferon alfa for the treat-  ment of chronic hepatitis C infection (see Viral Hepat-  itis, p. 397). Ribavirin is also effective in Lassa fever  [unlicensed indication].    Palivizumab is a monoclonal antibody licensed for  preventing serious lower respiratory-tract disease  caused by respiratory syncytial virus in children at  high risk of the disease; it should be prescribed under  specialist supervision and on the basis of the likelihood  of hospitalisation.   • children under 9 months of age with chronic lung  disease (defined as requiring oxygen for at least 28  days from birth) and who were bom preterm 1 ;   • children under 6 months of age with haemodyna-  mically significant, acyanotic congenital heart dis-  ease who were bom preterm 1 .   • children under 2 years of age with severe combined  immunodeficiency syndrome;   • children under 1 year of age who require long-term  ventilation;   • children 1-2 years of age who require long-term  ventilation and have an additional co-morbidity  (including cardiac disease or pulmonary hyper-  tension).   Cautions moderate to severe acute infection or febrile  illness; thrombocytopenia; serum-palivizumab con-  centration may be reduced after cardiac surgery   Side-effects fever, injection-site reactions, nervous-  ness; less commonly diarrhoea, vomiting, constipa-  tion, haemorrhage, rhinitis, cough, wheeze, pain,  drowsiness, asthenia, hyperkinesia, leucopenia, and  rash; also reported, apnoea, hypersensitivity reactions  (including anaphylaxis), convulsions and thombocy-  topenia   • By intramuscular injection (preferably in anterolateral  thigh), 15 mg/kg once a month during season of RSV  risk (child undergoing cardiac bypass surgery, 15 mg/  kg as soon as stable after surgery, then once a month  during season of risk); injection volume over 1 mL  should be divided between more than one site   Injection, powder for reconstitution, palivizumab, net  price 50-mg vial = £360.40; 100-mg vial = £663.11   Indications severe respiratory syncytial virus  bronchiolitis in infants and children; in combination  with peginterferon alfa or interferon alfa for chronic  hepatitis C in patients without liver decompensation  (see also section 5.3.3)   Specific cautions for inhaled treatment Maintain stan-  dard supportive respiratory and fluid management therapy;  monitor electrolytes closely; monitor equipment for preci-  pitation; pregnant women (and those planning pregnancy)  should avoid exposure to aerosol  Specific cautions for oral treatment Exclude pregnancy  before treatment; effective contraception essential during    1. For details of the preterm age groups included in the    treatment and for 4 months after treatment in women and for  7 months after treatment in men; routine monthly pregnancy  tests recommended; condoms must be used if partner of  male patient is pregnant (ribavirin excreted in semen); car-  diac disease (assessment including ECG recommended  before and during treatment — discontinue if deterioration);  gout; determine full blood count, platelets, electrolytes,  serum creatinine, liver function tests and uric acid before  starting treatment and then on weeks 2 and 4 of treatment,  then as indicated clinically — adjust dose if adverse reactions  or laboratory abnormalities develop (consult product litera-  ture); eye examination recommended before treatment; eye  examination also recommended during treatment if pre-  existing ophthalmological disorder or if decrease in vision  reported— discontinue treatment if ophthalmological disor-  der deteriorates or if new ophthalmological disorder devel-  ops; test thyroid function before treatment and then every 3  months in children; risk of growth retardation in children, the  reversibility of which is uncertain — if possible, consider  starting treatment after pubertal growth spurt   Specific contra-indications for oral treatment Severe  cardiac disease, including unstable or uncontrolled cardiac  disease in previous 6 months; haemoglobinopathies; severe  debilitating medical conditions; autoimmune disease  (including autoimmune hepatitis); uncontrolled severe psy-  chiatric condition; history of severe psychiatric condition in  children    Hepatic impairment no dosage adjustment required;  use oral ribavirin with caution in severe hepatic dys-  function or decompensated cirrhosis   Specific side-effects for inhaled treatment Worsening  respiration, bacterial pneumonia, and pneumothorax  reported; rarely non-specific anaemia and haemolysis  Specific side-effects for oral treatment Haemolytic  anaemia (anaemia may be improved by epoetin); also (in  combination with peginterferon alfa or interferon alfa)  nausea, vomiting, dyspepsia, abdominal pain, flatulence,  constipation, diarrhoea, colitis, chest pain, palpitation,  tachycardia, peripheral oedema, changes in blood pressure,  syncope, flushing, cough, dyspnoea, headache, dizziness,  asthenia, impaired concentration and memory, sleep distur-  bances, abnormal dreams, anxiety, depression, suicidal  ideation (more frequent in children), psychoses, dysphagia,  weight loss, dysphonia, paraesthesia, hypoaesthesia, ataxia,  hypertonia, influenza-like symptoms, thyroid disorders,  hyperglycaemia, menstrual disturbances, breast pain,  prostatitis, sexual dysfunction, micturition disorders, leuco-  penia, thrombocytopenia, lymphadenopathy, dehydration,  hypocalcaemia, myalgia, arthralgia, hyperuricaemia, visual  disturbances, eye pain, dry eyes, hearing impairment, tinni-  tus, earache, dry mouth, taste disturbances, mouth ulcers,  stomatitis, glossitis, tooth disorder, gingivitis, alopecia, pru-  ritus, dry skin, rash (including very rarely Stevens-Johnson  syndrome and toxic epidermal necrolysis), increased  sweating, psoriasis, photosensitivity, and acne; less com-  monly pancreatitis, gastro-intestinal bleeding, and hypertri-  glyceridaemia; rarely peptic ulcer, arrhythmias, cardiomyo-  pathy, myocardial infarction, pericarditis, stroke, interstitial  pneumonitis, pulmonary embolism, seizures, renal failure,  vasculitis, rheumatoid arthritis, systemic lupus erythemato-  sus, sarcoidosis, optic neuropathy, and retinal haemorrhage;  very rarely aplastic anaemia and peripheral ischaemia; in  children also growth retardation (including decrease in  height and weight), pallor, tachypnoea, hyperkinesia, viri-  lism, and skin discoloration   Tablets, f/c, ribavirin 200 mg (pink), net price 42-tab  pack = £92.50, 112-tab pack = £246.65, 168-tab pack  = £369.98; 400 mg (red-brown), 56-tab pack =  £246.65. Label: 21   Dose chronic hepatitis C (in combination with interferon alfa or  peginterferon alfa), ADULT over 18 years, body-weight under 75 kg,  400 mg in the morning and 600 mg in the evening; body-weight  75 kg and over, 600 mg twice daily   Note Patients with chronic hepatitis C genotype 2 or 3 (not  previously treated), or patients infected with HIV and hepatitis  C require a lower dose of Copegus ® (in combination with  peginterferon alfa), usual dose 400 mg twice daily   Rebetol® (Schering-Plough) (MI  Capsules, ribavirin 200 mg, net price 84-cap pack =  £160.69, 140-cap pack = £267.81, 168-cap pack =  £321.38. Label: 21   Oral solution, ribavirin 200 mg/5 mL, net price  100 mL (bubble-gum-flavoured) = £67.08. Label: 21  Dose chronic hepatitis C (in combination with interferon alfa or  peginterferon alfa), ADULT over 18 years, body-weight under 65 kg,  400 mg twice daily; body-weight 65-81 kg, 400 mg in the morning  and 600 mg in the evening; body-weight 81-105 kg, 600 mg twice  daily; body-weight over 105 kg, 600 mg in the morning and  800 mg in the evening; CHILD 3-18 years, body-weight under  47 kg, 15 mg/kg daily in 2 divided doses; body-weight 47-50 kg,  200 mg in the morning and 400 mg in the evening; body-weight  50-65 kg, 400 mg twice daily; body-weight over 65 kg, as adult   Dose bronchiolitis, by aerosol inhalation or nebulisation (via  small particle aerosol generator) of solution containing 20 mg/mL  for 12-18 hours for at least 3 days; max. 7 days   HPA (Health Protection Agency) Malaria (020) 7637 0248  Reference Laboratory (fax)   Travel Medicine Team, Health Protection (0141) 300 1100  Scotland (weekdays 2-4   Recommendations on the prophylaxis and treatment of  malaria reflect guidelines agreed by UK malaria specia-  lists.   The centres listed above should be consulted for advice  on special problems.   If the infective species is not known, or if the infection is  mixed, initial treatment should be as for falciparum  malaria with quinine, Malarone® (proguanil with  atovaquone), or Riamet® (artemether with lumefan-  trine). Falciparum malaria can progress rapidly in  unprotected individuals and antimalarial treatment  should be considered in those with features of severe  malaria and possible exposure, even if the initial blood  tests for the organism are negative.   Falciparum malaria (malignant malaria) is caused by  Plasmodium falciparum. In most parts of the world P.  falciparum is now resistant to chloroquine which should  not therefore be given for treatment.   Quinine, Malarone® (proguanil with atovaquone), or  Riamet® (artemether with lumefantrine) can be given by  mouth if the patient can swallow and retain tablets and  there are no serious manifestations (e.g. impaired  consciousness); quinine should be given by intravenous  infusion (see below) if the patient is seriously ill or  unable to take tablets. Mefloquine is now rarely used for  treatment because of concerns about resistance.   600 mg (of quinine salt 1 ) every 8 hours for 5-7 days  together with or followed by  either doxycycline 200 mg once daily for 7 days  or clindamycin 450 mg every 8 hours for 7 days  [unlicensed indication].   If the parasite is likely to be sensitive, pyrimeth-  amine 75 mg with sulfadoxine 1.5 g as a single  dose [unlicensed] may be given (instead of either  clindamycin or doxycycline) together with, or after,  a course of quinine.   Alternatively, Malarone® or Riamet® may be given  instead of quinine. It is not necessary to give   1. Valid for quinine hydrochloride, dihydrochloride, and  sulphate; not valid for quinine bisulphate which contains  a correspondingly smaller amount of quinine.   body-weight 5-8 kg, 2 ‘paediatric’ tablets once daily  for 3 days; body-weight 9-10 kg, 3 ‘paediatric’  tablets once daily for 3 days; body-weight 11-  20 kg, 1 ‘standard’ tablet once daily for 3 days;  body-weight 2 1-30 kg, 2 ‘standard’ tablets once  daily for 3 days; body-weight 3 1-40 kg, 3 ‘standard’  tablets once daily for 3 days.   The dose regimen of Riamet!® by mouth for children  over 12 years and body-weight over 35 kg is the same as  for adults (see above). The dose regimen for Riamet®  for children under 12 years is as follows:    doxycycline, clindamycin or pyrimethamine with sulfa-  doxine after Malarone® or Riamet® treatment.   The dose of Riamet® by mouth for adult with body-  weight over 35 kg is:   4 tablets initially, followed by 5 further doses of 4  tablets each given at 8, 24, 36, 48, and 60 hours  (total 24 tablets over 60 hours).   Parenteral. If the patient is seriously ill or unable to  take tablets, quinine should be given by intra-  venous infusion [unlicensed]. The adult dosage regi-  men for quinine by infusion is:  loading dose 1 of 20 mg/kg 2 (up to maximum 1.4 g)  of quinine salt 3 infused over 4 hours then 8 hours  after the start of the loading dose, maintenance  dose of 10 mg/kg 4 (up to maximum 700 mg) of  quinine salt 3 infused over 4 hours every 8 hours  (until patient can swallow tablets to complete the 7-  day course together with or followed by either  doxycycline or clindamycin as above).   Specialist advice should be sought in difficult cases  (e.g. very high parasite count, deterioration on  optimal doses of quinine, infection acquired in quin-  ine-resistant areas of south east Asia) because intra-  venous artesunate may be available for ‘named-  patient’ use.   Oral. Quinine is well tolerated by children although  the salts are bitter. The dosage regimen for quinine  by mouth for children is:   10 mg/kg (of quinine salt 3 ; max. 600 mg) every 8  hours for 7 days together with or followed by  Clindamycin 7-13 mg/kg (max. 450 mg) every 8  hours for 7 days [unlicensed indication]  or in children over 12 years, doxycycline 200 mg  once daily for 7 days   or if the parasite is likely to be sensitive, pyri-  methamine with sulfadoxine as a single dose [unli-  censed]: up to 4 years and body- weight over 5 kg,  pyrimethamine 12.5 mg with sulfadoxine 250 mg;  5-6 years, pyrimethamine 25 mg with sulfadoxine  500 mg; 7-9 years, pyrimethamine 37.5 mg with  sulfadoxine 750 mg; 10-14 years, pyrimethamine  50 mg with sulfadoxine 1 g; 14-18 years, pyrimeth-  amine 75 mg with sulfadoxine 1.5 g   Alternatively, Malarone® or Riamet !® may be given  instead of quinine; it is not necessary to give clinda-  mycin, doxycycline, or pyrimethamine with sulfadoxine  after Malarone® or Riamet® treatment. The dose  regimen for Malarone® by mouth for children over  40 kg is the same as for adults (see above); the dose   1. In intensive care units the loading dose can alternatively be  given as quinine salt 3 7 mg/kg infused over 30 minutes  followed immediately by 10 mg/kg over 4 hours then (after  8 hours) maintenance dose as described.   2 . Important: the loading dose of 20 mg/kg should not be  used if the patient has received quinine or mefloquine  during the previous 12 hours.   3. Valid for quinine hydrochloride, dihydrochloride, and  sulphate; not valid for quinine bisulphate which contains  a correspondingly smaller amount of quinine.   4. Maintenance dose should be reduced to 5-7 mg/kg of  quinine salt 3 in patients with severe renal impairment,  severe hepatic impairment, or if parenteral treatment is    body-weight 5-1 5 kg 1 tablet initially, followed by 5  further doses of 1 tablet each given at 8, 24, 36, 48,  and 60 hours (total 6 tablets over 60 hours); body-  weight 15-25 kg 2 tablets initially, followed by 5  further doses of 2 tablets each given at 8, 24, 36,  48, and 60 hours (total 12 tablets over 60 hours);  body-weight 25-35 kg 3 tablets initially, followed by  5 further doses of 3 tablets each given at 8, 24, 36,  48, and 60 hours (total 18 tablets over 60 hours)   Benign malaria is usually caused by Plasmodium vivax  and less commonly by P. ovale and P. malariae.  Chloroquine 5 is the drug of choice for the treatment  of benign malarias (but chloroquine-resistant P. vivax  infection has been reported from Indonesia, New  Guinea and some adjacent islands).   The adult dosage regimen for chloroquine by mouth is:  initial dose of 620 mg of base then  a single dose of 310 mg of base after 6 to 8 hours  then   a single dose of 310 mg of base daily for 2 days  (approximate total cumulative dose of 25 mg/kg of  base)   Chloroquine alone is adequate for P. malariae infec-  tions but in the case of P. vivax and P. ovale, a radical    5. For the treatment of chloroquine-resistant benign malaria,  Malarone ® [unlicensed indication], quinine, or Riamet®  [unlicensed indication] can be used; as with chloroquine,  primaquine should be given for radical cure.    Parenteral. The dose regimen for quinine by intra-  venous infusion for children is calculated on a mg/kg  basis as for adults (see above).    Pregnancy Falciparum malaria is particularly danger-  ous in pregnancy, especially in the last trimester. The  adult treatment doses of oral and intravenous quinine  given above (including the loading dose) can safely be  given to pregnant women. Clindamycin 450 mg every 8  hours for 7 days [unlicensed indication] should be given  with or after quinine. Doxycycline should be avoided in  pregnancy (affects teeth and skeletal development);  pyrimethamine with sulfadoxine, Malarone®, and  Riamet® are also best avoided until more information  is available. Specialist advice should be sought in  difficult cases (e.g. very high parasite count, deteriora-  tion on optimal doses of quinine, infection acquired in  quinine-resistant areas of south east Asia) because  intravenous artesunate may be available for ‘named  patient’ use.    cure (to destroy parasites in the liver and thus prevent  relapses) is required. This is achieved with primaquine 1  [unlicensed] given after chloroquine; in P. vivax infec-  tion primaquine is given in an adult dosage of 30 mg  daily for 14 days and for P. ovale infection it is given in  an adult dosage of 15 mg daily for 14 days.   Children The dosage regimen of chloroquine for  benign malaria in children is:   initial dose of 10 mg/kg of base (max. 620 mg) then  a single dose of 5 mg/kg of base (max. 310 mg) after  6-8 hours then   a single dose of 5 mg/kg of base (max. 3 10 mg)  daily for 2 days   For a radical cure, primaquine 1 [unlicensed] is then  given to children over 6 months of age; specialist advice  should be sought for children under 6 months of age. In  P. vivax infection primaquine is given in a dose of  500 micrograms/kg (max. 30 mg) daily for 14 days,  and for P. ovale infection it is given in a dose of  250 micrograms/kg (max. 15 mg) daily for 14 days.   Parenteral If the patient is unable to take oral therapy,  quinine can be given by intravenous infusion [unli-  censed]. The dose (for adults and children) is 10 mg/  kg 2 (max. 700 mg) of quinine salt 3 infused over 4 hours  every 8 hours, changed to oral chloroquine as soon as  the patient’s condition permits.   Pregnancy The adult treatment doses of chloroquine  can be given for benign malaria. In the case of P. vivax  or P. ovale, however, the radical cure with primaquine  should be postponed until the pregnancy is over;  instead chloroquine should be continued at a dose of  310 mg each week during the pregnancy.   The recommendations on prophylaxis reflect guidelines  agreed by UK malaria specialists; the advice is aimed at  residents of the UK who travel to endemic areas. The  choice of drug for a particular individual should take  into account:   risk of exposure to malaria;  extent of drug resistance;  efficacy of the recommended drugs;  side-effects of the drugs;   patient-related factors (e.g. age, pregnancy, renal or  hepatic impairment, compliance with prophylactic  regimen).   Protection against bites Prophylaxis is not abso-  lute, and breakthrough infection can occur with any of  the drugs recommended. Personal protection against    1. Before starting primaquine, blood should be tested for  glucose-6-phosphate dehydrogenase (G6PD) activity since  the drug can cause haemolysis in G6PD-deficient patients.  Specialist advice should be obtained in G6PD deficiency; in  mild G6PD deficiency primaquine in a dose for adults of  45 mg once a week (children 750 micrograms /kg once a  week; max. 45 mg once a week) for 8 weeks, has been  found useful and without undue harmful effects.   2. Maintenance dose should be reduced to 5-7 mg/kg of  quinine salt 3 in patients with severe renal impairment,  severe hepatic impairment, or if parenteral treatment is  required for more than 48 hours.   3. Valid for quinine hydrochloride, dihydrochloride, and  sulphate; not valid for quinine bisulphate which contains  a correspondingly smaller amount of quinine.    being bitten is very important. Mosquito nets impreg-  nated with permethrin provide the most effective barrier  protection against insects; mats and vaporised insecti-  cides are also useful. Diethyltoluamide (DEET) 20-50%  in lotions, sprays, or roll-on formulations is safe and  effective when applied to the skin of adults and children  over 2 months of age. It can also be used during  pregnancy and breast-feeding. The duration of protec-  tion varies according to the concentration of DEET and  is longest for DEET 50%. Long sleeves and trousers  worn after dusk also provide protection.   Length of prophylaxis In order to determine toler-  ance and to establish habit, prophylaxis should generally  be started one week (preferably 2-3 weeks in the case of  mefloquine) before travel into an endemic area (or if not  possible at earliest opportunity up to 1 or 2 days before  travel); Malarone® or doxycycline prophylaxis should  be started 1-2 days before travel. Prophylaxis should be  continued for 4 weeks after leaving (except for  Malarone® prophylaxis which should be stopped 1  week after leaving).   In those requiring long-term prophylaxis, chloroquine  and proguanil may be used for periods of over 5 years.  Mefloquine is licensed for up to 1 year (although it has  been used for up to 3 years without undue problems).  Doxycycline can be used for up to 2 years. Malarone®  is licensed for use for up to 28 days but can be used for  up to 1 year (and possibly longer) with caution.  Specialist advice should be sought for long-term  prophylaxis.   Return from malarial region It is important to be  aware that any illness that occurs within 1 year and  especially within 3 months of return might be mal-  aria even if all recommended precautions against mal-  aria were taken. Travellers should be warned of this and  told that if they develop any illness particularly within  3 months of their return they should go immediately to  a doctor and specifically mention their exposure to  malaria.   Epilepsy Both chloroquine and mefloquine are unsui-  table for malaria prophylaxis in individuals with a his-  tory of epilepsy. In areas without chloroquine resistance  proguanil 200 mg daily alone is recommended; in areas  with chloroquine resistance, doxycycline or Malarone®  may be considered; the metabolism of doxycycline may  be influenced by antiepileptics (see interactions:  Appendix 1 (tetracyclines)).   Asplenia Asplenic individuals (or those with severe  splenic dysfunction) are at particular risk of severe  malaria. If travel to malarious areas is unavoidable,  rigorous precautions are required against contracting  the disease.   Renal impairment Avoidance (or dosage reduction)  of proguanil is recommended since it is excreted by the  kidneys. Malarone® should not be used for prophylaxis  in patients with estimated glomerular filtration rate less  than 30 mL/minute/ 1.73 m 2 . Chloroquine is only par-  tially excreted by the kidneys and reduction of the dose  for prophylaxis is not required except in severe  impairment. Mefloquine is considered to be appropriate    to use in renal impairment and does not require dosage  reduction. Doxycycline is also considered to be appro-  priate.   Pregnancy Travel to malarious areas should be  avoided during pregnancy; if travel is unavoidable,  effective prophylaxis must be used. Chloroquine and  proguanil can be given in the usual doses during  pregnancy, but these drugs are not appropriate for  most areas because their effectiveness has declined,  particularly in Sub-Saharan Africa; in the case of pro-  guanil, folic acid 5 mg daily should be given. The centres  listed on p. 402 should be consulted for advice on  prophylaxis in chloroquine-resistant areas. Although  the manufacturer advises that mefloquine should not  be used during pregnancy, particularly in the first trime-  ster, unless the potential benefit outweighs the risk,  studies of mefloquine in pregnancy (including use in  the first trimester) indicate that it can be considered for  travel to chloroquine-resistant areas. Doxycycline is  contra-indicated during pregnancy. Malarone ® should  be avoided during pregnancy unless there is no suitable  alternative.   Breast-feeding Prophylaxis is required in breast-fed  infants; although antimalarials are present in milk, the  amounts are too variable to give reliable protection.   Anticoagulants Travellers taking warfarin should  begin chemoprophylaxis at least 1 week (2-3 weeks  for mefloquine) before departure. The INR should be  stable before departure. It should be measured before  starting chemoprophylaxis, 7 days after starting, and  after completing the course. For prolonged stays, the  INR should be checked at regular intervals.    Low risk Risk low in Armenia (June-October), Azer-  baijan (southern border areas, June-September), Egypt  (El Faiyum only, June-October), Iran (northern border  with Azerbaijan, May-October; variable risk in rural  south-east provinces; see below), rural north Iraq  (May-November), Kyrgystan (south-west, May-Octo-  ber), north border of Syria (May-October), Turkey  (plain around Adana and east of there, border with  Syria, March-November):    Variable risk Risk variable and chloroquine resistance  present in Afghanistan (below 2000 m, May-November),  Iran (rural south-east provinces, March-November, see  also Low Risk above), Oman (remote rural areas only),  Saudi Arabia (south-west and rural areas of western  region; no risk in Mecca, Medina, Jeddah, or high-  altitude areas of Asir Province), Tajikistan (June-Octo-  ber), Yemen (no risk in Sana’a):   chloroquine + proguanil hydrochloride or (if  chloroquine + proguanil not appropriate) doxycy-  cline   Where a journey requires two regimens, the regimen for  the higher risk area should be used for the whole  journey. Those travelling to remote or little-visited  areas may require expert advice.    Important Settled immigrants (or long-term visi-  tors) to the UK may be unaware that they will have  lost some of their immunity and also that the areas  where they previously lived may now be malarious   Very low risk Risk very low in Algeria, Egypt (but low  risk in El Faiyum, see below), Georgia (south-east, July-  October), Kyrgystan (but low risk in south-west, see  below), Libya, most tourist areas of Turkey (but low risk  in Adana and border with Syria, see below), Uzbekistan  (extreme south-east only):   No chemoprophylaxis recommended for Cape Verde  (some risk on Sao Tiago) and Mauritius (but avoid  mosquito bites and consider malaria if fever presents)    Very high risk Risk very high (or locally very high)  and chloroquine resistance very widespread in Angola,  Benin, Botswana (northern half, November-June), Bur-  kina Faso, Burundi, Cameroon, Central African Repub-  lic, Chad, Comoros, Congo, Democratic Republic of the  Congo (formely Zaire), Djibouti, Equatorial Guinea,  Eritrea, Ethiopia (below 2000 m; no risk in Addis  Ababa), Gabon, Gambia, Ghana, Guinea, Guinea-Bissau,  Ivory Coast, Kenya, Liberia, Madagascar, Malawi, Mali,  Mauritania (all year in south; July-October in north),  Mozambique, Namibia (all year along Kavango and  Kunene rivers; November-June in northern third),  Niger, Nigeria, Principe, Rwanda, Sao Tome, Senegal,  Sierra Leone, Somalia, South Africa (low-altitude areas  of Mpumalanga and Limpopo Provinces, Kruger  National Park, and north-east KwaZulu-Natal as far  south as Jozini), Sudan, Swaziland, Tanzania, Togo,  Uganda, Zambia, Zimbabwe (all year in Zambezi valley;  November-June in other areas below 1200 m; risk neg-  ligible in Harare and Bulawayo):   Note In Zimbabwe and neighbouring countries, pyrimethamine  with dapsone (also known as Deltaprim ®) prophylaxis is used  by local residents (sometimes with chloroquine)— this regimen  is not recommended.   Low risk Risk low in Bangladesh (but high risk in  Chittagong Hill Tracts, see below), India (Kerala [south-  ern states], Tamil Nadu, Karnataka, Southern Andhra  Pradesh [including Hyderabad], Mumbai, Rajasthan  [including Jaipur], Uttar Pradesh [including Agra], Har-  yana, Uttaranchal, Himachal Pradesh, Jammu, Kashmir,  Punjab, Delhi; variable risk in other areas, see below;  high risk in Assam), Sri Lanka (but variable risk north of  Vavuniya, see below):    Variable risk Risk variable and chloroquine resistance  usually moderate in southern districts of Bhutan, India  (low risk in some areas, see above; high risk in Assam,  see below), Nepal (below 1500 m, especially Terai dis-  tricts; no risk in Kathmandu), Pakistan (below 2000 m),  Sri Lanka (north of Vavuniya; low risk in other areas, see  above):    chloroquine + proguanil hydrochloride or (if  chloroquine + proguanil not appropriate) meflo-  quine or doxycycline or Malarone®   High risk Risk high and chloroquine resistance high in  Bangladesh (only in Chittagong Hill Tracts; low risk in  other areas, see above), India (Assam only; see also Low  Risk and Variable Risk above):    mefloquine or doxycycline or Malarone® or (if  mefloquine, doxycycline, or Malarone® not appro-  priate) chloroquine + proguanil hydrochloride    Lombok, see below), rural Philippines below 600 m  (no risk in cities, Cebu, Bohol, and Catanduanes), deep  forests of peninsular Malaysia and Sarawak (but sub-  stantial risk in Sabah, see below):   chloroquine + proguanil hydrochloride or (if  chloroquine + proguanil not appropriate) meflo-  quine or doxycycline or Malarone®    Substantial risk Risk substantial and drug resistance  common in Cambodia (no risk or very low risk in some  areas, see above; great risk in western provinces, see  below), China (Yunnan and Hainan; chloroquine  prophylaxis appropriate for other remote areas; see  also Very Low Risk above), East Timor, Irian Jaya  [West Papua], Laos (no risk in Vientiane), Lombok,  Malaysia (Sabah; see also Very Low Risk and Variable  Risk above), Myanmar (formerly Burma; see also Great  Risk below), Vietnam ( very low risk in some areas, see  above):    Great risk and drug resistance present Risk great  and widespread chloroquine and mefloquine resistance  present in western provinces of Cambodia (see also  Very Low Risk and Substantial Risk above), borders  of Thailand with Cambodia, Laos and Myanmar ( very  low risk in Chang Rai and Kwai Bridge, see above),  Myanmar (eastern Shan State):   Very low risk Risk very low in Bali, Brunei, Cambodia  (Angkor Wat and Siem Reap, but no risk in Phnom Penh;  substantial risk in other areas, see below; great risk in  western provinces, see below), main tourist areas of  China (but substantial risk in Yunnan and Hainan, see  below; chloroquine prophylaxis appropriate for other  remote areas), Hong Kong, Korea (both North and  South), Malaysia (both East and West including Camer-  on Highlands, but substantial risk in Sabah [except Kota  Kinabalu], and variable risk in deep forests, see below),  Singapore, Thailand (important: regional risk exists, see  under Great Risk, below), Vietnam (cities, coast  between Ho Chi Minh and Hanoi, and Mekong River  until close to Cambodian border; substantial risk in  other areas, see below):    Variable risk Risk variable and some chloroquine  resistance in Indonesia (very low risk in Bali, and cities  but substantial risk in Irian Jaya [West Papua] and   Risk Risk high and chloroquine resistance high in  Papua New Guinea (below 1800 m), Solomon Islands,  Vanuatu:    Variable to low risk Risk variable to low in Argentina  (rural areas along northern borders only), rural Belize  (except Belize district), Costa Rica (Limon Province  except Puerto Limon and northern canton of Pococci),  Dominican Republic, El Salvador (Santa Ana province in  west), Guatemala (below 1500 m), Haiti, Honduras,  Mexico (states of Oaxaca and Chiapas), Nicaragua,    Panama (west of Panama Canal but variable to high risk  east of Panama Canal, see below), rural Paraguay:   Artemether with lumefantrine is licensed for the treat-  ment of acute uncomplicated falciparum malaria.    Variable to high risk Risk variable to high and  chloroquine resistance present in rural areas of Bolivia  (below 2500 m), Ecuador (below 1500 m; no malaria in  Galapagos Islands and Guayaquil; see below for Esmer-  aldas Province), Panama (east of Panama Canal), Peru  (rural areas east of the Andes and west of the Amazon  basin area below 1500 m; see below for Amazon basin  area), Venezuela (north of Orinoco river; high risk south  of and including Orinoco river and Amazon basin area,  see below; Caracas free of malaria):    chloroquine + proguanil hydrochloride or (if  chloroquine + proguanil not appropriate) meflo-  quine or doxycycline or Malarone®    High risk Risk high and marked chloroquine resis-  tance in Bolivia (Amazon basin area; see also variable to  high risk above), Brazil (throughout ‘Legal Amazon’ area  which includes the Amazon basin area, Mato Grosso  and Maranhao only; elsewhere very low risk — no che-  moprophylaxis), Colombia (most areas below 800 m),  Ecuador (Esmeraldas Province; variable to high risk in  other areas, see above), French Guiana, all interior  regions of Guyana, Peru (Amazon basin area), Suriname  (except Paramaribo and coast), Venezuela (Amazon  basin area, areas south of and including Orinoco river):   Travellers visiting remote, malarious areas for pro-  longed periods should carry standby treatment if  they are likely to be more than 24 hours away  from medical care. Self-medication should be  avoided if medical help is accessible.   In order to avoid excessive self-medication, the  traveller should be provided with written instruc-  tions that urgent medical attention should be sought  if fever (38°C or more) develops 7 days (or more)  after arriving in a malarious area and that self-treat-  ment is indicated if medical help is not available  within 24 hours of fever onset.   In view of the continuing emergence of resistant  strains and of the different regimens required for  different areas expert advice should be sought on  the best treatment course for an individual traveller.  A drug used for chemoprophylaxis should not be  considered for standby treatment for the same tra-  veller.   Cautions electrolyte disturbances, concomitant use  with other drugs known to cause QT-interval prolon-  gation; monitor patients unable to take food (greater  risk of recrudescence); interactions: Appendix 1  (artemether with lumefantrine)   Contra-indications history of arrhythmias, of clini-  cally relevant bradycardia, and of congestive heart  failure accompanied by reduced left ventricular ejec-  tion fraction; family history of sudden death or of  congenital QT interval prolongation   Pregnancy toxicity in animal studies with artemether;  manufacturer advises use only if potential benefit  outweighs risk   Breast-feeding manufacturer advises avoid breast-  feeding for at least 1 week after last dose; present in  milk in animal studies   Side-effects abdominal pain, anorexia, diarrhoea,  vomiting, nausea; palpitation, prolonged QT interval;  cough; headache, dizziness, sleep disturbances, asth-  enia, paraesthesia; arthralgia, myalgia; pruritus, rash;  less commonly ataxia, hypoaesthesia, and clonus  Dose    Riamet® (Novartis) T (Ml  Tablets, yellow, artemether 20 mg, lumefantrine  120 mg, net price 24-tab pack = £22.50. Label: 21,  counselling, driving   Chloroquine is used for the prophylaxis of malaria in  areas of the world where the risk of chloroquine-resis-  tant falciparum malaria is still low. It is also used with  proguanil when chloroquine-resistant falciparum mal-  aria is present but this regimen may not give optimal  protection (see specific recommendations by country,  p. 405).   Chloroquine is no longer recommended for the treat-  ment of falciparum malaria owing to widespread resis-  tance, nor is it recommended if the infective species is  not known or if the infection is mixed, in these cases  treatment should be with quinine, Malarone®, or  Riamet ‘® (for details, see p. 402). It is still recommended  for the treatment of benign malarias (for details, see  p. 403).   Cautions may exacerbate psoriasis; neurological dis-  orders (avoid for prophylaxis if history of epilepsy, see  notes above); may aggravate myasthenia gravis;  severe gastro-intestinal disorders; G6PD deficiency  (see section 9.1.5); ophthalmic examination and long-  term therapy, see under Chloroquine, section 10.1.3;  avoid concurrent therapy with hepatotoxic drugs —  other interactions: Appendix 1 (chloroquine and  hydroxychloroquine)   Pregnancy benefit of prophylaxis and treatment in  malaria outweighs risk; see also Benign Malarias  (treatment), p. 404 and Prophylaxis Against Malaria,  p. 405   Breast-feeding amount in milk probably too small to  be harmful; see also Prophylaxis Against Malaria,  p. 405   Side-effects gastro-intestinal disturbances, headache;  also hypotension, convulsions, visual disturbances,  depigmentation or loss of hair, skin reactions (rashes,  pruritus); rarely, bone-marrow suppression, hyper-  sensitivity reactions such as urticaria and angio-  edema; other side-effects (not usually associated with  malaria prophylaxis or treatment), see under Chloro-  quine, section 10.1.3; very toxic in overdosage —  immediate advice from poisons centres essential (see  also p. 37)   • Prophylaxis of malaria, preferably started 1 week  before entering endemic area and continued for 4  weeks after leaving (see notes above), 3 10 mg once  weekly; INFANT up to 12 weeks body-weight under  6 kg, 37.5 mg once weekly; 12 weeks-1 year body-  weight 6-10 kg, 75 mg once weekly; CHILD 1-4 years  body-weight 10- 16 kg, 112.5 mg once weekly; 4-8  years body- weight 16-25 kg, 150 mg once weekly (or  155 mg once weekly if tablets used); 8-13 years body-  weight 25-45 kg, 225 mg once weekly (or 232.5 mg  once weekly if tablets used); over 13 years body-  weight over 45 kg, adult dose   • Treatment of benign malarias, see p. 403  Counselling Warn travellers about importance of avoiding  mosquito bites, importance of taking prophylaxis regularly,  and importance of immediate visit to doctor if ill within 1  year and especially within 3 months of return. For details,  see notes above    J Avloclor® (AstraZeneca) (Ml  Tablets, scored, chloroquine phosphate 250 mg  (= chloroquine base 155 mg). Net price 20-tab pack =  £1.22. Label: 5, counselling, prophylaxis, see above    1. Can be sold to the public provided it is licensed and  labelled for the prophylaxis of malaria. Drugs for malaria  prophylaxis not prescribable on the NHS; health authorities  may investigate circumstances under which antimalarials  are prescribed    ^alarivon® (Wallace Mfg) (Ml  Syrup, chloroquine phosphate 80 mg/5 mL ( =  chloroquine base 50 mg/5 mL), net price 75 mL =  £8.75. Label: 5, counselling, prophylaxis, see above   ^ivaquine® (Sanofi-Aventis) (M  Syrup, golden, chloroquine sulphate 68 mg/5 mL  (= chloroquine base 50 mg/5 mL), net price 100 mL  = £4.60. Label: 5, counselling, prophylaxis, see above   For cautions and side-effects of proguanil see Pro-  guanil; for dose see Chloroquine and Proguanil   Tablets, travel pack of 14 tablets of chloroquine  phosphate 250 mg ( = chloroquine base 155 mg) and  98 tablets of proguanil hydrochloride 100 mg, net  price 112-tab pack = £8.79. Label: 5, 21, counselling,  prophylaxis, see above   Mefloquine is used for the prophylaxis of malaria in  areas of the world where there is a high risk of chloro-  quine-resistant falciparum malaria (for details, see spe-  cific recommendations by country, p. 405).   Mefloquine is now rarely used for the treatment of  falciparum malaria because of increased resistance. It  is rarely used for the treatment of benign malarias  because better tolerated alternatives are available.  Mefloquine should not be used for treatment if it has  been used for prophylaxis.   Cautions cardiac conduction disorders; epilepsy  (avoid for prophylaxis); not recommended in infants  under 3 months (5 kg); interactions: Appendix 1  (mefloquine)   Driving Dizziness or a disturbed sense of balance may affect  performance of skilled tasks (e.g. driving); effects may persist  for up to 3 weeks   Contra-indications hypersensitivity to quinine; avoid  for prophylaxis if history of psychiatric disorders  (including depression) or convulsions   Side-effects nausea, vomiting, dyspepsia, abdominal  pain, diarrhoea; headache, dizziness, sleep distur-  bances; less frequently anorexia, bradycardia, fatigue,  abnormal dreams, fever, tinnitus, and neuropsych-  iatric reactions (including sensory and motor neuro-  pathies, tremor, ataxia, anxiety, depression, panic  attacks, agitation, hallucinations, psychosis, con-  vulsions); rarely suicidal ideation; very rarely pneu-  monitis; also reported, circulatory disorders (includ-  ing hypotension and hypertension), chest pain,  tachycardia, palpitation, cardiac conduction disor-  ders, oedema, dyspnoea, encephalopathy, leucopenia,    leucocytosis, thrombocytopenia, muscle weakness,  myalgia, arthralgia, visual disturbances, vestibular  disorders, rash (including Stevens- Johnson  syndrome), pruritus, and alopecia   • Prophylaxis of malaria, preferably started 2Vz weeks  before entering endemic area and continued for 4  weeks after leaving (see notes above), ADULT and CHILD  body-weight over 45 kg, 250 mg once weekly; body-  weight 6-16 kg, 62.5 mg once weekly; body-weight  16-25 kg, 125 mg once weekly; body- weight 25-45 kg,  187.5 mg once weekly   • Treatment of malaria, see notes above  Counselling Inform travellers about adverse reactions of  mefloquine and, if they occur, to seek medical advice on  alternative antimalarials before the next dose is due. Also  warn travellers about importance of avoiding mosquito  bites, importance of taking prophylaxis regularly, and  importance of immediate visit to doctor if ill within 1 year  and especially within 3 months of return. For details, see  notes above   250 mg. Net price 8-tab pack = £14.53. Label: 21, 25,  27, counselling, driving, prophylaxis, see above  Note Tablet may be crushed and mixed with food such as  jam or honey just before administration   Primaquine is used to eliminate the liver stages of P.  vivax or P. ovale following chloroquine treatment (for  details, see p. 403).   Indications adjunct in the treatment of Plasmodium  vivax and P. ovale malaria (eradication of liver stages)  Cautions G6PD deficiency (test blood, see under  Benign Malarias (treatment), p. 403); systemic dis-  eases associated with granulocytopenia (e.g. rheu-  matoid arthritis, lupus erythematosus); interactions:  Appendix 1 (primaquine)   Pregnancy risk of neonatal haemolysis and  methaemoglobinaemia in third trimester; see also  p. 404   Breast-feeding no information available; theoretical  risk of haemolysis in G6PD-deficient infants  Side-effects nausea, vomiting, anorexia, abdominal  pain; less commonly methaemoglobinaemia, haemo-  lytic anaemia especially in G6PD deficiency, leuco-  penia  Dose   Proguanil is used (usually with chloroquine, but occa-  sionally alone) for the prophylaxis of malaria, (for  details, see specific recommendations by country,  p. 405).    1. Drugs for malaria prophylaxis not prescribable on the  NHS; health authorities may investigate circumstances  under which antimalarials prescribed    Proguanil used alone is not suitable for the treatment of  malaria', however, Malarone® (a combination of  atovaquone with proguanil) is licensed for the treatment  of acute uncomplicated falciparum malaria. Malarone®  is also used for the prophylaxis of falciparum malaria  in areas of widespread mefloquine or chloroquine  resistance. Malarone® is also used as an alternative to  mefloquine or doxycycline. Malarone® is particularly  suitable for short trips to highly chloroquine-resistant  areas because it needs to be taken only for 7 days after  leaving an endemic area.   Renal impairment 100 mg once daily if eGFR 20-  60mL/minute/1.73m 2 ; 50 mg on alternate days if  eGFR 10-20 mL/minute/1.73 m 2 ; 50 mg once weekly  if eGFR less than 10 mL/minute/1.73 m 2 (increased  risk of haematological toxicity)   Pregnancy benefit of prophylaxis in malaria outweighs  risk; adequate folate supplements should be given to  mother; see also p. 405   Breast-feeding amount in milk probably too small to  be harmful when used for malaria prophylaxis; see  also p. 405   Side-effects mild gastric intolerance, diarrhoea, and  constipation; occasionally mouth ulcers and stomat-  itis; very rarely cholestasis, vasculitis, skin reactions,  and hair loss   • Prophylaxis of malaria, preferably started 1 week  before entering endemic area and continued for 4  weeks after leaving (see notes above), 200 mg once  daily; INFANT up to 12 weeks body-weight under 6 kg,  25 mg once daily; 12 weeks-1 year body-weight 6-  10 kg, 50 mg once daily; CHILD 1-4 years body-weight  10-16 kg, 75 mg once daily; 4-8 years body-weight  16-25 kg, 100 mg once daily; 8-13 years, body-weight  25-45 kg, 150 mg once daily; over 13 years body-  weight over 45 kg, adult dose   Counselling Warn travellers about importance of avoiding  mosquito bites, importance of taking prophylaxis regularly,  and importance of immediate visit to doctor if ill within 1  year and especially within 3 months of return. For details,  see notes above   Note Proguanil doses in BNF may differ from those in  product literature.   Note Tablet may be crushed and mixed with food such as  milk, jam, or honey just before administration   Indications treatment of acute uncomplicated falci-  parum malaria and prophylaxis of falciparum malaria,  particularly where resistance to other antimalarial    2. Can be sold to the public provided it is licensed and  labelled for the prophylaxis of malaria. Drugs for malaria  prophylaxis not prescribable on the NHS; health authorities  may investigate circumstances under which antimalarials  are prescribed   Cautions diarrhoea or vomiting (reduced absorption  of atovaquone); efficacy not evaluated in cerebral or  complicated malaria (including hyperparasitaemia,  pulmonary oedema or renal failure); interactions: see  Appendix 1 (proguanil, atovaquone)   Renal impairment avoid for malaria prophylaxis (and  if possible for malaria treatment) if eGFR less than  30 mL/minute/ 1.73 m 1 2   Side-effects abdominal pain, nausea, vomiting, diarr-  hoea; cough; headache, dizziness, insomnia, abnormal  dreams, depression, anorexia, fever; rash, pruritus;  less frequently stomatitis, palpitation, anxiety, blood  disorders, hyponatraemia, and hair loss; also reported,  hepatitis, cholestasis, tachycardia, hallucinations, sei-  zures, vasculitis, mouth ulcers, and Stevens- Johnson  syndrome  Dose   Counselling Warn travellers about importance of avoiding  mosquito bites, importance of taking prophylaxis regularly,  and importance of immediate visit to doctor if ill within 1  year and especially within 3 months of return. For details,  see notes above    Dose prophylaxis of malaria, started 1-2 days before entering  endemic area and continued for 1 week after leaving, ADULT and  CHILD over 40kg, 1 tablet daily   Treatment of malaria, ADULT and CHILD body-weight over 40 kg, 4  tablets once daily for 3 days; CHILD body-weight 11-21 kg 1 tablet  daily for 3 days; body-weight 21-31 kg 2 tablets once daily for 3  days; body-weight 3 1-40 kg 3 tablets once daily for 3 days   Paediatric tablets, pink, f/c proguanil hydrochloride  25 mg, atovaquone 62.5 mg, net price 12-tab pack =  £6.26. Label: 21, counselling, prophylaxis, see above  Dose prophylaxis of malaria, started 1-2 days before entering  endemic area and continued for 1 week after leaving, CHILD body-  weight 11-21 kg, 1 tablet once daily; body-weight 21-31 kg, 2  tablets once daily; body-weight 3 1-40 kg, 3 tablets once daily;  body-weight over 40 kg use Malarone ® (‘standard’) tablets  Treatment of malaria, CHILD body-weight 5-9 kg, 2 tablets once  daily for 3 days; body-weight 9-1 1 kg, 3 tablets once daily for 3  days; body-weight 1 1 kg and over use Malarone ® (‘standard’)  tablets   Note Tablets may be crushed and mixed with food or milky drink  just before administration   Pyrimethamine should not be used alone, but is used  with sulfadoxine.   Pyrimethamine with sulfadoxine is not recommended  for the prophylaxis of malaria, but it can be used in the  treatment of falciparum malaria with (or following)  quinine.   1. Drugs for malaria prophylaxis not prescribable on the  NHS; health authorities may investigate circumstances   Hepatic impairment manufacturer advises caution  Renal impairment manufacturer advises caution  Pregnancy theoretical teratogenic risk in first trimester  (folate antagonist); adequate folate supplements  should be given to mother  Breast-feeding significant amount in milk — avoid  administration of other folate antagonists to infant;  avoid breast-feeding during toxoplasmosis treatment  Side-effects depression of haematopoiesis with high  doses, rashes, insomnia  Dose   Indications adjunct to quinine in treatment of Plas-  modium falciparum malaria; not recommended for  prophylaxis   Cautions see under Pyrimethamine and under Co-  trimoxazole (section 5.1.8); not recommended for  prophylaxis (severe side-effects on long-term use);  interactions: Appendix 1 (pyrimethamine, sulfona-  mides)   Pregnancy possible teratogenic risk in first trimester  (pyrimethamine a folate antagonist); in third trime-  ster — risk of neonatal haemolysis and methaemo-  globinaemia; fear of increased risk of kemicterus in  neonates appears to be unfounded; see also p. 403   Breast-feeding small risk of kemicterus in jaundiced  infants and of haemolysis in G6PD-deficient infants  (due to sulfadoxine)   Side-effects see under Pyrimethamine and under Co-  trimoxazole (section 5.1.8); pulmonary infiltrates (e.g.  eosinophilic or allergic alveolitis) reported — discon-  tinue if cough or shortness of breath   Tablets, scored, pyrimethamine 25 mg, sulfadoxine  500 mg, net price 3-tab pack = 74p   Quinine is used for the treatment of falciparum malaria  or if the infective species is not known or if the infection  is mixed (for details see p. 402).   Cautions cardiac disease (including atrial fibrillation,  conduction defects, heart block), elderly — monitor  ECG during parenteral treatment; monitor blood glu-  cose and electrolyte concentration during parenteral  treatment; G6PD deficiency (see section 9.1.5);  interactions: Appendix 1 (quinine)   Hepatic impairment for treatment of malaria in  severe impairment, reduce parenteral maintenance  dose to 5-7 mg/kg of quinine salt   Renal impairment for treatment of malaria in severe  impairment, reduce parenteral maintenance dose to  5-7 mg/kg of quinine salt   Pregnancy high doses are teratogenic in first trimester,  but in malaria benefit of treatment outweighs risk; see  also p. 403   Side-effects cinchonism, including tinnitus, hearing  impairment, vertigo, headache, nausea, vomiting,  abdominal pain, diarrhoea, visual disturbances  (including temporary blindness), confusion; cardio-  vascular effects (see Cautions); dyspnoea; hyper-  sensitivity reactions including angioedema, rashes,  hot and flushed skin; hypoglycaemia (especially after  parenteral administration); blood disorders (including  thrombocytopenia and intravascular coagulation);  acute renal failure; muscle weakness; photosensitivity;  very toxic in overdosage — immediate advice from  poisons centres essential (see also p. 37)   • Treatment of malaria, see p. 402  Note Quinine (anhydrous base) 100 mg = quinine bisulphate  169 mg = quinine dihydrochloride 122 mg = quinine hydro-  chloride 122 mg = quinine sulphate 121 mg. Quinine bisul-  phate 300-mg tablets are available but provide less quinine  than 300 mg of the dihydrochloride, hydrochloride, or sul-  phate   Quinine Sulphate (Non-proprietary) (Ml  Tablets, coated, quinine sulphate 200 mg, net price  28-tab pack = £2.20; 300 mg, 28-tab pack = £2.12   Note Intravenous injection of quinine is so hazardous that it has  been superseded by infusion    native to mefloquine or Malarone® (for details, see  specific recommendations by country, p. 405).   Doxycycline is also used as an adjunct to quinine in the  treatment of falciparum malaria (for details see p. 402).   Indications prophylaxis of malaria; adjunct to quinine  in treatment of Plasmodium falciparum malaria; see  also section 5.1.3  Cautions section 5.1.3   Contra-indications section 5.1.3  Hepatic impairment section 5.1.3  Renal impairment section 5.1.3  Pregnancy section 5.1.3  Breast-feeding section 5.1.3  Side-effects section 5.1.3  Dose   • Prophylaxis of malaria, started 1-2 days before  entering endemic area and continued for 4 weeks after  leaving (see notes above), ADULT and CHILD over 12  years, 100 mg once daily    Metronidazole is the drug of choice for acute invasive  amoebic dysentery since it is very effective against  vegetative forms of Entamoeba histolytica in ulcers; it  is given in an adult dose of 800 mg three times daily for 5  days. Tinidazole is also effective. Metronidazole and  tinidazole are also active against amoebae which may  have migrated to the liver. Treatment with metronid-  azole (or tinidazole) is followed by a 10-day course of  diloxanide furoate.   Diloxanide furoate is the drug of choice for asympto-  matic patients with E. histolytica cysts in the faeces;  metronidazole and tinidazole are relatively ineffective.  Diloxanide furoate is relatively free from toxic effects  and the usual course is of 10 days, given alone for  chronic infections or following metronidazole or tinid-  azole treatment.    For amoebic abscesses of the liver metronidazole is  effective; tinidazole is an alternative. Aspiration of the  abscess is indicated where it is suspected that it may  rupture or where there is no improvement after 72 hours  of metronidazole; the aspiration may need to be  repeated. Aspiration aids penetration of metronidazole  and, for abscesses with more than 100 mL of pus, if  carried out in conjunction with drug therapy, may  reduce the period of disability.   Diloxanide furoate is not effective against hepatic  amoebiasis, but a 10-day course should be given at  the completion of metronidazole or tinidazole treatment  to destroy any amoebae in the gut.   Doxycycline (section 5.1.3) is used for the prophylaxis  of malaria in areas of widespread mefloquine or chloro-  quine resistance. Doxycycline is also used as an alter-   Indications see notes above; chronic amoebiasis and  as adjunct to metronidazole or tinidazole in acute  amoebiasis   • 500 mg every 8 hours for 10 days; CHILD body-weight  over 25 kg, 20 mg/kg daily in 3 divided doses for 10  days; body-weight under 25 kg, see BNF for Children  See also notes above   Tablets, diloxanide furoate 500 mg, net price 30-tab  pack = £93.50. Label: 9   Hepatic impairment section 5.1.11  Pregnancy section 5.1.11  Breast-feeding section 5.1.11  Side-effects section 5.1.11   • By mouth, invasive intestinal amoebiasis, extra-intes-  tinal amoebiasis (including liver abcess), 800 mg  every 8 hours for 5 days in intestinal infection (for 5-  10 days in extra-intestinal infection); CHILD 1-3 years  200 mg every 8 hours; 3-7 years 200 mg every 6  hours; 7-10 years 400 mg every 8 hours  Urogenital trichomoniasis, 200 mg every 8 hours for 7  days or 400-500 mg every 12 hours for 5-7 days, or  2 g as a single dose; CHILD 1-3 years 50 mg every 8  hours for 7 days; 3-7 years 100 mg every 12 hours; 7-  10 years 100 mg every 8 hours  Giardiasis, 2 g daily for 3 days or 400 mg 3 times daily  for 5 days or 500 mg twice daily for 7-10 days; CHILD  1-3 years 500 mg daily for 3 days; 3-7 years 600-  800 mg daily; 7-10 years 1 g daily    Metronidazole (section 5.4.2) is the treatment of choice  for Trichomonas vaginalis infection. Contact tracing is  recommended and sexual contacts should be treated  simultaneously. If metronidazole is ineffective, tinid-  azole (section 5.4.2) may be tried.   Metronidazole (section 5.4.2) is the treatment of choice  for Giardia lamblia infections. Alternative treatments  are tinidazole (section 5.4.2) or mepacrine hydro-  chloride.   Cautions hepatic impairment, elderly, history of psy-  chosis; avoid in psoriasis; interactions: Appendix 1  (mepacrine)   Side-effects gastro-intestinal disturbances; dizziness,  headache; with large doses nausea, vomiting and  occasionally transient acute toxic psychosis and CNS  stimulation; on prolonged treatment yellow disco-  loration of skin and urine, chronic dermatoses  (including severe exfoliative dermatitis), hepatitis,  aplastic anaemia; also reported blue/black disco-  loration of palate and nails and corneal deposits with  visual disturbances   • Giardiasis [unlicensed], 100 mg every 8 hours for 5-7  days   • Intestinal amoebiasis, 2 g daily for 2-3 days; CHILD 50-  60 mg/kg daily for 3 days   • Amoebic involvement of liver, 1.5-2 g daily for 3-6  days; CHILD 50-60 mg/kg daily for 5 days   • Urogenital trichomoniasis and giardiasis, single 2 g  dose; CHILD single dose of 50-75 mg/kg (repeated  once if necessary)    Cutaneous leishmaniasis frequently heals sponta-  neously but if skin lesions are extensive or unsightly,  treatment is indicated, as it is in visceral leishmaniasis  (kala-azar). Leishmaniasis should be treated under spe-  cialist supervision.    Sodium stibogluconate, an organic pentavalent anti-  mony compound, is used for visceral leishmaniasis. The  dose is 20 mg/kg daily (max. 850 mg) by intramuscular  or intravenous injection for 28 days in visceral leish-  maniasis and for 20 days in cutaneous infection; the  dosage varies with different geographical regions and  expert advice should be obtained. Some early non-  inflamed lesions of cutaneous leishmaniasis can be  treated with intralesional injections of sodium stibo-  gluconate under specialist supervision.    Amphotericin is used with or after an antimony com-  pound for visceral leishmaniasis unresponsive to the  antimonial alone; side-effects may be reduced by  using liposomal amphotericin ( AmBisome ® — section  5.2) at a dose of 1-3 mg/kg daily for 10-21 days to a  cumulative dose of 21-30 mg/kg or at a dose of 3 mg/  kg for 5 consecutive days followed by a single dose of    3 mg/kg 6 days later. Abelcet®, a lipid formulation of  amphotericin is also likely to be effective but less  information is available.   Pentamidine isetionate (pentamidine isethionate) (sec-  tion 5.4.8) has been used in antimony-resistant visceral  leishmaniasis, but although the initial response is often  good, the relapse rate is high; it is associated with  serious side-effects. Other treatments include paromo-  mycin [unlicensed] (available from ‘special-order’ man-  ufacturers or specialist importing companies, see  p. 988).   Cautions intravenous injections must be given slowly  over 5 minutes (to reduce risk of local thrombosis)  and stopped if coughing or substernal pain; mucocu-  taneous disease (see below); monitor ECG before and  during treatment; heart disease (withdraw if conduc-  tion disturbances occur); treat intercurrent infection  (e.g. pneumonia)   Mucocutaneous disease Successful treatment of mucocu-  taneous leishmaniasis may induce severe inflammation  around the lesions (may be life-threatening if pharyngeal or  tracheal involvement) — may require corticosteroid   Side-effects anorexia, nausea, vomiting, abdominal  pain, diarrhoea; ECG changes; coughing (see Cau-  tions); headache, lethargy; arthralgia, myalgia; rarely  jaundice, flushing, bleeding from nose or gum, sub-  sternal pain (see Cautions), vertigo, fever, sweating,  and rash; also reported pancreatitis and anaphylaxis;  pain and thrombosis on intravenous administration,  intramuscular injection also painful  Dose   Note Injection should be filtered immediately before admin-  istration using a filter of 5 microns or less   The prophylaxis and treatment of trypanosomiasis is  difficult and differs according to the strain of organism.  Expert advice should therefore be obtained.   Most infections caused by Toxoplasma gondii are self-  limiting, and treatment is not necessary. Exceptions are  patients with eye involvement (toxoplasma choroido-  retinitis), and those who are immunosuppressed. Tox-  oplasmic encephalitis is a common complication of  AIDS. The treatment of choice is a combination of  pyrimethamine and sulfadiazine, given for several  weeks (expert advice essential). Pyrimethamine is a  folate antagonist, and adverse reactions to this combi-  nation are relatively common (folinic acid supplements   and weekly blood counts needed). Alternative regimens  use combinations of pyrimethamine with clindamycin or  clarithromycin or azithromycin. Long-term secondary  prophylaxis is required after treatment of toxoplasmosis  in immunocompromised patients; prophylaxis should  continue until immunity recovers.   If toxoplasmosis is acquired in pregnancy, transplacen-  tal infection may lead to severe disease in the fetus.  Spiramycin [unlicensed] (available from ‘special-order’  manufacturers or specialist importing companies, see  p. 988) may reduce the risk of transmission of maternal  infection to the fetus.    Pneumonia caused by Pneumocystis jirovecii (Pneumo-  cystis carinii) occurs in immunosuppressed patients; it is  a common cause of pneumonia in AIDS. Pneumocystis  pneumonia should generally be treated by those experi-  enced in its management. Blood gas measurement is  used to assess disease severity.    Mild to moderate disease Co-trimoxazole (section  5.1.8) in high dosage is the drug of choice for the  treatment of mild to moderate pneumocystis pneu-  monia.   Atovaquone is licensed for the treatment of mild to  moderate pneumocystis infection in patients who can-  not tolerate co-trimoxazole. A combination of dapsone  100 mg daily (section 5.1.10) with trimethoprim 5 mg/  kg every 6-8 hours (section 5.1.8) is given by mouth for  the treatment of mild to moderate disease [unlicensed  indication].   A combination of clindamycin 600 mg by mouth every  8 hours (section 5.1.6) and primaquine 30 mg daily by  mouth (section 5.4.1) is used in the treatment of mild to  moderate disease [unlicensed indication]; this combina-  tion is associated with considerable toxicity.    Severe disease Co-trimoxazole (section 5.1.8) in  high dosage, given by mouth or by intravenous infusion,  is the drug of choice for the treatment of severe  pneumocystis pneumonia. Pentamidine isetionate  given by intravenous infusion is an alternative for  patients who cannot tolerate co-trimoxazole, or who  have not responded to it. Pentamidine isetionate is a  potentially toxic drug that can cause severe hypotension  during or immediately after infusion.   Corticosteroid treatment can be lifesaving in those with  severe pneumocystis pneumonia (see Adjunctive Ther-  apy below).    Adjunctive therapy In moderate to severe infections  associated with HIV infection, prednisolone 50-80 mg  daily is given by mouth for 5 days (alternatively, hydro-  cortisone may be given parenterally); the dose is then  reduced to complete 21 days of treatment. Cortico-  steroid treatment should ideally be started at the same  time as the anti-pneumocystis therapy and certainly no  later than 24-72 hours afterwards. The corticosteroid  should be withdrawn before anti-pneumocystis treat-  ment is complete.   Prophylaxis against pneumocystis pneumonia should be  given to all patients with a history of the infection.  Prophylaxis against pneumocystis pneumonia should  also be considered for severely immunocompromised  patients. Prophylaxis should continue until immunity  recovers sufficiently. It should not be discontinued if  the patient has oral candidiasis, continues to lose  weight, or is receiving cytotoxic therapy or long-term  immunosuppressant therapy.   Co-trimoxazole by mouth is the drug of choice for  prophylaxis against pneumocystis pneumonia. It is  given in a dose of 960 mg daily or 960 mg on alternate  days (3 times a week); the dose may be reduced to co-  trimoxazole 480 mg daily to improve tolerance.   Inhaled pentamidine isetionate is better tolerated than  parenteral pentamidine. Intermittent inhalation of pent-  amidine isetionate is used for prophylaxis against  pneumocystis pneumonia in patients unable to tolerate  co-trimoxazole. It is effective but patients may be prone  to extrapulmonary infection. Alternatively, dapsone  100 mg daily (section 5.1.10) can be used. Atovaquone  750 mg twice daily has also been used for prophylaxis  [unlicensed indication].   Indications treatment of mild to moderate Pneumo-  cystis jirovecii (Pneumocystis carinii) pneumonia in  patients intolerant of co-trimoxazole  Cautions initial diarrhoea and difficulty in taking with  food may reduce absorption (and require alternative  therapy); other causes of pulmonary disease should be  sought and treated; elderly; interactions: Appendix 1  (atovaquone)   Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk — no information available  Breast-feeding manufacturer advises avoid  Side-effects nausea, diarrhoea, vomiting; headache,  insomnia; fever; anaemia, neutropenia, hyponatr-  aemia; rash, pruritus; also reported, Stevens- Johnson  syndrome  Dose   • 750 mg twice daily with food (particularly high fat) for  21 days; CHILD not recommended   Suspension, sugar-free, atovaquone 750 mg/5 mL,  net price 226 mL (tutti-frutti-flavoured) = £405.31.  Label: 21    intervals, until treatment concluded; patient should be  lying down when receiving drug parenterally); hypo-  kalaemia, hypomagnesaemia, coronary heart disease,  bradycardia, history of ventricular arrhythmias, con-  comitant use with other drugs which prolong QT-  interval; hypertension or hypotension; hyperglyc-  aemia or hypoglycaemia; leucopenia, thrombocyto-  penia, or anaemia; carry out laboratory monitoring  according to product literature; care required to pro-  tect personnel during handling and administration;  interactions: Appendix 1 (pentamidine isetionate)   Renal impairment reduce intravenous dose for  pneumocystis pneumonia if creatinine clearance less  than lOmL/minute: in life-threatening infection, use  4 mg/kg once daily for 7-10 days, then 4 mg/kg on  alternate days to complete course of at least 14 doses;  in less severe infection, use 4 mg/kg on alternate days  for at least 14 doses   Side-effects severe reactions, sometimes fatal, due to  hypotension, hypoglycaemia, pancreatitis, and arrhy-  thmias; also leucopenia, thrombocytopenia, acute  renal failure, hypocalcaemia; also reported: azotae-  mia, abnormal liver-function tests, anaemia, hyper-  kalaemia, nausea and vomiting, dizziness, syncope,  flushing, hyperglycaemia, rash, and taste distur-  bances; Stevens- Johnson syndrome reported; on  inhalation, bronchoconstriction (may be prevented by  prior use of bronchodilators), cough, and shortness of  breath; discomfort, pain, induration, abscess forma-  tion, and muscle necrosis at injection site  Dose   • Treatment of Pneumocystis jirovecii (Pneumocystis  carinii) pneumonia, by intravenous infusion, 4 mg/kg  once daily for at least 14 days   • Prophylaxis of Pneumocystis jirovecii (Pneumocystis  carinii) pneumonia, by inhalation of nebulised solu-  tion (using suitable equipment — consult product lit-  erature), 300 mg every 4 weeks or 150 mg every 2  weeks [unlicensed for primary prevention]   • Visceral leishmaniasis (kala-azar, section 5.4.5), by  deep intramuscular injection, 3-4 mg/kg on alternate  days to max. total of 10 injections; course may be  repeated if necessary   • Cutaneous leishmaniasis, by deep intramuscular  injection, 3-4 mg/kg once or twice weekly until con-  dition resolves (but see also section 5.4.5)   • Trypanosomiasis, by deep intramuscular injection or  intravenous infusion, 4 mg/kg daily or on alternate  days to total of 7-10 injections   Note Direct intravenous injection should be avoided when-  ever possible and never given rapidly; intramuscular injec-  tions should be deep and preferably given into the buttock   Cautions risk of severe hypotension following admin-  istration (monitor blood pressure before starting  treatment, during administration, and at regular    Pentacarinat® (Sanofi-Aventis) (Ml  Injection, powder for reconstitution, pentamidine  isetionate, net price 300-mg vial = £30.45  Nebuliser solution, pentamidine isetionate, net price  300-mg bottle = £32.15   • Threadworms, ADULT and CHILD over 2 years, 100 mg  as a single dose; if reinfection occurs second dose  may be needed after 2 weeks; CHILD under 2 years, see  BNF for Children   • Whipworms, ADULT and CHILD over 2 years, 100 mg  twice daily for 3 days; CHILD under 2 years, see BNF  for Children   Advice on prophylaxis and treatment of helminth infec-  tions is available from:    Scottish Centre for Infection and  Environmental Health (registered  users of Travax only)    Mebendazole (Non-proprietary) (Ml  Tablets, chewable, mebendazole 100 mg  1 . Mebendazole tablets can be sold to the public if supplied for  oral use in the treatment of enterobiasis in adults and  children over 2 years provided its container or package is  labelled to show a max. single dose of 100 mg and it is  supplied in a container or package containing not more than  800 mg   Anthelmintics are effective in threadworm infections,  but their use needs to be combined with hygienic  measures to break the cycle of auto-infection. All mem-  bers of the family require treatment.   Adult threadworms do not live for longer than 6 weeks  and for development of fresh worms, ova must be  swallowed and exposed to the action of digestive juices  in the upper intestinal tract. Direct multiplication of  worms does not take place in the large bowel. Adult  female worms lay ova on the perianal skin which causes  pruritus; scratching the area then leads to ova being  transmitted on fingers to the mouth, often via food eaten  with unwashed hands. Washing hands and scrubbing  nails before each meal and after each visit to the toilet is  essential. A bath taken immediately after rising will  remove ova laid during the night.   Mebendazole is the drug of choice for treating thread-  worm infection in patients of all ages over 2 years. It is  given as a single dose; as reinfection is very common, a  second dose may be given after 2 weeks.   Piperazine is available in combination with sennosides  as a single-dose preparation.   Vermox® Qanssen-Cilag) (Ml  Tablets, orange, scored, chewable, mebendazole  100 mg. Net price 6-tab pack = £1.36  Oral suspension, mebendazole 100 mg/5 mL (bana-  na-flavoured). Net price 30 mL = £1.59    Indications threadworm and roundworm infections  Cautions epilepsy; packs on sale to the general public  carry a warning to avoid in epilepsy, or in liver or  kidney disease, and to seek medical advice in  pregnancy   Hepatic impairment manufacturer advises avoid  Renal impairment use with caution; avoid in severe  renal impairment; risk of neurotoxicity  Pregnancy not known to be harmful but manufacturer  advises avoid in first trimester  Breast-feeding present in milk — manufacturer  advises avoid breast-feeding for 8 hours after dose  (express and discard milk during this time)  Side-effects nausea, vomiting, colic, diarrhoea, aller-  gic reactions including urticaria, bronchospasm, and  rare reports of arthralgia, fever, Stevens-Johnson  syndrome and angioedema; rarely dizziness, muscular  incoordination (‘worm wobble’); drowsiness, nystag-  mus, vertigo, blurred vision, confusion and clonic  contractions in patients with neurological or renal  abnormalities   Cautions interactions: Appendix 1 (mebendazole)  Note The package insert in the Vermox ® pack includes the  statement that it is not suitable for women known to be  pregnant or children under 2 years   Breast-feeding amount too small to be harmful but  manufacturer advises avoid   Side-effects abdominal pain; less commonly diarr-  hoea, flatulence, rash; very rarely hepatitis, con-   Oral powder, piperazine phosphate 4g, total senno-  sides (calculated as sennoside B) 15.3 mg/sachet. Net  price two-dose sachet pack = £1.98. Label: 13  Dose threadworms, stirred into milk or water, ADULT and CHILD  over 6 years, content of 1 sachet as a single dose (bedtime in  adults or morning in children), repeated after 14 days; INFANT 3  months-1 year, 1 level 2.5-mL spoonful in the morning, repeated  after 14 days; CHILD 1-6 years, 1 level 5-mL spoonful in the  morning, repeated after 14 days   Roundworms, first dose as for threadworms; repeat at monthly  intervals for up to 3 months if reinfection risk   Mebendazole (section 5.5.1) is effective against Ascaris  lumbricoides and is generally considered to be the drug  of choice; the usual dose is 100 mg twice daily for 3 days  or 500 mg as a single dose [unlicensed single dose],  Levamisole [unlicensed] (available from ‘special-order’  manufacturers or specialist importing companies, see  p. 988) is an alternative when mebendazole cannot be  used. It is very well tolerated; mild nausea or vomiting  has been reported in about 1% of treated patients; it is  given as a single dose of 120-150 mg in adults.   Piperazine may be given in a single adult dose, see  Piperazine, above.   Niclosamide [unlicensed] (available from ‘special-  order’ manufacturers or specialist importing companies,  see p. 988) is the most widely used drug for tapeworm  infections and side-effects are limited to occasional  gastro-intestinal upset, lightheadedness, and pruritus;  it is not effective against larval worms. Fears of devel-  oping cysticercosis in Taenia solium infections have  proved unfounded. All the same, an antiemetic can be  given before treatment and a laxative can be given 2  hours after niclosamide.    Praziquantel [unlicensed] (available from ‘special-  order’ manufacturers or specialist importing companies,  see p. 988) is as effective as niclosamide and is given as  a single dose of 5-10 mg/kg after a light breakfast (a  single dose of 25 mg/kg for Hymenolepis nana).   Cysts caused by Echinococcus granulosus grow slowly  and asymptomatic patients do not always require treat-  ment. Surgical treatment remains the method of choice  in many situations. Albendazole [unlicensed] (available  from ‘special-order’ manufacturers or specialist import-  ing companies, see p. 988) is used in conjunction with  surgery to reduce the risk of recurrence or as primary  treatment in inoperable cases. Alveolar echinococcosis  due to E. multilocularis is usually fatal if untreated.  Surgical removal with albendazole cover is the treat-  ment of choice, but where effective surgery is impos-  sible, repeated cycles of albendazole (for a year or more)  may help. Careful monitoring of liver function is parti-  cularly important during drug treatment.   Hookworms live in the upper small intestine and draw  blood from the point of their attachment to their host.  An iron-deficiency anaemia may occur and, if present,   effective treatment of the infection requires not only  expulsion of the worms but treatment of the anaemia.   Mebendazole (section 5.5.1) has a useful broad-spec-  trum activity, and is effective against hookworms; the  usual dose is 100 mg twice daily for 3 days. Albend-  azole [unlicensed] (available from ‘special-order’ man-  ufacturers or specialist importing companies, see  p. 988) given as a single dose of 400 mg, is an alter-  native.    Adult Schistosoma haematobium worms live in the  genito-urinary veins and adult S. mansoni in those of  the colon and mesentery. S. japonicum is more widely  distributed in veins of the alimentary tract and portal  system.   Praziquantel [unlicensed] is available from Merck Ser-  ono ( Cysticide ®) and is effective against all human  schistosomes. The dose is 20 mg/kg followed after 4-6  hours by one further dose of 20 mg/kg (20 mg/kg given  3 times on one day for S. japonicum infections). No  serious adverse effects have been reported. Of all the  available schistosomicides, it has the most attractive  combination of effectiveness, broad-spectrum activity,  and low toxicity.   Hycanthone, lucanthone, niridazole, oxamniquine, and  sodium stibocaptate have now been superseded.   Diethylcarbamazine [unlicensed] (available from ‘spe-  cial-order’ manufacturers or specialist importing com-  panies, see p. 988) is effective against microfilariae and  adults of Loa loa, Wuchereria bancrofti, and Brugia  malayi. To minimise reactions treatment is commenced  with a dose of diethylcarbamazine citrate 1 mg/kg on  the first day and increased gradually over 3 days to  6 mg/kg daily in divided doses (up to 9 mg/kg daily in  divided doses for Loa loa)] this dosage is maintained for  a further period. Close medical supervision is necessary  particularly in the early phase of treatment.   In heavy infections there may be a febrile reaction, and  in heavy Loa loa infection there is a small risk of  encephalopathy. In such cases specialist advice should  be sought, and treatment must be given under careful  in-patient supervision and stopped at the first sign of  cerebral involvement.   Ivermectin [unlicensed] (available from ‘special-order’  manufacturers or specialist importing companies, see  p. 988) is very effective in onchocerciasis and it is now  the drug of choice. A single dose of 150 micrograms/kg  by mouth produces a prolonged reduction in microfilar-  ial levels. Retreatment at intervals of 6 to 12 months  depending on symptoms must be given until the adult  worms die out. Reactions are usually slight and most  commonly take the form of temporary aggravation of  itching and rash. Diethylcarbamazine or suramin should  no longer be used for onchocerciasis because of their  toxicity.   Dog and cat hookworm larvae may enter human skin  where they produce slowly extending itching tracks  usually on the foot. Single tracks can be treated with  topical tiabendazole (no commercial preparation avail-  able). Multiple infections respond to ivermectin,  albendazole or tiabendazole (thiabendazole) by  mouth [all unlicensed] and available from ‘special-  order’ manufacturers or specialist importing companies,  see p. 988).   Adult Strongyloides stercoralis live in the gut and pro-  duce larvae which penetrate the gut wall and invade the  tissues, setting up a cycle of auto-infection. Ivermectin  [unlicensed] (available from ‘special-order’ manufac-  turers or specialist importing companies, see p. 988) in  a dose of 200 micrograms/kg daily for 2 days is the  treatment of choice for chronic Strongyloides infection.  Albendazole [unlicensed] (available from ‘special-  order’ manufacturers or specialist importing companies,  see p. 988) is an alternative given in a dose of 400 mg  twice daily for 3 days, repeated after 3 weeks if neces-  sary.   This chapter also includes advice on the drug man-  agement of the following:   Serious infections in patients taking corticoster-  oids, p. 444  Osteoporosis, p. 469  Breast pain (mastalgia), p. 482   Antidiabetic drugs  Diabetic ketoacidosis  Treatment of hypoglycaemia  Treatment of diabetic nephropathy  and neuropathy   Diabetes mellitus occurs because of a lack of insulin or  resistance to its action. It is diagnosed by measuring  fasting or random blood-glucose concentration (and  occasionally by oral glucose tolerance test). Although  there are many subtypes, the two principal classes of  diabetes are type 1 diabetes and type 2 diabetes.   Type 1 diabetes, (formerly referred to as insulin-depen-  dent diabetes mellitus (IDDM)), occurs as a result of a  deficiency of insulin following autoimmune destruction  of pancreatic beta cells. Patients with type 1 diabetes  require administration of insulin.   Type 2 diabetes, (formerly referred to as non-insulin-  dependent diabetes (NIDDM)), is due to reduced secre-  tion of insulin or to peripheral resistance to the action of  insulin or to a combination of both. Although patients  may be controlled on diet alone, many also require oral  antidiabetic drugs or insulin (or both) to maintain satis-  factory control. In overweight individuals, type 2 dia-  betes may be prevented by losing weight and increasing  physical activity; use of the anti-obesity drug orlistat  (section 4.5.1) may be considered in obese patients.   Treatment of diabetes Treatment of all forms of  diabetes should be aimed at alleviating symptoms and  minimising the risk of long-term complications (see  below); tight control of diabetes is essential.   Diabetes is a strong risk factor for cardiovascular dis-  ease (section 2.12). Other risk factors for cardiovascular  disease such as smoking (section 4.10.2), hypertension  (section 2.5), obesity (section 4.5), and hyperlipidaemia    (section 2.12) should be addressed. Cardiovascular risk  in patients with diabetes can be further reduced by the  use of an ACE inhibitor (section 2.5.5. 1), low-dose  aspirin (section 2.9) and a lipid-regulating drug (section  2 . 12 ).   Prevention of diabetic complications Optimal  glycaemic control in both type 1 diabetes and type 2  diabetes reduces, in the long term, the risk of micro-  vascular complications including retinopathy, develop-  ment of proteinuria and to some extent neuropathy.  However, a temporary deterioration in established dia-  betic retinopathy may occur when normalising blood-  glucose concentration. For reference to the use of an  ACE inhibitor or an angiotensin-II receptor antagonist in  the management of diabetic nephropathy, see section  6.1.5.   A measure of the total glycosylated (or glycated) hae-  moglobin (HbAJ or a specific fraction (HbA lc ) provides  a good indication of glycaemic control over the previous  2-3 months. Overall it is ideal to aim for an HbA lc  (glycosylated haemoglobin) concentration of 48-  59 mmol/mol (6.5— 7.5%) or less (reference range 20-  42 mmol/mol or 4-6%) but this cannot always be  achieved and for those using insulin there is a signifi-  cantly increased risk of disabling hypoglycaemia; in  those at risk of arterial disease, the aim should be to  maintain the HbA lc concentration at 48 mmol/mol  (6.5%) or less. HbA lc should be measured every 3-6  months.   HbA lc values currently expressed as a percentage,  are aligned to the assay used in the Diabetes Con-  trol and Complications Trial (DCCT). A new stan-  dard, specific for HbA lc , has been created by the  International Federation of Clinical Chemistry and  Laboratory Medicine (IFCC), which expresses  HbA lc values in mmol of glycosylated haemoglobin  per mol of haemoglobin. UK laboratories now  express results in both IFCC-standardised units  (mmol/mol) and DCCT-aligned units . From 1  June 2011, results will only be reported in IFCC-  standardised units.    Laboratory measurement of serum-fructosamine con-  centration is technically simpler and cheaper than the  measurement of HbA lc and can be used to assess  control over short periods of time, particularly when  HbA lc monitoring is invalid (e.g. disturbed erythrocyte  turnover or abnormal haemoglobin type).   Tight control of blood pressure in hypertensive patients  with type 2 diabetes reduces mortality and protects  visual acuity (by reducing considerably the risks of  maculopathy and retinal photocoagulation) (see also  section 2.5).    Driving Drivers with diabetes are required to notify the  Driver and Vehicle Licensing Agency (DVLA) of their  condition if they are treated with insulin or if they are  treated with oral antidiabetic drugs and also have com-  plications. Detailed guidance on eligibility to drive is  available from the DVLA (www.dvla.gov.uk/  medical.aspx). Driving is not permitted when hypogly-  caemic awareness is impaired or frequent hypoglycae-  mic episodes occur.   Drivers need to be particularly careful to avoid hypo-  glycaemia (see also above) and should be warned of the  problems. Drivers treated with insulin should normally  check their blood-glucose concentration before driving  and, on long journeys, at 2-hour intervals; these pre-  cautions may also be necessary for drivers taking oral  antidiabetic drugs who are at particular risk of hypo-  glycaemia. Drivers treated with insulin should ensure  that a supply of sugar is always available in the vehicle  and they should avoid driving if their meal is delayed. If  hypoglycaemia occurs, or warning signs develop, the  driver should:   • wait until recovery is complete before continuing  journey; recovery may take 15 minutes or longer  and should preferably be confirmed by checking  blood-glucose concentration.   Insulin plays a key role in the regulation of carbohy-  drate, fat, and protein metabolism. It is a polypeptide  hormone of complex structure. There are differences in  the amino-acid sequence of animal insulins, human  insulins and the human insulin analogues. Insulin may  be extracted from pork pancreas and purified by crystal-  lisation; it may also be extracted from beef pancreas, but  beef insulins are now rarely used. Human sequence  insulin may be produced semisynthetically by enzy-  matic modification of porcine insulin (emp) or bio-  synthetically by recombinant DNA technology using  bacteria (crb, prb) or yeast (pyr).   All insulin preparations are to a greater or lesser extent  immunogenic in man but immunological resistance to  insulin action is uncommon. Preparations of human  sequence insulin should theoretically be less immuno-  genic, but no real advantage has been shown in trials.  Insulin is inactivated by gastro-intestinal enzymes, and  must therefore be given by injection; the subcutaneous  route is ideal in most circumstances. Insulin is usually  injected into the upper arms, thighs, buttocks, or abdo-  men; absorption from a limb site may be increased if the  limb is used in strenuous exercise after the injection.  Generally subcutaneous insulin injections cause few  problems; lipodystrophy may occur but can be mini-  mised by using different injection sites in rotation. Local  allergic reactions are rare.    Insulin is needed by all patients with ketoacidosis, and it  is likely to be needed by most patients with:   Insulin is required by almost all children with diabetes. It  is also needed for type 2 diabetes when other methods  have failed to achieve good control, and temporarily in  the presence of intercurrent illness or peri-operatively.  Pregnant women with type 2 diabetes may be treated  with insulin when diet alone fails. For advice on use of  oral antidiabetic drugs in the management of diabetes in  pregnancy, see section 6.1.2.    with certain endocrine disorders (e.g. Addison’s disease,  hypopituitarism), or in coeliac disease.   • Multiple injection regimen: short-acting insulin or  rapid-acting insulin analogue, before meals   • Short-acting insulin or rapid-acting insulin analogue  mixed with intermediate-acting or long-acting insu-  lin, once or twice daily (before meals);   Hepatic impairment Insulin requirements may be  decreased in patients with hepatic impairment.   treatment is to achieve the best possible control of  blood-glucose concentration without making the patient  obsessional and to avoid disabling hypoglycaemia; close  co-operation is needed between the patient and the  medical team because good control reduces the risk of  complications.   those of short duration which have a relatively  rapid onset of action, namely soluble insulin and  the rapid-acting insulin analogues, insulin aspart,  insulin glulisine, and insulin lispro (section 6. 1.1.1);  those with an intermediate action, e.g. isophane  insulin (section 6. 1.1.2); and    • those whose action is slower in onset and lasts for  long periods, e.g. protamine zinc insulin, insulin  detemir, and insulin glargine (section 6. 1.1.2).    The duration of action of a particular type of insulin  varies considerably from one patient to another, and  needs to be assessed individually.    Mixtures of insulin preparations may be required and  appropriate combinations have to be determined for the  individual patient. Treatment should be started with a  short-acting insulin (e.g. soluble insulin) or a rapid-act-  ing insulin analogue (e.g. insulin aspart) given before  meals with intermediate-acting or long-acting insulin  once or twice daily. Alternatively, for those who have  difficulty with, or prefer not to use, multiple injection  regimens, a mixture of premixed short-acting insulin or  rapid acting insulin analogue with an intermediate-act-  ing or long-acting insulin (most commonly in a propor-  tion of 30% soluble insulin and 70% isophane insulin)  can be given once or twice daily. The dose of short-  acting or rapid-acting insulin (or the proportion of the  short-acting soluble insulin component in premixed  insulin) can be increased in those with excessive post-  prandial hyperglycaemia. The dose of insulin is  increased gradually according to the patient’s individual  requirements, taking care to avoid troublesome hypo-  glycaemic reactions.    Insulin requirements may be increased by infection,  stress, accidental or surgical trauma, and during  puberty. Requirements may be decreased in those    Renal impairment Insulin requirements may fall in  patients with renal impairment and therefore dose  reduction may be necessary. The compensatory  response to hypoglycaemia is impaired in renal impair-  ment.    Pregnancy and breast-feeding During pregnancy  and breast-feeding, insulin requirements may alter and  doses should be assessed frequently by an experienced  diabetes physician. The dose of insulin generally needs  to be increased in the second and third trimesters of  pregnancy. The short-acting insulin analogues, insulin  aspart and insulin lispro, are not known to be harmful,  and may be used during pregnancy and lactation. The  safety of long-acting insulin analogues in pregnancy has  not been established, therefore isophane insulin is  recommended where longer-acting insulins are needed.    Insulin administration Insulin is generally given by  subcutaneous injection ; the injection site should be  rotated to prevent lipodystrophy. Injection devices  (‘pens’) (section 6.1. 1.3), which hold the insulin in a  cartridge and meter the required dose, are convenient  to use. Insulin syringes (for use with needles) are  required for insulins not available in cartridge form.   For intensive insulin regimens multiple subcutaneous  injections (3 or more times daily) are usually recom-  mended.   Short-acting injectable insulins (soluble insulin, insulin  aspart, insulin glulisine, and insulin lispro) can also be  given by continuous subcutaneous infusion using a  portable infusion pump. This device delivers a contin-  uous basal insulin infusion and patient-activated bolus  doses at meal times. This technique can be useful for  patients who suffer recurrent hypoglycaemia or marked  morning rise in blood-glucose concentration despite  optimised multiple-injection regimens (see also NICE  guidance, below). Patients on subcutaneous insulin infu-  sion must be highly motivated, able to monitor their  blood-glucose concentration, and have expert training,  advice and supervision from an experienced healthcare  team.   Continuous subcutaneous insulin infusion  for the treatment of diabetes mellitus (type  1 ) (July 2008 )   Continuous subcutaneous insulin infusion is recom-  mended as an option in adults and children over 12  years with type 1 diabetes:   • who suffer repeated or unpredictable hypoglyc-  aemia, whilst attempting to achieve optimal  glycaemic control with multiple-injection regi-  mens, or   • whose glycaemic control remains inadequate  (HbA lc over 8.5%) despite optimised multiple-  injection regimens (including the use of long-  acting insulin analogues where appropriate).   Continuous subcutaneous insulin infusion is also  recommended as an option for children under 12  years with type 1 diabetes for whom multiple-injec-  tion regimens are considered impractical or inap-  propriate. Children on insulin pumps should undergo  a trial of multiple-injection therapy between the ages  of 12 and 18 years.    Soluble insulin by the intravenous route is reserved for  urgent treatment, e.g. in diabetic ketoacidosis, and for  fine control in serious illness and in the peri-operative  period (see under Diabetes and Surgery, below).   Monitoring Many patients now monitor their own  blood-glucose concentrations (section 6.1.6). Since  blood-glucose concentration varies substantially  throughout the day, ‘normoglycaemia’ cannot always  be achieved throughout a 24-hour period without caus-  ing damaging hypoglycaemia. It is therefore best to  recommend that patients should maintain a blood-glu-  cose concentration of between 4 and 9 mmol/litre for  most of the time (4-7 mmol/litre before meals and less  than 9 mmol/litre after meals), while accepting that on  occasions, for brief periods, it will be above these values;  strenuous efforts should be made to prevent the blood-  glucose concentration from falling below 4 mmol/litre.  Patients using multiple injection regimens should under-  stand how to adjust their insulin dose according to their  carbohydrate intake. With fixed-dose insulin regimens,  the carbohydrate intake needs to be regulated, and  should be distributed throughout the day to match the  insulin regimen. The intake of energy and of simple and  complex carbohydrates should be adequate to allow  normal growth and development but obesity must be  avoided.   Hypoglycaemia Hypoglycaemia is a potential pro-  blem with insulin therapy. All patients must be carefully  instructed on how to avoid it.   Loss of warning of hypoglycaemia among insulin-trea-  ted patients can be a serious hazard, especially for  drivers and those in dangerous occupations. Very tight  control of diabetes lowers the blood-glucose concentra-  tion needed to trigger hypoglycaemic symptoms; an  increase in the frequency of hypoglycaemic episodes  may reduce the warning symptoms experienced by the  patient. Beta-blockers can also blunt hypoglycaemic  awareness (and also delay recovery).   To restore the warning signs, episodes of hypoglycaemia  must be minimised; this involves appropriate adjust-    ment of insulin type, dose and frequency together with  suitable timing and quantity of meals and snacks.   Some patients have reported loss of hypoglycaemia  warning after transfer to human insulin. Clinical studies  do not confirm that human insulin decreases hypoglyc-  aemia awareness. If a patient believes that human insu-  lin is responsible for the loss of warning it is reasonable  to revert to animal insulin and essential to educate the  patient about avoiding hypoglycaemia. Great care  should be taken to specify whether a human or an  animal preparation is required.   Few patients are now treated with beef insulins; when  undertaking conversion from beef to human insulin, the  total dose should be reduced by about 10% with careful  monitoring for the first few days. When changing  between pork and human-sequence insulins, a dose  change is not usually needed, but careful monitoring is  still advised.    Diabetes and surgery Perioperative control of blood-  glucose concentrations in patients with type 1 diabetes  is achieved via an adjustable, continuous, intravenous  infusion of insulin. Detailed local protocols should be  available to all healthcare professionals involved in the  treatment of these patients; in general, the following  steps should be followed:   • Give an injection of the patient’s usual insulin on the  night before the operation;    • Early on the day of the operation, start an intra-  venous infusion of glucose containing potassium  chloride (provided that the patient is not hyperka-  laemic) and infuse at a constant rate appropriate to  the patient’s fluid requirements (usually 125 mL per  hour); make up a solution of soluble insulin in sod-  ium chloride 0.9% and infuse intravenously using a  syringe pump piggy-backed to the intravenous infu-  sion. Glucose and potassium infusions, and insulin  infusions should be made up according to locally  agreed protocols;   • The rate of the insulin infusion should be adjusted  according to blood-glucose concentration (frequent  monitoring necessary) in line with locally agreed  protocols. Other factors affecting the rate of infu-  sion include the patient’s volume depletion, cardiac  function, and age.    Protocols should include specific instructions on how to  manage resistant cases (such as patients who are in  shock or severely ill or those receiving corticosteroids or  sympathomimetics) and those with hypoglycaemia.    If a syringe pump is not available, soluble insulin should  be added to the intravenous infusion of glucose and  potassium chloride (provided the patient is not hyper-  kalaemic), and the infusion run at the rate appropriate to  the patient’s fluid requirements (usually 125 mL per  hour) with the insulin dose adjusted according to  blood-glucose concentration in line with locally agreed  protocols.    Once the patient starts to eat and drink, give subcuta-  neous insulin before breakfast and stop intravenous  insulin 30 minutes later; the dose may need to be 10-  20% more than usual if the patient is still in bed or  unwell. If the patient was not previously receiving insu-  lin, an appropriate initial dose is 30-40 units daily in four  divided doses using soluble insulin before meals and  intermediate-acting insulin at bedtime and the dose  adjusted from day to day. Patients with hyperglycaemia    often relapse after conversion back to subcutaneous  insulin calling for one of the following approaches:   • additional doses of soluble insulin at any of the four  injection times (before meals or bedtime) or   • temporary addition of intravenous insulin infusion  (while continuing the subcutaneous regimen) until  blood-glucose concentration is satisfactory or   • complete reversion to the intravenous regimen  (especially if the patient is unwell).   Soluble insulin is a short-acting form of insulin. For  maintenance regimens it is usual to inject it 15 to 30  minutes before meals.   Soluble insulin is the most appropriate form of insulin  for use in diabetic emergencies e.g. diabetic ketoacid-  osis (section 6.1.3) and at the time of surgery. It can be  given intravenously and intramuscularly, as well as sub-  cutaneously.   When injected subcutaneously, soluble insulin has a  rapid onset of action (30 to 60 minutes), a peak action  between 2 and 4 hours, and a duration of action of up to  8 hours.   When injected intravenously, soluble insulin has a very  short half-life of only about 5 minutes and its effect  disappears within 30 minutes.   The rapid-acting human insulin analogues, insulin  aspart, insulin glulisine, and insulin lispro have a  faster onset and shorter duration of action than soluble  insulin; as a result, compared to soluble insulin, fasting  and preprandial blood-glucose concentrations are a  little higher, postprandial blood-glucose concentration  is a little lower, and hypoglycaemia occurs slightly less  frequently. Subcutaneous injection of insulin analogues  may be convenient for those who wish to inject shortly  before or, when necessary, shortly after a meal. They  can also help those susceptible to hypoglycaemia before  lunch and those who eat late in the evening and are  prone to nocturnal hypoglycaemia. They can also be  administered by subcutaneous infusion (see Insulin  Administration, above). Insulin aspart and insulin lispro  can be administered intravenously and can be used as  alternatives to soluble insulin for diabetic emergencies  and at the time of surgery.   A sterile solution of insulin (i.e. bovine or porcine) or  of human insulin; pH 6.6-8.0   Hepatic impairment section 6.1.1  Renal impairment section 6.1.1  Pregnancy section 6.1.1  Breast-feeding section 6.1.1   Side-effects see notes above; transient oedema; local  reactions and fat hypertrophy at injection site; rarely  hypersensitivity reactions including urticaria, rash;  overdose causes hypoglycaemia   • By subcutaneous, intramuscular or intravenous  injection or intravenous infusion, according to  requirements   Injection, soluble insulin (bovine, highly purified)  lOOunits/mL. Net price 10-mL vial = £18.48; car-  tridges (for Autopen ® Classic ) 5x3 mL = £27.72   Injection, soluble insulin (porcine, highly purified)  lOOunits/mL. Net price 10-mL vial = £16.80; car-  tridges (for Autopen® Classic ) 5 x 3mL =£25.20   Injection, soluble insulin (human, prb) lOOunits/mL.  Net price 10-mL vial = £15.68; 5 x 3-mL cartridge (for  most Autopen® Classic or HumaPen ®) = £19.08   Insuman® Rapid (Sanofi-Aventis) [Mi  Injection, soluble insulin (human, crb) lOOunits/mL,  net price 5 x 3-mL cartridge (for ClikSTAR® and  OptiPen® Pro 1) = £17.50; 5 x 3-mL Insuman®  Rapid OptiSet® prefilled disposable injection devices  (range 2-40 units, allowing 2-unit dosage adjustment)  = £17.50   • By subcutaneous injection, ADULT and CHILD over 2  years, immediately before meals or when necessary  shortly after meals, according to requirements   • By subcutaneous infusion, intravenous injection or  intravenous infusion, ADULT and CHILD over 2 years,  according to requirements   NovoRapid® (Novo Nordisk) (Ml  Injection, insulin aspart (recombinant human insulin  analogue) lOOunits/mL, net price 10-mL vial =  £16.28; Penfill® cartridge (for NovoPen® devices) 5 x  3-mL = £28.84; 5 x 3-mL FlexPen® prefilled   Hepatic impairment section 6.1.1  Renal impairment section 6.1.1  Pregnancy section 6.1.1  Breast-feeding section 6.1.1  Side-effects see under Insulin  Dose   • By subcutaneous injection, ADULT and CHILD over 6  years, immediately before meals or when necessary  shortly after meals, according to requirements   • By subcutaneous infusion, or intravenous infusion  ADULT and CHILD over 6 years, according to require-  ments   Apidra® (Sanofi-Aventis) [Ml  Injection, insulin glulisine (recombinant human insu-  lin analogue) lOOunits/mL, net price 10-mL vial =  £16.60; 5x 3-mL cartridge (for ClikSTAR®, OptiPen®  Pro 1, and Autopen® 24) = £28.30; 5 x 3-mL  OptiClik® cartridge (for OptiCIik® Pen) = £30.27; 5 x  3-mL Apidra® Optiset® prefilled disposable injection  devices (range 2-40 units, allowing 2-unit dosage  adjustment) = £28.30; 5 x 3-mL Apidra® SoloStar®  prefilled disposable injection devices (range 1-  80 units, allowing 1-unit dosage adjustment) = £25.00  Counselling Show container to patient and confirm that  patient is expecting the version dispensed  Note The Scottish Medicines Consortium (p. 4) has advised  (October 2008) that Apidra ® is accepted for restricted use  within NHS Scotland for the treatment of adults and children  over 6 years with diabetes mellitus in whom the use of a short-  acting insulin analogue is appropriate   Indications diabetes mellitus  Cautions section 6.1.1; children (use only if benefit  likely compared to soluble insulin); interactions:  Appendix 1 (antidiabetics)   Hepatic impairment section 6.1.1  Renal impairment section 6.1.1  Pregnancy section 6.1.1  Breast-feeding section 6.1.1  Side-effects see under Insulin  Dose   • By subcutaneous injection shortly before meals or  when necessary shortly after meals, according to  requirements   • By subcutaneous infusion, or intravenous injection,  or intravenous infusion, according to requirements   Injection, insulin lispro (recombinant human insulin  analogue) lOOunits/mL, net price 10-mL vial =  £16.61; 5 x 3-mL cartridge (for Autopen® Classic or  HumaPen®) = £28.31; 5 x 3-mL Humalog® -Pen  prefilled disposable injection devices (range 1-  60 units, allowing 1-unit dosage adjustment) = £29.46;    5 x 3-mL Humalog® KwikPen prefilled disposable  injection devices (range 1-60 units, allowing 1-unit  dosage adjustment) = £29.46   When given by subcutaneous injection, intermediate-  and long-acting insulins have an onset of action of  approximately 1-2 hours, a maximal effect at 4-12  hours, and a duration of 16-35 hours. Some are given  twice daily in conjunction with short-acting (soluble)  insulin, and others are given once daily, particularly in  elderly patients. Soluble insulin can be mixed with  intermediate and long-acting insulins (except insulin  detemir and insulin glargine) in the syringe, essentially  retaining the properties of the two components,  although there may be some blunting of the initial effect  of the soluble insulin component (especially on mixing  with protamine zinc insulin, see below).   Isophane insulin is a suspension of insulin with prot-  amine; it is of particular value for initiation of twice-daily  insulin regimens. Patients usually mix isophane with  soluble insulin but ready-mixed preparations may be  appropriate (biphasic isophane insulin, biphasic insu-  lin aspart, or biphasic insulin lispro).   Insulin zinc suspension (30% amorphous, 70% cryst-  alline) has a more prolonged duration of action.   Protamine zinc insulin is usually given once daily with  short-acting (soluble) insulin. It has the drawback of  binding with the soluble insulin when mixed in the  same syringe and is now rarely used.   Insulin glargine and insulin detemir are both long-  acting human insulin analogues with a prolonged dura-  tion of action; insulin glargine is given once daily and  insulin detemir is given once or twice daily. NICE  (December 2002) has recommended that insulin glar-  gine should be available as an option for patients with  type 1 diabetes.   NICE (May 2009) has recommended that, if insulin is  required in patients with type 2 diabetes, insulin detemir  or insulin glargine may be considered for those:   • who require assistance with injecting insulin or  • whose lifestyle is significantly restricted by recur-  rent symptomatic hypoglycaemia or  • who would otherwise need twice-daily basal insulin  injections in combination with oral antidiabetic  drugs or   Hepatic impairment section 6.1.1  Renal impairment section 6.1.1  Pregnancy section 6.1.1   • By subcutaneous injection, ADULT and CHILD over 6  years, according to requirements   Levemir® (Novo Nordisk) (Ml  Injection, insulin detemir (recombinant human insulin  analogue) lOOunits/mL, net price 5 x 3-mL cartridge  (for NovoPen® devices) =£42.00; 5 x 3-mL FlexPen®  prefilled disposable injection device (range 1-60 units,  allowing 1-unit dosage adjustment) = £42.00; 5x3-  mL Levemir InnoLet® prefilled disposable injection  devices (range 1-50 units, allowing 1-unit dosage  adjustment) = £44.85   • By subcutaneous injection, ADULT and CHILD over 6  years, according to requirements   Lantus® (Sanofi-Aventis) ImO  Injection, insulin glargine (recombinant human insu-  lin analogue) lOOunits/mL, net price 10-mL vial =  £26.00; 5 x 3-mL cartridge (for ClikSTAR®,  OptiPen® Pro 1, and Autopen® 24) = £39.00; 5x3-  mL OptiClik® cartridge (for OptiClik® Peri) = £40.36;  5 x 3-mL Lantus® OptiSet® prefilled disposable  injection devices (range 2-40 units, allowing 2-unit  dosage adjustment) = £39.00; 5 x 3-mL Lantus®  Solo Star® prefilled disposable injection devices  (range 1-80 units, allowing 1-unit dosage adjustment)  = £40.36   Note The Scottish Medicines Consortium (p. 4) has advised  (October 2002) that insulin glargine is accepted for restricted  use within NHS Scotland for the treatment of type 1 diabetes:   • in those who are at risk of or experience unacceptable  frequency or severity of nocturnal hypoglycaemia on  attempting to achieve better hypoglycaemic control  during treatment with other insulins   • as a once daily insulin therapy for patients who require a  carer to administer their insulin.   It is not recommended for routine use in patients with type 2  diabetes unless they suffer from recurrent episodes of  hypoglycaemia or require assistance with their insulin  injections.   A sterile neutral suspension of bovine and/or porcine insulin or  of human insulin in the form of a complex obtained by the  addition of a suitable zinc salt; consists of rhombohedral  crystals (10-40 microns) and of particles of no uniform shape  (not exceeding 2 microns)   (Isophane Insulin Injection; Isophane Prot-  amine Insulin Injection; Isophane Insulin  (NPH)— intermediate acting)   A sterile suspension of bovine or porcine insulin or of human  insulin in the form of a complex obtained by the addition of  protamine sulphate or another suitable protamine   Hepatic impairment section 6.1.1  Renal impairment section 6.1.1  Pregnancy section 6.1.1   Hypurin® Bovine Isophane (Wockhardt) 1M1  Injection, isophane insulin (bovine, highly purified)  lOOunits/mL. Net price 10-mL vial = £27.72; car-  tridges (for Autopen® Classic) 5 x 3mL =£41.58   Hypurin® Porcine Isophane (Wockhardt) tMl  Injection, isophane insulin (porcine, highly purified)  lOOunits/mL. Net price 10-mL vial = £25.20; car-  tridges (for Autopen® Classic) 5x3 mL = £37.80   Insulatard® (Novo Nordisk) (Ml  Injection, isophane insulin (human, pyr) 100 units/  mL. Net price 10-mL vial = £7.48; Insulatard Penfill®  cartridge (for Novopen® devices) 5x3 mL = £22.90;  5 x 3-mL Insulatard InnoLet® prefilled disposable  injection devices (range 1-50 units, allowing 1-unit  dosage adjustment) = £20.40   Injection, isophane insulin (human, prb) 100 units/  mL. Net price 10-mL vial = £15.68; 5 x 3-mL cartridge  (for Autopen® Classic or HumaPen®) =£19.08; 5 x  3-mL Humulin I-Pen® prefilled disposable injection  devices (range 1-60 units, allowing 1-unit dosage  adjustment) = £28.44; 5 x 3-mL Humulin IKwikPen®  prefilled disposable injection devices (range 1-  60 units, allowing 1-unit dosage adjustment) = £21.70    Insuman® Basal (Sanofi-Aventis) [Ml  Injection, isophane insulin (human, crb) 100 units/  mL, net price 5-mL vial = £5.61; 5 x 3-mL cartridge  (for ClikSTAR® and OptiPen® Pro 1) = £17.50; 5x3-  mL Insuman® Basal OptiSet® prefilled disposable  injection devices (range 2-40 units, allowing 2-unit  dosage adjustment) = £17.50   A sterile suspension of insulin in the form of a complex  obtained by the addition of a suitable protamine and zinc  chloride; this preparation was included in BP 1980 but is not  included in BP 1988   Hepatic impairment section 6.1.1  Renal impairment section 6.1.1  Pregnancy section 6.1.1   • By subcutaneous injection, up to 10 minutes before or  soon after a meal, according to requirements   NovoMix® 30 (Novo Nordisk) (S  Injection, biphasic insulin aspart (recombinant  human insulin analogue), 30% insulin aspart, 70%  insulin aspart protamine, lOOunits/mL, net price 5 x  3-mL Penfill® cartridges (for NovoPen® devices) =  £28.84; 5 x 3-mL FlexPen® prefilled disposable  injection devices (range 1-60 units, allowing 1-unit  dosage adjustment) = £32.00   Counselling Show container to patient and confirm that  patient is expecting the version dispensed; the proportions of  the two components should be checked carefully (the order  in which the proportions are stated may not be the same in  other countries)   Cautions see section 6. 1.1.1 and Insulin Lispro;  interactions: Appendix 1 (antidiabetics)   • By subcutaneous injection, up to 15 minutes before or  soon after a meal, according to requirements   Humalog® Mix25 (Lilly) (Ml  Injection, biphasic insulin lispro (recombinant human  insulin analogue), 25% insulin lispro, 75% insulin  lispro protamine, lOOunits/mL, net price 10-mL vial  = £16.61; 5 x 3-mL cartridge (for A utopen® Classic or  HumaPen ®) = £29.46; 5 x 3-mL prefilled disposable  injection devices (range 1-60 units, allowing 1-unit  dosage adjustment) = £30.98; 5 x 3-mL Humalog®  Mix25 KwikPen prefilled disposable injection devices  (range 1-60 units, allowing 1-unit dosage adjustment)  = £30.98   Counselling Show container to patient and confirm that  patient is expecting the version dispensed; the proportions of  the two components should be checked carefully (the order  in which the proportions are stated may not be the same in  other countries)   Injection, biphasic insulin lispro (recombinant human  insulin analogue), 50% insulin lispro, 50% insulin  lispro protamine, lOOunits/mL, net price 5 x 3-mL  cartridge (for Autopen® Classic or HumaPen ®) =  £29.46; 5 x 3-mL prefilled disposable injection  devices (range 1-60 units, allowing 1-unit dosage  adjustment) = £29.46; 5 x 3-mL Humalog® Mix50  KwikPen prefilled disposable injection devices (range  1-60 units, allowing 1-unit dosage adjustment) =  £30.98   Counselling Show container to patient and confirm that  patient is expecting the version dispensed; the proportions of  the two components should be checked carefully (the order  in which the proportions are stated may not be the same in  other countries)   A sterile buffered suspension of either porcine or human insulin  complexed with protamine sulphate (or another suitable prot-  amine) in a solution of insulin of the same species   Hepatic impairment section 6.1.1  Renal impairment section 6.1.1  Pregnancy section 6.1.1    ^Highly purified animal  Counselling Show container to patient and confirm that  patient is expecting the version dispensed; the proportions of  the two components should be checked carefully (the order  in which the proportions are stated may not be the same in  other countries)    Hypurin® Porcine 30/70 Mix (Wockhardt) (Ml  Injection, biphasic isophane insulin (porcine, highly  purified), 30% soluble, 70% isophane, lOOunits/mL.  Net price 10-mL vial = £16.80; cartridges ( for Autop-  en® Classic) 5x3 mL = £25.20   Counselling Show container to patient and confirm that  patient is expecting the version dispensed; the proportions of  the two components should be checked carefully (the order  in which the proportions are stated may not be the same in  other countries)   Injection, biphasic isophane insulin (human, prb),  30% soluble, 70% isophane, lOOunits/mL. Net price  10-mL vial = £15.68; 5 x 3-mL cartridge (for most  Autopen® Classic or HumaPen®) =£19.08; 5 x 3-mL  Humulin M3 KwikPen® prefilled disposable injection  devices (range 1-60 units, allowing 1-unit dosage  adjustment) = £21.70   Insuman® Comb 15 (Sanofi-Aventis) (Ml  Injection, biphasic isophane insulin (human, crb),  15% soluble, 85% isophane, lOOunits/mL, net price 5  x 3-mL Insuman® Comb 15 OptiSet® prefilled  disposable injection devices (range 2-40 units, allow-  ing 2-unit dosage adjustment) = £17.50   Injection device, Autopen ® 24 (for use with Sanofi-Aventis  3-mL insulin cartridges), allowing 1-unit dosage adjustment,  max. 21 units (single-unit version) or 2-unit dosage adjust-  ment, max. 42 units (2-unit version), net price (both) =  £15.73; Autopen® Classic (for use with Lilly and Wockhardt  3-mL insulin cartridges), allowing 1-unit dosage adjustment,  max. 21 units (single-unit version) or 2-unit dosage adjust-  ment, max. 42 units (2-unit version), net price (all) = £15.97   Injection device, for use with Lantus®, Apidra®, and  Insuman® 3-mL insulin cartridges; allowing 1-unit  dose adjustment, max. 80 units, net price = £25.00   Injection device, for use with Humulin ® and Humalog ® 3-  mL cartridges; allowing 1-unit dosage adjustment, max.   Injection device, for use with Humulin ® and Humalog ® 3-  mL cartridges; allowing 0.5-unit dosage adjustment, max.   Injection device; for use with Penfill ® insulin cartridges;  NovoPen ® Junior (for 3-mL cartridges), allowing 0.5-unit  dosage adjustment, max. 35 units, net price = £24.79;  NovoPen ® 3 Demi (for 3-mL cartridges), allowing 0.5-unit  dosage adjustment, max. 35 units, net price = £25.21;  NovoPen ® 4 (for 3-mL cartridges), allowing 1-unit dosage  adjustment, max. 60 units, net price = £26.56   Injection device, for use with Lantus OptiClik® or Apidra  Opticlik® insulin cartridges, allowing 1-unit dosage adjust-  ment, max. 80 units, net price = £20.13   Injection device, for use with Insuman® insulin cartridges;  allowing 1-unit dosage adjustment, max. 60 units, net price =  £ 22.00    Insuman® Comb 25 (Sanofi-Aventis) (5°M1  Injection, biphasic isophane insulin (human, crb),  25% soluble, 75% isophane, lOOunits/mL, net price  5-mL vial = £5.61; 5 x 3-mL cartridge (for ClikSTAR®  and OptiPen® Pro 1) = £17.50; 5 x 3-mL Insuman®  Comb 25 OptiSet® prefilled disposable injection  devices (range 2-40 units, allowing 2-unit dosage  adjustment) = £17.50; 5 x 3-mL Insuman® Comb 25  SoloStar ® prefilled disposable injection devices  (range 1-80 units, allowing 1-unit dosage adjustment)  = £19.80   Insuman® Comb 50 (Sanofi-Aventis) (5°M1  Injection, biphasic isophane insulin (human, crb),  50% soluble, 50% isophane, lOOunits/mL, net price 5  x 3-mL cartridge (for ClikSTAR® and OptiPen® Pro  1) = £17.50; 5 x 3-mL Insuman® Comb 50 OptiSet®  prefilled disposable injection devices (range 2-  40 units, allowing 2-unit dosage adjustment) = £17.50   Patients should be advised on the safe disposal of  lancets, single-use syringes, and needles. Suitable  arrangements for the safe disposal of contaminated  waste must be made before these products are pre-  scribed for patients who are carriers of infectious dis-  eases.   1 Ascensia Microlet® 100 = £3.76, 200 = £7.17; BD Micro-  Fine® + 100 = £3.16, 200 = £6.13; CareSens® 100 = £2.95;  Cleanlet Fine® 100 = £3.19, 200 = £6.13; Fastclix® 204 =  £9.20; 1 Finepoint® 100 = £3.54; 1 FreeStyle® 200 = £7.02;  1 Milward Steri-Let®, 23 gauge, 100 = £3.00, 200 = £5.70, 28  gauge, 100 =£3.00, 200 = £5.70; l Monole1® 100 =£3.28, 200  = £6.24; Monolet Extra® 100 = £3.28; MPD Ultra Thin® 100  = £3.30, 200 = £6.50; Multiclix® 204 = £9.27; One Touch  Comfort® 200 = £7.22; 1 One Touch UltraSoft® 100 =£3.61;  2 SoftclixP 200 = £7.40; 2 SoftclixXL® 50 = £1.85; Thin  Lancets (formerly MediSense Thin®), 200 = £7.16; 1 Unilet  ComforTouch® 100 = £3.60, 200 = £6.83; Unilet Eco® 100 =  £2.94, 200 = £5.49; 1 Unilet General Purpose Superlite ® 100  = £3.67, 200 = £6.96; Unistik 3 Comfort®, 28-gauge, 100 =  £6.24, 200 =£12.20; Unistik 3 Extra® , 21-gauge, 100 =£6.24,  200 = £12.20; Unistik 3 Normal®, 23-gauge, 100 = £6.24,  200 = £12.20; Universal® (formerly VitalCare®), 200 =  £6.37; Vitrex Soft®, 23-gauge, 100 = £3.00, 200 = £5.70;  Vitrex Gentle® 28-gauge, 100 = £3.19, 200 = £6.13;   Wave Sense Ultra-Thin® , 28-gauge, 200 = £6.90, 33-gauge,  200 = £6.90   Compatible finger-pricking devices (unless indicated otherwise,  see footnotes), all B-D Optimus ®, Glucolet ®, Monojector® ,   1. [SHH Auto let® and (SHH Autolet Impression® are also  compatible finger-pricking devices   For use with reusable glass syringe, sizes 0.5 mm (25G),  0.45 mm (26G), 0.4 mm (27G). Net price 100-needle pack =  £2.74   Screw on, needle length 6.1 mm or less, net price 100-needle  pack = £12.53; 6. 2-9. 9 mm, 100-needle pack = £8.89; 10 mm  or more, 100-needle pack = £8.89   Brands include BD Micro-Fine 9 +, Novo Fine ®, NovoTwist® ,  Unifine ® Pentips   Snap on, needle length 6.1 mm or less, net price 100-needle  pack = £12.02; 6. 2-9. 9 mm, 100-needle pack = £8.52; 10 mm  or more, 100-needle pack = £8.52  Brands include Penfine ®   U100 Insulin Syringe with Needle (Drug Tariff)  Disposable with fixed or separate needle for single use or  single patient-use, colour coded orange. Needle length 8 mm,  diameters 0.33 mm (29G), 0.3 mm (30G), net price 10 (with  needle), 0.3 mL = £1.38, 0.5 mL = £1.33, 1 mL = £1.32; needle  length 12 mm, diameters 0.45 mm (26G), 0.4 mm (27G),  0.36 mm (28G), 0.33 mm (29G), net price 10 (with needle),  0.3 mL = £1.45; 0.5 mL = £1.43; 1 mL = £1.44  Brands include BD Micro-Fine 9 +, Clinipak 9 , Insupak 9 , Mono-  ject 9 Ultra, Omnikan 9 , Plastipak 9   Needle Clipping (Chopping) Device (Drug Tariff)  Consisting of a clipper to remove needle from its hub and  container from which cut-off needles cannot be retrieved;  designed to hold 1500 needles, not suitable for use with  lancets. Net price = £1.35  Brands include BD Safe-Clip 9   Oral antidiabetic drugs are used for the treatment of  type 2 diabetes mellitus. They should be prescribed only  if the patient fails to respond adequately to at least 3  months’ restriction of energy and carbohydrate intake  and an increase in physical activity. They should be used  to augment the effect of diet and exercise, and not to  replace them.   For patients not adequately controlled by diet and oral  hypoglycaemic drugs, insulin may be added to the  treatment regimen or substituted for oral therapy.  When insulin is added to oral therapy, it is generally  given at bedtime as isophane or long-acting insulin, and  when insulin replaces an oral regimen it may be given as  twice-daily injections of a biphasic insulin (or isophane  insulin mixed with soluble insulin), or a multiple injec-  tion regimen. Weight gain and hypoglycaemia may be  complications of insulin therapy but weight gain may be  reduced if the insulin is given in combination with met-  formin.   Exenatide and liraglutide, both given by subcutaneous  injection, are also available for the treatment of type 2  diabetes, see section 6.1. 2. 3.   Pregnancy and breast-feeding During pregnancy,  women with pre-existing diabetes can be treated with  metformin [unlicensed use], either alone or in combina-  tion with insulin (section 6.1.1). Metformin can be  continued, or glibenclamide resumed, during breast-  feeding for those with pre-existing diabetes. Women  with gestational diabetes may be treated, with or with-  out concomitant insulin (section 6.1.1), with gliben-  clamide from 1 1 weeks gestation (after organogenesis)  [unlicensed use] or with metformin [unlicensed use].  Women with gestational diabetes should discontinue  hypoglycaemic treatment after giving birth.   Other oral hypoglycaemic drugs, exenatide, and liraglu-  tide are contra-indicated in pregnancy.   The sulfonylureas act mainly by augmenting insulin  secretion and consequently are effective only when  some residual pancreatic beta-cell activity is present;  during long-term administration they also have an  extrapancreatic action. All may cause hypoglycaemia  but this is uncommon and usually indicates excessive  dosage. Sulfonylurea-induced hypoglycaemia may per-  sist for many hours and must always be treated in  hospital.   Sulfonylureas are considered for patients who are not  overweight, or in whom metformin is contra-indicated  or not tolerated. Several sulfonylureas are available and  choice is determined by side-effects and the duration of  action as well as the patient’s age and renal function.  Glibenclamide, a long-acting sulfonylurea, is associated  with a greater risk of hypoglycaemia; for this reason it  should be avoided in the elderly, and shorter-acting  alternatives, such as gliclazide or tolbutamide, should  be used instead.   When the combination of strict diet and sulfonylurea  treatment fails, other options include:   • combining with saxagliptin, sitagliptin, or vildaglip-  tin (section 6. 1.2. 3);   • combining with acarbose (section 6. 1.2.3), which  may have a small beneficial effect, but flatulence  can be a problem;   • combining with bedtime isophane insulin (section  6.1.1) but weight gain and hypoglycaemia can  occur.   The risk of hypoglycaemia associated with sulfonylureas  (see notes above) should be discussed with the patient,  especially when concomitant glucose-lowering drugs  are prescribed.   Insulin therapy should be instituted temporarily during  intercurrent illness (such as myocardial infarction,  coma, infection, and trauma). Sulfonylureas should be    omitted on the morning of surgery; insulin is required  because of the ensuing hyperglycaemia in these circum-  stances.   Cautions Sulfonylureas can encourage weight gain  and should be prescribed only if poor control and  symptoms persist despite adequate attempts at dieting;  metformin (section 6. 1.2. 2) is considered the drug of  choice in obese patients. Caution is needed in the  elderly.   Contra-indications Sulfonylureas should be avoided  where possible in acute porphyria (section 9.8.2). Sulfo-  nylureas are contra-indicated in the presence of keto-  acidosis.    Hepatic impairment Sulfonylureas should be avoided  or a reduced dose should be used in severe hepatic  impairment, because there is an increased risk of hypo-  glycaemia. Jaundice may occur.   Renal impairment Sulfonylureas should be used with  care in those with mild to moderate renal impairment,  because of the hazard of hypoglycaemia; they should be  avoided where possible in severe renal impairment.  Glipizide should also be avoided if the patient has  both renal and hepatic impairment. If necessary, the  short-acting drug tolbutamide can be used in renal  impairment, as can gliclazide which is principally meta-  bolised in the liver, but careful monitoring of blood-  glucose concentration is essential; care is required to  use the lowest dose that adequately controls blood  glucose.   Pregnancy The use of sulfonylureas in pregnancy  should generally be avoided because of the risk of neo-  natal hypoglycaemia; however, glibenclamide can be  used during the second and third trimesters of  pregnancy in women with gestational diabetes, see  section 6.1.2.    Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above   • Initially 5 mg daily with or immediately after break-  fast, dose adjusted according to response (ELDERLY  avoid, see notes above); max. 15 mg daily   Glibenclamide (Non-proprietary) [Ml  Tablets, glibenclamide 2.5 mg, net price 28-tab pack  = 95p; 5 mg, 28-tab pack = £1.07   • Initially, 40-80 mg daily, adjusted according to  response; up to 160 mg as a single dose, with break-  fast; higher doses divided; max. 320 mg daily   Gliclazide (Non-proprietary) Ml  Tablets, scored, gliclazide 80 mg, net price 28-tab  pack = £1.10, 60-tab pack = £1.52  Brands include DIAGLYK®   Diamicron® (Servier) M  Tablets, scored, gliclazide 80 mg, net price 60-tab  pack = £4.38    Breast-feeding The use of sulfonylureas (except  glibenclamide [unlicensed use], see section 6.1.2) in  breast-feeding should be avoided because there is a  theoretical possibility of hypoglycaemia in the infant.   Side-effects Side-effects of sulfonylureas are gener-  ally mild and infrequent and include gastro-intestinal  disturbances such as nausea, vomiting, diarrhoea, and  constipation. Hyponatraemia has been reported with  glimepiride and glipizide.   Sulfonylureas can occasionally cause a disturbance in  liver function, which may rarely lead to cholestatic  jaundice, hepatitis, and hepatic failure. Hypersensitivity  reactions can occur, usually in the first 6-8 weeks of  therapy. They consist mainly of allergic skin reactions  which progress rarely to erythema multiforme and  exfoliative dermatitis, fever, and jaundice; photosensit-  ivity has rarely been reported with glipizide. Blood  disorders are also rare but may include leucopenia,  thrombocytopenia, agranulocytosis, pancytopenia,  haemolytic anaemia, and aplastic anaemia.   Indications type 2 diabetes mellitus  Cautions see notes above; interactions: Appendix 1  (antidiabetics)   Diamicron® MR (Servier) Ml  Tablets, m/r, gliclazide 30 mg, net price 28-tab pack =  £2.81, 56-tab pack = £5.62. Label: 25  Dose initially 30 mg daily with breakfast, adjusted according to  response every 4 weeks (after 2 weeks if no decrease in blood  glucose); max. 120 mg daily   Note Diamicron ® MR 30 mg may be considered to be  approximately equivalent in therapeutic effect to standard  formulation Diamicron ® 80 mg   Indications type 2 diabetes mellitus  Cautions see notes above; manufacturer recommends  regular hepatic and haematological monitoring but  limited evidence of clinical value; interactions:  Appendix 1 (antidiabetics)   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • Initially 1 mg daily, adjusted according to response in  1-mg steps at 1-2 week intervals; usual max. 4 mg  daily (exceptionally, up to 6 mg daily may be used);  taken shortly before or with first main meal   Tablets, glimepiride 1 mg, net price 30-tab pack =  £1.40; 2 mg, 30-tab pack = £1.38; 3 mg, 30-tab pack =  £4.57; 4 mg, 30-tab pack = £1.75   Amaryl® (Sanofi-Aventis) [Ml  Tablets, all scored, glimepiride 1 mg (pink), net price  30-tab pack = £4.33; 2 mg (green), 30-tab pack =  £7.13; 3 mg (yellow), 30-tab pack = £10.75; 4 mg  (blue), 30-tab pack = £14.24   • Initially 2.5-5 mg daily shortly before breakfast or  lunch, adjusted according to response; max. 20 mg  daily; up to 15 mg may be given as a single dose;  higher doses divided   Glipizide (Non-proprietary) (MO  Tablets, glipizide 5 mg, net price 56-tab pack = £4.23   Minodiab® (Pharmacia) (Ml  Tablets, scored, glipizide 5 mg, net price 28-tab pack  = £1.26   • 0.5-1. 5 g (max. 2 g) daily in divided doses with or  immediately after meals or as a single dose with or  immediately after breakfast   Tolbutamide (Non-proprietary) (Ml  Tablets, tolbutamide 500 mg, net price 28-tab pack =  £1.74    Metformin, the only available biguanide, has a different  mode of action from the sulfonylureas, and is not inter-  changeable with them. It exerts its effect mainly by  decreasing gluconeogenesis and by increasing periph-  eral utilisation of glucose; since it acts only in the  presence of endogenous insulin it is effective only if    Metformin is the drug of first choice in overweight  patients in whom strict dieting has failed to control  diabetes, if appropriate it may also be considered as  an option in patients who are not overweight. It is also  used when diabetes is inadequately controlled with  sulfonylurea treatment. When the combination of strict  diet and metformin treatment fails, other options  include:    • combining with a sulfonylurea (section 6. 1.2.1)  (reports of increased hazard with this combination  remain unconfirmed);   • combining with saxagliptin, sitagliptin, or vildaglip-  tin (section 6. 1.2. 3);   • combining with acarbose (section 6. 1.2. 3), which  may have a small beneficial effect, but flatulence  can be a problem;   • combining with insulin (section 6.1.1) but weight  gain and hypoglycaemia can be problems (weight  gain minimised if insulin given at night).    Insulin treatment is almost always required in medical  and surgical emergencies; insulin should also be sub-  stituted before elective surgery (omit metformin on the  morning of surgery and give insulin if required).  Hypoglycaemia does not usually occur with metformin;  other advantages are the lower incidence of weight gain  and lower plasma-insulin concentration. It does not  exert a hypoglycaemic action in non-diabetic subjects  unless given in overdose.   Gastro-intestinal side-effects are initially common with  metformin, and may persist in some patients, particu-  larly when very high doses such as 3 g daily are given.    Very rarely, metformin can provoke lactic acidosis. It is  most likely to occur in patients with renal impairment,  see Lactic Acidosis below.    Metformin is used for the symptomatic management of  polycystic ovary syndrome [unlicensed indication];  however, treatment should be initiated by a specialist.  Metformin improves insulin sensitivity, may aid weight  reduction, helps to normalise menstrual cycle (increas-  ing the rate of spontaneous ovulation), and may  improve hirsutism.   Indications diabetes mellitus (see notes above); poly-  cystic ovary syndrome [unlicensed indication]  Cautions see notes above; determine renal function  before treatment and at least annually (at least twice a  year in patients with additional risk factors for renal  impairment, or if deterioration suspected); interac-  tions: Appendix 1 (antidiabetics)   Lactic acidosis Use with caution in renal impairment —  increased risk of lactic acidosis; avoid in significant renal  impairment. NICE 1 recommends that the dose should be  reviewed if eGFR less than 45 mL/minute/ 1.73 m 2 and to    avoid if eGFR less than 30 mL/minute/ 1.73 m 2 . Withdraw or  interrupt treatment in those at risk of tissue hypoxia or  sudden deterioration in renal function, such as those with  dehydration, severe infection, shock, sepsis, acute heart  failure, respiratory failure or hepatic impairment, or those  who have recently had a myocardial infarction  Contra-indications ketoacidosis, see also Lactic Aci-  dosis above; use of general anaesthesia (suspend  metformin on the morning of surgery and restart  when renal function returns to baseline)  Iodine-containing X-ray contrast media Intravascular  administration of iodinated contrast agents can cause renal  failure. Suspend metformin prior to the test; restart at least  48 hours after the test if renal function has returned to  baseline   Side-effects anorexia, nausea, vomiting, diarrhoea  (usually transient), abdominal pain, taste disturbance,  rarely lactic acidosis (withdraw treatment), decreased  vitamin-B 12 absorption, erythema, pruritus and urti-  caria; hepatitis also reported  Dose   • Diabetes mellitus, ADULT and CHILD over 10 years  initially 500 mg with breakfast for at least 1 week then  500 mg with breakfast and evening meal for at least 1  week then 500 mg with breakfast, lunch and evening  meal; usual max. 2 g daily in divided doses   • Polycystic ovary syndrome [unlicensed], initially  500 mg with breakfast for 1 week, then 500 mg with  breakfast and evening meal for 1 week, then 1.5— 1.7 g  daily in 2-3 divided doses   Note Metformin doses in the BNF may differ from those in the  product literature    Metformin (Non-proprietary) (Ml  Tablets, coated, metformin hydrochloride 500 mg, net  price 28-tab pack = £1.07, 84-tab pack = £1.57;   850 mg, 56-tab pack = £1.67. Label: 21  Oral solution, sugar-free, metformin hydrochloride  500 mg/5 mL, net price 100 mL = £62.48. Label: 21  Brands include Metsol ®   Tablets, f/c, metformin hydrochloride 500 mg, net  price 84-tab pack = £2.88; 850 mg, 56-tab pack =  £3.20. Label: 21   Oral powder, sugar-free, metformin hydrochloride  500 mg/sachet, net price 30-sachet pack = £3.29, 60-  sachet pack = £6.58; 1 g/sachet, 30-sachet pack =  £6.58, 60-sachet pack = £13.16. Label: 13, 21, coun-  selling, administration   use within NHS Scotland for the treatment of type 2 diabetes   mellitus in patients who are unable to swallow the solid dosage   Tablets, m/r, metformin hydrochloride 500 mg, net  price 28 tab-pack = £3.07, 56 tab-pack = £6.14.  Label: 21, 25   Dose initially 500 mg once daily, increased every 10-15 days,  max. 2 g once daily with evening meal; if control not achieved, use    1 g twice daily with meals, and if control still not achieved change  to standard-release tablets   Note Patients taking up to 2 g daily of the standard-release met-  formin may start with the same daily dose of metformin modified  release; not suitable if dose of standard-release tablets more than   Glucophage® SR (Merck Serono) (Ml  Tablets, m/r, metformin hydrochloride 500 mg, net  price 28-tab pack = £3.07, 56-tab pack = £6.14;   750 mg, 28-tab pack = £3.20, 56-tab pack = £6.40; 1 g,  28-tab pack = £4.26, 56-tab pack = £8.52. Label: 21,  25   Dose initially 500 mg once daily, increased every 10-15 days,  max. 2 g once daily with evening meal; if control not achieved, use  1 g twice daily with meals, and if control still not achieved change  to standard-release tablets   Note Patients taking up to 2 g daily of the standard-release met-  formin may start with the same daily dose of Glucophage ® SR;  not suitable if dose of standard-release tablets more than 2 g daily  The Scottish Medicines Consortium (p. 4) has advised (September  2009) that Glucophage ® SR is accepted for restricted use within  NHS Scotland for the treatment of type 2 diabetes mellitus in adult  patients who are intolerant of standard-release metformin, and in  whom the prolonged-release tablet allows the use of a dose of  metformin not previously tolerated, or in patients for whom a  once daily preparation offers a clinically significant benefit.    Acarbose, an inhibitor of intestinal alpha glucosidases,  delays the digestion and absorption of starch and suc-  rose; it has a small but significant effect in lowering  blood glucose. Use of acarbose is usually reserved for  when other oral hypoglycaemics are not tolerated or are  contra-indicated. Postprandial hyperglycaemia in type 1  diabetes can be reduced by acarbose, but it has been  little used for this purpose. Flatulence deters some from  using acarbose although this side-effect tends to  decrease with time.    Nateglinide and repaglinide stimulate insulin release.  Both drugs have a rapid onset of action and short  duration of activity, and should be administered shortly  before each main meal. Repaglinide may be given as  monotherapy for patients who are not overweight or for  those in whom metformin is contra-indicated or not  tolerated, or it may be given in combination with met-  formin. Nateglinide is licensed only for use with met-  formin.    The thiazolidinedione, pioglitazone, reduces peripheral  insulin resistance, leading to a reduction of blood-glu-  cose concentration. Pioglitazone can be used alone or in  combination with metformin or with a sulfonylurea (if  metformin inappropriate), or with both; the combination  of pioglitazone plus metformin is preferred to pioglita-  zone plus sulfonylurea, particularly for obese patients.  Inadequate response to a combination of metformin and  sulfonylurea may indicate failing insulin release; the  introduction of pioglitazone has a limited role in these  circumstances and the initiation of insulin is often more  appropriate. Pioglitazone is also licensed in combination    with insulin, in patients who have not achieved ade-  quate glycaemic control with insulin alone, when met-  formin is inappropriate. Blood-glucose control may  deteriorate temporarily when pioglitazone is substituted  for an oral antidiabetic drug that is being used in  combination with another. Long-term benefits of piogli-  tazone have not yet been demonstrated. NICE (May  2009) has recommended that, when glycaemic control  is inadequate with existing treatment, pioglitazone can  be added to:   • a combination of metformin and a sulfonylurea, if  insulin is unacceptable because of lifestyle or other  personal issues, or because the patient is obese.   NICE has recommended that treatment with pioglita-  zone is continued only if HbA lc concentration is reduced  by at least 0.5% within 6 months of starting treatment.   The Scottish Medicines Consortium (p. 4) accepts use of  pioglitazone (February 2007) with metformin and a  sulfonylurea, for patients (especially if overweight)  whose glycaemic control is inadequate despite the use  of 2 oral hypoglycaemic drugs and who are unable or  unwilling to take insulin; treatment should be initiated  and monitored by an experienced diabetes physician.   Incidence of heart failure is increased when piogli-  tazone is combined with insulin especially in  patients with predisposing factors e.g. previous myo-  cardial infarction. Patients who take pioglitazone  should be closely monitored for signs of heart fail-  ure; treatment should be discontinued if any dete-  rioration in cardiac status occurs.   Pioglitazone should not be used in patients with  heart failure or a history of heart failure.   The marketing authorisation for rosiglitazone  ( Avandia ®, Avandamet®) has been suspended  (September 2010) following a review by the  European Medicines Agency. The European Medi-  cines Agency concluded that the benefits of  rosiglitazone treatment do not outweigh the cardi-  ovascular risks. Prescribers should not issue new or  repeat prescriptions for rosiglitazone. Treatment of  patients who are taking rosiglitazone should be  reviewed.    Saxagliptin, sitagliptin, and vildagliptin inhibit dipep-  tidylpeptidase-4 to increase insulin secretion and lower  glucagon secretion. They are licensed for use in type 2  diabetes in combination with metformin or a sulfonylur-  ea (if metformin inappropriate) or pioglitazone, when  treatment with either metformin or a sulfonylurea or  pioglitazone fails to achieve adequate glycaemic con-  trol. Sitagliptin is also licensed for use as monotherapy  (if metformin inappropriate), or in combination with  both metformin and a sulfonylurea, or both metformin  and pioglitazone when dual therapy with these drugs  fails to achieve adequate glycaemic control. The com-    bination of sitagliptin and insulin (with or without met-  formin) is also licensed for use when a stable dose of  insulin has not provided adequate glycaemic control.  NICE (May 2009) has recommended that, when glycae-  mic control is inadequate with existing treatment:   • sitagliptin or vildagliptin (instead of a sulfonylurea)  can be added to metformin, if there is a significant  risk of hypoglycaemia or if a sulfonylurea is contra-  indicated or not tolerated;   • sitagliptin or vildagliptin can be added to a sulfo-  nylurea, if metformin is contra-indicated or not  tolerated;   • sitagliptin can be added to both metformin and a  sulfonylurea, if insulin is unacceptable because of  lifestyle or other personal issues, or because the  patient is obese.   NICE has recommended that treatment with sitagliptin  or vildagliptin is continued only if HbA lc concentration  is reduced by at least 0.5% within 6 months of starting  treatment.   The Scottish Medicines Consortium (p. 4) has advised  that vildagliptin ( Galvus ®) is accepted for restricted use  within NHS Scotland for the treatment of type 2  diabetes mellitus in combination with metformin when  addition of a sulfonylurea is inappropriate (March 2008),  and also in combination with a sulfonylurea if metformin  is inappropriate (September 2009).    NICE (May 2009) has recommended that, when glycae-  mic control is inadequate with metformin and sulfony-  lurea treatment, the addition of exenatide may be con-  sidered if the patient has:   • a body mass index of 35 kg/m 2 or over and is of  European descent (with appropriate adjustment for  other ethnic groups) and weight-related psycholo-  gical or medical problems or   • a body mass index less than 35 kg/m 2 , and insulin  would be unacceptable for occupational reasons or  weight loss would benefit other significant obesity-  related comorbidities.   NICE has recommended that treatment with exenatide  is continued only if HbA lc concentration is reduced by at  least 1% and a weight loss of at least 3% is achieved  within 6 months of starting treatment.   The Scottish Medicines Consortium (p. 4) has advised  (June 2007) that exenatide ( Byetta ®) is accepted for  restricted use within NHS Scotland for the treatment of  type 2 diabetes in combination with metformin or  sulfonylurea (or both), as an alternative to treatment  with insulin in patients where treatment with metformin  or sulfonylurea (or both) at maximally tolerated doses    Exenatide and liraglutide both bind to, and activate,  the GLP-1 (glucagon-like peptide- 1) receptor to increase  insulin secretion, suppress glucagon secretion, and slow  gastric emptying. Treatment with exenatide and liraglu-  tide is associated with the prevention of weight gain and  possible promotion of weight loss which can be bene-  ficial in overweight patients. They are both given by  subcutaneous injection for the treatment of type 2 dia-  betes mellitus.   Exenatide is licensed in combination with metformin or  a sulfonylurea, or both, or with pioglitazone, or with  both metformin and pioglitazone, in patients who have  not achieved adequate glycaemic control with these  drugs alone or in combination.    has been inadequate, and treatment with insulin would  be the next option.   Liraglutide is licensed for the treatment of type 2 dia-  betes mellitus in combination with metformin or a  sulfonylurea, or both, in patients who have not achieved  adequate glycaemic control with these drugs alone or in  combination. Liraglutide is also licensed for use in  combination with both metformin and pioglitazone  when dual therapy with these drugs fails to achieve  adequate glycaemic control.   Liraglutide for the treatment of type 2  diabetes mellitus (October 2010)   Liraglutide in triple therapy regimens (in combina-  tion with metformin and a sulfonylurea, or met-  formin and a thiazolidinedione) is recommended  for the treatment of type 2 diabetes, only when  glycaemic control is inadequate, and the patient has:   • a body mass index of 35 kg/m 2 or over and is of  European descent (with appropriate adjustment  for other ethnic groups) and weight-related psy-  chological or medical problems, or   • a body mass index of less than 35kg/m z , and  insulin would be unacceptable for occupational  reasons or weight loss would benefit other sig-  nificant obesity-related comorbidities.   Treatment with liraglutide in a triple therapy regi-  men should be continued only if HbA lc concentra-  tion is reduced by at least 1% and a weight loss of at  least 3% is achieved within 6 months of starting  treatment.   Liraglutide in dual therapy regimens (in combination  with metformin or a sulfonylurea) is recommended  only if:   • treatment with metformin or a sulfonylurea is  contra-indicated or not tolerated, and   • treatment with thiazolidinediones and dipepti-  dylpeptidase-4 inhibitors is contra-indicated or  not tolerated.   Liraglutide, in combination with metformin or a  sulfonylurea should be continued only if HbA lc con-  centration is reduced by at least 1% within 6 months  of starting treatment.   Indications diabetes mellitus inadequately controlled  by diet or by diet with oral antidiabetic drugs  Cautions monitor liver function; may enhance hypo-  glycaemic effects of insulin and sulfonylureas (hypo-  glycaemic episodes may be treated with oral glucose  but not with sucrose); interactions: Appendix 1  (antidiabetics)   Contra-indications inflammatory bowel disease, pre-  disposition to partial intestinal obstruction; hernia,  previous abdominal surgery   Hepatic impairment avoid  Renal impairment avoid if eGFR less than 25 mL/  minute/ 1.73 m 2  Pregnancy avoid  Breast-feeding avoid   Side-effects flatulence, soft stools, diarrhoea (may  need to reduce dose or withdraw), abdominal dis-    tention and pain; rarely, nausea, abnormal liver  function tests and skin reactions; very rarely ileus,  oedema, jaundice, and hepatitis  Note Antacids unlikely to be beneficial for treating side-  effects  Dose   • ADULT over 18 years, initially 50 mg daily increased to  50 mg 3 times daily, then increased if necessary after  6-8 weeks to 100 mg 3 times daily; max. 200 mg 3  times daily   Counselling Tablets should be chewed with first mouthful of  food or swallowed whole with a little liquid immediately  before food. To counteract possible hypoglycaemia, patients  receiving insulin or a sulfonylurea as well as acarbose need  to carry glucose (not sucrose — acarbose interferes with  sucrose absorption)   Glucobay® (Bayer Schering) tMl  Tablets, acarbose 50 mg, net price 90-tab pack =  £6.15; 100 mg (scored), 90-tab pack = £11.35. Coun-  selling, administration   Pancreatitis Severe pancreatitis (sometimes fatal), includ-  ing haemorrhagic or necrotising pancreatitis, has been  reported rarely. Patients or their carers should be told how to  recognise signs and symptoms of pancreatitis and advised to  seek prompt medical attention if symptoms such as abdo-  minal pain, nausea, and vomiting develop; discontinue per-  manently if pancreatitis is diagnosed   Renal impairment use with caution if eGFR 30-  50 mL/minute/ 1.73 m 2 ; avoid if eGFR less than  30 mL/minute/ 1.73m 2   Side-effects gastro-intestinal disturbances including  nausea, vomiting, diarrhoea, dyspepsia, abdominal  pain and distension, gastro-oesophageal reflux dis-  ease, decreased appetite; headache, dizziness, agita-  tion, asthenia; hypoglycaemia; increased sweating,  injection-site reactions; antibody formation; less  commonly pancreatitis (see Cautions above); very  rarely anaphylactic reactions; also reported consti-  pation, flatulence, eructation, dehydration, taste dis-  turbance, renal impairment, drowsiness, rash, pru-  ritus, urticaria, and angioedema   • By subcutaneous injection, ADULT over 18 years,  initially 5 micrograms twice daily within 1 hour before  2 main meals (at least 6 hours apart), increased if  necessary after at least 1 month to max. 10 micr-  ograms twice daily   Counselling If a dose is missed, continue with the next  scheduled dose — do not administer after a meal. Some oral  medications should be taken at least 1 hour before or 4 hours  after exenatide injection — consult product literature for  details   Injection, exenatide 250micrograms/mL, net price  5 microgram/dose prefilled pen (60 doses) = £68.24,  10 microgram/ dose prefilled pen (60 doses) = £68.24.  Counselling, administration   Cautions discontinue if symptoms of acute pancreat-  itis (persistent, severe abdominal pain); interactions:  Appendix 1 (antidiabetics)   Contra-indications ketoacidosis; inflammatory bowel  disease; diabetic gastroparesis  Hepatic impairment avoid — limited experience  Renal impairment avoid if eGFR less than 60 mL/  minute/ 1.73 m 2 — limited experience  Pregnancy avoid — toxicity in animal studies  Breast-feeding avoid — no information available  Side-effects gastro-intestinal disturbances including  nausea, vomiting, constipation, diarrhoea, dyspepsia,  abdominal pain and distension, flatulence, gastritis,  gastro-oesophageal reflux disease, decreased appe-  tite; headache, dizziness, fatigue; fever, bronchitis,  nasopharyngitis; hypoglycaemia; injection site reac-  tions; also reported acute pancreatitis, thyroid neo-  plasm, goitre, increased blood calcitonin, angioedema  Dose   • By subcutaneous injection, ADULT over 18 years,  initially 0.6 mg once daily, increased after at least 1  week to 1.2 mg once daily, further increased if  necessary after an interval of at least 1 week to max.  1.8 mg once daily   Victoza® (Novo Nordisk) ▼ (Ml  Injection, liraglutide 6mg/mL, net price 2 x 3-mL  prefilled pens = £78.48, 3 x 3-mL prefilled pens =  £117.72. Counselling, administration    Indications type 2 diabetes mellitus (alone or com-  bined with metformin or a sulfonylurea, or with both,  or with insulin — see also notes above)   Cautions monitor liver function (see below); cardio-  vascular disease or in combination with insulin (risk of  heart failure — see MHRA/CHM advice p. 431); sub-  stitute insulin during peri-operative period (omit pio-  glitazone on morning of surgery and recommence  when eating and drinking normally); increased risk of  bone fractures, particularly in women; avoid in acute  porphyria (but see section 9.8.2); interactions:  Appendix 1 (antidiabetics)   Liver toxicity Rare reports of liver dysfunction; monitor  liver function before treatment, and periodically thereafter;  advise patients to seek immediate medical attention if  symptoms such as nausea, vomiting, abdominal pain, fatigue  and dark urine develop; discontinue if jaundice occurs  Contra-indications history of heart failure  Hepatic impairment avoid; see also Cautions above  Pregnancy avoid — toxicity in animal studies  Breast-feeding avoid — present in milk in animal  studies   Side-effects gastro-intestinal disturbances, weight  gain, oedema, anaemia, headache, visual distur-  bances, dizziness, arthralgia, hypoaesthesia, haema-  turia, impotence; less commonly hypoglycaemia,  fatigue, insomnia, vertigo, sweating, altered blood  lipids, proteinuria; see also Liver Toxicity above  Dose    • ADULT over 18 years, initially 15-30 mg once daily  increased to 45 mg once daily according to response  Note Dose of concomitant sulfonylurea or insulin may need  to be reduced   Tablets, pioglitazone (as hydrochloride) 15 mg, net  price 28-tab pack = £25.83; 30 mg, 28-tab pack =  £35.89; 45 mg, 28-tab pack = £39.55    Indications type 2 diabetes mellitus in combination  with metformin (section 6. 1.2.2) when metformin  alone inadequate   Cautions substitute insulin during intercurrent illness  (such as myocardial infarction, coma, infection, and  trauma) and during surgery (omit nateglinide on  morning of surgery and recommence when eating and  drinking normally); elderly, debilitated and malnour-  ished patients; interactions: Appendix 1 (anti-  diabetics)   • ADULT over 18 years, initially 60 mg 3 times daily  within 30 minutes before main meals, adjusted  according to response up to max. 180 mg 3 times daily   Tablets, f/c, nateglinide 60 mg (pink), net price 84-tab  pack = £22.71; 120 mg (yellow), 84-tab pack = £25.88;  180 mg (red), 84-tab pack = £25.88   Competact® (Takeda) ▼ [MI  Tablets, f/c, pioglitazone (as hydrochloride) 15 mg,  metformin hydrochloride 850 mg, net price 56-tab  pack = £35.89. Label: 21   Dose ADULT over 18 years, type 2 diabetes not controlled by  metformin alone, 1 tablet twice daily    Indications type 2 diabetes mellitus (as monotherapy  or in combination with metformin when metformin  alone inadequate)   Cautions substitute insulin during intercurrent illness  (such as myocardial infarction, coma, infection, and  trauma) and during surgery (omit repaglinide on  morning of surgery and recommence when eating and  drinking normally); debilitated and malnourished  patients; interactions: Appendix 1 (antidiabetics)  Contra-indications ketoacidosis  Hepatic impairment avoid in severe liver disease  Renal impairment use with caution  Pregnancy avoid   Side-effects abdominal pain, diarrhoea, constipation,  nausea, vomiting; rarely hypoglycaemia, hypersensi-  tivity reactions including pruritus, rashes, vasculitis,  urticaria, and visual disturbances   • ADULT over 18 years, initially 500 micrograms within  30 minutes before main meals (1 mg if transferring  from another oral hypoglycaemic), adjusted according  to response at intervals of 1-2 weeks; up to 4 mg may  be given as a single dose, max. 16 mg daily; ELDERLY  over 75 years, not recommended   Prandin® (Daiichi Sankyo) (Ml  Tablets, repaglinide 500 micrograms, net price 30-tab  pack = £3.92, 90-tab pack = £1 1.76; 1 mg (yellow), 30-  tab pack = £3.92, 90-tab pack = £1 1.76; 2 mg (peach),  90-tab pack = £11.76  Formerly marketed as NovoNorm ®   Hepatic impairment use with caution in moderate  impairment; avoid in severe impairment  Renal impairment avoid if eGFR less than 50 mL/  minute/ 1.73m 2   Side-effects vomiting, dyspepsia, gastritis; peripheral  oedema; headache, dizziness, fatigue; upper respir-  atory tract infection, urinary tract infection, gastro-  enteritis, sinusitis, nasopharyngitis; hypoglycaemia,  myalgia; less commonly dyslipidaemia, hypertrigly-  ceridaemia, erectile dysfunction, arthralgia; also  reported rash  Dose   Onglyza® (Bristol-Myers Squibb) ▼ (Ml  Tablets, pink, f/c, saxagliptin (as hydrochloride) 5 mg,  net price 28-tab pack = £31.60   Indications see notes above  Cautions interactions: Appendix 1 (antidiabetics)  Contra-indications ketoacidosis  Renal impairment avoid if eGFR less than 50 mL/  minute/ 1.73 m 2   Side-effects gastro-intestinal disturbances; peripheral  oedema; upper respiratory tract infection, nasophar-  yngitis; pain; less commonly dry mouth, anorexia,  headache, drowsiness, dizziness, hypoglycaemia,  osteoarthritis; also reported pancreatitis, rash, cuta-  neous vasculitis, and Stevens- Johnson syndrome   Tablets, beige, f/c, sitagliptin (as phosphate) 100 mg,  net price 28-tab pack = £33.26   The Scottish Medicines Consortium (p. 4) has advised (June 2010)  that Januvia ® is accepted for restricted use within NHS Scotland  as monotherapy, to improve glycaemic control in patients with  type 2 diabetes mellitus, for whom both metformin and  sulfonylureas are not appropriate   Tablets, f/c, red, sitagliptin 50 mg, metformin hydro-  chloride 1 g, net price 56-tab pack = £34.56. Label: 21  Dose type 2 diabetes mellitus not controlled by metformin alone  or by metformin in combination with either a sulfonylurea or  pioglitazone or insulin, ADULT over 18 years, 1 tablet twice daily  Note Dose of concomitant sulfonylurea or insulin may need to be  reduced   The Scottish Medicines Consortium (p. 4) has advised (July 2008)  that Janumet® is accepted for restricted use within NHS Scotland  for the treatment of type 2 diabetes mellitus when the addition of a  sulfonylurea to metformin is not appropriate; it is also accepted  for use in NHS Scotland in combination with a sulfonylurea in  patients inadequately controlled on maximum tolerated doses of  metformin and a sulfonylurea.   Cautions elderly; monitor liver function (see below);  heart failure (avoid if moderate or severe); interac-  tions: Appendix 1 (antidiabetics)   Liver toxicity Rare reports of liver dysfunction; monitor  liver function before treatment and every 3 months for first  year and periodically thereafter; advise patients to seek  prompt medical attention if symptoms such as nausea,  vomiting, abdominal pain, fatigue, and dark urine develop;  discontinue if jaundice or other signs of liver dysfunction  occur   Renal impairment avoid if eGFR less than 50 mL/  minute/ 1.73 m 2   Side-effects nausea, peripheral oedema, headache,  tremor, asthenia, dizziness; less commonly constipa-  tion, hypoglycaemia, arthralgia; rarely hepatic dys-  function (see also Liver Toxicity above); very rarely  nasopharyngitis, upper respiratory tract infection;  pancreatitis also reported  Dose   • ADULT over 18 years, in combination with metformin or  pioglitazone, 50 mg twice daily; in combination with a  sulfonylurea, 50 mg daily in the morning   Tablets, pale yellow, vildagliptin 50 mg, net price 56-  tab pack = £31.76   For prescribing information on metformin, see section  6 . 1 . 2. 2   Eucreas® (Novartis) T (Ml  Eucreas® 50 mg/850 mg tablets, f/c, yellow, vilda-  gliptin 50 mg, metformin hydrochloride 850 mg, net  price 60-tab pack = £31.76. Label: 21  Eucreas® 50 mg/1 g tablets, f/c, dark yellow,  vildagliptin 50 mg, metformin hydrochloride 1 g, net  price 60-tab pack = £31.76. Label: 21  Dose type 2 diabetes mellitus not controlled by metformin alone,  ADULT over 18 years, 1 Eucreas ® tablet twice daily (based on  patient’s current metformin dose)   The Scottish Medicines Consortium (p. 4) has advised (June 2008)  that Eucreas ® is accepted for restricted use within NHS Scotland  for the treatment of type 2 diabetes mellitus in patients unable to  achieve adequate glycaemic control with metformin alone or  those already treated with vildagliptin and metformin as separate  tablets   The management of diabetic ketoacidosis involves the  replacement of fluid and electrolytes and the adminis-  tration of insulin. Guidelines for the Management of  Diabetic Ketoacidosis in Adults, published by the Joint  British Diabetes Societies Inpatient Care Group 1 , should  be followed.   • To restore circulating volume if systolic blood pres-  sure is below 90 mmHg (adjusted for age, sex, and  medication as appropriate), give 500 mL sodium  chloride 0.9% by intravenous infusion over 10-15  minutes; repeat if blood pressure remains below  90 mmHg and seek senior medical advice.   • When blood pressure is over 90 mmHg, sodium  chloride 0.9% should be given by intravenous infu-  sion at a rate that replaces deficit and provides  maintenance; see guideline for suggested regimen.   • Include potassium chloride in the fluids unless  anuria is suspected; adjust according to plasma-  potassium concentration (measure at 60 minutes,  2 hours, and 2 hourly thereafter; measure hourly if  outside the normal range).   • Start an intravenous insulin infusion: soluble insu-  lin should be diluted (and mixed thoroughly) with  sodium chloride 0.9% intravenous infusion to a  concentration of 1 unit/mL; infuse at a fixed rate of  0.1 units/kg/hour.   • Established subcutaneous therapy with long-acting  insulin analogues (insulin detemir or insulin glar-  gine) should be continued during treatment of dia-  betic ketoacidosis.   • Monitor blood-ketone and blood-glucose concen-  trations hourly and adjust the insulin infusion rate  accordingly. Blood-ketone concentration should fall  by at least 0.5 mmol/litre/hour and blood-glucose  concentration should fall by at least 3 mmol/litre/  hour.   • Once blood-glucose concentration falls below  14 mmol/litre, glucose 10% should be given by  intravenous infusion (into a large vein through a  large-gauge needle) at a rate of 125mL/hour, in  addition to the sodium chloride 0.9% infusion.   above 7.3 and the patient is able to eat and drink;  ideally give subcutaneous fast-acting insulin and a  meal, and stop the insulin infusion 1 hour later.   For the management of diabetic ketoacidosis in children  under 18 years, see BNF for Children.   The management of hyperosmolar hyperglycaemic  state or hyperosmolar hyperglycaemic nonketotic  coma is similar to that of diabetic ketoacidosis, although  lower rates of insulin infusion are usually necessary and  slower rehydration may be required.   Initially glucose 10-20 g is given by mouth either in  liquid form or as granulated sugar or sugar lumps.  Approximately 10 g of glucose is available from non-  diet versions of Lucozade® Energy Original 55 mL,  Coca-Cola® 100 mL, Ribena® Blackcurrant 18mL (to  be diluted), 2 teaspoons of sugar, and also from 3 sugar  lumps 2 . If necessary this may be repeated in 10-15  minutes. After initial treatment, a snack providing  sustained availability of carbohydrate (e.g. a sandwich,  fruit, milk, or biscuits) or the next meal, if it is due, can  prevent blood-glucose concentration from falling again.  Hypoglycaemia which causes unconsciousness is an  emergency Glucagon, a polypeptide hormone pro-  duced by the alpha cells of the islets of Langerhans,  increases plasma-glucose concentration by mobilising  glycogen stored in the liver. In hypoglycaemia, if sugar  cannot be given by mouth, glucagon can be given by  injection. Carbohydrates should be given as soon as  possible to restore liver glycogen; glucagon is not appro-  priate for chronic hypoglycaemia. Glucagon may be  issued to close relatives of insulin-treated patients for  emergency use in hypoglycaemic attacks. It is often  advisable to prescribe on an ‘if necessary’ basis to  hospitalised insulin-treated patients, so that it may be  given rapidly by the nurses during an hypoglycaemic  emergency. If not effective in 10 minutes intravenous  glucose should be given.   Alternatively, 50 mL of glucose intravenous infusion  20% (section 9.2.2) may be given intravenously into a  large vein through a large-gauge needle; care is required  since this concentration is irritant especially if extrava-  sation occurs. Glucose intravenous infusion 10% may  also be used but larger volumes are needed. Glucose  intravenous infusion 50% is not recommended because  of the higher risk of extravasation injury and because  administration is difficult. Close monitoring is necessary  in the case of an overdose with a long-acting insulin  because further administration of glucose may be  required. Patients whose hypoglycaemia is caused by  an oral antidiabetic drug should be transferred to hos-  pital because the hypoglycaemic effects of these drugs  may persist for many hours.   For advice on the emergency management of hypoglyc-  aemia in dental practice, see p. 28.   • Continue insulin infusion until blood-ketone con-  centration is below 0.3 mmol/litre, blood pH is    2. Proprietary products of quick-acting carbohydrate (e.g.  GlucoGel ®, Dextrogel ®, Hypo-Fit®) are available on  prescription for the patient to keep to hand in case of  hypoglycaemia.   Cautions see notes above, insulinoma, glucagonoma;  ineffective in chronic hypoglycaemia, starvation, and  adrenal insufficiency   • Insulin-induced hypoglycaemia, by subcutaneous,  intramuscular, or intravenous injection, ADULT and  CHILD over 8 years (or body-weight over 25 kg), 1 mg;  CHILD under 8 years (or body-weight under 25 kg),  500 micrograms; if no response within 10 minutes  intravenous glucose must be given   Injection, powder for reconstitution, glucagon (rys) as  hydrochloride with lactose, net price 1-mg vial with  prefilled syringe containing water for injection =  £11.52   Regular review of diabetic patients should include an  annual test for urinary protein (using Albustix®) and  serum creatinine measurement. If the urinary protein  test is negative, the urine should be tested for  microalbuminuria (the earliest sign of nephropathy). If  reagent strip tests ( Micral-Test II® [Ml or Micro-  bumintest® (JmZ) are used and prove positive, the result  should be confirmed by laboratory analysis of a urine  sample. Provided there are no contra-indications, all  diabetic patients with nephropathy causing proteinuria  or with established microalbuminuria (at least 3 positive  tests) should be treated with an ACE inhibitor (section   2.5. 5.2) even if the blood pressure is normal; in any case,  to minimise the risk of renal deterioration, blood  pressure should be carefully controlled (section 2.5).   ACE inhibitors can potentiate the hypoglycaemic effect  of insulin and oral antidiabetic drugs; this effect is more  likely during the first weeks of combined treatment and  in patients with renal impairment.   For the treatment of hypertension in diabetes, see sec-  tion 2.5.   Diazoxide, administered by mouth, is useful in the  management of patients with chronic hypoglycaemia  from excess endogenous insulin secretion, either from  an islet cell tumour or islet cell hyperplasia. It has no  place in the management of acute hypoglycaemia.   Cautions ischaemic heart disease; monitor blood  pressure; during prolonged use monitor white cell and  platelet count, and in children, regularly assess  growth, bone, and psychological development; inter-  actions: Appendix 1 (diazoxide)   Renal impairment dose reduction may be required  Pregnancy prolonged use in second or third trimesters  may produce alopecia and impaired glucose tolerance  in neonate; inhibits uterine activity during labour  Side-effects anorexia, nausea, vomiting, hyperuric-  aemia, hypotension, oedema, tachycardia, arrhyth-  mias, extrapyramidal effects; hypertrichosis on pro-  longed treatment  Dose   • By mouth, ADULT and CHILD, initially 5 mg/kg daily in  2-3 divided doses   Optimal diabetic control is beneficial for the manage-  ment of painful neuropathy in patients with type 1  diabetes (see also section 4.7.3). Paracetamol (p. 259)  or a non-steroidal anti-inflammatory drug such as ibu-  profen (p. 636) may relieve mild to moderate pain.  Duloxetine (p. 243) is effective for the treatment of  painful diabetic neuropathy; amitriptyline (p. 235)  [unlicensed use] can be used if duloxetine is ineffective  or unsuitable. Nortriptyline (p. 236) [unlicensed] may  be better tolerated than amitriptyline. If treatment with  amitriptyline or duloxetine is inadequate, treatment with  pregabalin (p. 284) should be tried. Combination ther-  apy of duloxetine or amitriptyline with pregabalin can be  used if monotherapy at the maximum tolerated dose  does not control symptoms.   Neuropathic pain may respond to opioid analgesics.  There is evidence of efficacy for tramadol (p. 271),  morphine (p. 268), and oxycodone (p. 269); however,  treatment with morphine or oxycodone should be  initiated only under specialist supervision. Tramadol  can be prescribed while the patient is waiting for assess-  ment by a specialist if other treatments have been  unsuccessful.   Gabapentin (p. 284) and carbamazepine (p. 281) are  sometimes used for the treatment of neuropathic pain.  Capsaicin cream 0.075% (p. 664) is licensed for painful  diabetic neuropathy and may have some effect, but it  produces an intense burning sensation during the initial  treatment period.   In autonomic neuropathy diabetic diarrhoea can often  be managed by 2 or 3 doses of tetracycline 250 mg  [unlicensed use] (p. 347). Otherwise codeine (p. 58) is    the best drug, but other antidiarrhoeal preparations can  be tried. An antiemetic which promotes gastric transit,  such as metoclopramide (p. 253) or domperidone  (p. 253), is helpful for gastroparesis. In rare cases  when an antiemetic does not help, erythromycin (espe-  cially when given intravenously) may be beneficial but  this needs confirmation.   In neuropathic postural hypotension increased salt  intake and the use of the mineralocorticoid fludrocorti-  sone 100-400 micrograms daily [unlicensed use]  (p. 442) may help by increasing plasma volume, but  uncomfortable oedema is a common side-effect. Fludro-  cortisone can also be combined with flurbiprofen  (p. 636) and ephedrine hydrochloride (p. 179) [both  unlicensed], Midodrine [unlicensed], an alpha agonist,  may also be useful in postural hypotension.   Gustatory sweating can be treated with an anti-  muscarinic such as propantheline bromide (p. 48);  side-effects are common. For the management of hyper-  hidrosis, see section 13.12.   In some patients with neuropathic oedema, ephedrine  hydrochloride [unlicensed use] 30-60 mg 3 times daily  offers effective relief.    If the patient is unwell and diabetic ketoacidosis is  suspected, blood ketones should be measured accord-  ing to local guidelines (section 6.1.3). Patients and their  carers should be trained in the use of blood ketone  monitoring systems and to take appropriate action on  the results obtained, including when to seek medical  attention.   Tests for glucose range from reagent strips specific to  glucose to reagent tablets which detect all reducing  sugars. Few patients still use Clinitest ®; Clinistix® is  suitable for screening purposes only. Tests for ketones  by patients are rarely required unless they become  unwell — see also Blood Monitoring, above.  Microalbuminuria can be detected with Micral-Test  II® Ml but this should be followed by confirmation in  the laboratory, since false positive results are common.   Reagent strips, for detection of glucose in urine. Net price  50-strip pack = £3.27   Blood glucose monitoring using a meter gives a direct  measure of the glucose concentration at the time of the  test and can detect hypoglycaemia as well as hyperglyc-  aemia. Patients should be properly trained in the use of  blood glucose monitoring systems and to take appro-  priate action on the results obtained. Inadequate under-  standing of the normal fluctuations in blood glucose can  lead to confusion and inappropriate action.   Patients using multiple injection regimens should under-  stand how to adjust their insulin dose according to their  carbohydrate intake. With fixed-dose insulin regimens,  the carbohydrate intake needs to be regulated, and  should be distributed throughout the day to match the  insulin regimen.   Self-monitoring of blood-glucose concentration is  appropriate for patients with type 2 diabetes:   • who are treated with oral hypoglycaemic drugs e.g.  sulfonylureas, to provide information on hypoglyc-  aemia;   • to monitor changes in blood-glucose concentration  resulting from changes in lifestyle or medication,  and during intercurrent illness;   Note In the UK blood-glucose concentration is expressed in  mmol/litre and Diabetes UK advises that these units should be  used for self-monitoring of blood glucose. In other European  countries units of mg/ 100 mL (or mg/dL) are commonly used.  It is advisable to check that the meter is pre-set in the correct  units.    Clinitest® (Bayer Diabetes Care) Ml  Reagent tablets, for detection of glucose and other reducing  substances in urine. Net price 36-tab pack = £2.00   Reagent strips, for detection of glucose in urine. Net price  50-strip pack = £2.87   Reagent strips, for detection of glucose in urine. Net price  50-strip pack = £2.78   Reagent strips, for detection of glucose in urine. Net price  50-strip pack = £2.33   Reagent strips, for detection of ketones in urine. Net price  50-strip pack = £2.95   Reagent strips, for detection of ketones in urine. Net price  50-strip pack = £2.76   Reagent strips, for detection of protein in urine. Net price  50-strip pack = £4.10   Reagent strips, for detection of protein in urine. Net price  50-strip pack = £3.27   Combur-3 Test® (M (glucose and protein — Roche  Diagnostics), Clinitek Microalbumin® Ml (albumin and  creatinine — Siemens), Ketodiastix® Ml (glucose and  ketones — Bayer Diagnostics), Medi-Test Combi 2® Ml  (glucose and protein — BHR), Micral-Test II® Ml  (albumin — Roche Diagnostics), Microalbustix® Ml  (albumin and creatinine — Siemens), Uristix® M I (glu-  cose and protein — Siemens)   The oral glucose tolerance test is used mainly for  diagnosis of impaired glucose tolerance; it is not recom-  mended or necessary for routine diagnostic use when  severe symptoms of hyperglycaemia are present. In  patients who have less severe symptoms and blood  glucose levels that do not establish or exclude diabetes  (e.g. impaired fasting glycaemia), an oral glucose toler-  ance test may be required. It is also used to establish the  presence of gestational diabetes. The oral glucose tol-  erance test generally involves giving anhydrous glucose  75 g (equivalent to Glucose BP 82.5 g) by mouth to the  fasting patient, and measuring blood-glucose concen-  trations at intervals.   The appropriate amount of glucose should be given with  200-300 mL fluid. Anhydrous glucose 75 g may alter-  natively be given as 1 13 mL Poly cal® (Nutricia Clinical)  with extra fluid to administer a total volume of 200-  300 mL.   Thyroid hormones are used in hypothyroidism (myx-  oedema), and also in diffuse non-toxic goitre, Hashimo-  to’s thyroiditis (lymphadenoid goitre), and thyroid carci-  noma. Neonatal hypothyroidism requires prompt  treatment for normal development. Levothyroxine  sodium (thyroxine sodium) is the treatment of choice  for maintenance therapy.   In infants and children with congenital hypothyroidism  and juvenile myxoedema, the dose of levothyroxine  should be titrated according to clinical response, growth  assessment, and measurements of plasma thyroxine and  thyroid-stimulating hormone. See BNF for Children  (section 6.2.1) for suitable dosage regimens.    Liothyronine sodium has a similar action to levothyr-  oxine but is more rapidly metabolised and has a more  rapid effect; 20 micrograms is equivalent to 100 micr-  ograms of levothyroxine. Its effects develop after a few  hours and disappear within 24 to 48 hours of disconti-  nuing treatment. It may be used in severe hypothyroid  states when a rapid response is desired.   Liothyronine by intravenous injection is the treatment of  choice in hypothyroid coma. Adjunctive therapy  includes intravenous fluids, hydrocortisone, and treat-  ment of infection; assisted ventilation is often required.   Indications hypothyroidism; see also notes above  Cautions panhypopituitarism or predisposition to  adrenal insufficiency (initiate corticosteroid therapy  before starting levothyroxine), elderly, cardiovascular  disorders (including hypertension, myocardial insuf-  ficiency or myocardial infarction, see Initial Dosage  below), long-standing hypothyroidism, diabetes insi-  pidus, diabetes mellitus (dose of antidiabetic drugs  including insulin may need to be increased); inter-  actions: Appendix 1 (thyroid hormones)   Initial dosage Baseline ECG is valuable because changes  induced by hypothyroidism can be confused with ischaemia.  If metabolism increases too rapidly (causing diarrhoea, ner-  vousness, rapid pulse, insomnia, tremors and sometimes  anginal pain where there is latent myocardial ischaemia),  reduce dose or withhold for 1-2 days and start again at a  lower dose   Contra-indications thyrotoxicosis  Pregnancy monitor maternal serum-thyrotrophin  concentration — levothyroxine may cross the placenta  and excessive maternal concentration can be detri-  mental to fetus   Side-effects usually at excessive dosage (see Initial  Dosage above) include diarrhoea, vomiting, anginal  pain, arrhythmias, palpitation, tachycardia, tremor,  restlessness, excitability, insomnia; headache, flush-  ing, sweating, fever, heat intolerance, weight-loss,  muscle cramp, and muscular weakness; transient hair  loss in children; hypersensitivity reactions including  rash, pruritus and oedema also reported  Dose   • ADULT over 18 years, initially 50-100 micrograms once  daily, preferably before breakfast, adjusted in steps of  25-50 micrograms every 3-4 weeks according to  response (usual maintenance dose 100-200 micr-  ograms once daily); in cardiac disease, severe hypo-  thyroidism, and patients over 50 years, initially   25 micrograms once daily, adjusted in steps of  25 micrograms every 4 weeks according to response;  usual maintenance dose 50-200 micrograms once  daily; CHILD under 18 years see BNF for Children  (section 6.2.1)   Levothyroxine (Non-proprietary) LmD  Tablets, levothyroxine sodium 25 micrograms, net  price 28-tab pack = £2.22; 50 micrograms, 28-tab pack  = £1.09; 100 micrograms, 28-tab pack = £1.09  Brands include Eltroxin ®   Oral solution, levothyroxine sodium 25 micrograms/  5mL, net price 100 mL = £42.75; 50 micrograms/   Note All strengths of levothyroxine oral solution by Almus  and branded as Evotrox ®, have been reformulated (August  2010) leading to an increase in potency of approximately  10%; the manufacturer advises that the recommended dose  has not changed, but recommends increased monitoring of  patients on these preparations as dose adjustments may be  necessary   Indications see notes above  Cautions see under Levothyroxine Sodium; interac-  tions: Appendix 1 (thyroid hormones)  Contra-indications see under Levothyroxine Sodium  Pregnancy does not cross the placenta in significant  amounts; monitor maternal thyroid function tests —  dosage adjustment may be necessary  Breast-feeding amount too small to affect tests for  neonatal hypothyroidism  Side-effects see under Levothyroxine Sodium  Dose   • By mouth, initially 10-20 micrograms daily gradually  increased to 60 micrograms daily in 2-3 divided  doses; ELDERLY smaller initial doses; CHILD, adult dose  reduced in proportion to body-weight   • By slow intravenous injection, hypothyroid coma, 5-  20 micrograms repeated every 12 hours or as often as  every 4 hours if necessary; alternatively initially   50 micrograms then 25 micrograms every 8 hours  reducing to 25 micrograms twice daily   Antithyroid drugs are used for hyperthyroidism either to  prepare patients for thyroidectomy or for long-term  management. In the UK carbimazole is the most com-  monly used drug. Propylthiouracil should be reserved  for patients who are intolerant of carbimazole or for  those who suffer sensitivity reactions to carbimazole,  because sensitivity is not necessarily displayed to both  drugs. Both drugs act primarily by interfering with the  synthesis of thyroid hormones.    Neutropenia and agranulocytosis  Doctors are reminded of the importance of recog-  nising bone marrow suppression induced by carbim-  azole and the need to stop treatment promptly.   1 . Patient should be asked to report symptoms and  signs suggestive of infection, especially sore  throat.   2. A white blood cell count should be performed if  there is any clinical evidence of infection.   3. Carbimazole should be stopped promptly if  there is clinical or laboratory evidence of neu-  tropenia.    Carbimazole is given in a dose of 15 to 40 mg daily;  higher doses should be prescribed under specialist  supervision only. This dose is continued until the patient  becomes euthyroid, usually after 4 to 8 weeks and the  dose is then gradually reduced to a maintenance dose of   5 to 1 5 mg. Therapy is usually given for 12 to 18 months.  Children may be given carbimazole in an initial dose of  250 micrograms/kg three times daily, adjusted accord-  ing to response; treatment in children should be under-  taken by a specialist. Rashes and pruritus are common  but they can be treated with antihistamines without  discontinuing therapy; alternatively propylthiouracil  can be substituted. All patients should be advised to  report any sore throat immediately because of the rare  complication of agranulocytosis (see Neutropenia and  Agranulocytosis, above).   Propylthiouracil is given in a dose of 200 to 400 mg  daily in divided doses in adults and this dose is main-  tained until the patient becomes euthyroid; the dose  may then be gradually reduced to a maintenance dose  of 50 to 150 mg daily in divided doses.   Over-treatment with antithyroid drugs can result in the  rapid development of hypothyroidism and should be  avoided particularly during pregnancy because it can  cause fetal goitre.   A combination of carbimazole, 40 to 60 mg daily with  levothyroxine, 50 to 150 micrograms daily, may be used  in a blocking-replacement regimen ; therapy is usually  given for 18 months. The blocking-replacement regimen  is not suitable during pregnancy.   Iodine has been used as an adjunct to antithyroid drugs  for 10 to 14 days before partial thyroidectomy; however,  there is little evidence of a beneficial effect. Iodine  should not be used for long-term treatment because  its antithyroid action tends to diminish.   Radioactive sodium iodide ( 131 I) solution is used increas-  ingly for the treatment of thyrotoxicosis at all ages,  particularly where medical therapy or compliance is a  problem, in patients with cardiac disease, and in patients  who relapse after thyroidectomy.   Propranolol is useful for rapid relief of thyrotoxic  symptoms and may be used in conjunction with anti-  thyroid drugs or as an adjunct to radioactive iodine.  Beta-blockers are also useful in neonatal thyrotoxicosis  and in supraventricular arrhythmias due to hyper-  thyroidism. Propranolol has been used in conjunction  with iodine to prepare mildly thyrotoxic patients for  surgery but it is preferable to make the patient euthyroid  with carbimazole. Laboratory tests of thyroid function  are not altered by beta-blockers. Most experience in  treating thyrotoxicosis has been gained with propranolol  but nadolol is also used. For doses and preparations of  beta-blockers see section 2.4.   Thyrotoxic crisis (‘thyroid storm’) requires emergency  treatment with intravenous administration of fluids,  propranolol (5 mg) and hydrocortisone (100 mg every   6 hours, as sodium succinate), as well as oral iodine  solution and carbimazole or propylthiouracil which may  need to be administered by nasogastric tube.   Pregnancy and breast-feeding Radioactive iodine  therapy is contra-indicated during pregnancy. Propyl-  thiouracil and carbimazole can be given but the block-  ing-replacement regimen (see above) is not suitable.  Rarely, carbimazole has been associated with congenital  defects, including aplasia cutis of the neonate — use car-    bimazole in pregnancy only if propylthiouracil is not  suitable. Both propylthiouracil and carbimazole cross  the placenta and in high doses may cause fetal goitre  and hypothyroidism — the lowest dose that will control  the hyperthyroid state should be used (requirements in  Graves’ disease tend to fall during pregnancy).   Carbimazole and propylthiouracil appear in breast milk  but this does not preclude breast-feeding as long as  neonatal development is closely monitored and the  lowest effective dose is used.    Hepatic impairment use with caution in mild to  moderate impairment; avoid in severe impairment  Pregnancy neonatal goitre and hypothyroidism; has  been associated with congenital defects including  aplasia cutis of the neonate; see also notes above  Breast-feeding amount in milk may be sufficient to  affect neonatal thyroid function therefore lowest  effective dose should be used; see also notes above    Side-effects nausea, mild gastro-intestinal distur-  bances, taste disturbance, headache; fever, malaise;  rash, pruritus, arthralgia; rarely myopathy, alopecia,  bone marrow suppression (including pancytopenia  and agranulocytosis, see Neutropenia and Agranulo-  cytosis above), and jaundice   Counselling Warn patient to tell doctor immediately if sore  throat, mouth ulcers, bruising, fever, malaise, or non-specific  illness develops   Tablets, carbimazole 5 mg, net price 100-tab pack =  £4.53; 20 mg, 100-tab pack = £16.83. Counselling,  blood disorder symptoms   Neo-Mercazole® (Amdipharm) (Ml  Tablets, both pink, carbimazole 5 mg, net price 100-  tab pack = £3.85; 20 mg, 100-tab pack = £11.44.  Counselling, blood disorder symptoms   Breast-feeding stop breast-feeding; danger of neo-  natal hypothyroidism or goitre; appears to be con-  centrated in milk; see also notes above  Side-effects hypersensitivity reactions including cor-  yza-like symptoms, headache, lacrimation, con-  junctivitis, pain in salivary glands, laryngitis, bronch-  itis, rashes; on prolonged treatment depression,  insomnia, impotence; goitre in infants of mothers  taking iodides  Dose   Oral solution, iodine 5%, potassium iodide 10% in  purified water, freshly boiled and cooled, total iodine  130mg/mL, net price 500 mL = £6.24. Label: 27  Dose 0. 1-0.3 mL 3 times daily well diluted with milk or water   Cautions monitor for hepatotoxicity  Hepatotoxicity Severe hepatic reactions have been  reported, including fatal cases and cases requiring liver  transplant — discontinue if significant liver-enzyme abnorm-  alities develop   Counselling Patients should be told how to recognise signs  of liver disorder and advised to seek prompt medical atten-  tion if symptoms such as anorexia, nausea, vomiting, fatigue,  abdominal pain, jaundice, dark urine, or pruritus develop   Renal impairment use three-quarters normal dose if  eGFR 10-50 mL/minute/1. 73 m 2 ; use half normal  dose if eGFR less than lOmL/minute/1.73 m 2   Breast-feeding monitor infant’s thyroid status but  amount in milk probably too small to affect infant;  high doses may affect neonatal thyroid function; see  also notes above   Side-effects see under Carbimazole; leucopenia;  rarely cutaneous vasculitis, thrombocytopenia, aplas-  tic anaemia, hypoprothrombinaemia, hepatic disor-  ders (including hepatitis, hepatic failure, encephalo-  pathy, hepatic necrosis; see also Hepatotoxicity  above), nephritis, lupus erythematous-like syndromes  Dose   Propylthiouracil (Non-proprietary) [Ml  Tablets, propylthiouracil 50 mg. Net price 56-tab pack  = £47.11, 100-tab pack = £67.38   The adrenal cortex normally secretes hydrocortisone  (cortisol) which has glucocorticoid activity and weak  mineralocorticoid activity. It also secretes the minera-  locorticoid aldosterone.   In deficiency states, physiological replacement is best  achieved with a combination of hydrocortisone (sec-  tion 6.3.2) and the mineralocorticoid fludrocortisone;  hydrocortisone alone does not usually provide sufficient  mineralocorticoid activity for complete replacement.   In Addison’s disease or following adrenalectomy,  hydrocortisone 20 to 30 mg daily by mouth is usually  required. This is given in 2 doses, the larger in the  morning and the smaller in the evening, mimicking  the normal diurnal rhythm of cortisol secretion. The  optimum daily dose is determined on the basis of  clinical response. Glucocorticoid therapy is supplemen-  ted by fludrocortisone 50 to 300 micrograms daily.   In acute adrenocortical insufficiency, hydrocortisone  is given intravenously (preferably as sodium succinate)  in doses of 100 mg every 6 to 8 hours in sodium chloride  intravenous infusion 0.9%.   In hypopituitarism glucocorticoids should be given as in  adrenocortical insufficiency, but since production of  aldosterone is also regulated by the renin-angiotensin  system a mineralocorticoid is not usually required.  Additional replacement therapy with levothyroxine  (section 6.2.1) and sex hormones (section 6.4) should  be given as indicated by the pattern of hormone defi-  ciency.   Contra-indications section 6.3.2  Hepatic impairment section 6.3.2  Renal impairment section 6.3.2  Pregnancy section 6.3.2  Breast-feeding section 6.3.2  Side-effects section 6.3.2  Dose   In comparing the relative potencies of corticosteroids in  terms of their anti-inflammatory (glucocorticoid) effects  it should be borne in mind that high glucocorticoid  activity in itself is of no advantage unless it is accom-  panied by relatively low mineralocorticoid activity (see  Disadvantages of Corticosteroids below). The minera-  locorticoid activity of fludrocortisone (section 6.3.1) is  so high that its anti-inflammatory activity is of no  clinical relevance. The table below shows equivalent  anti-inflammatory doses.    This table takes no account of mineralocorticoid effects,  nor does it take account of variations in duration of  action   Prednisolone 5 mg  = Betamethasone 750 micrograms  = Cortisone acetate 25 mg  = Deflazacort 6 mg  = Dexamethasone 750 micrograms  = Hydrocortisone 20 mg  = Methylprednisolone 4 mg  = Prednisone 5 mg  = Triamcinolone 4 mg   The relatively high mineralocorticoid activity of corti-  sone and hydrocortisone, and the resulting fluid reten-  tion, make them unsuitable for disease suppression on a  long-term basis. However, they can be used for adrenal  replacement therapy (section 6.3.1); hydrocortisone is  preferred because cortisone requires conversion in the    liver to hydrocortisone. Hydrocortisone is used on a  short-term basis by intravenous injection for the emer-  gency management of some conditions. The relatively  moderate anti-inflammatory potency of hydrocortisone  also makes it a useful topical corticosteroid for the  management of inflammatory skin conditions because  side-effects (both topical and systemic) are less marked  (section 13.4); cortisone is not active topically.  Prednisolone and prednisone have predominantly glu-  cocorticoid activity. Prednisolone is the corticosteroid  most commonly used by mouth for long-term disease  suppression.   Betamethasone and dexamethasone have very high  glucocorticoid activity in conjunction with insignificant  mineralocorticoid activity. This makes them particularly  suitable for high-dose therapy in conditions where fluid  retention would be a disadvantage.   Betamethasone and dexamethasone also have a long  duration of action and this, coupled with their lack of  mineralocorticoid action makes them particularly suita-  ble for conditions which require suppression of cortico-  tropin (corticotrophin) secretion (e.g. congenital adrenal  hyperplasia). Some esters of betamethasone and of  beclometasone (beclomethasone) exert a considerably  more marked topical effect (e.g. on the skin or the lungs)  than when given by mouth; use is made of this to obtain  topical effects whilst minimising systemic side-effects  (e.g. for skin applications and asthma inhalations).   Deflazacort has a high glucocorticoid activity; it is  derived from prednisolone.   Dosages of corticosteroids vary widely in different dis-  eases and in different patients. If the use of a cortico-  steroid can save or prolong life, as in exfoliative  dermatitis, pemphigus, acute leukaemia or acute trans-  plant rejection, high doses may need to be given,  because the complications of therapy are likely to be  less serious than the effects of the disease itself.   When long-term corticosteroid therapy is used in some  chronic diseases, the adverse effects of treatment may  become greater than the disabilities caused by the  disease. To minimise side-effects the maintenance  dose should be kept as low as possible.   When potentially less harmful measures are ineffective  corticosteroids are used topically for the treatment of  inflammatory conditions of the skin (section 13.4). Cor-  ticosteroids should be avoided or used only under  specialist supervision in psoriasis (section 13.5).   Corticosteroids are used both topically (by rectum) and  systemically (by mouth or intravenously) in the manage-  ment of ulcerative colitis and Crohn’s disease (section  1.5). They are also included in locally applied creams for  haemorrhoids (section 1.7.2).   Use can be made of the mineralocorticoid activity of  fludrocortisone to treat postural hypotension in auto-  nomic neuropathy (section 6.1.5).   High-dose corticosteroids should be avoided for the  management of septic shock. However, there is evi-  dence that administration of lower doses of hydrocorti-  sone (50 mg intravenously every 6 hours) and fludro-  cortisone (50 micrograms daily by mouth) is of benefit in  adrenocortical insufficiency resulting from septic shock.    Dexamethasone and betamethasone have little if any  mineralocorticoid action and their long duration of  action makes them particularly suitable for suppressing  corticotropin secretion in congenital adrenal hyper-  plasia where the dose should be tailored to clinical  response and by measurement of adrenal androgens  and 17-hydroxyprogesterone. In common with all gluco-  corticoids their suppressive action on the hypothalamic-  pituitary-adrenal axis is greatest and most prolonged  when they are given at night. In most individuals a single  dose of 1 mg of dexamethasone at night, is sufficient to  inhibit corticotropin secretion for 24 hours. This is the  basis of the ‘overnight dexamethasone suppression test’  for diagnosing Cushing’s syndrome.   Betamethasone and dexamethasone are also appropri-  ate for conditions where water retention would be a  disadvantage.   A corticosteroid may be used in the management of  raised intracranial pressure or cerebral oedema that  occurs as a result of malignancy (see also p. 22); high  doses of betamethasone or dexamethasone are gener-  ally used. However, a corticosteroid should not be used  for the management of head injury or stroke because it  is unlikely to be of benefit and may even be harmful.   In acute hypersensitivity reactions such as angioedema  of the upper respiratory tract and anaphylaxis, corticos-  teroids are indicated as an adjunct to emergency treat-  ment with adrenaline (epinephrine) (section 3.4.3). In  such cases hydrocortisone (as sodium succinate) by  intravenous injection in a dose of 100 to 300 mg may  be required.    Corticosteroids are preferably used by inhalation in the  management of asthma (section 3.2) but systemic ther-  apy in association with bronchodilators is required for  the emergency treatment of severe acute asthma (sec-  tion 3.1.1).   Corticosteroids may also be useful in conditions such as  autoimmune hepatitis, rheumatoid arthritis and sarcoi-  dosis; they may also lead to remissions of acquired  haemolytic anaemia (section 9.1.3), and some cases of  the nephrotic syndrome (particularly in children) and  thrombocytopenic purpura (section 9.1.4).    Corticosteroids can improve the prognosis of serious  conditions such as systemic lupus erythematosus, tem-  poral arteritis, and polyarteritis nodosa; the effects of the  disease process may be suppressed and symptoms  relieved, but the underlying condition is not cured,  although it may ultimately remit. It is usual to begin  therapy in these conditions at fairly high dose, such as  40 to 60 mg prednisolone daily, and then to reduce the  dose to the lowest commensurate with disease control.    For other references to the use of corticosteroids see  Prescribing in Palliative Care, section 8.2.2 (immuno-  suppression), section 10.1.2 (rheumatic diseases), sec-  tion 11.4 (eye), section 12.1.1 (otitis externa), section  12.2.1 (allergic rhinitis), and section 12.3.1 (aphthous  ulcers).   Whenever possible local treatment with creams, intra-  articular injections, inhalations, eye-drops, or enemas  should be used in preference to systemic treatment. The  suppressive action of a corticosteroid on cortisol secre-  tion is least when it is given as a single dose in the  morning. In an attempt to reduce pituitary-adrenal  suppression further, the total dose for two days can    sometimes be taken as a single dose on alternate days;  alternate-day administration has not been very success-  ful in the management of asthma (section 3.2). Pituitary-  adrenal suppression can also be reduced by means of  intermittent therapy with short courses. In some condi-  tions it may be possible to reduce the dose of cortico-  steroid by adding a small dose of an immunosuppressive  drug (section 8.2.1).   During prolonged therapy with corticosteroids, adrenal  atrophy develops and can persist for years after stop-  ping. Abrupt withdrawal after a prolonged period can  lead to acute adrenal insufficiency, hypotension or death  (see Withdrawal of Corticosteroids, below). Withdrawal  can also be associated with fever, myalgia, arthralgia,  rhinitis, conjunctivitis, painful itchy skin nodules and  weight loss.   To compensate for a diminished adrenocortical  response caused by prolonged corticosteroid treatment,  any significant intercurrent illness, trauma, or surgical  procedure requires a temporary increase in cortico-  steroid dose, or if already stopped, a temporary re-  introduction of corticosteroid treatment. To avoid a  precipitous fall in blood pressure during anaesthesia or  in the immediate postoperative period, anaesthetists  must know whether a patient is taking or has been  taking a corticosteroid. A suitable regimen for cortico-  steroid replacement, in patients who have taken more  than 10 mg prednisolone daily (or equivalent) within 3  months of surgery, is:    • Minor surgery under general anaesthesia — usual  oral corticosteroid dose on the morning of surgery  or hydrocortisone 25-50 mg (usually the sodium  succinate) intravenously at induction; the usual  oral corticosteroid dose is recommenced after sur-  gery    • Moderate or major surgery — usual oral cortico-  steroid dose on the morning of surgery and hydro-  cortisone 25-50 mg intravenously at induction, fol-  lowed by hydrocortisone 25-50 mg 3 times a day by  intravenous injection for 24 hours after moderate  surgery or for 48-72 hours after major surgery; the  usual pre-operative oral corticosteroid dose is  recommenced on stopping hydrocortisone injec-  tions    Patients on long-term corticosteroid treatment should  carry a Steroid Treatment Card (see p. 445) which gives  guidance on minimising risk and provides details of  prescriber, drug, dosage and duration of treatment.    Chickenpox Unless they have had chickenpox,  patients receiving oral or parenteral corticosteroids for  purposes other than replacement should be regarded as  being at risk of severe chickenpox (see Steroid Treat-  ment Card). Manifestations of fulminant illness include  pneumonia, hepatitis and disseminated intravascular  coagulation; rash is not necessarily a prominent feature.   Passive immunisation with varicella-zoster immuno-  globulin (section 14.5.2) is needed for exposed non-  immune patients receiving systemic corticosteroids or  for those who have used them within the previous 3  months. Confirmed chickenpox warrants specialist care  and urgent treatment (section 5.3.2. 1). Corticosteroids  should not be stopped and dosage may need to be  increased.   Topical, inhaled or rectal corticosteroids are less likely  to be associated with an increased risk of severe  chickenpox.   Measles Patients taking corticosteroids should be  advised to take particular care to avoid exposure to  measles and to seek immediate medical advice if expo-  sure occurs. Prophylaxis with intramuscular normal  immunoglobulin (section 14.5.1) may be needed.   The magnitude and speed of dose reduction in cortico-  steroid withdrawal should be determined on a case-by-  case basis, taking into consideration the underlying  condition that is being treated, and individual patient  factors such as the likelihood of relapse and the duration  of corticosteriod treatment. Gradual withdrawal of sys-  temic corticosteroids should be considered in those  whose disease is unlikely to relapse and have:   • received more than 40 mg prednisolone (or equivalent)  daily for more than 1 week;   • recently received repeated courses (particularly if taken  for longer than 3 weeks);   • taken a short course within 1 year of stopping long-term  therapy;   Systemic corticosteroids may be stopped abruptly in  those whose disease is unlikely to relapse and who have  received treatment for 3 weeks or less and who are not  included in the patient groups described above.   During corticosteroid withdrawal the dose may be  reduced rapidly down to physiological doses (equivalent  to prednisolone 7.5 mg daily) and then reduced more  slowly. Assessment of the disease may be needed during  withdrawal to ensure that relapse does not occur.   Prolonged courses of corticosteroids increase suscept-  ibility to infections and severity of infections; clinical  presentation of infections may also be atypical. Serious  infections e.g. septicaemia and tuberculosis may reach  an advanced stage before being recognised, and amoeb-  iasis or strongyloidiasis may be activated or exacer-  bated (exclude before initiating a corticosteroid in those  at risk or with suggestive symptoms). Fungal or viral  ocular infections may also be exacerbated (see also  section 11.4.1).    Systemic corticosteroids, particularly in high doses, are  linked to psychiatric reactions including euphoria, night-  mares, insomnia, irritability, mood lability, suicidal  thoughts, psychotic reactions, and behavioural distur-  bances. A serious paranoid state or depression with risk  of suicide can be induced, particularly in patients with a  history of mental disorder. These reactions frequently  subside on reducing the dose or discontinuing the  corticosteroid but they may also require specific man-  agement. Patients should be advised to seek medical  advice if psychiatric symptoms (especially depression  and suicidal thoughts) occur and they should also be    alert to the rare possibility of such reactions during  withdrawal of corticosteroid treatment.   Systemic corticosteroids should be prescribed with care  in those predisposed to psychiatric reactions, including  those who have previously suffered corticosteroid-  induced psychosis, or who have a personal or family  history of psychiatric disorders.   A patient information leaflet should be supplied to  every patient when a systemic corticosteroid is  prescribed. Patients should especially be advised of  the following (for details, see Infections, Adrenal  Suppression, Psychiatric Reactions, and Withdrawal  of Corticosteroids above):   • Immunosuppression Prolonged courses of cor-  ticosteroids can increase susceptibility to infec-  tion and serious infections can go unrecognised.  Unless already immune, patients are at risk of  severe chickenpox and should avoid close con-  tact with people who have chickenpox or shin-  gles. Similarly, precautions should also be taken  against contracting measles;   • Adrenal suppression If the corticosteroid is  given for longer than 3 weeks, treatment must  not be stopped abruptly. Adrenal suppression  can last for a year or more after stopping treat-  ment and the patient must mention the course of  corticosteroid when receiving treatment for any  illness or injury;   • Mood and behaviour changes Corticosteroid  treatment, especially with high doses, can alter  mood and behaviour early in treatment — the  patient can become confused, irritable and suf-  fer from delusion and suicidal thoughts. These  effects can also occur when corticosteroid treat-  ment is being withdrawn. Medical advice should  be sought if worrying psychological changes  occur;   • Other serious effects Serious gastro-intestinal,  musculoskeletal, and ophthalmic effects which  require medical help can also occur; for details  see Side-effects of Corticosteroids, p. 446.    Steroid treatment cards (see below) should be issued  where appropriate. Doctors and pharmacists can  obtain supplies of the card from:   I am a patient on STEROID  treatment which must  not be stopped suddenly   • If you have been taking this medicine  for more than three weeks, the dose  should be reduced gradually when  you stop taking steroids unless your  doctor says otherwise.   • Always carry this card with you and  show it to anyone who treats you  (for example a doctor, nurse,  pharmacist or dentist). For one year  after you stop the treatment, you  must mention that you have taken  steroids.   • If you become ill, or if you come into  contact with anyone who has an  infectious disease, consult your  doctor promptly. If you have never  had chickenpox, you should avoid  close contact with people who have  chickenpox or shingles. If you do  come into contact with chickenpox,  see your doctor urgently.   • Make sure that the information on  the card is kept up to date.   Other cautions include: children and adolescents  (growth restriction possibly irreversible), elderly (close  supervision required particularly on long-term treat-  ment); frequent monitoring required if history of tuber-  culosis (or X-ray changes), hypertension, recent myo-  cardial infarction (rupture reported), congestive heart  failure, diabetes mellitus including family history, osteo-  porosis (post-menopausal women at special risk), glauc-  oma (including family history), ocular herpes simplex —  risk of comeal perforation, severe affective disorders  (particularly if history of steroid-induced psychosis — see  also Psychiatric Reactions, p. 444), epilepsy, peptic ulcer,  hypothyroidism, history of steroid myopathy, ulcerative  colitis, diverticulitis, recent intestinal anastomoses,  thromboembolic disorders; myasthenia gravis; interac-  tions: Appendix 1 (corticosteroids).   Other contra-indications include: systemic infection  (unless specific therapy given); avoid live virus vaccines  in those receiving immunosuppressive doses (serum  antibody response diminished).   When corticosteroids are administered orally or parent-  erally, the plasma-drug concentration may be increased  in patients with hepatic impairment. Corticosteroids  should be used with caution in hepatic impairment  and the patient should be monitored closely.   Oral and parenteral preparations of corticosteroids  should be used with caution in patients with renal  impairment.   The benefit of treatment with corticosteroids during  pregnancy and breast-feeding outweighs the risk; preg-  nant women with fluid retention should be monitored  closely. Corticosteroid cover is required during labour.    Following a review of the data on the safety of systemic  corticosteroids used in pregnancy and breast-feeding  the CSM (May 1998) has concluded:   • corticosteroids vary in their ability to cross the  placenta; betamethasone and dexamethasone  cross the placenta readily while 88% of predniso-  lone is inactivated as it crosses the placenta;   • there is no convincing evidence that systemic cor-  ticosteroids increase the incidence of congenital  abnormalities such as cleft palate or lip;   when administration is prolonged or repeated dur-  ing pregnancy, systemic corticosteroids increase  the risk of intra-uterine growth restriction; there is  no evidence of intra-uterine growth restriction fol-  lowing short-term treatment (e.g. prophylactic  treatment for neonatal respiratory distress  syndrome);    • any adrenal suppression in the neonate following  prenatal exposure usually resolves spontaneously  after birth and is rarely clinically important;    • prednisolone appears in small amounts in breast  milk but maternal doses of up to 40 mg daily are  unlikely to cause systemic effects in the infant;  infants should be monitored for adrenal suppression  if the mothers are taking a higher dose.   Overdosage or prolonged use can exaggerate some of  the normal physiological actions of corticosteroids lead-  ing to mineralocorticoid and glucocorticoid side-effects.  Mineralocorticoid side-effects include hypertension,  sodium and water retention, and potassium and calcium  loss. They are most marked with fludrocortisone, but  are significant with cortisone, hydrocortisone, cortico-  tropin, and tetracosactide (tetracosactrin). Mineralocor-  ticoid actions are negligible with the high potency gluco-  corticoids, betamethasone and dexamethasone, and  occur only slightly with methylprednisolone, predniso-  lone, and triamcinolone.   Glucocorticoid side-effects include diabetes and osteo-  porosis (section 6.6), which is a danger, particularly in  the elderly, as it can result in osteoporotic fractures for  example of the hip or vertebrae; in addition high doses  are associated with avascular necrosis of the femoral  head. Muscle wasting (proximal myopathy) can also  occur. Corticosteroid therapy is also weakly linked  with peptic ulceration and perforation (the potential    advantage of soluble or enteric-coated preparations to  reduce the risk is speculative only). See also Psychiatric  Reactions, p. 444.   High doses of corticosteroids can cause Cushing’s  syndrome, with moon face, striae, and acne; it is usually  reversible on withdrawal of treatment, but this must  always be gradually tapered to avoid symptoms of  acute adrenal insufficiency (important: see also Adr-  enal Suppression, p. 444).   In children, administration of corticosteroids may result  in suppression of growth. For the effect of corticoster-  oids given in pregnancy, see Pregnancy and Breast-  feeding, above.   Side-effects can be minimised by using lowest effective  dose for minimum period possible.   Other side-effects include : gastro-intestinal effects : dys-  pepsia, abdominal distension, acute pancreatitis, oeso-  phageal ulceration and candidiasis; musculoskeletal  effects : muscle weakness, vertebral and long bone frac-  tures, tendon rupture; endocrine effects : menstrual irre-  gularities and amenorrhoea, hirsutism, weight gain,  hypercholesterolaemia, hyperlipidaemia, negative nitro-  gen and calcium balance, increased appetite; increased  susceptibility to and severity of infection, reactivation of  dormant tuberculosis; neuropsychiatric effects: psycho-  logical dependence, insomnia, increased intracranial  pressure with papilloedema in children (usually after  withdrawal), aggravation of schizophrenia, aggravation  of epilepsy; ophthalmic effects: glaucoma, papilloede-  ma, posterior subcapsular cataracts, comeal or scleral  thinning and exacerbation of ophthalmic viral or fungal  disease, increased intra-ocular pressure, exophthalmos;  also impaired healing, petechiae, ecchymoses, facial  erythema, suppression of skin test reactions, urticaria,  hyperhidrosis, skin atrophy, bruising, telangiectasia,  myocardial rupture following recent myocardial infarc-  tion, congestive heart failure, leucocytosis, hyperglyc-  aemia, thromboembolism, nausea, malaise, hiccups,  headache, vertigo.   For other references to the side-effects of corticoster-  oids see section 3.2 (asthma), section 11.4 (eye) and  section 13.4 (skin).   Indications suppression of inflammatory and allergic  disorders; congenital adrenal hyperplasia; see also  notes above; ear (section 12.1.1); eye (section 11.4.1);  nose (section 12.2.1); oral ulceration (section 12.3.1)  Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above; transient effect on fetal  movements and heart rate  Breast-feeding see notes above  Side-effects see notes above  Dose   • By intramuscular injection or slow intravenous  injection or infusion, 4-20 mg, repeated up to 4 times  in 24 hours; CHILD, by slow intravenous injection, up to  1 year 1 mg, 1-5 years 2 mg, 6-12 years 4 mg,  repeated up to 4 times in 24 hours according to  response   Betnesol® (UCB Pharma) (Ml  Soluble tablets, pink, scored, betamethasone  500 micrograms (as sodium phosphate). Net price  100-tab pack = £4.97. Label: 10, steroid card, 13, 21  Injection, betamethasone 4 mg (as sodium phos-  phate) /mL. Net price 1-mL amp = £1.17. Label: 10,  steroid card   Cortisone (Non-proprietary) (MI  Tablets, cortisone acetate 25 mg, net price 56-tab  pack = £10.54. Label: 10, steroid card, 21   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • Usual maintenance 3-18 mg daily (acute disorders,  initially up to 120 mg daily); see also Administration  (above)   CHILD 0.25-1.5 mg/kg daily (or on alternate days); see  also Administration (above)   Calcort® (Sanofi-Aventis) (Ml  Tablets, deflazacort 6 mg, net price 60-tab pack =  £15.82. Label: 5, 10, steroid card   Indications suppression of inflammatory and allergic  disorders; diagnosis of Cushing’s disease, congenital  adrenal hyperplasia; cerebral oedema associated with  malignancy; croup (section 3.1); nausea and vomiting  with chemotherapy (section 8.1); rheumatic disease  (section 10.1.2); eye (section 11.4.1); see also notes  above   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above    Breast-feeding see notes above  Side-effects see notes above; also perineal irritation  may follow intravenous administration of the phos-  phate ester   • By mouth, usual range 0.5-10 mg daily; CHILD 10-  100 micrograms/kg daily; see also Administration  (above)   Note Dexamethasone lmg = dexamethasone phosphate  1.2 mg = dexamethasone sodium phosphate 1.3 mg    Dexamethasone (Non-proprietary) (Ml  Tablets, dexamethasone 500 micrograms, net price  28-tab pack = £38.00; 2 mg, 50-tab pack = £7.46, 100-  tab pack = £13.85. Label: 10, steroid card, 21  Oral solution, sugar-free, dexamethasone (as sodium  phosphate) 2mg/5mL, net price 150-mL = £42.30.  Label: 10, steroid card, 21  Brands include Dexsol ®   Dose By intramuscular injection orslow intravenous injection or  infusion, 0.4-20 mg; CHILD 200-400 micrograms/kg daily  Cerebral oedema, by intravenous injection 8-16 mg initially, then  5 mg by intramuscular injection or intravenous injection every 6  hours as required for 2-4 days then gradually reduced and  stopped over 5-7 days   Adjunctive treatment of bacterial meningitis, (starting before or  with first dose of antibacterial treatment), [unlicensed indication],  by intravenous injection 8.3 mg every 6 hours for 4 days; CHILD  125 micrograms/kg every 6 hours for 4 days   Dose by intramuscular injection orslow intravenous injection or  infusion, 0.4-20 mg; CHILD 167-333 micrograms/kg daily  Cerebral oedema associated with malignancy, by intravenous  injection 8.3 mg initially, then 3.3 mg by intramuscular injection  every 6 hours as required for 2-4 days then gradually reduced and  stopped over 5-7 days   Adjunctive treatment of bacterial meningitis, (starting before or  with first dose of antibacterial treatment), [unlicensed indication],  by intravenous injection 8.3 mg every 6 hours for 4 days; CHILD  125 micrograms/kg every 6 hours for 4 days   6.3.1) ; shock; see also notes above; hypersensitivity  reactions e.g. anaphylaxis and angioedema (section  3.4.3); asthma (section 3.1); severe inflammatory  bowel disease (section 1.5); haemorrhoids (section   1.7.2) ; rheumatic disease (section 10.1.2); eye (section  11.4.1); skin (section 13.4)   Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; also phosphate ester  associated with paraesthesia and pain (particularly in  the perineal region)   • By intramuscular injection orslow intravenous injec-  tion or infusion, 100-500 mg, 3-4 times in 24 hours or    as required; CHILD by slow intravenous injection up to  1 year 25 mg, 1-5 years 50 mg, 6-12 years 100 mg   Hydrocortisone (Non-proprietary) (Ml  Tablets, scored, hydrocortisone 10 mg, net price 30-  tab pack = £44.25; 20 mg, 30-tab pack = £47.17.  Label: 10, steroid card, 21   1 Efcortesol® (Sovereign) [Ml  Injection, hydrocortisone 100 mg (as sodium phos-  phate)/mL, net price 1-mL amp = £1.08, 5-mL amp =  £4.89. Label: 10, steroid card   Note Paraesthesia and pain (particularly in the perineal region)  may follow intravenous injection of the phosphate ester  1. [Ml restriction does not apply where administration is for  saving life in emergency   ^olu-Cortef® (Pharmacia) (Ml  Injection, powder for reconstitution, hydrocortisone  (as sodium succinate). Net price 100-mg vial = 92p,  100-mg vial with 2-mL amp water for injections =  £1.16. Label: 10, steroid card  1. [Ml restriction does not apply where administration is for  saving life in emergency   Indications suppression of inflammatory and allergic  disorders; severe inflammatory bowel disease (sec-  tion 1.5); cerebral oedema associated with malig-  nancy; see also notes above; rheumatic disease (sec-  tion 10.1.2); skin (section 13.4)   Cautions see notes above; also rapid intravenous  administration of large doses associated with cardio-  vascular collapse   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • By intramuscular injection or slow intravenous  injection or infusion, initially 10-500 mg; graft rejec-  tion, up to 1 g daily by intravenous infusion for up to 3  days   Medrone® (Pharmacia) (Ml  Tablets, scored, methylprednisolone 2 mg (pink), net  price 30-tab pack = £3.88; 4 mg, 30-tab pack = £6.19;  16 mg, 30-tab pack = £17.17; 100 mg (blue), 20-tab  pack = £48.32. Label: 10, steroid card, 21   Solu-Medrone® (Pharmacia) Ml  Injection, powder for reconstitution, methyl-  prednisolone (as sodium succinate) (all with solvent).  Net price 40-mg vial = £1.58; 125-mg vial = £4.75;  500-mg vial = £9.60; 1-g vial = £17.30; 2-g vial =  £32.86. Label: 10, steroid card   Injection (aqueous suspension), methylprednisolone  acetate 40 mg/mL. Net price 1-mL vial = £2.87; 2-mL  vial = £5.15; 3-mL vial = £7.47. Label: 10, steroid card  Dose by deep intramuscular injection into gluteal muscle, 40-  120 mg, a second injection may be given after 2-3 weeks if  required   Indications suppression of inflammatory and allergic  disorders; see also notes above; inflammatory bowel  disease (section 1.5); asthma (section 3.1 and section   8.2.2) ; rheumatic disease (section 10.1.2); eye (section  11.4.1); ear (section 12.1.1)   Cautions see notes above; also Duchenne’s muscular  dystrophy (possible transient rhabdomyolysis and  myoglobinuria following strenuous physical activity)   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   • By mouth, initially, up to 10-20 mg daily (severe  disease, up to 60 mg daily), preferably taken in the  morning after breakfast; can often be reduced within a  few days but may need to be continued for several  weeks or months   Maintenance, usual range, 2.5-15 mg daily, but higher  doses may be needed; Cushingoid side-effects  increasingly likely with doses above 7.5 mg daily   • By intramuscular injection, prednisolone acetate  (section 10.1.2.2), 25-100 mg once or twice weekly   Prednisolone (Non-proprietary) Ml  Tablets, prednisolone 1 mg, net price 28-tab pack =  93p; 5 mg, 28-tab pack = £1.03; 25 mg, 56-tab pack =  £30.00. Label: 10, steroid card, 21  Tablets, e/c, prednisolone 2.5 mg (brown), net price  30-tab pack = £4.65, 100-tab pack = £30.79; 5 mg  (red), 28-tab pack = £8.69, 100-tab pack = £31.04.  Label: 5, 10, steroid card, 25   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • ADULT over 18 years, initially 10-20 mg at bedtime,  adjusted according to response   Tablets, m/r, yellow, prednisone 1 mg, net price 30-  tab pack = £26.70; 2 mg, 30-tab pack = £26.70, 100-  tab pack = £89.00; 5 mg, 30-tab pack = £26.70, 100-  tab pack = £89.00. Label: 10, steroid card, 21, 25   Indications suppression of inflammatory and allergic  disorders; see also notes above; rheumatic disease  (section 10.1.2); skin (section 13.4)   Cautions see notes above; also high dosage may cause  proximal myopathy, avoid in chronic therapy  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above  Dose   • By deep intramuscular injection, into gluteal muscle,  40 mg of acetonide for depot effect, repeated at  intervals according to the patient’s response; max.  single dose 100 mg   Kenalog® Intra-articular/lntramuscular (Squibb) (Mi  Injection (aqueous suspension), triamcinolone  acetonide 40mg/mL, net price 1-mL vial = £1.49.  Label: 10, steroid card    Oestrogens are necessary for the development of  female secondary sexual characteristics; they also sti-  mulate myometrial hypertrophy with endometrial  hyperplasia.    In terms of oestrogenic activity natural oestrogens  (estradiol (oestradiol), estrone (oestrone), and estriol  (oestriol)) have a more appropriate profile for hormone  replacement therapy (HRT) than synthetic oestrogens  (ethinylestradiol (ethinyloestradiol) and mestranol).  Tibolone has oestrogenic, progestogenic and weak  androgenic activity.    Oestrogen therapy is given cyclically or continuously for  a number of gynaecological conditions. If long-term  therapy is required in women with a uterus, a progesto-  gen should normally be added to reduce the risk of  cystic hyperplasia of the endometrium (or of endome-  triotic foci in women who have had a hysterectomy) and  possible transformation to cancer.    Oestrogens are no longer used to suppress lactation  because of their association with thromboembolism.   Hormone replacement therapy (HRT) with small doses  of an oestrogen (together with a progestogen in women  with a uterus) is appropriate for alleviating menopausal    symptoms such as vaginal atrophy or vasomotor  instability. Oestrogen given systemically in the perime-  nopausal and postmenopausal period or tibolone given  in the postmenopausal period also diminish postmeno-  pausal osteoporosis (section 6.6.1) but other drugs (sec-  tion 6.6) are preferred. Menopausal atrophic vaginitis  may respond to a short course of a topical vaginal  oestrogen preparation (section 7.2.1) used for a few  weeks and repeated if necessary.   Systemic therapy with an oestrogen or drugs with  oestrogenic properties alleviates the symptoms of oes-  trogen deficiency such as vasomotor symptoms. Tibol-  one combines oestrogenic and progestogenic activity  with weak androgenic activity; it is given continuously,  without cyclical progestogen.   HRT may be used in women with early natural or  surgical menopause (before age 45 years), since they  are at high risk of osteoporosis. For early menopause,  HRT can be given until the approximate age of natural  menopause (i.e. until age 50 years). Alternatives to HRT  should be considered if osteoporosis is the main con-  cern (section 6.6).    Clonidine (section 2.5.2 and section 4.7. 4.2) may be  used to reduce vasomotor symptoms in women who  cannot take an oestrogen, but clonidine may cause  unacceptable side-effects.    HRT increases the risk of venous thromboembolism,  stroke, endometrial cancer (reduced by a progestogen),  breast cancer, and ovarian cancer; there is an increased  risk of coronary heart disease in women who start  combined HRT more than 10 years after menopause.  For details of these risks see HRT Risk table, p. 450.  The minimum effective dose of HRT should be used for  the shortest duration. Treatment should be reviewed at  least annually and for osteoporosis alternative treat-  ments considered (section 6.6). HRT does not prevent  coronary heart disease or protect against a decline in  cognitive function and it should not be prescribed for  these purposes. Experience of treating women over 65  years with HRT is limited.   For the treatment of menopausal symptoms the benefits  of short-term HRT outweigh the risks in the majority of  women, especially in those aged under 60 years.    Risk of breast cancer It is estimated that using all  types of HRT, including tibolone, increases the risk of  breast cancer within 1-2 years of initiating treatment,  see HRT Risk table, p. 450 for details. The increased risk  is related to the duration of HRT use (but not to the age  at which HRT is started) and this excess risk disappears  within 5 years of stopping.   Radiological detection of breast cancer can be made  more difficult as mammographic density can increase  with HRT use; tibolone has only a limited effect on  mammographic density.    Risk of endometrial cancer The increased risk of  endometrial cancer depends on the dose and duration of  oestrogen-only HRT, see HRT Risk table, p. 450 for  details.   In women with a uterus, the addition of a progestogen  cyclically (for at least 10 days per 28-day cycle) reduces  the additional risk of endometrial cancer; this additional  risk is eliminated if a progestogen is given continuously.  However, this should be weighed against the increased  risk of breast cancer.    stroke. Combined HRT or oestrogen-only HRT slightly  increases the risk of stroke. Tibolone increases the risk  of stroke about 2.2 times from the first year of treatment,  see HRT Risk table, below for details.   Risk of coronary heart disease HRT does not  prevent coronary heart disease and should not be pre-  scribed for this purpose. There is an increased risk of  coronary heart disease in women who start combined  HRT more than 10 years after menopause, see HRT Risk  table, below for details. Although very little information  is available on the risk of coronary heart disease in  younger women who start HRT close to the menopause,  studies suggest a lower relative risk compared with  older women.   Choice The choice of HRT for an individual depends  on an overall balance of indication, risk, and conveni-  ence. A woman with a uterus normally requires oestro-  gen with cyclical progestogen for the last 12 to 14 days  of the cycle or a preparation which involves continuous  administration of an oestrogen and a progestogen (or  one which provides both oestrogenic and progestogenic   Note Where background incidence or additional cases have not been included in the table, this indicates a lack of available  data. NS indicates a non-significant difference   Taken from MHRA/CHM ( Drug Safety Update 2007; 1 (2): 2-6) available at www.mhra.gov.uk/drugsafetyupdate   Risk of ovarian cancer Long-term use of combined  HRT or oestrogen-only HRT is associated with a small  increased risk of ovarian cancer, see HRT Risk table,  below for details; this excess risk disappears within a  few years of stopping.   Risk of venous thromboembolism Women using  combined or oestrogen-only HRT are at an increased  risk of deep vein thrombosis and of pulmonary embo-  lism especially in the first year of use, see HRT Risk  table, below for details.   In women who have predisposing factors (such as a  personal or family history of deep vein thrombosis or  pulmonary embolism, severe varicose veins, obesity,  trauma, or prolonged bed-rest) it is prudent to review  the need for HRT, as in some cases the risks of HRT may  exceed the benefits. See below for advice on surgery.  Travel involving prolonged immobility further increases  the risk of deep vein thrombosis, see under Travel in  section 7.3.1.   Risk of stroke Risk of stroke increases with age,  therefore older women have a greater absolute risk of    1. Tibolone increases the risk of breast cancer but to a lesser extent than with combined HRT.   2. Evidence suggests an increased risk of endometrial cancer with tibolone. After 2.7 years of use (in women of average age 68  years), 1 extra case of endometrial hyperplasia and 4 extra cases of endometrial cancer were diagnosed compared with  placebo users.   3. The risk of endometrial cancer cannot be reliably estimated in those using combined HRT because the addition of  progestogen for at least 10 days per 28-day cycle greatly reduces the additional risk, and addition of a daily progestogen  eliminates the additional risk. The risk of endometrial cancer in women who have not used HRT increases with body mass  index (BMI); the increased risk of endometrial cancer in users of oestrogen-only HRT or tibolone is more apparent in women  who are not overweight.   4. Limited data does not suggest an increased risk of thromboembolism with tibolone compared with combined HRT or women  not taking HRT.   5. Although the level of risk of thromboembolism associated with non-oral routes of administration of HRT has not been  established, it may be lower for the transdermal route.   6. Tibolone increases the risk of stroke about 2.2 times from the first year of treatment; risk of stroke is age-dependent and  therefore the absolute risk of stroke with tibolone increases with age.   7. Increased risk of coronary heart disease in women who start combined HRT more than 10 years after menopause.   8. There is insufficient data to draw a conclusion on the risk of coronary heart disease with tibolone.    activity in a single preparation). Continuous combined  preparations or tibolone are not suitable for use in the  perimenopause or within 12 months of the last men-  strual period; women who use such preparations may  bleed irregularly in the early stages of treatment — if  bleeding continues endometrial abnormality should be  ruled out and consideration given to changing to cycli-  cal HRT.   An oestrogen alone is suitable for continuous use in  women without a uterus. However, in endometriosis,  endometrial foci may remain despite hysterectomy and  the addition of a progestogen should be considered in  these circumstances.   An oestrogen may be given by mouth or it may be given  by subcutaneous or transdermal administration, which  avoids first-pass metabolism. In the case of subcuta-  neous implants, recurrence of vasomotor symptoms at  supraphysiological plasma concentrations may occur;  moreover, there is evidence of prolonged endometrial  stimulation after discontinuation (calling for continued  cyclical progestogen). For the use of topical HRT pre-  parations see section 7.2.1.   Contraception HRT does not provide contraception  and a woman is considered potentially fertile for 2 years  after her last menstrual period if she is under 50 years,  and for 1 year if she is over 50 years. A woman who is  under 50 years and free of all risk factors for venous and  arterial disease can use a low-oestrogen combined oral  contraceptive pill (section 7.3.1) to provide both relief of  menopausal symptoms and contraception; it is recom-  mended that the oral contraceptive be stopped at 50  years of age since there are more suitable alternatives. If  any potentially fertile woman needs HRT, non-hormonal  contraceptive measures (such as condoms) are neces-  sary.   Measurement of follicle-stimulating hormone can help  to determine fertility, but high measurements alone  (particularly in women aged under 50 years) do not  necessarily preclude the possibility of becoming preg-  nant.   Surgery Major surgery under general anaesthesia,  including orthopaedic and vascular leg surgery, is a  predisposing factor for venous thromboembolism and  it may be prudent to stop HRT 4-6 weeks before  surgery (see Risk of Venous Thromboembolism,  above); it should be restarted only after full mobilisation.  If HRT is continued or if discontinuation is not possible  (e.g. in non-elective surgery), prophylaxis with unfrac-  tionated or low molecular weight heparin and graduated  compression hosiery is advised. Oestrogenic activity  may persist after removing an estradiol implant (see  above).   Reasons to stop HRT For circumstances in which  HRT should be stopped, see p. 496.   Note Relates only to small amounts of oestrogens given for  hormone replacement therapy   Indications see notes above and under preparations  Cautions prolonged exposure to unopposed oestro-  gens may increase risk of developing endometrial    cancer (see notes above); migraine (or migraine-like  headaches); diabetes (increased risk of heart disease);  history of breast nodules or fibrocystic disease — clo-  sely monitor breast status (risk of breast cancer, see  notes above); risk factors for oestrogen-dependent  tumours (e.g. breast cancer in first-degree relative);  uterine fibroids may increase in size, symptoms of  endometriosis may be exacerbated; history of endo-  metrial hyperplasia; factors predisposing to throm-  boembolism (see notes above); presence of anti-  phospholipid antibodies (increased risk of thrombotic  events); increased risk of gall-bladder disease  reported; hypophyseal tumours; acute porphyria (see  section 9.8.2); interactions: Appendix 1 (oestrogens)  Other conditions The product literature advises caution in  other conditions including hypertension, renal disease,  asthma, epilepsy, sickle-cell disease, melanoma, otosclerosis,  multiple sclerosis, and systemic lupus erythematosus (but  care required if antiphospholipid antibodies present, see  above). Evidence for caution in these conditions is unsatis-  factory and many women with these conditions may stand to  benefit from HRT.    Contra-indications oestrogen-dependent cancer, his-  tory of breast cancer, active thrombophlebitis, active  or recent arterial thromboembolic disease (e.g. angina  or myocardial infarction), venous thromboembolism,  or history of recurrent venous thromboembolism  (unless already on anticoagulant treatment), liver  disease (where liver function tests have failed to  return to normal), Dubin-Johnson and Rotor syn-  dromes (or monitor closely), untreated endometrial  hyperplasia, undiagnosed vaginal bleeding  Hepatic impairment see Combined Hormonal  Contraceptives, section 7.3.1  Renal impairment see Other Conditions, above  Pregnancy see Combined Hormonal Contraceptives,  section 7.3.1    Side-effects see notes above for risks of long-term  use; nausea and vomiting, abdominal cramps and  bloating, weight changes, breast enlargement and  tenderness, premenstrual-like syndrome, sodium and  fluid retention, cholestatic jaundice, glucose intoler-  ance, altered blood lipids — may lead to pancreatitis,  rashes and chloasma, changes in libido, depression,  mood changes, headache, migraine, dizziness, leg  cramps (rule out venous thrombosis), vaginal candi-  diasis, contact lenses may irritate; transdermal deliv-  ery systems may cause contact sensitisation (possible  severe hypersensitivity reaction on continued expo-  sure), and headache has been reported on vigorous  exercise   Withdrawal bleeding Cyclical HRT (where a progestogen  is taken for 12-14 days of each 28-day oestrogen treatment  cycle) usually results in regular withdrawal bleeding towards  the end of the progestogen. The aim of continuous combined  HRT (where a combination of oestrogen and progestogen is  taken, usually in a single tablet, throughout each 28-day  treatment cycle) is to avoid bleeding, but irregular bleeding  may occur during the early treatment stages (if it continues  endometrial abnormality should be excluded and consid-  eration given to cyclical HRT instead)   Counselling on patches Patch should be removed after 3-  4 days (or once a week in case of 7-day patch) and replaced  with fresh patch on slightly different site; recommended  sites: clean, dry, unbroken areas of skin on trunk below  waistline; not to be applied on or near breasts or under  waistband. If patch falls off in bath allow skin to cool before  applying new patch   Premique® (Wyeth) (Ml  Premique® Low Dose tablets, m/r, ivory, s/c,  conjugated oestrogen (equine) 300 micrograms and  medroxyprogesterone acetate 1.5 mg, net price 3 x  28-tab pack = £6.52   Dose menopausal symptoms in women with a uterus, 1 tablet  daily continuously   Premique® tablets, s/c, blue, conjugated oestrogen  (equine) 625 micrograms and medroxyprogesterone  acetate 5 mg, net price 3 x 28-tab pack = £10.61  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 tablet daily continuously   Prempak C® 0.625 Calendar pack, s/c, 28 maroon  tablets, conjugated oestrogens (equine) 625 micr-  ograms; 12 light brown tablets, norgestrel 150 micr-  ograms (= levonorgestrel 75 micrograms), net price 3  x 40-tab pack = £6.25   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 maroon tablet daily  continuously, starting on day 1 of menstruation (or at any time if  cycles have ceased or are infrequent), and 1 brown tablet daily on  days 17-28 of each 28-day treatment cycle; subsequent courses  are repeated without interval   Prempak C® 1.25 Calendar pack, s/c, 28 yellow  tablets, conjugated oestrogens (equine) 1.25 mg; 12  light brown tablets, norgestrel 150 micrograms ( =  levonorgestrel 75 micrograms), net price 3 x 40-tab  pack = £7.40   Dose see under 0.625 Calendar pack, but taking 1 yellow tablet  daily continuously (instead of 1 maroon tablet) if symptoms not  fully controlled with lower strength   Angeliq® (Bayer Schering) Ml  Tablets, f/c, red, estradiol lmg, drospirenone 2 mg,  net price 3 x 28-tab pack = £24.32  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus whose last menstrual period  occurred over 12 months previously, 1 tablet daily continuously (if  changing from cyclical HRT begin treatment the day after finish-  ing oestrogen plus progestogen phase)   Cautions use with care if an increased concentration of potas-  sium might be hazardous    Climagest® (Novartis) (Ml  Climagest® 1-mg tablets, 16 grey-blue, estradiol  valerate 1 mg; 12 white, estradiol valerate 1 mg and  norethisterone 1 mg, net price 28-tab pack = £4.59; 3  x 28-tab pack = £13.35   Dose menopausal symptoms, 1 grey-blue tablet daily for 16  days, starting on day 1 of menstruation (or at any time if cycles  have ceased or are infrequent) then 1 white tablet for 12 days;  subsequent courses are repeated without interval   Climagest® 2-mg tablets, 16 blue, estradiol valerate  2 mg; 12 yellow, estradiol valerate 2 mg and norethi-  sterone 1 mg, net price 28-tab pack = £4.59; 3 x 28-  tab pack = £13.35   Dose see Climagest ® 1-mg, but starting with 1 blue tablet daily  (instead of 1 grey-blue tablet) if symptoms not controlled with  lower strength   Tablets, pink, estradiol valerate 2 mg, norethisterone  700 micrograms, net price 1 x 28-tab pack = £8.27; 3  x 28-tab pack = £24.82   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus whose last menstrual period  occurred over 12 months previously, 1 tablet daily continuously   Tablets, f/c, 16 white, estradiol 2 mg; 12 pink, estra-  diol 2 mg and norethisterone 1 mg, net price 3 x 28-  tab pack = £9.23   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 white tablet daily for 16  days starting on day 5 of menstruation (or at any time if cycles  have ceased or are infrequent), then 1 pink tablet daily for 12 days;  subsequent courses repeated without interval   Cyclo-Progynova® (Meda) (Ml  Cyclo-Progynova® 2-mg tablets, s/c, 11 white,  estradiol valerate 2 mg; 10 brown, estradiol valerate  2 mg and norgestrel 500 micrograms (= levonor-  gestrel 250 micrograms), net price per pack = £3.11  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus, 1 white tablet daily for 1 1  days, starting on day 5 of menstruation (or at any time if cycles  have ceased or are infrequent), then 1 brown tablet daily for 10  days, followed by a 7-day tablet-free interval   Elleste-Duet® 1-mg tablets, 16 white, estradiol 1 mg;  12 green, estradiol 1 mg and norethisterone acetate   Dose menopausal symptoms, 1 white tablet daily for 16 days  starting on day 1 of menstruation (or at any time if cycles have  ceased or are infrequent), then 1 green tablet daily for 12 days;  subsequent courses are repeated without interval   2 mg; 12 grey, estradiol 2 mg, norethisterone acetate  1 mg, net price 3 x 28-tab pack = £9.72   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1 orange tablet daily for 16 days, starting on day 1 of  menstruation (or at any time if cycles have ceased or are infre-  quent) then 1 grey tablet daily for 12 days; subsequent courses are  repeated without interval   Elleste-Duet Conti® tablets, f/c, grey, estradiol 2 mg,  norethisterone acetate 1 mg, net price 3 x 28-tab pack  = £16.93   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus whose last menstrual period  occurred over 12 months previously, 1 tablet daily on a contin-  uous basis (if changing from cyclical HRT begin treatment at the  end of scheduled bleed)   Evorel® (Janssen-Cilag) (Ml  Evorel® Conti patches, self-adhesive, (releasing  estradiol approx. 50 micrograms/24 hours and nor-  ethisterone acetate approx. 170 micrograms/   24 hours), net price 8-patch pack = £13.00, 24-patch  pack = £37.22. Counselling, administration  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 patch to be applied twice  weekly continuously   Evorel® Sequi combination pack, 4 self-adhesive  patches of Evorel® 50 (releasing estradiol approx.   50 micrograms/24 hours) and 4 self-adhesive patches  of Evorel® Conti (releasing estradiol approx.   50 micrograms/24 hours and norethisterone acetate  approx. 170 micrograms/24 hours), net price 8-patch  pack = £11.09. Counselling, administration  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 Evorel '® 50 patch to be  applied twice weekly for 2 weeks, starting within 5 days of onset of  menstruation (or at any time if cycles have ceased or are  infrequent), followed by 1 Evorel ® Conti patch twice weekly for 2  weeks; subsequent courses are repeated without interval    Femapak® (Abbott Healthcare) (MO  Femapak® 40 combination pack of 8 self-adhesive  patches of Fematrix® 40 (releasing estradiol approx.  40 micrograms/24 hours) and 14 tablets of dydro-  gesterone 10 mg, net price per pack = £7.61.  Counselling, administration  Dose see under Femapak 9 80   Femapak® 80 combination pack of 8 self-adhesive  patches of Fematrix® 80 (releasing estradiol approx.  80 micrograms/24 hours) and 14 tablets of dydro-  gesterone 10 mg, net price per pack = £8.06.  Counselling, administration   Dose menopausal symptoms (and osteoporosis prophylaxis (see  section 6.6) in case of Femapak 9 80 only), in women with a  uterus, starting within 5 days of onset of menstruation (or any  time if cycles have ceased or are infrequent), apply 1 patch twice  weekly continuously and take 1 tablet daily on days 15-28 of each  28-day treatment cycle; therapy should be initiated with  Femapak ® 40 in those with menopausal symptoms, prolonged  oestrogen deficiency or anticipated intolerance to higher  strengths, subsequendy adjusted to lowest effective dose    Femoston® (Abbott Healthcare) (Ml  Femoston® 1/10 tablets, f/c, 14 white, estradiol  lmg; 14 grey, estradiol lmg, dydrogesterone 10 mg,  net price 3 x 28-tab pack = £13.47  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 white tablet daily for 14  days, starting within 5 days of onset of menstruation (or any time  if cycles have ceased or are infrequent) then 1 grey tablet daily for  14 days; subsequent courses repeated without interval   Femoston® 2/10 tablets, f/c, 14 red, estradiol 2 mg;  14 yellow, estradiol 2 mg, dydrogesterone 10 mg, net  price 3 x 28-tab pack = £13.47   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 red tablet daily for 14 days,  starting within 5 days of onset of menstruation (or any time if  cycles have ceased or are infrequent) then 1 yellow tablet daily for  14 days; subsequent courses repeated without interval; where  therapy required for menopausal symptoms alone, Femoston ® 1 /  10 given initially and Femoston 9 2/10 substituted if symptoms  not controlled   Femoston®-conti tablets, f/c, salmon, estradiol  1 mg, dydrogesterone 5 mg, net price 3 x 28-tab pack  = £22.44   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus whose last menstrual period  occurred over 12 months previously, 1 tablet daily continuously (if  changing from cyclical HRT begin treatment the day after finish-  ing oestrogen plus progestogen phase)   50 micrograms/24 hours and levonorgestrel approx.  7 micrograms/24 hours); net price 4-patch pack =  £15.48, 12-patch pack = £ 44.12. Counselling,  administration   Dose menopausal symptoms in women with a uterus whose last  menstrual period occurred over 12 months previously, 1 patch to  be applied once a week continuously    FemSeven® Sequi (Merck Serono) (Ml  Combination pack, self-adhesive patches of FemSe-  ven® Sequi Phase 1 (releasing estradiol approx.   50 micrograms/24 hours) and of FemSeven® Sequi  Phase 2 (releasing estradiol approx. 50 micrograms/  24 hours and levonorgestrel approx. 10 micrograms/  24 hours); net price 1-month pack (2 of each) =  £13.18, 3-month pack (6 of each) = £37.54. Counsel-  ling, administration   Dose menopausal symptoms in women with a uterus, 1 Phase 1  patch applied once a week for 2 weeks followed by 1 Phase 2  patch once a week for 2 weeks; subsequent courses are repeated  without interval   Indivina® 1 mg/2.5 mg tablets, estradiol valerate  lmg, medroxyprogesterone acetate 2.5 mg, net price  3 x 28-tab pack = £20.58  Indivina® 1 mg/5 mg tablets, estradiol valerate   1 mg, medroxyprogesterone acetate 5 mg, net price 3  x 28-tab pack = £20.58   2 mg, medroxyprogesterone acetate 5 mg, net price 3  x 28-tab pack = £20.58   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus whose last menstrual period  occurred over 3 years previously, 1 tablet daily continuously;  initiate therapy with Indivina 9 1 mg/ 2.5 mg tablets and adjust  according to response; start at end of scheduled bleed if changing  from cyclical HRT    Kliofem® (Novo Nordisk) (5°M1  Tablets, f/c yellow, estradiol 2 mg, norethisterone  acetate 1 mg, net price 3 x 28-tab pack = £11.43  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus whose last menstrual period  occurred over 12 months previously, 1 tablet daily continuously;  start at end of scheduled bleed if changing from cyclical HRT   Tablets, f/c, estradiol 1 mg, norethisterone acetate  500 micrograms, net price 3 x 28-tab pack = £13.20  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus whose last menstrual period  occurred over 12 months previously, 1 tablet daily continuously;  start at end of scheduled bleed if changing from cyclical HRT    Novofem® (Novo Nordisk) (Ml  Tablets, f/c, 16 red, estradiol 1 mg; 12 white, estradiol  1 mg, norethisterone acetate 1 mg, net price 3 x 28-  tab pack = £13.50   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 red tablet daily for 16 days  then 1 white tablet daily for 12 days; subsequent courses are  repeated without interval; start treatment with red tablet at any  time or if changing from cyclical HRT, start treatment the day after  finishing oestrogen plus progestogen phase   Nuvelle® Continuous (Bayer Schering) (Ml  Tablets, f/c, pink, estradiol 2 mg, norethisterone  acetate 1 mg, net price 3 x 28-tab pack = £15.89  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6) in women with a uterus whose last menstrual period  occurred over 12 months previously, 1 tablet daily continuously; if  changing from cyclical HRT, start treatment the day after finishing  oestrogen plus progestogen phase   Tablets, 70 white, estradiol valerate 2 mg; 14 blue,  estradiol valerate 2 mg and medroxyprogesterone  acetate 20 mg; 7 yellow, inactive, net price 91-tab  pack = £20.49   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 white tablet daily for 70  days, then 1 blue tablet daily for 14 days, then 1 yellow tablet daily  for 7 days; subsequent courses are repeated without interval    Trisequens® (Novo Nordisk) (Ml  Tablets, 12 blue, estradiol 2 mg; 10 white, estradiol  2 mg, norethisterone acetate 1 mg; 6 red, estradiol  1 mg, net price 3 x 28-tab pack = £11.10  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), in women with a uterus, 1 blue tablet daily, starting on  day 5 of menstruation (or at any time if cycles have ceased or are  infrequent), then 1 tablet daily in sequence (without interruption)   300 micrograms (green) net price 3 x 28-tab pack =  £6.07; 625 micrograms (maroon), 3 x 28-tab pack =  £4.02; 1.25 mg (yellow), 3 x 28-tab pack = £3.58  Dose menopausal symptoms, 0.3-1.25 mg daily continuously;  osteoporosis prophylaxis (see section 6.6), 0.625-1.25 mg daily  continuously; with cyclical progestogen for 12-14 days of each  cycle in women with a uterus   Dose by implantation, oestrogen replacement, and osteoporosis  prophylaxis (see section 6.6) (with cyclical progestogen for 12-14  days of each cycle in women with a uterus, see notes above), 25-  100 mg as required (usually every 4-8 months) according to  oestrogen levels — check before each implant  Note On cessation of treatment or if implants are removed from  those with a uterus, cyclical progestogen should be continued  until withdrawal bleed stops   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), with cyclical progestogen for 12-14 days of each  cycle in women with a uterus, 2 mg daily starting on day 1-5 of  menstruation (or at any time if cycles have ceased or are infre-  quent)   Tablets, estradiol valerate 1 mg (grey-blue), net price  1 x 28-tab pack = £2.45, 3 x 28-tab pack = £7.35;   B 2 mg (blue), 1 x 28-tab pack = £2.45, 3 x 28-tab pack  = £7.35   Dose menopausal symptoms (if patient has had a hysterectomy),  1-2 mg daily   Elleste-Solo® 1-mg tablets, estradiol 1 mg, net price  3 x 28-tab pack = £5.03   Dose menopausal symptoms, with cyclical progestogen for 12-  14 days of each cycle in women with a uterus, 1 mg daily starting  on day 1 of menstruation (or at any time if cycles have ceased or  are infrequent)   Elleste-Solo® 2-mg tablets, orange, estradiol 2 mg,  net price 3 x 28-tab pack = £5.34  Dose menopausal symptoms not controlled with lower strength  and osteoporosis prophylaxis (see section 6.6), with cyclical  progestogen for 12-14 days of each cycle in women with a uterus,  2 mg daily starting on day 1 of menstruation (or at any time if  cycles have ceased or are infrequent)   Elleste Solo® MX (Meda) (Ml  Patches, self-adhesive, estradiol, MX 40 patch  (releasing approx. 40 micrograms/ 24 hours), net price  8-patch pack = £5.19; MX 80 patch (releasing approx.  80 micrograms/24 hours), 8-patch pack = £5.99.  Counselling, administration.   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1 patch to be applied twice weekly continuously  starting within 5 days of onset of menstruation (or at any time if  cycles have ceased or are infrequent); with cyclical progestogen  for 12-14 days of each cycle in women with a uterus; for meno-  pausal symptoms initiate therapy with MX 40, subsequently  adjust according to response; for osteoporosis prophylaxis, initiate  therapy with MX 80   Estraderm MX® (Novartis) (Ml  Patches, self-adhesive, estradiol, MX 25 patch  (releasing approx. 25 micrograms/24 hours), net price  8-patch pack = £4.58, 24-patch pack = £13.72; MX 50  patch (releasing approx. 50 micrograms/24 hours), 8-    patch pack = £4.59, 24-patch pack = £13.72, 20-patch  pack (hosp. only) = £13.04; MX 75 patch (releasing  approx. 75 micrograms/24 hours), 8-patch pack =  £5.35, 24-patch pack = £16.06; MX 100 patch  (releasing approx. 100 micrograms/ 24 hours), 8-patch  pack = £5.55, 24-patch pack = £16.66. Counselling,  administration   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1 patch to be applied twice weekly continuously  starting within 5 days of onset of menstruation (or at any time if  cycles have ceased or are infrequent), with cyclical progestogen  for at least 12 days of each cycle in women with a uterus; for  menopausal symptoms, initiate therapy with MX25 for first 3  months; for osteoporosis prophylaxis, initiate therapy with MX50-,  subsequently adjust according to response   Estraderm TTS® (Novartis) (Ml  Patches, self-adhesive, estradiol, TTS 25 patch  (releasing approx. 25 micrograms/24 hours), net  price, 8-patch pack = £5.96, 24-patch pack = £17.88;  TTS 100 patch (releasing approx. 100 micrograms/24  hours), 8-patch pack = £7.22, 24-patch pack = £21.72,  20-patch pack (hosp. only) = £16.76. Counselling,  administration   Dose menopausal symptoms, 1 patch to be applied twice weekly  continuously starting within 5 days of onset of menstruation (or at  any time if cycles have ceased or are infrequent), with cyclical  progestogen for at least 12 days of each cycle in women with a  uterus; initiate therapy with TTS 25 for first 3 months, subse-  quently adjust according to response   37.5 micrograms/24 hours), 8-patch pack = £4.17;  ‘50’ patch (releasing approx. 50 micrograms/24  hours), 8-patch pack = £4.18; ‘75’ patch (releasing  approx. 75 micrograms/24 hours), 8-patch pack =  £4.86; ‘100’ patch (releasing approx. 100 micr-  ograms/24 hours), 8-patch pack = £5.05. Counselling,  administration   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1 patch to be applied twice weekly continuously, with  cyclical progestogen for 12-14 days of each cycle in women with a  uterus; for menopausal symptoms, initiate therapy with 25 patch  for 3 months; for osteoporosis prophylaxis initiate therapy with 50  patch, subsequently adjust according to response   Evorel® Oanssen-Cilag) (Ml  Patches, self-adhesive, estradiol, ‘25’ patch (releasing  approx. 25 micrograms/24 hours), net price 8-patch  pack = £3.42; ‘50’ patch (releasing approx. 50 micr-  ograms/24 hours), 8-patch pack = £3.88, 24-patch  pack = £11.66; ‘75’ patch (releasing approx. 75 micr-  ograms/24 hours), 8-patch pack = £4.12; ‘100’ patch  (releasing approx. 100 micrograms/ 24 hours), 8-patch  pack = £4.28. Counselling, administration  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1 patch to be applied twice weekly continuously  starting within 5 days of onset of menstruation (or at any time if  cycles have ceased or are infrequent), with cyclical progestogen  for 12-14 days of each cycle in women with a uterus; therapy  should be initiated with Evorel 50 patch; subsequently adjust  according to response; dose may be reduced to Evorel 25 patch  after first month if necessary for menopausal symptoms only   Fematrix® (Abbott Healthcare) (Ml  Patches, self-adhesive, estradiol, ‘40’ patch (releasing  approx. 40 micrograms/24 hours), net price 8-patch  pack = £4.95; ‘80’ patch (releasing approx. 80 micr-  ograms/24 hours), 8-patch pack = £5.40. Counselling,  administration   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1 patch to be applied twice weekly continuously  starting within 5 days of onset of menstruation (or at any time if    cycles have ceased or are infrequent), with cyclical progestogen  for 12-14 days of each cycle in women with a uterus; for meno-  pausal symptoms, initiate therapy with Fematrix 40, subsequently  adjust according to response; for osteoporosis prophylaxis, initiate  therapy with Fematrix 80   FemSeven® (Merck Serono) (Ml  Patches, self-adhesive, estradiol, ‘50’ patch (releasing  approx. 50 micrograms/24 hours), net price 4-patch  pack = £6.04, 12-patch pack = £18.02; ‘75’ patch  (releasing approx. 75 micrograms/24 hours), net price  4-patch pack = £6.98; ‘100’ patch (releasing approx.  100 micrograms/24 hours), net price 4-patch pack =  £7.28. Counselling, administration  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1 patch to be applied once a week continuously, with  cyclical progestogen for 12-14 days of each cycle in women with a  uterus; initiate therapy with FemSeven 50 patches for the first few  months, subsequently adjust according to response   Gel, estradiol 0.06%, net price 64-dose pump pack =  £4.80. Counselling, administration  Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 2 measures (estradiol 1.5 mg) to be applied over an  area twice that of the template provided once daily continuously,  starting within 5 days of menstruation (or anytime if cycles have  ceased or are infrequent), with cyclical progestogen for at least 12  days of each cycle in women with a uterus; for menopausal  symptoms may be increased if necessary after 1 month to max. 4  measures daily   Counselling Apply gel to clean, dry, intact skin such as arms,  shoulders or inner thighs and allow to dry for 5 minutes before  covering with clothing. Not to be applied on or near breasts or on  vulval region. Avoid skin contact with another person (particularly  male) and avoid other skin products or washing the area for at  least 1 hour after application   Progynova® (Bayer Schering) (Ml  Tablets, s/c, estradiol valerate 1 mg (beige), net price  3 x 28-tab pack = £6.18; 2 mg (blue), 3 x 28-tab pack  = £6.18   Dose menopausal symptoms, 1-2 mg daily continuously starting  on day 1 of menstruation (or at any time if cycles have ceased or  are infrequent); osteoporosis prophylaxis (see section 6.6), 2 mg  daily continuously; with cyclical progestogen for 12-14 days of  each cycle in women with a uterus   Progynova® TS (Bayer Schering) (Ml  Patches, self-adhesive, Progynova® TS 50 (releasing  estradiol approx. 50 micrograms/24 hours), net price  12-patch pack = £15.75; Progynova® TS 100  (releasing estradiol approx. 100 micrograms/24  hours), 12-patch pack = £17.34. Counselling, admin-  istration   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1 patch to be applied once a week continuously or 1  patch per week for 3 weeks followed by a 7-day patch-free interval  (cyclical); with cyclical progestogen for 12-14 days of each cycle  in women with a uterus; initiate therapy with Progynova TS 50,  subsequently adjust according to response  Note Women receiving Progynova TS 100 patches for meno-  pausal symptoms may continue with this strength for osteoporosis  prophylaxis (see section 6.6)   Gel, estradiol (0.1%), 500 microgram/ 500 mg sachet,  net price 28-sachet pack = £5.08, 1 mg/1 g sachet, 28-  sachet pack = £5.85. Counselling, administration   Dose menopausal symptoms, estradiol 1 mg (1 g gel) to be  applied once daily over area 1-2 times size of hand; with cyclical  progestogen for 12-14 days of each cycle in women with a uterus;  dose may be adjusted after 2-3 cycles to lowest effective dose  (usual dose of estradiol 0.5-1. 5 mg (0.5-1. 5 g gel) daily)  Counselling Apply gel to intact areas of skin such as lower trunk  or thighs, using right and left sides on alternate days. Wash hands  after application. Not to be applied on the breasts or face and  avoid contact with eyes. Allow area of application to dry for 5  minutes and do not wash area for at least 1 hour   Tablets, f/c, estradiol 1 mg, net price 84-tab pack =  £6.89; 2 mg (red), 84-tab pack = £6.89  Dose menopausal symptoms, initially 1 mg daily starting within  5 days of onset of menstruation (or any time if cycles have ceased  or are infrequent) increased to 2 mg daily if required; osteoporosis  prophylaxis (see section 6.6), 2 mg daily; with cyclical progesto-  gen for 12-14 days of each cycle in women with a uterus    4 Estradiol, estriol and estrone  Hormonin® (Amdipharm) (Ml  Tablets, pink, estradiol 600 micrograms, estriol  270 micrograms, estrone 1.4 mg, net price 84-tab pack  = £6.94   Dose menopausal symptoms and osteoporosis prophylaxis (see  section 6.6), 1-2 tablets daily starting within 5 days of onset of  menstruation (or at any time if cycles have ceased or are infre-  quent), with cyclical progestogen for 12-14 days of each cycle in  women with a uterus   Note Hormonin tablets can be given continuously or cyclically (21  days out of 28)    Indications short-term treatment of symptoms of  oestrogen deficiency (including women being treated  with gonadotrophin releasing hormone analogues);  osteoporosis prophylaxis in women at risk of fractures  (second-line)   Cautions see Hormone Replacement Therapy, p. 449  and under Oestrogens for HRT; vaginal bleeding  (investigate for endometrial cancer if bleeding con-  tinues beyond 6 months or after stopping treatment);  history of liver disease, epilepsy, migraine, diabetes  mellitus, hypercholesterolaemia; withdraw if signs of  thromboembolic disease, abnormal liver function  tests or cholestatic jaundice; see also Note below;  interactions: Appendix 1 (tibolone)   Contra-indications see notes above and under  Oestrogens for HRT; hormone-dependent tumours,  history of cardiovascular or cerebrovascular disease  (e.g. thrombophlebitis, thromboembolism), uninvesti-  gated vaginal bleeding   Renal impairment risk of fluid retention — patients  with renal impairment should be closely monitored   Side-effects see notes above; also abdominal pain,  weight changes, vaginal bleeding, leucorrhoea, facial  hair, and rarely amnesia; gastro-intestinal distur-  bances, oedema, dizziness, headache, migraine,  depression, breast cancer (see notes above and sec-  tion 6.4. 1.1), arthralgia, myalgia, visual disturbances,  seborrhoeic dermatitis, rash and pruritus also  reported   Note Unsuitable for use in the premenopause (unless being  treated with gonadotrophin-releasing hormone analogue)  and as (or with) an oral contraceptive; also unsuitable for use  within 12 months of last menstrual period (may cause  irregular bleeding); induce withdrawal bleed with progesto-  gen if transferring from another form of HRT   Tablets, tibolone 2.5 mg, net price 28-tab pack =  £10.36; 3 x 28-tab pack = £31.08   Ethinylestradiol (ethinyloestradiol) is licensed for short-  term treatment of symptoms of oestrogen deficiency, for  osteoporosis prophylaxis if other drugs (section 6.6)  cannot be used and for the treatment of female hypo-  gonadism and menstrual disorders.   Ethinylestradiol is occasionally used under specialist  supervision for the management of hereditary haemor-  rhagic telangiectasia (but evidence of benefit is limited).  Side-effects include nausea, fluid retention, and  thrombosis. Impotence and gynaecomastia have been  reported in men.   Cautions cardiovascular disease (sodium retention  with oedema, thromboembolism); see also under  Combined Hormonal Contraceptives (section 7.3.1)  and under Oestrogens for HRT (p. 451)   Contra-indications see under Combined Hormonal  Contraceptives (section 7.3.1) and under Oestrogens  for HRT (p. 451)   Side-effects feminising effects in men; see also under  Combined Hormonal Contraceptives (section 7.3.1)  and under Oestrogens for HRT (p. 451)   • Menopausal symptoms and osteoporosis prophylaxis,  (with progestogen for 12-14 days per cycle in women  with intact uterus), 10-50 micrograms daily for 21  days, repeated after 7-day tablet-free period   • Female hypogonadism, 10-50 micrograms daily,  usually on cyclical basis; initial oestrogen therapy  should be followed by combined oestrogen and pro-  gestogen therapy   • Menstrual disorders, 20-50 micrograms daily from  day 5 to 25 of each cycle, with progestogen added  either throughout the cycle or from day 15 to 25   Ethinylestradiol (Non-proprietary) (Ml  Tablets, ethinylestradiol 10 micrograms, net price 21-  tab pack = £29.95; 50 micrograms, 21-tab pack =  £38.20; 1 mg, 28-tab pack = £49.50   Raloxifene is licensed for the treatment and prevention  of postmenopausal osteoporosis', unlike hormone repla-  cement therapy, raloxifene does not reduce menopausal  vasomotor symptoms.   Raloxifene may reduce the incidence of oestrogen-  receptor-positive breast cancer but its role in estab-  lished breast cancer is not yet clear. The manufacturer  advises avoiding its use during treatment for breast  cancer.   Cautions risk factors for venous thromboembolism  (discontinue if prolonged immobilisation); risk factors  for stroke; breast cancer (see notes above); history of  oestrogen-induced hypertriglyceridaemia (monitor  serum triglycerides); interactions: Appendix 1  (raloxifene)   Contra-indications history of venous thromboembo-  lism, undiagnosed uterine bleeding, endometrial can-  cer, cholestasis  Hepatic impairment avoid  Renal impairment caution in mild to moderate  impairment; avoid in severe impairment  Side-effects hot flushes, leg cramps, peripheral  oedema, influenza-like symptoms; less commonly  venous thromboembolism, thrombophlebitis; rarely  rashes, gastro-intestinal disturbances, hypertension,  arterial thromboembolism, headache (including  migraine), breast discomfort, thrombocytopenia  Dose   Tablets, f/c, raloxifene hydrochloride 60 mg, net price  28-tab pack = £17.06; 84-tab pack = £59.59   There are two main groups of progestogen, progester-  one and its analogues (dydrogesterone and medroxy-  progesterone) and testosterone analogues (norethi-  sterone and norgestrel). The newer progestogens  (desogestrel, norgestimate, and gestodene) are all deri-  vatives of norgestrel; levonorgestrel is the active isomer  of norgestrel and has twice its potency. Progesterone  and its analogues are less androgenic than the testo-  sterone derivatives and neither progesterone nor dydro-  gesterone causes virilisation.   Where endometriosis requires drug treatment, it may  respond to a progestogen, e.g. norethisterone, adminis-  tered on a continuous basis. Danazol and gonadorelin  analogues are also available (section 6.7.2).   Although oral progestogens have been used widely for  menorrhagia they are relatively ineffective compared  with tranexamic acid (section 2.11) or, particularly  where dysmenorrhoea is also a factor, mefenamic acid  (section 10.1.1); the levonorgestrel-releasing intra-  uterine system (section 7.3. 2. 3) may be particularly  useful for women also requiring contraception. Oral  progestogens have also been used for severe dys-  menorrhoea, but where contraception is also required  in younger women the best choice is a combined oral  contraceptive (section 7.3.1).   Progestogens have also been advocated for the allevia-  tion of premenstrual symptoms, but no convincing  physiological basis for such treatment has been shown.   Progestogens have been used for the prevention of  spontaneous abortion in women with a history of recur-  rent miscarriage (habitual abortion) but there is no  evidence of benefit and they are not recommended  for this purpose. In pregnant women with anti-  phospholipid antibody syndrome who have suffered  recurrent miscarriage, administration of low-dose    aspirin (section 2.9) and a prophylactic dose of a low  molecular weight heparin (section 2.8.1) may decrease  the risk of fetal loss (use under specialist supervision  only).   Hormone replacement therapy In women with a  uterus a progestogen needs to be added to long-term  oestrogen therapy for hormone replacement, to prevent  cystic hyperplasia of the endometrium and possible  transformation to cancer; it can be added on a cyclical  or a continuous basis (see section 6.4. 1.1). Combined  packs incorporating suitable progestogen tablets are  available, see p. 452.   Oral contraception Desogestrel, etynodiol (ethyno-  diol), gestodene, levonorgestrel, norethisterone, and  norgestimate are used in combined oral contraceptives  and in progestogen-only contraceptives (section 7.3.1  and section 7.3.2).   Cancer Progestogens also have a role in neoplastic  disease (section 8.3.2).   Cautions Progestogens should be used with caution in  conditions that may worsen with fluid retention e.g.  epilepsy, hypertension, migraine, asthma, or cardiac  dysfunction, and in those susceptible to thromboembo-  lism (particular caution with high dose). Care is also  required in those with a history of depression. Progesto-  gens can decrease glucose tolerance and patients with  diabetes should be monitored closely. For interactions  see Appendix 1 (progestogens).   • By mouth, 2.5-10 mg daily for 5-10 days beginning on  day 16 to 21 of cycle, repeated for 2 cycles in dys-  functional uterine bleeding and 3 cycles in secondary  amenorrhoea   • Mild to moderate endometriosis, 10 mg 3 times daily  for 90 consecutive days, beginning on day 1 of cycle   • Progestogenic opposition of oestrogen HRT, 10 mg  daily for the last 14 days of each 28-day oestrogen  HRT cycle   Tablets, all scored, medroxyprogesterone acetate  2.5 mg (orange), net price 30-tab pack = £1.84; 5 mg  (blue), 10-tab pack = £1.23; 10 mg (white), 10-tab pack  = £2.47, 90-tab pack = £22.16   Climanor® (Resource Medical) [Ml  Tablets, f/c, medroxyprogesterone acetate 5 mg, net  price 28-tab pack = £3.27   Indications see under Dose; HRT (section 6.4. 1.1);  contraception (section 7.3.1 and section 7.3.2);  malignant disease (section 8.3.2)   Contra-indications see notes above  Hepatic impairment section 8.3.2  Renal impairment use with caution  Pregnancy section 8.3.2  Breast-feeding section 8.3.2  Side-effects see notes above  Dose    Contra-indications Progestogens should be avoided  in patients with a history of liver tumours. They are also  contra-indicated in those with genital or breast cancer  (unless progestogens are being used in the management  of these conditions), severe arterial disease, undiag-  nosed vaginal bleeding and acute porphyria (section  9.8.2). Progestogens should not be used if there is a  history during pregnancy of idiopathic jaundice, severe  pruritus, or pemphigoid gestationis.   Side-effects Side-effects of progestogens include  menstrual disturbances, premenstrual-like syndrome  (including bloating, fluid retention, breast tenderness),  weight change, nausea, headache, dizziness, insomnia,  drowsiness, depression, change in libido; also skin reac-  tions (including urticaria, pruritus, rash, and acne),  hirsutism and alopecia. Jaundice and anaphylactoid  reactions have also been reported.    • Endometriosis, by mouth, 10-15 mg daily for 4-6  months or longer, starting on day 5 of cycle (if spot-  ting occurs increase dose to 20-25 mg daily, reduced  once bleeding has stopped)   • Dysfunctional uterine bleeding, menorrhagia (but see  notes above), by mouth, 5 mg 3 times daily for 10 days  to arrest bleeding; to prevent bleeding 5 mg twice  daily from day 19 to 26   5 mg 3 times daily from day 5 to 24 for 3-4 cycles   • Premenstrual syndrome (but not recommended, see  notes above), by mouth, 5 mg 2-3 times daily from  day 19 to 26 for several cycles   • Postponement of menstruation, by mouth, 5 mg 3  times daily starting 3 days before expected onset  (menstruation occurs 2-3 days after stopping)    Norethisterone (Non-proprietary) [Ml  Tablets, norethisterone 5 mg, net price 30-tab pack =  £2.18   Primolut N® (Bayer Schering) (Ml  Tablets, norethisterone 5 mg, net price 30-tab pack =  £1.89   Tablets, norethisterone 5 mg, net price 30-tab pack =  £1.40, 90-tab pack = £4.21   Crinone® (Merck Serono) (Ml  Vaginal gel, progesterone 90 mg/application (8%), 15  = £30.83    Dose by vagina, infertility due to inadequate luteal phase, insert  1 applicatorful daily starting either after documented ovulation or  on day 18-21 of cycle. In vitro fertilisation, daily application  continued for 30 days after laboratory evidence of pregnancy   Androgens cause masculinisation; they may be used as  replacement therapy in castrated adults and in those  who are hypogonadal due to either pituitary or testicular  disease. In the normal male they inhibit pituitary  gonadotrophin secretion and depress spermatogenesis.  Androgens also have an anabolic action which led to the  development of anabolic steroids (section 6.4.3).   Androgens are useless as a treatment of impotence and  impaired spermatogenesis unless there is associated  hypogonadism; they should not be given until the hypo-  gonadism has been properly investigated. Treatment  should be under expert supervision.   When given to patients with hypopituitarism they can  lead to normal sexual development and potency but not  to fertility. If fertility is desired, the usual treatment is  with gonadotrophins or pulsatile gonadotrophin-releas-  ing hormone (section 6.5.1) which will stimulate sper-  matogenesis as well as androgen production.   Caution should be used when androgens or chorionic  gonadotrophin are used in treating boys with delayed  puberty since the fusion of epiphyses is hastened and  may result in short stature; skeletal maturation should  be monitored.   Intramuscular depot preparations of testosterone  esters are preferred for replacement therapy. Testo-  sterone enantate, propionate or undecanoate, or alter-  natively Sustanon®, which consists of a mixture of  testosterone esters and has a longer duration of action,  may be used. Satisfactory replacement therapy can  sometimes be obtained with lmL of Sustanon 250®,  given by intramuscular injection once a month, although  more frequent dose intervals are often necessary.  Implants of testosterone can be used for hypogonadism;  the implants are replaced every 4 to 5 months.   Cyclogest® (Actavis) (Ml £4  Pessaries, progesterone 200 mg, net price 15 = £7.03;  400 mg, 15 =£10.18   Dose by vagina or rectum, premenstrual syndrome and post-  natal depression, 200 mg daily to 400 mg twice daily; for pre-  menstrual syndrome start on day 12-14 and continue until onset  of menstruation (but not recommended, see notes above); rectally  if barrier methods of contraception are used, in patients who have  recently given birth or in those who suffer from vaginal infection  or recurrent cystitis   Injection, progesterone 50mg/mL, net price 1-mL  amp = £4.50, 2-mL amp = £4.50  Dose by deep intramuscular injection into buttock, dysfunc-  tional uterine bleeding, 5-10 mg daily for 5-10 days until 2 days  before expected onset of menstruation  Recurrent miscarriage due to inadequate luteal phase (but not  recommended, see notes above) or following in vitro fertilisation  or gamete intra-fallopian transfer, 25-100 mg 2-7 times a week  from day 15, or day of embryo or gamete transfer, until 8-16  weeks of pregnancy; max. 200 mg daily   Utrogestan® (Ferring) (Ml  Capsules, progesterone (micronised) 100 mg, net  price 30-cap pack = £5.13; 200 mg 15-cap pack =  £5.13. Counselling, administration   Counselling Capsules should be taken at bedtime on an empty  stomach   Dose progestogenic opposition of oestrogen HRT 200 mg once  daily on days 15-26, or 100 mg once daily on days 1-25, of each  28-day oestrogen HRT cycle    Testosterone implants can be used in postmenopausal  women as an adjunct to hormone replacement therapy.  A testosterone patch is also licensed to improve libido in  surgically induced menopausal women (receiving con-  comitant oestrogen therapy).   Cautions cardiac impairment, elderly, ischaemic heart  disease, hypertension, epilepsy, migraine, diabetes  mellitus, skeletal metastases (risk of hypercalcaemia),  undertake regular examination of the prostate and  breast during treatment; monitor full blood count,  lipid profile and liver function; pre-pubertal boys (see  notes above and under Side-effects); interactions:  Appendix 1 (testosterone)   Women Regularly assess for androgenic side-effects; women  should be advised to report any signs of virilisation e.g.  deepening of the voice or hirsutism   Contra-indications breast cancer in men, prostate  cancer, history of primary liver tumours, hypercal-  caemia, nephrotic syndrome   Breast-feeding avoid; may cause masculinisation in  the female infant or precocious development in the  male infant; high doses suppress lactation  Side-effects prostate abnormalities and prostate  cancer, headache, depression, gastro-intestinal  bleeding, nausea, vomiting, cholestatic jaundice,  changes in libido, gynaecomastia, polycythaemia,  anxiety, irritability, nervousness, asthenia, paraes-  thesia, hypertension, electrolyte disturbances includ-  ing sodium retention with oedema and hypercal-  caemia, weight gain; increased bone growth, muscle  cramps, arthralgia; androgenic effects such as hirsut-  ism, male-pattern baldness, seborrhoea, acne, pru-  ritus, excessive frequency and duration of penile  erection, precocious sexual development and pre-  mature closure of epiphyses in pre-pubertal males,  suppression of spermatogenesis in men and virilism in  women; rarely liver tumours; sleep apnoea also  reported; with patches, buccal tablets, and gel, local  irritation and allergic reactions (including burn-like  lesions with patches), and taste disturbances  Dose   Restandol® Testocaps (Organon) (Ml  Capsules, orange, testosterone undecanoate 40 mg in  oily solution, net price 30-cap pack = £8.55; 60-cap  pack = £17.10. Label: 21, 25   Dose androgen deficiency, 120-160 mg daily for 2-3 weeks;  maintenance 40-120 mg daily   Dose hypogonadism, 30 mg every 12 hours; CHILD and ADO-  LESCENT under 18 years not recommended  Counselling Place rounded side of tablet on gum above front  teeth and hold lip firmly over the gum for 30 seconds. If tablet  detaches within 4 hours of next dose, replace with new tablet  which is considered the second dose for the day.   Testosterone Enantate (Non-proprietary) (M  Injection (oily), testosterone enantate 250mg/mL,  net price 1-mL amp = £13.33   Dose by slow intramuscular injection, hypogonadism, initially  250 mg every 2-3 weeks; maintenance 250 mg every 3-6 weeks  Breast cancer, 250 mg every 2-3 weeks   Nebido® (Bayer Schering) ▼ (M  Injection (oily), testosterone undecanoate 250 mg/  mL, net price 4-mL amp = £76.70  Dose by deep intramuscular injection, hypogonadism in men  over 18 years, 1 g every 10-14 weeks; if necessary, second dose  may be given after 6 weeks to achieve rapid steady state plasma  testosterone levels and then every 10-14 weeks   Sustanon 250® (Organon) (M  Injection (oily), testosterone propionate 30 mg,  testosterone phenylpropionate 60 mg, testosterone  isocaproate 60 mg, and testosterone decanoate  lOOmg/mL, net price 1-mL amp = £2.45   Excipients include arachis (peanut) oil, benzyl alcohol (see Excipients  P 2)    Virormone® (Nordic) Ml  Injection, testosterone propionate 50mg/mL, net  price 2-mL amp = £4.50   Dose by intramuscular injection, androgen deficiency, 50 mg 2-3  times weekly   Implant, testosterone 100 mg, net price = £7.40;  200 mg = £13.79   600 mg usually maintains plasma-testosterone concentration  within the normal range for 4-5 months  Postmenopausal women, 50-100 mg every 4-8 months, as an  adjunct to oestrogen replacement therapy    ^Transdermal preparations  Intrinsa® (Warner Chilcott) ▼ iM  Patches, self-adhesive, releasing testosterone approx.  300 micrograms/ 24 hours, net price 8-patch pack =  £26.91. Counselling, administration  Dose hypoactive sexual desire disorder associated with surgi-  cally induced menopause (in women receiving concomitant oes-  trogen therapy (section 6.4. 1.1)), apply 1 patch twice weekly  continuously to clean, dry, unbroken skin on lower abdomen  below waistline; site replacement patch on a different area (avoid  using same area for 7 days); assess treatment after 3-6 months,  discontinue if no benefit   Note Not recommended for women naturally menopausal or  those taking conjugated oestrogens. Safety and efficacy of use  beyond 1 year not established   Dose hypogonadism due to testosterone deficiency in men (over  18 years), 50 mg testosterone (5 g gel) applied once daily; sub-  sequent application adjusted according to response; max. 100 mg  (10 g gel) daily   Counselling Squeeze entire content of tube on to one palm  and apply as a thin layer on clean, dry, healthy skin of  shoulder or upper arm, preferably in the morning after  washing or bathing (if 2 tubes required use 1 per shoulder or  upper arm); rub in and allow to dry before putting on  clothing to cover site; wash hands with soap after applica-  tion; avoid washing application site for at least 6 hours  Avoid skin contact with application sites to prevent testo-  sterone transfer to other people, especially pregnant women  and children — consult product literature   Testogel® (Bayer Schering) (M  Gel, testosterone 50 mg/ 5 g sachet, net price 30-  sachet pack = £31.11. Counselling, administration  Dose hypogonadism due to androgen deficiency in men (over 18  years), 50 mg testosterone (5 g gel) to be applied once daily;  subsequent application adjusted according to response in 25-mg  (2.5 g gel) increments to max. 100 mg (10 g gel) daily  Counselling Apply thin layer of gel on clean, dry, healthy skin  such as shoulders, arms or abdomen, immediately after sachet is  opened. Not to be applied on genital area as high alcohol content  may cause local irritation. Allow to dry for 3-5 minutes before  dressing. Wash hands with soap and water after applying gel,  avoid shower or bath for at least 6 hours  Avoid skin contact with gel application sites to prevent testo-  sterone transfer to other people, especially pregnant women and  children — consult product literature   Dose hypogonadism due to testosterone deficiency in men (over  18 years), initially 60 mg testosterone (3 g gel) applied    once daily; subsequent applications adjusted according to  response; max. 80 mg (4 g gel) daily   Counselling Apply gel on clean, dry, intact skin of abdomen or  both inner thighs, preferably in the morning. Gently rub in with a  finger until dry before dressing. Wash hands with soap and water  after applying gel; avoid washing application site for at least 2  hours. Not to be applied on genital area.   Indications see under Dose  Cautions see under Testosterone and Esters  Contra-indications see under Testosterone and Esters  Hepatic impairment see under Testosterone and  Esters   Renal impairment see under Testosterone and Esters  Pregnancy see under Testosterone and Esters  Breast-feeding see under Testosterone and Esters  Side-effects see under Testosterone and Esters but  spermatogenesis unimpaired  Dose   • Androgen deficiency and male infertility associated  with hypogonadism, 25 mg 3-4 times daily for several  months, reduced to 50-75 mg daily in divided doses  for maintenance; CHILD not recommended  Pro-Viron® (Bayer Schering) (Ml  Tablets, scored, mesterolone 25 mg. Net price 30-tab  pack = £4.19   Cyproterone acetate is an anti-androgen used in the  treatment of severe hypersexuality and sexual deviation  in the male. It inhibits spermatogenesis and produces  reversible infertility (but is not a male contraceptive);  abnormal sperm forms are produced. Fully informed  consent is recommended and an initial spermatogram.  As hepatic tumours have been produced in animal  studies, careful consideration should be given to the  risk/benefit ratio before treatment. Cyproterone acetate  is also used as an adjunct in prostatic cancer (section  8. 3. 4.2) and in the treatment of acne and hirsutism in  women (section 13.6.2).   Cautions ineffective for male hypersexuality in  chronic alcoholism (relevance to prostate cancer not  known); blood counts initially and throughout treat-  ment; monitor hepatic function regularly (liver func-  tion tests should be performed before treatment, see  also under Side-effects below); monitor adrenocorti-  cal function regularly; diabetes mellitus (see also  Contra-indications)   Driving Fatigue and lassitude may impair performance of  skilled tasks (e.g. driving)   Contra-indications (do not apply in prostate cancer),  severe diabetes (with vascular changes), sickle-cell  anaemia, liver-disease including Dubin-Johnson and  Rotor syndromes, previous or existing liver tumours,  malignant or wasting diseases, meningioma or history  of meningioma, severe depression, history of throm-  boembolic disorders; youths under 18 years (may  arrest bone maturation and testicular development)   Side-effects fatigue and lassitude, breathlessness,  weight changes, reduced sebum production (may  clear acne), changes in hair pattern, gynaecomastia  (rarely leading to galactorrhoea and benign breast  nodules); rarely hypersensitivity reactions, rash and  osteoporosis; inhibition of spermatogenesis (see notes  above); hepatotoxicity reported (including jaundice,  hepatitis and hepatic failure usually in men given 200-  300 mg daily for prostatic cancer, see section 8.3. 4.2  for details and warnings)   • ADULT over 18 years, male hypersexuality, 50 mg twice  daily after food   Cyproterone Acetate (Non-proprietary) (Ml  Tablets, cyproterone acetate 50 mg, net price 56-tab  pack = £31.54. Label: 21 counselling, driving  Androcur® (Bayer Schering) (MO  Tablets, scored, cyproterone acetate 50 mg, net price  56-tab pack = £24.41. Label: 21 counselling, driving   Dutasteride and finasteride are specific inhibitors of  the enzyme 5a-reductase, which metabolises testo-  sterone into the more potent androgen, dihydrotestos-  terone. This inhibition of testosterone metabolism leads  to reduction in prostate size, with improvement in  urinary flow rate and in obstructive symptoms. Dutaste-  ride and finasteride are alternatives to alpha-blockers  (section 7.4.1) particularly in men with a significantly  enlarged prostate. Finasteride is also licensed for use  with doxazosin in the management of benign prostatic  hyperplasia.   A low strength of finasteride is licensed for treating  male-pattern baldness in men (section 13.9).   Cautions Dutasteride and finasteride decrease serum  concentration of prostate cancer markers such as  prostate-specific antigen; reference values may need  adjustment. Both dutasteride and finasteride are  excreted in semen and use of a condom is recom-  mended if sexual partner is pregnant or likely to become  pregnant. Women of childbearing potential should avoid  handling crushed or broken tablets of finasteride and  leaking capsules of dutasteride.   Side-effects The side-effects of dutasteride and finas-  teride include impotence, decreased libido, ejaculation  disorders, and breast tenderness and enlargement.   Indications benign prostatic hyperplasia  Cautions see notes above; interactions: Appendix 1  (dutasteride)   • 500 micrograms daily, review treatment at 3-6  months and then every 6-12 months (may require  several months treatment before benefit is obtained)   Cautions see notes above; also obstructive uropathy  Male breast cancer Cases of male breast cancer have been  reported. Patients or their carers should be told to promptly  report to their doctor any changes in breast tissue such as  lumps, pain, or nipple discharge   Side-effects see notes above; also testicular pain,  hypersensitivity reactions (including lip and face  swelling, pruritus and rash); male breast cancer also  reported (see Cautions above)   • 5 mg daily, review treatment at 3-6 months and then  every 6-12 months (may require several months’  treatment before benefit is obtained)   Finasteride (Non-proprietary) (Ml  Tablets, finasteride 5 mg, net price 28-tab pack =  £2.19   Tablets, blue, f/c, finasteride 5 mg, net price 28-tab  pack = £13.94   Injection (oily), nandrolone decanoate 50 mg/mL, net  price 1-mL amp = £3.17   6.5.1 Hypothalamic and anterior pituitary  hormones and anti-oestrogens  6.5.2 Posterior pituitary hormones and  antagonists    Use of preparations in these sections requires  detailed prior investigation of the patient and should  be reserved for specialist centres.    Anabolic steroids have some androgenic activity but  they cause less virilisation than androgens in women.  They are used in the treatment of some aplastic anae-  mias (section 9.1.3). Anabolic steroids have been given  for osteoporosis in women but they are no longer  advocated for this purpose.    The protein-building properties of anabolic steroids  have not proved beneficial in the clinical setting. Their  use as body builders or tonics is unjustified; some  athletes abuse them.   Indications osteoporosis in postmenopausal women  (but not recommended, see notes above); aplastic  anaemia (section 9.1.3)   Cautions cardiac impairment, hypertension, diabetes  mellitus, epilepsy, migraine; monitor skeletal matura-  tion in young patients; skeletal metastases (risk of  hypercalcaemia); interactions: Appendix 1 (anabolic  steroids)   Contra-indications prostate cancer, male breast can-  cer, acute porphyria (section 9.8.2)   Hepatic impairment use in severe hepatic impair-  ment only if benefit outweighs risk  Renal impairment use with caution — may cause  sodium and water retention  Side-effects acne, sodium retention with oedema,  virilisation with high doses including voice changes  (sometimes irreversible), amenorrhoea, inhibition of  spermatogenesis, premature epiphyseal closure;  abnormal liver-function tests reported with high  doses; liver tumours reported occasionally on pro-  longed treatment with anabolic steroids  Dose   The anti-oestrogens clomifene (clomiphene) and tam-  oxifen (section 8.3.4. 1) are used in the treatment of  female infertility due to oligomenorrhoea or secondary  amenorrhoea (e.g. associated with polycystic ovarian  disease). They induce gonadotrophin release by occu-  pying oestrogen receptors in the hypothalamus, thereby  interfering with feedback mechanisms; chorionic  gonadotrophin is sometimes used as an adjunct.  Patients should be warned that there is a risk of multiple  pregnancy ( rarely more than twins).   Indications anovulatory infertility — see notes above  Cautions see notes above; polycystic ovary syndrome  (cysts may enlarge during treatment, also risk of  exaggerated response to usual doses), ovarian  hyperstimulation syndrome, uterine fibroids, ectopic  pregnancy, incidence of multiple births increased  (consider ultrasound monitoring), visual symptoms  (discontinue and initiate ophthalmological examina-  tion)   CSM Advice The CSM has recommended that clomifene  should not normally be used for longer than 6 cycles (pos-  sibly increased risk of ovarian cancer)  Contra-indications ovarian cysts, hormone-depen-  dent tumours or abnormal uterine bleeding of unde-  termined cause    Pregnancy exclude pregnancy before treatment; pos-  sible effects on fetal development  Breast-feeding may inhibit lactation  Side-effects visual disturbances (withdraw), ovarian  hyperstimulation (withdraw), hot flushes, abdominal  discomfort, occasionally nausea, vomiting, depres-  sion, insomnia, breast tenderness, headache, inter-  menstrual spotting, menorrhagia, endometriosis,  convulsions, weight gain, rashes, dizziness, hair loss  Dose   • 50 mg daily for 5 days, starting within about 5 days of  onset of menstruation (preferably on 2nd day) or at  any time (normally preceded by a progestogen-  induced withdrawal bleed) if cycles have ceased;  second course of 100 mg daily for 5 days may be given  in absence of ovulation; most patients who are going  to respond will do so to first course; 3 courses should  constitute adequate therapeutic trial; long-term  cyclical therapy not recommended — see CSM advice,  above   Clomifene (Non-proprietary) (MU  Tablets, clomifene citrate 50 mg, net price 30-tab  pack = £15.94   Clomid® (Sanofi-Aventis) (Ml  Tablets, yellow, scored, clomifene citrate 50 mg. Net  price 30-tab pack = £8.46   Tetracosactide (tetracosactrin), an analogue of cortico-  tropin (ACTH), is used to test adrenocortical function;  failure of the plasma cortisol concentration to rise after  administration of tetracosactide indicates adrenocorti-  cal insufficiency.   Both corticotropin and tetracosactide were formerly  used as alternatives to corticosteroids in conditions  such as Crohn’s disease or rheumatoid arthritis; their  value was limited by the variable and unpredictable  therapeutic response and by the waning of their effect  with time.   Indications see notes above  Cautions as for corticosteroids, section 6.3.2; impor-  tant: risk of anaphylaxis (medical supervision; consult  product literature); interactions: Appendix 1 (corti-  costeroids)   Hepatic impairment see section 6.3.2  Renal impairment see section 6.3.2  Pregnancy avoid (but may be used diagnostically if  essential)    Synacthen® (Alliance) (Ml  Injection, tetracosactide 250 micrograms (as  acetate)/mL. Net price 1-mL amp = £2.70  Dose diagnostic (30-minute test), by intramuscular or intra-  venous injection, 250 micrograms as a single dose   Synacthen Depot® (Alliance) (Ml  Injection (aqueous suspension), tetracosactide  acetate 1 mg/mL, with zinc phosphate complex. Net  price 1-mL amp = £3.87   Dose diagnostic (5-hour test), by intramuscular injection, lmg  as a single dose   Note Formerly used therapeutically by intramuscular injection, in  an initial dose of 1 mg daily (or every 12 hours in acute cases);  reduced to 1 mg every 2-3 days, then 1 mg weekly (or 500 micr-  ograms every 2-3 days) but value was limited (see notes above)   Follicle-stimulating hormone (FSH) and luteinising  hormone (LH) together (as in human menopausal  gonadotrophin), follicle-stimulating hormone alone  (as in follitropin), or chorionic gonadotrophin, are  used in the treatment of infertility in women with proven  hypopituitarism or who have not responded to clomi-  fene, or in superovulation treatment for assisted con-  ception (such as in vitro fertilisation).   The gonadotrophins are also occasionally used in the  treatment of hypogonadotrophic hypogonadism and  associated oligospermia. There is no justification for  their use in primary gonadal failure.   Chorionic gonadotrophin has also been used in delayed  puberty in the male to stimulate endogenous testo-  sterone production, but has little advantage over testo-  sterone (section 6.4.2).   A preparation of a glycoprotein fraction secreted by the pla-  centa and obtained from the urine of pregnant women having  the action of the pituitary luteinising hormone   Indications see notes above  Cautions cardiac impairment, asthma, epilepsy,  migraine; prepubertal boys (risk of premature epi-  physeal closure or precocious puberty); acute por-  phyria (section 9.8.2)   Contra-indications androgen-dependent tumours  Renal impairment use with caution  Side-effects oedema (particularly in males — reduce  dose), headache, tiredness, mood changes, gynaeco-  mastia, local reactions; may aggravate ovarian  hyperstimulation, multiple pregnancy  Dose   Injection, powder for reconstitution, chorionic  gonadotrophin. Net price 1500-unit amp = £2.12;  5000-unit amp = £3.15 (both with solvent). For sub-  cutaneous or intramuscular injection   Indications see notes above  Cautions acute porphyria (section 9.8.2)  Contra-indications ovarian enlargement or cyst  (unless caused by polycystic ovarian disease); ectopic  pregnancy in previous 3 months; active thromboem-  bolic disorders; hypothalamus, pituitary, ovarian,  uterine or mammary malignancy  Side-effects nausea, vomiting, abdominal pain;  headache, tiredness; injection-site reactions; ovarian  hyperstimulation syndrome; rarely diarrhoea,  depression, irritability, breast pain; ectopic pregnancy  and ovarian torsion reported  Dose   Ovitrelle® (Merck Serono) (Mi  Injection, choriogonadotropin alfa, net price 6500-  unit/0.5mL (250-micrograms/0.5 mL) prefilled  syringe = £31.38   Indications controlled ovarian stimulation in combi-  nation with a gonadotrophin-releasing hormone  antagonist   Cautions risk factors for thromboembolism; risk of  ovarian hyperstimulation syndrome; acute porphyria  (section 9.8.2)   Contra-indications ovarian enlargement or cyst;  polycystic ovarian syndrome; tumours of hypothala-  mus, pituitary, ovaries, uterus, or breast; vaginal  bleeding of unknown cause; history of ovarian  hyperstimulation syndrome  Renal impairment avoid  Breast-feeding avoid   Side-effects nausea; headache, fatigue; ovarian  hyperstimulation, pelvic pain, breast pain; less com-  monly vomiting, abdominal distension and pain,  diarrhoea, constipation, dizziness, ovarian torsion;  also reported ectopic pregnancy, miscarriage, and  multiple pregnancies  Dose   • By subcutaneous injection, body-weight under 60 kg,  100 micrograms; body-weight over 60 kg, 150 micr-  ograms   Elonva® (Organon) T (Ml  Injection, prefilled syringe, corifollitropin alfa, net  price 100 micrograms/0.5 mL =£638.00; 150 micr-  ograms/0.5 mL = £638.00   Gonal-F® (Merck Serono) (Ml  Injection, powder for reconstitution, follitropin alfa.  Net price 75-unit amp = £21.02; 450 units/0.75 mL,  multidose vial = £126.10; 1050 units/ 1.75 mL, multi-  dose vial = £294.22 (all with solvent). For subcuta-  neous injection   Injection, prefilled pen, follitropin alfa 600units/mL,  net price 0.5 mL (300 units) = £94.00, 0.75 mL  (450 units) = £141.00, 1.5 mL (900 units) = £282.00.  For subcutaneous injection   Pergoveris® (Merck Serono) (Ml  Injection, powder for reconstitution, follitropin alfa  150 units (11 micrograms), lutropin alfa 75 units  (3 micrograms), net price per vial (with solvent) =  £60.29. For subcutaneous injection   Injection, follitropin beta lOOunits/mL, net price 0.5-  mL (50-unit) vial = £18.03; 200units/mL, 0.5-mL  (100-unit) vial = £36.06; 300units/mL, 0.5-mL (150-  unit) vial = £50.62; 400units/mL, 0.5-mL (200-unit)  vial = £67.49; 0.36-mL (300-unit) cartridge = £97.41,  0.72-mL (600-unit) cartridge = £194.82, 1.08-mL (900-  unit) cartridge = £292.23, (cartridges for use with  Puregon ® pen). For subcutaneous (cartridges and  vials) or intramuscular injection (vials)    Indications see notes above  Cautions acute porphyria (section 9.8.2)  Contra-indications ovarian cysts (not caused by  polycystic ovarian syndrome); tumours of pituitary,  hypothalamus, breast, uterus, ovaries, testes or  prostate; vaginal bleeding of unknown cause  Pregnancy avoid  Breast-feeding avoid   Side-effects ovarian hyperstimulation, increased risk  of multiple pregnancy and miscarriage, hypersensi-  tivity reactions, gastro-intestinal disturbances, head-  ache, joint pain, fever, injection site reactions, very  rarely thromboembolism; gynaecomastia, acne, and  weight gain reported in men  Dose   Purified extract of human post-menopausal urine con-  taining follicle-stimulating hormone (FSH) and lutein-  ising hormone (LH) in a ratio of 1:1   Merional® (Pharmasure) (MO  Injection, powder for reconstitution, menotrophin as  follicle-stimulating hormone 75 units and luteinising  hormone 75 units, net price per vial (with solvent) =  £13.95; follicle-stimulating hormone 150 units, lutein-  ising hormone 150 units, net price per vial (with  solvent) = £27.90. For intramuscular injection   Injection, powder for reconstitution, menotrophin as  follicle-stimulating hormone 75 units and luteinising  hormone 75 units, net price per vial (with solvent) =  £13.38. For intramuscular or subcutaneous injection   Purified extract of human post-menopausal urine con-  taining follicle-stimulating hormone (FSH)   Fostimon® (Pharmasure) CmD  Injection, powder for reconstitution, urofollitropin as  follicle-stimulating hormone 75 units, net price per  vial (with solvent) = £27.90; follicle-stimulating  hormone 150 units, net price per vial (with solvent) =  £55.80. For intramuscular or subcutaneous injection   Indications see notes above  Cautions acute porphyria (section 9.8.2)  Contra-indications ovarian enlargement or cyst  (unless caused by polycystic ovarian disease);  undiagnosed vaginal bleeding; tumours of hypotha-  lamus and pituitary; ovarian, uterine or mammary  carcinoma   Side-effects nausea, vomiting, abdominal and pelvic  pain; headache, somnolence; injection-site reactions;  ovarian hyperstimulation syndrome, ovarian cyst,  breast pain, ectopic pregnancy; thromboembolism,  adnexal torsion, and haemoperitoneum  Dose   • By subcutaneous injection, in conjunction with  follicle-stimulating hormone, according to response   Luveris® (Merck Serono) fMl  Injection, powder for reconstitution, lutropin alfa, net  price 75-unit vial = £31.38 (with solvent)   Growth hormone is used to treat deficiency of the  hormone in children and in adults (see NICE guidance  below). In children it is used in Prader-Willi syndrome,  Turner syndrome, chronic renal insufficiency, short chil-  dren considered small for gestational age at birth, and  short stature homeobox-containing gene (SHOX) defi-  ciency.   Growth hormone of human origin (HGH; somato-  trophin) has been replaced by a growth hormone of  human sequence, somatropin, produced using recom-  binant DNA technology.   Somatropin for the treatment of growth  failure in children (May 2010)   • are bom small for gestational age with subse-  quent growth failure at 4 years of age or later;   Treatment should be discontinued if growth velocity  increases by less than 50% from baseline in the first  year of treatment.   Somatropin is recommended in adults only if the  following 3 criteria are fulfilled:   • Impaired quality of life, measured by means of a  specific questionnaire,   Somatropin treatment should be discontinued if the  quality of life has not improved sufficiently by 9  months.   Severe growth hormone deficiency developing after  linear growth is complete but before the age of 25  years should be treated with growth hormone; treat-  ment should continue until adult peak bone mass  has been achieved. Treatment for adult-onset  growth hormone deficiency should be stopped  only when the patient and the patient’s physician  consider it appropriate.   Treatment with somatropin should be initiated and  managed by a physician with expertise in growth  hormone disorders; maintenance treatment can be  prescribed in the community under a shared-care  protocol.    Mecasermin, a human insulin-like growth factor-I  (rhIGF-I), is licensed to treat growth failure in children  and adolescents with severe primary insulin-like growth  factor-I deficiency (section 6.7.4).   Cautions diabetes mellitus (adjustment of antidiabetic  therapy may be necessary), papilloedema (see under  Side-effects), relative deficiencies of other pituitary  hormones (notably hypothyroidism — manufacturers  recommend periodic thyroid function tests but limited  evidence of clinical value), history of malignant dis-  ease, disorders of the epiphysis of the hip (monitor for  limping), resolved intracranial hypertension (monitor  closely), initiation of treatment close to puberty not  recommended in child born small for gestational age;  Silver-Russell syndrome; rotate subcutaneous injec-  tion sites to prevent lipoatrophy; interactions:  Appendix 1 (somatropin)   Contra-indications evidence of tumour activity  (complete antitumour therapy and ensure intracranial  lesions inactive before starting); not to be used after  renal transplantation or for growth promotion in  children with closed epiphyses (or near closure in  Prader-Willi syndrome); severe obesity or severe  respiratory impairment in Prader-Willi syndrome  Pregnancy discontinue if pregnancy occurs — no  information available  Breast-feeding no information available  Side-effects headache, funduscopy for papilloedema  recommended if severe or recurrent headache, visual  problems, nausea and vomiting occur — if papilloede-  ma confirmed consider benign intracranial hyper-  tension (rare cases reported); fluid retention (periph-  eral oedema), arthralgia, myalgia, carpal tunnel  syndrome, paraesthesia, antibody formation, hypo-  thyroidism, insulin resistance, hyperglycaemia, hypo-    glycaemia, reactions at injection site; leukaemia in  children with growth hormone deficiency also  reported   • Gonadal dysgenesis (Turner syndrome), by subcuta-  neous injection, 45-50 micrograms/kg daily or   • Deficiency of growth hormone in children, by sub-  cutaneous or intramuscular injection, 23-39 micr-  ograms/kg daily or 0.7-1 mg/m 2 daily   • Growth disturbance in short children bom small for  gestational age whose growth has not caught up by 4  years or later, by subcutaneous injection, 35 micr-  ograms/kg daily or 1 mg/m 2 daily   • Prader-Willi syndrome, by subcutaneous injection in  children with growth velocity greater than 1 cm/year,  in combination with energy-restricted diet, 35 micr-  ograms/kg daily or 1 mg/m 2 daily; max. 2.7 mg daily   • Chronic renal insufficiency in children (renal function  decreased to less than 50%), by subcutaneous injec-  tion, 45-50 micrograms/kg daily or 1.4 mg/m 2 daily  (higher doses may be needed) adjusted if necessary  after 6 months   • Adult growth hormone deficiency, by subcutaneous  injection, initially 150-300 micrograms daily, gradu-  ally increased if required to max. 1 mg daily; use  minimum effective dose (requirements may decrease  with age)   • SHOX deficiency in children, by subcutaneous injec-  tion, 45-50 micrograms/kg daily   Genotropin® (Pharmacia) tMl  Injection, two-compartment cartridge containing  powder for reconstitution, somatropin (rbe) and dilu-  ent, net price 5.3-mg (16-unit) cartridge = £122.87, 12-  mg (36-unit) cartridge = £278.20. For use with Gen-  otropin® Pen device (available free of charge  from clinics). For subcutaneous injection  GoQuick® injection, two-compartment, multi-dose  disposable, prefilled pen containing powder for  reconstitution, somatropin (rbe) and diluent, net price  5.3-mg (16-unit) prefilled pen = £122.87; 12-mg (36-  unit) prefilled pen = £278.20. For subcutaneous  injection   MiniQuick injection, two-compartment single-dose  syringe containing powder for reconstitution, soma-  tropin (rbe) and diluent, net price 0.2-mg (0.6-unit)  syringe = £4.64; 0.4-mg (1.2-unit) syringe = £9.27; 0.6-  mg (1.8-unit) syringe = £13.91; 0.8-mg (2.4-unit)  syringe = £18.55; 1-mg (3-unit) syringe = £23.18; 1.2-  mg (3.6-unit) syringe = £27.82; 1.4-mg (4.2-unit)  syringe = £32.46; 1.6-mg (4.8-unit) syringe = £37.09;  1.8-mg (5.4-unit) syringe = £41.73; 2-mg (6-unit)  syringe = £46.37. For subcutaneous injection   Injection, powder for reconstitution, somatropin  (rbe), net price 6-mg (18-unit) cartridge = £108.00; 12-  mg (36-unit) cartridge = £216.00; 24-mg (72-unit)  cartridge = £432.00; all supplied with diluent. For  subcutaneous or intramuscular injection; cartridges  for subcutaneous injection   Norditropin® (Novo Nordisk) (Ml  SimpleXx injection, somatropin (epr) 3.3 mg  (10units)/mL, net price 1.5-mL (5-mg, 15-unit) car-  tridge = £106.35; 6.7 mg (20 units)/mL, 1.5-mL (10-    mg, 30-unit) cartridge = £212.70; 10 mg (30 units)/  mL, 1.5-mL (15-mg, 45-unit) cartridge = £319.05. For  use with appropriate NordiPen® (&&\ device (available  free of charge from clinics). For subcutaneous  injection   Injection, somatropin (rbe), net price 10 mg (30 units)  2-ml cartridge = £203.00. For use with NutropinAq®  Pen device (available free of charge from clinics).  For subcutaneous injection   Injection, somatropin (rbe) 3.3 mg (10units)/mL, net  price 1.5 mL (5-mg, 15-unit) cartridge = £86.77;   6.7 mg (20units)/mL, 1.5 mL (10-mg, 30-unit) car-  tridge = £173.50. For use with Omnitrope Pen 5®(^\  and Omnitrope Pen 10 ® ] devices respectively   Excipients include benzyl alcohol (in 5-mg cartridge) (avoid in neonates,  see Excipients, p. 2)   Injection, powder for reconstitution, somatropin  (rmc), net price 1.33-mg (4-unit) vial (with diluent) =  £29.28; 3.33-mg (10-unit) vial (with diluent) = £73.20.  For subcutaneous or intramuscular injection    Click.easy®, powder for reconstitution, somatropin  (rmc), net price 8-mg (24-unit) vial (in Click.easy®  device with diluent) = £185.44. For use with  One. click® autoinjector device or Cool. Click®   (SEsD needle-free device (both available free of charge  from clinics). For subcutaneous injection   Excipients include benzyl alcohol (in diluent for 3.33 mg vial) (avoid in  neonates, see Excipients p. 2)   Note Saizen ® 3.33 mg vial may be reconstituted with sodium  chloride intravenous infusion or water for injections for immediate  use when administering to children under 3 years of age   Zomacton® (Ferring) (Ml  Injection, powder for reconstitution, somatropin  (rbe), net price 4-mg (12-unit) vial (with diluent) =  £79.69, for use with ZomaJet 2® Vision [SEf] needle-  free device (available free of charge from clinics) or  with needles and syringes; 10 mg (30-unit) vial (with  diluent) = £199.23, for use with ZomaJet Vision X  ® (M] needle-free device (available free of charge from  clinics) or with needles and syringes. For subcuta-  neous injection   Excipients include benzyl alcohol (in 4-mg vial) (avoid in neonates, see  Excipients p. 2)   Pegvisomant is a genetically modified analogue of  human growth hormone and is a highly selective growth  hormone receptor antagonist. Pegvisomant is licensed  for the treatment of acromegaly in patients with inade-  quate response to surgery, radiation, or both, and to  treatment with somatostatin analogues. Pegvisomant  should be initiated only by physicians experienced in  the treatment of acromegaly.   Indications see notes above  Cautions liver disease (monitor liver enzymes every  4-6 weeks for 6 months or if symptoms of hepatitis  develop); diabetes mellitus (adjustment of antidiabetic  therapy may be necessary); possible increase in  female fertility   Side-effects diarrhoea, constipation, nausea, vomi-  ting, abdominal distension, dyspepsia, flatulence,  elevated liver enzymes; hypertension; headache,  asthenia, dizziness, drowsiness, tremor, sleep distur-  bances; influenza-like syndrome, weight gain, hyper-  glycaemia, hypoglycaemia; arthralgia, myalgia; injec-  tion-site reactions, sweating, pruritus, rash; fatigue;  hypercholesterolaemia; less commonly thrombocyto-  penia, leucopenia, leucocytosis, bleeding tendency  Dose   • By subcutaneous injection, initially 80 mg, then 10 mg  daily, increased in steps of 5 mg daily according to  response; max. 30 mg daily; CHILD not recommended   Injection, powder for reconstitution, pegvisomant,  net price 10-mg vial = £50.00; 15-mg vial = £75.00;  20-mg vial = £100.00 (all with solvent)   Thyrotropin alfa is a recombinant form of thyrotrophin  (thyroid stimulating hormone). It is licensed for use with  or without radioiodine imaging, together with serum  thyroglobulin testing, for the detection of thyroid rem-  nants and thyroid cancer in post-thyroidectomy  patients. It is also licensed to increase radio-iodine  uptake for the ablation of thyroid remnant tissue in  suitable post-thyroidectomy patients.   Indications see notes above and product literature  Cautions presence of thyroglobulin autoantibodies  may give false negative results  Contra-indications hypersensitivity to bovine or  human thyrotrophin  Pregnancy avoid  Breast-feeding avoid   Side-effects nausea, vomiting; headache, dizziness,  fatigue; less commonly asthenia, paraesthesia, back  pain, influenza-like symptoms, rash, urticaria; rarely  diarrhoea; very rarely palpitation, flushing, dyspnoea,  pain at site of metastases, tremor, arthralgia, myalgia,  hyperhidrosis, and injection-site reactions including  pain, pruritus, and rash  Dose   • By intramuscular injection into the gluteal muscle,  900 micrograms every 24 hours for 2 doses, consult  product literature   Gonadorelin when injected intravenously in normal  subjects leads to a rapid rise in plasma concentrations  of both luteinising hormone (LH) and follicle-stimulating  hormone (FSH). It has not proved to be very helpful,  however, in distinguishing hypothalamic from pituitary  lesions. Gonadorelin analogues are indicated in endo-  metriosis and infertility (section 6.7.2) and in breast and  prostate cancer (section 8.3.4).   Side-effects rarely, nausea, headache, abdominal  pain, increased menstrual bleeding; rarely, hyper-  sensitivity reaction on repeated administration of  large doses; irritation at injection site   Injection, powder for reconstitution, gonadorelin. Net  price 100-microgram vial (with diluent) = £13.72  (hosp. only)   Dose for assessment of pituitary function (adults), by subcuta-  neous or intravenous injection, 100 micrograms   Diabetes insipidus Vasopressin (antidiuretic horm-  one, ADH) is used in the treatment of pituitary (‘cra-  nial’) diabetes insipidus as is its analogue desmo-  pressin. Dosage is tailored to produce a slight diuresis  every 24 hours to avoid water intoxication. Treatment  may be required for a limited period only in diabetes  insipidus following trauma or pituitary surgery.  Desmopressin is more potent and has a longer duration  of action than vasopressin; unlike vasopressin it has no  vasoconstrictor effect. It is given by mouth or intrana-  sally for maintenance therapy, and by injection in the  postoperative period or in unconscious patients.  Desmopressin is also used in the differential diagnosis  of diabetes insipidus. Following a dose of 2 micrograms  intramuscularly or 20 micrograms intranasally, restora-  tion of the ability to concentrate urine after water  deprivation confirms a diagnosis of cranial diabetes  insipidus. Failure to respond occurs in nephrogenic dia-  betes insipidus.   In nephrogenic and partial pituitary diabetes insipidus  benefit may be gained from the paradoxical antidiuretic  effect of thiazides (section 2.2.1) e.g. chlortalidone  100 mg twice daily reduced to maintenance dose of  50 mg daily.   Carbamazepine (section 4.8.1) is sometimes useful in  partial pituitary diabetes insipidus (in a dose of 200 mg  once or twice daily) [unlicensed]; it may act by sensitis-  ing the renal tubules to the action of remaining endo-  genous vasopressin.   Other uses Desmopressin is also used to boost factor  VIII concentration in mild to moderate haemophilia and  in von Willebrand’s disease; it is also used to test fibrino-  lytic response. For a comment on use of desmopressin  in nocturnal enuresis see section 7.4.2.    Vasopressin infusion is used to control variceal bleeding  in portal hypertension, prior to more definitive treat-  ment and with variable results. Terlipressin, a deriva-  tive of vasopressin, is used similarly.   Oxytocin, another posterior pituitary hormone, is indi-  cated in obstetrics (section 7.1.1).   Cautions see under Vasopressin; less pressor activity,  but still considerable caution in cardiovascular dis-  ease and in hypertension (not indicated for nocturnal  enuresis or nocturia in these circumstances); elderly  (avoid for nocturnal enuresis and nocturia in those  over 65 years); also considerable caution in cystic  fibrosis; in nocturia and nocturnal enuresis limit fluid  intake to minimum from 1 hour before dose until 8  hours afterwards; in nocturia periodic blood pressure  and weight checks needed to monitor for fluid over-  load; interactions: Appendix 1 (desmopressin)  Hyponatraemic convulsions Patients being treated for  primary nocturnal enuresis should be warned to avoid fluid  overload (including during swimming) and to stop taking  desmopressin during an episode of vomiting or diarrhoea  (until fluid balance normal). The risk of hyponatraemic  convulsions can also be minimised by keeping to the  recommended starting doses and by avoiding concomitant  use of drugs which increase secretion of vasopressin (e.g.  tricyclic antidepressants)   Contra-indications cardiac insufficiency and other  conditions treated with diuretics; psychogenic poly-  dipsia and polydipsia in alcohol dependence  Renal impairment use with caution; antidiuretic  effect may be reduced   increased risk of pre-eclampsia  Breast-feeding not known to be harmful  Side-effects fluid retention, and hyponatraemia (in  more serious cases with convulsions) on administra-  tion without restricting fluid intake; stomach pain,  headache, nausea, vomiting, allergic reactions, and  emotional disturbance in children also reported;  epistaxis, nasal congestion, rhinitis with nasal spray  Dose   Diabetes insipidus, treatment, ADULT and CHILD initially  300 micrograms daily (in 3 divided doses); mainte-  nance, 300-600 micrograms daily in 3 divided doses;  range 0.2-1. 2 mg daily   Primary nocturnal enuresis, ADULT (under 65 years)  and CHILD over 5 years (preferably over 7 years)   200 micrograms at bedtime, only increased to  400 micrograms if lower dose not effective (impor-  tant: see also Cautions); withdraw for at least 1 week  for reassessment after 3 months  Postoperative polyuria or polydipsia, adjust dose  according to urine osmolality   Diabetes insipidus, treatment, ADULT and CHILD initially  180 micrograms daily in 3 divided doses; range 120—  720 micrograms daily   Primary nocturnal enuresis, ADULT (under 65 years)  and CHILD over 5 years (preferably over 7 years)   120 micrograms at bedtime, only increased to  240 micrograms if lower dose not effective (impor-  tant: see also Cautions); withdraw for at least 1 week  for reassessment after 3 months  Polyuria or polydipsia after hypophysectomy, adjust  dose according to urine osmolality   20 micrograms (limit fluid intake to 500 mL from 1  hour before to 8 hours after administration)   Diabetes insipidus, treatment, ADULT 10-40 micr-  ograms daily (in 1-2 divided doses); CHILD 5-  20 micrograms daily; infants may require lower doses  Nocturia associated with multiple sclerosis (when  other treatments have failed), ADULT (under 65 years)  10-20 micrograms at bedtime (important: see also  Cautions), dose not to be repeated within 24 hours  Renal function testing (empty bladder at time of  administration and limit fluid intake to 500 mL from 1  hour before until 8 hours after administration), ADULT  40 micrograms; INFANT under 1 year 10 micrograms  (restrict fluid intake to 50% at next 2 feeds to avoid  fluid overload), CHILD 1-15 years 20 micrograms  Mild to moderate haemophilia and von Willebrand’s  disease, ADULT 300 micrograms (one 150-microgram  spray into each nostril) 30 minutes before surgery or  when bleeding; may be repeated at intervals of 12  hours (or at intervals of at least 3 days if self-admi-  nistered)   Fibrinolytic response testing, ADULT 300 micrograms  (one 150-microgram spray into each nostril); blood  sampled after 1 hour for fibrinolytic activity   Diabetes insipidus, diagnosis (subcutaneous or intra-  muscular), ADULT and CHILD 2 micrograms (limit fluid  intake to 500 mL from 1 hour before to 8 hours after  administration)   Diabetes insipidus, treatment (subcutaneous, intra-  muscular or intravenous), ADULT 1-4 micrograms  daily; INFANT and CHILD 400 nanograms  Renal function testing (empty bladder at time of  administration and limit fluid intake to 500 mL from 1  hour before until 8 hours after administration) (sub-  cutaneous or intramuscular), ADULT and CHILD  2 micrograms; INFANT 400 nanograms (restrict fluid  intake to 50% at next 2 feeds)   Mild to moderate haemophilia and von Willebrand’s  disease, (subcutaneous or intravenous), ADULT and  CHILD over 1 month 300 nanograms/kg as a single  dose immediately before surgery or after trauma; may  be repeated at intervals of 12 hours  Fibrinolytic response testing, (subcutaneous or  intravenous), ADULT and CHILD 300 nanograms/kg;  blood sampled after 20 minutes for fibrinolytic activity  Lumbar-puncture-associated headache, consult pro-  duct literature   Desmopressin acetate (Non-proprietary) (Ml  Tablets, desmopressin acetate 100 micrograms, net  price 90-tab pack = £50.57; 200 micrograms, 30-tab  pack = £24.36, 90-tab pack = 69.82  Nasal spray, desmopressin acetate 10 micrograms/  metered spray, net price 6-mL unit (60 metered  sprays) = £18.74. Counselling, fluid intake, see above  Brands include Presinex ®   Oral lyophilisates (DDAVP® Melt), desmopressin (as  acetate) 60 micrograms, net price 100-tab pack =   240 micrograms, 100-tab pack = £202.14. Label: 26,  counselling, fluid intake, see above  Intranasal solution, desmopressin acetate lOOmicr-  ograms/mL. Net price 2.5-mL dropper bottle and  catheter = £9.72. Counselling, fluid intake, see above  Injection, desmopressin acetate 4 micrograms/mL.  Net price 1-mL amp = £1.10   Desmospray® (Ferring) (Ml  Nasal spray, desmopressin acetate 10 micrograms/  metered spray. Net price 6-mL unit (60 metered  sprays) = £25.02. Counselling, fluid intake, see above  Note Children requiring dose of less than 10 micrograms should  be given DDA VP ® intranasal solution   Nasal spray, desmopressin acetate 150 micrograms/  metered spray, net price 2.5-mL unit (25 metered  sprays) = £576.60. Counselling, fluid intake, see above  Injection, desmopressin acetate 15 micrograms/mL,  net price 1-mL amp = £19.22   Indications bleeding from oesophageal varices  Cautions see under Vasopressin  Contra-indications see under Vasopressin  Breast-feeding see under Vasopressin  Side-effects see under Vasopressin, but effects milder  Dose   • By intravenous injection, 2 mg followed by 1 or 2 mg  every 4 to 6 hours until bleeding is controlled, for up  to 72 hours   Side-effects fluid retention, pallor, tremor, sweating,  vertigo, headache, nausea, vomiting, belching, abdo-  minal cramps, desire to defaecate, hypersensitivity  reactions (including anaphylaxis), constriction of  coronary arteries (may cause anginal attacks and  myocardial ischaemia), peripheral ischaemia and  rarely gangrene   • By subcutaneous or intramuscular injection, diabetes  insipidus, 5-20 units every four hours   • By intravenous infusion, initial control of variceal  bleeding, 20 units over 1 5 minutes   Demeclocycline (section 5.1.3) can be used in the  treatment of hyponatraemia resulting from inappropri-  ate secretion of antidiuretic hormone, if fluid restriction  alone does not restore sodium concentration or is not  tolerable. Demeclocycline is thought to act by directly  blocking the renal tubular effect of antidiuretic horm-  one. Initially 0.9-1.2g is given daily in divided doses,  reduced to 600-900 mg daily for maintenance.   Tolvaptan is a vasopressin V 2 -receptor antagonist  licensed for the treatment of hyponatraemia secondary  to syndrome of inappropriate antidiuretic hormone  secretion; treatment duration with tolvaptan is deter-  mined by the underlying disease and its treatment.   Injection, terlipressin, powder for reconstitution, net  price 1-mg vial with 5 mL diluent = £18.47  Injection, terlipressin 0.12mg/mL, solution for  injection, net price 1-mg (8.5 mL) vial = £19.39   Cautions heart failure, hypertension, asthma, epilepsy,  migraine or other conditions which might be aggra-  vated by water retention; avoid fluid overload  Contra-indications vascular disease (especially dis-  ease of coronary arteries) unless extreme caution,  chronic nephritis (until reasonable blood nitrogen  concentrations attained)   Renal impairment see Contra-indications  Pregnancy oxytocic effect in third trimester  Breast-feeding not known to be harmful   Cautions ensure adequate fluid intake (monitor for  dehydration in patients who are fluid-restricted); dis-  continue if rapid rise in serum sodium (greater than  12 mmol/litre in 24 hours); diabetes mellitus; pseu-  dohyponatraemia associated with diabetes mellitus  (exclude before treatment); interactions: Appendix 1  (tolvaptan)   Contra-indications anuria; volume depletion; hypo-  volaemic hyponatraemia; hypematraemia; impaired  perception of thirst   Side-effects nausea, constipation, dry mouth; pos-  tural hypotension; thirst, decreased appetite, fever,  asthenia; hyperglycaemia; urinary frequency;    hyperkalaemia, dehydration, ecchymosis, increased  blood creatinine; pruritus; less commonly taste dis-  turbance; also reported hypematraemia, hyperuric-  aemia, hypoglycaemia, syncope, and dizziness   • ADULT over 18 years, 15 mg once daily, increased as  required to max. 60 mg daily   Tablets, blue, tolvaptan 15 mg, net price 10-tab pack  = £746.80; 30 mg, 10-tab pack = £746.80   6.6.1 Calcitonin and parathyroid hormone  6.6.2 Bisphosphonates and other drugs  affecting bone metabolism   See also calcium (section 9.5. 1.1), phosphorus (section  9.5.2), vitamin D (section 9.6.4), and oestrogens in  postmenopausal osteoporosis (section 6.4. 1.1).   Osteoporosis occurs most commonly in postmenopau-  sal women and in those taking long-term oral corticos-  teroids (glucocorticosteroids). Other risk factors for  osteoporosis include low body weight, cigarette  smoking, excess alcohol intake, lack of physical activity,  family history of osteoporosis, and early menopause.   Those at risk of osteoporosis should maintain an  adequate intake of calcium and vitamin D and any  deficiency should be corrected by increasing dietary  intake or taking supplements.    Elderly patients, especially those who are housebound  or live in residential or nursing homes, are at increased  risk of calcium and vitamin D deficiency and may  benefit from supplements (section 9.5. 1.1 and section  9.6.4). Reversible secondary causes of osteoporosis  such as hyperthyroidism, hyperparathyroidism, osteo-  malacia or hypogonadism should be excluded, in both  men and women, before treatment for osteoporosis is  initiated.   Postmenopausal osteoporosis The bisphosphon-  ates (alendronic acid, disodium etidronate, and risedro-  nate, section 6.6.2) are effective for preventing postme-  nopausal osteoporosis. Hormone replacement  therapy (HRT section 6.4. 1.1) is an option where  other therapies are contra-indicated, cannot be toler-  ated, or if there is a lack of response. The CSM has  advised that HRT should not be considered first-line  therapy for long-term prevention of osteoporosis in  women over 50 years of age. HRT is of most benefit  for the prophylaxis of postmenopausal osteoporosis if  started early in menopause and continued for up to 5  years, but bone loss resumes (possibly at an accelerated  rate) on stopping HRT. Calcitonin (section 6.6.1) may  be considered for those at high risk of osteoporosis for  whom a bisphosphonate is unsuitable. Women of Afro-    Caribbean origin appear to be less susceptible to osteo-  porosis than those who are white or of Asian origin.   Postmenopausal osteoporosis may be treated with a  bisphosphonate (section 6.6.2). The bisphosphonates  (such as alendronate, etidronate, and risedronate)  decrease the risk of vertebral fracture; alendronate and  risedronate have also been shown to reduce non-ver-  tebral fractures. If bisphosphonates are unsuitable calci-  triol (section 9.6.4), calcitonin or strontium ranelate  (section 6.6.2) may be considered. Calcitonin [unli-  censed indication] may also be useful for pain relief  for up to 3 months after a vertebral fracture if other  analgesics are ineffective. Parathyroid hormone, and  teriparatide (section 6.6.1) have been introduced for  the treatment of postmenopausal osteoporosis.   Raloxifene (section 6.4. 1.1) is licensed for the prophy-  laxis and treatment of vertebral fractures in postmeno-  pausal women.   Alendronate, etidronate, risedronate,  raloxifene and strontium ranelate for the  primary prevention of osteoporotic fragility  fractures in postmenopausal women  (October 2008)   Alendronate is recommended as a treatment option  for the primary prevention of osteoporotic fractures  in the following susceptible postmenopausal  women:   • Women over 70 years who have an independent  risk factor for fracture (parental history of hip  fracture, alcohol intake of 4 or more units per  day, or rheumatoid arthritis) or an indicator of  low bone mineral density (body mass index  under 22 kg/m 2 , ankylosing spondylitis, Crohn’s  disease, prolonged immobility, untreated prema-  ture menopause, or rheumatoid arthritis) and  confirmed osteoporosis   • Women aged 65-69 years who have an inde-  pendent risk factor for fracture and confirmed  osteoporosis   • Women under 65 years who have an indepen-  dent risk factor for fracture and at least one  additional indicator of low bone mineral density  and confirmed osteoporosis   • who comply with particular combinations of  bone mineral density measurement, age, and  independent risk factors for fracture, as indi-  cated in the full NICE guidance 1   • in whom alendronate and either risedronate or  editronate are contra-indicated or not tolerated   • who comply with particular combinations of  bone mineral density measurement, age, and  independent risk factors for fracture, as indi-  cated in the full NICE guidance 1   Raloxifene is not recommended as a treatment  option in postmenopausal women for primary pre-  vention of osteoporotic fractures.   Alendronate, etidronate, risedronate,  raloxifene, strontium ranelate, and  teriparatide for the secondary prevention of  osteoporotic fragility fractures in  postmenopausal women (October 2008)   This guideline recommends treatment options for  the secondary prevention of osteoporotic fractures  in postmenopausal women with confirmed osteo-  porosis who have also sustained a clinically apparent  osteoporotic fracture.   Alendronate is recommended as a treatment option  for the secondary prevention of osteoporotic frac-  tures in susceptible postmenupausal women.  Risedronate or etidronate are recommended as  alternatives for women:   • who comply with particular combinations of  bone mineral density measurement, age, and  independent risk factors for fracture (parental  history of hip fracture, alcohol intake of 4 or  more units per day, or rheumatoid arthritis, as  indicated in the full NICE guidance 1   Strontium ranelate or raloxifene are recom-  mended as alternatives for women:   • in whom alendronate and either risedronate or  editronate are contra-indicated or not tolerated  and   • who comply with particular combinations of  bone mineral density measurement, age, and  independent risk factors for fracture, as indi-  cated in the full NICE guidance 1   • in whom alendronate and either risedronate or  editronate, or strontium ranelate are contra-  indicated or not tolerated, or where treatment  with alendronate, risedronate or editronate has  been unsatisfactory (indicated by another fragi-  lity fracture and a decline in bone mineral den-  sity despite treatment for 1 year) and   • who comply with particular combinations of  bone mineral density measurement, age, and  number of fractures, as indicated in the full  NICE guidance 1    oral corticosteroids who have sustained a low-trauma  fracture should receive treatment for osteoporosis. The  therapeutic options for prophylaxis and treatment of  corticosteroid-induced osteoporosis are the same:   • hormone replacement (HRT in women (section  6.4.1), testosterone in men [unlicensed indication]  (section 6.4.2)).   Calcitonin is involved with parathyroid hormone in the  regulation of bone turnover and hence in the mainte-  nance of calcium balance and homoeostasis. Calcitonin  (salmon) (salcatonin, synthetic or recombinant salmon  calcitonin) is used to lower the plasma-calcium concen-  tration in some patients with hypercalcaemia (notably  when associated with malignant disease). Calcitonin is  licensed for treatment of Paget’s disease of bone. It can  also be used in the prevention and treatment of post-  menopausal osteoporosis (see section 6.6).   Recombinant parathyroid hormone is used for the  treatment of postmenopausal osteoporosis. Teripara-  tide (a recombinant fragment of parathyroid hormone)  is used for the treatment of postmenopausal osteo-  porosis, osteoporosis in men at increased risk of frac-  ture, and corticosteroid-induced osteoporosis. The  Scottish Medicines Consortium, p. 4 has advised (Feb-  ruary 2007) that parathyroid hormone ( Preotact ®)  should be initiated by specialists experienced in the  treatment of osteoporosis; also that the use of teripara-  tide ( Forsteo ®) (December 2003) in postmenopausal  women should be restricted to the treatment of  established (severe) osteoporosis and should be initiated  by specialists experienced in the treatment of osteo-  porosis.   Cinacalcet (section 9.5. 1.2) is licensed for the treatment  of hypercalcaemia in parathyroid carcinoma.    Corticosteroid-induced osteoporosis To reduce  the risk of osteoporosis doses of oral corticosteroids  should be as low as possible and courses of treatment as  short as possible. The risk of osteoporosis may be  related to cumulative dose of corticosteroids; even  intermittent courses can therefore increase the risk.  The greatest rate of bone loss occurs during the first  6-12 months of corticosteroid use and so early steps to  prevent the development of osteoporosis are important.  Long-term use of high-dose inhaled corticosteroids may  also contribute to corticosteroid-induced osteoporosis  (section 3.2).   Patients taking (or who are likely to take) an oral cortico-  steroid for 3 months or longer should be assessed and  where necessary given prophylactic treatment; those  aged over 65 years are at greater risk. Patients taking   Contra-indications hypocalcaemia  Renal impairment use with caution  Pregnancy avoid unless potential benefit outweighs  risk (toxicity in animal studies)   Breast-feeding avoid; inhibits lactation in animals  Side-effects nausea, vomiting, diarrhoea, abdominal  pain; flushing; dizziness, headache, taste disturbances;  musculoskeletal pain; with nasal spray nose and  throat irritation, rhinitis, sinusitis and epistaxis; less  commonly diuresis, oedema, cough, visual distur-  bances, injection-site reactions, rash, hypersensitivity  reactions including pruritus   • Hypercalcaemia of malignancy (see also section  9.5. 1.2), ADULT over 18 years, by subcutaneous or  intramuscular injection, 100 units every 6-8 hours  adjusted according to response; max. 400 units every  6-8 hours; in severe or emergency cases, by intra-  venous infusion, up to 10 units/kg over at least 6  hours   • Paget’s disease of bone, ADULT over 18 years, by  subcutaneous or intramuscular injection, 50units 3  times weekly to 100 units daily adjusted according to  response   • Postmenopausal osteoporosis to reduce risk of ver-  tebral fractures, intranasally, 200 units (1 spray) into  one nostril daily, with dietary calcium and vitamin D  supplements (section 9.5. 1.1 and section 9.6.4)   • Prevention of acute bone loss due to sudden immo-  bility, ADULT over 18 years, by subcutaneous or intra-  muscular injection, 100 units daily in 1-2 divided  doses for 2-4 weeks, reduced to 50 units daily at start  of mobilisation and continued until fully mobile   Nasal spray Y, calcitonin (salmon) 200 units/metered  spray, net price 2-mL unit (approx. 14 metered sprays)  = £16.79   Injection, calcitonin (salmon) 50units/mL, net price  1-mL amp = £3.42; lOOunits/mL, 1-mL amp = £6.85;  200units/mL, 2-mL vial = £30.75  For subcutaneous or intramuscular injection and for dilution and  use as an intravenous infusion   Indications treatment of osteoporosis in postmeno-  pausal women at high risk of fractures (to reduce the  risk of vertebral fractures) (see also notes above)  Cautions monitor serum or urinary calcium concen-  tration at 1, 3 and 6 months after initiation of treat-  ment (consult product literature for guidance if  serum-calcium concentration raised); active or pre-  vious urolithiasis; concomitant cardiac glycosides  Contra-indications previous radiation therapy to  skeleton, pre-existing hypercalcaemia, metabolic  bone disease (including hyperparathyroidism and  Paget’s disease), unexplained raised levels of alkaline  phosphatase   Hepatic impairment avoid  Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73m 2  Pregnancy avoid  Breast-feeding avoid   Side-effects nausea, vomiting, dyspepsia, constipa-  tion, diarrhoea; palpitation; headache, dizziness, fati-  gue, asthenia; transient hypercalcaemia, hypercal-  ciuria; muscle cramp, pain in extremities, back pain;  injection-site reactions; less commonly abdominal  pain, altered sense of smell, taste disturbance, ano-  rexia, influenza, hyperuricaemia  Dose   • By subcutaneous injection, 100 micrograms daily,  max. duration of treatment 24 months    Indications treatment of osteoporosis in postmeno-  pausal women and in men at increased risk of frac-  tures; treatment of corticosteroid-induced osteo-  porosis; see also notes above  Contra-indications pre-existing hypercalcaemia,  skeletal malignancies or bone metastases, metabolic  bone diseases, including Paget’s disease and hyper-  parathyroidism, unexplained raised alkaline phos-  phatase, previous radiation therapy to the skeleton  Renal impairment caution in moderate impairment;   Side-effects gastro-intestinal disorders (including  nausea, reflux and haemorrhoids); palpitation; dys-  pnoea; headache, fatigue, asthenia, depression, dizzi-  ness, vertigo; anaemia, increased sweating, muscle  cramps, sciatica, myalgia, arthralgia; less commonly  urinary disorders, hypercalcaemia; injection-site  reactions; rarely hypersensitivity reactions  Dose    • By subcutaneous injection, 20 micrograms daily;  max. duration of treatment 18 months (course not to  be repeated)   Injection, teriparatide 250micrograms/mL, net price  2.4-mL prefilled pen = £271.88, 3-mL prefilled pen =  £271.88   Bisphosphonates are adsorbed onto hydroxyapatite  crystals in bone, slowing both their rate of growth and  dissolution, and therefore reducing the rate of bone  turnover. Bisphosphonates have an important role in  the prophylaxis and treatment of osteoporosis and  corticosteroid-induced osteoporosis; alendronic acid  or risedronate sodium are considered the drugs of  choice for these conditions, but disodium etidronate  may be considered if these drugs are unsuitable or not  tolerated (see also section 6.6).   Bisphosphonates are also used in the treatment of  Paget’s disease, hypercalcaemia of malignancy (section  9.5. 1.2), and in bone metastases in breast cancer (sec-  tion 8.3.4. 1). Disodium etidronate can impair bone    mineralisation when used continuously or in high doses  (such as in the treatment of Paget’s disease).   The risk of osteonecrosis of the jaw is substantially  greater for patients receiving intravenous bisphos-  phonates in the treatment of cancer than for patients  receiving oral bisphosphonates for osteoporosis or  Paget’s disease.   Risk factors for developing osteonecrosis of the jaw  that should be considered are: potency of bispho-  sphonate (highest for zolendronate), route of admin-  istration, cumulative dose, duration and type of  malignant disease, concomitant treatment, smoking,  comorbid conditions, and history of dental disease.  All patients receiving bisphosphonates for cancer  should have a dental check-up (and any necessary  remedial work should be performed) before bispho-  sphonate treatment. However, urgent bisphospho-  nate treatment should not be delayed, and a dental  check-up should be carried out as soon as possible in  these patients. All other patients who are prescribed  bisphosphonates should have a dental examination  only if they have poor dental health.   During bisphosphonate treatment patients should  maintain good oral hygiene, receive routine dental  check-ups, and report any oral symptoms.   Cautions upper gastro-intestinal disorders (dysphagia,  symptomatic oesophageal disease, gastritis, duodeni-  tis, or ulcers — see also under Contra-indications and  Side-effects); history (within 1 year) of ulcers, active  gastro-intestinal bleeding, or surgery of the upper  gastro-intestinal tract; correct disturbances of calcium  and mineral metabolism (e.g. vitamin-D deficiency,  hypocalcaemia) before starting and monitor serum-  calcium concentration during treatment; consider  dental check-up before initiating bisphosphonate (risk  of osteonecrosis of the jaw, see MHRA/CHM advice,  above); exclude other causes of osteoporosis; atypical  stress fractures reported (discontinue unless benefits  of continued treatment clearly outweigh risks); inter-  actions: Appendix 1 (bisphosphonates)   Contra-indications abnormalities of oesophagus and  other factors which delay emptying (e.g. stricture or  achalasia), hypocalcaemia   Renal impairment avoid if eGFR less than 35 mL/  minute/ 1.73 m 2  Pregnancy avoid   Side-effects oesophageal reactions (see below),  abdominal pain and distension, dyspepsia, regurgita-  tion, melaena, diarrhoea or constipation, flatulence,  musculoskeletal pain, headache; rarely rash, pruritus,  erythema, photosensitivity, uveitis, scleritis, transient  decrease in serum calcium and phosphate; nausea,  vomiting, gastritis, peptic ulceration, hypersensitivity  reactions (including urticaria and angioedema), and  atypical stress fractures with long-term use also  reported; myalgia, malaise, and fever at initiation of  treatment; very rarely severe skin reactions (including    Stevens- Johnson syndrome), osteonecrosis of the jaw  (see MHRA/CHM advice, above)   Oesophageal reactions Severe oesophageal reactions  (oesophagitis, oesophageal ulcers, oesophageal stricture  and oesophageal erosions) have been reported; patients  should be advised to stop taking the tablets and to seek  medical attention if they develop symptoms of oesophageal  irritation such as dysphagia, new or worsening heartburn,  pain on swallowing or retrosternal pain  Dose   • Treatment of postmenopausal osteoporosis, 10 mg  daily or 70 mg once weekly   • Prevention and treatment of corticosteroid-induced  osteoporosis in postmenopausal women not receiving  hormone replacement therapy, 10 mg daily  Counselling Tablets should be swallowed whole with plenty  of water while sitting or standing; to be taken on an empty  stomach at least 30 minutes before breakfast (or another oral  medicine); patient should stand or sit upright for at least 30  minutes after taking tablet   Alendronic Acid Once-Weekly (Non-proprietary) (Ml  Tablets, alendronic acid (as sodium alendronate)   Fosamax® Once Weekly (MSD) (Ml  Tablets, alendronic acid (as sodium alendronate)   70 mg, colecalciferol 70 micrograms (2 800 units), net  price 4-tab pack = £22.80. Counselling, administra-  tion   Dose treatment of postmenopausal osteoporosis in women at  risk of vitamin D deficiency, 1 tablet once weekly  Counselling Tablets should be swallowed whole with plenty of  water while sitting or standing; to be taken on an empty stomach  at least 30 minutes before breakfast (or another oral medicine);  patient should stand or sit upright for at least 30 minutes after  taking tablet   Cautions consider dental check-up before initiating  bisphosphonate (risk of osteonecrosis of the jaw, see  MHRA/CHM advice, above); interactions: Appendix  1 (bisphosphonates)   Contra-indications not indicated for osteoporosis in  presence of hypercalcaemia or hypercalciuria or for  osteomalacia   Renal impairment reduce dose in mild impairment;  avoid in moderate to severe renal impairment   Side-effects nausea, diarrhoea or constipation,  abdominal pain; increased bone pain in Paget’s dis-  ease, also increased risk of fractures with high doses  in Paget’s disease (discontinue if fractures occur);  rarely exacerbation of asthma, skin reactions  (including angioedema, rash, urticaria and pruritus),  transient hyperphosphataemia, headache, paraes-  thesia, peripheral neuropathy reported; blood disor-  ders (including leucopenia, agranulocytosis and pan-  cytopenia) also reported; very rarely osteonecrosis of  the jaw (see MHRA/CHM advice, p. 472)   • Paget’s disease of bone, by mouth, 5 mg/kg as a single  daily dose for up to 6 months; doses above 10 mg/kg  daily for up to 3 months may be used with caution but  doses above 20 mg/kg daily are not recommended;  after interval of not less than 3 months may be  repeated where evidence of reactivation — including  biochemical indices (avoid premature retreatment)  Monitoring Serum phosphate, serum alkaline phosphatase  and (if possible) urinary hydroxyproline should be measured  before starting and at intervals of 3 months — consult product  literature for further details   Counselling Avoid food for at least 2 hours before and after  oral treatment, particularly calcium-containing products e.g.  milk; also avoid iron and mineral supplements and antacids   Didronel® (Warner Chilcott) (Ml  Tablets, disodium etidronate 200 mg. Net price 60-tab  pack = £19.48. Counselling, food and calcium (see  above)   Didronel PMO® (Warner Chilcott) (Ml  Tablets, 14 white, disodium etidronate 400 mg; 76  pink, effervescent, calcium carbonate 1.25 g ( Cacit ®).  Net price per pack = £19.89. Label: 10, patient  information leaflet, counselling, food and calcium (see  above)   Dose treatment of osteoporosis, prevention of bone loss in  postmenopausal women (particularly if hormone replacement  therapy inappropriate), and prevention and treatment of cortico-  steroid-induced osteoporosis, given in 90-day cycles, 1 Didronel ®  tablet daily for 14 days, then 1 Cacit ® tablet daily for 76 days   Indications see under Dose  Cautions assess renal function before each dose;  ensure adequate hydration; cardiac disease (especially  in elderly); previous thyroid surgery (risk of hypo-  calcaemia); monitor serum electrolytes, calcium and  phosphate — possibility of convulsions due to electro-  lyte changes; avoid concurrent use with other bis-  phosphonates; consider dental check-up before initi-  ating bisphosphonate (risk of osteonecrosis of the jaw,  see MHRA/CHM advice, p. 472); interactions:  Appendix 1 (bisphosphonates)   Driving Patients should be warned against driving or oper-  ating machinery immediately after treatment (somnolence or  dizziness can occur)    Hepatic impairment caution in severe hepatic  impairment — no information available  Renal impairment max. infusion rate 20 mg/hour;  avoid if eGFR less than 30 mL/minute/ 1.73 m 2 ,  except in life-threatening hypercalcaemia if benefit  outweighs risk; if renal function deteriorates in  patients with bone metastases, withhold dose until  serum creatinine returns to within 10% of baseline  value   Side-effects hypophosphataemia, fever and influ-  enza-like symptoms (sometimes accompanied by  malaise, rigors, fatigue and flushes); nausea, vomiting,  anorexia, abdominal pain, diarrhoea, constipation;  symptomatic hypocalcaemia (paraesthesia, tetany),  hypomagnesaemia, headache, insomnia, drowsiness;  hypertension; anaemia, thrombocytopenia, lympho-  cytopenia; rash; arthralgia, myalgia, bone pain; rarely  muscle cramps, dyspepsia, agitation, confusion, diz-  ziness, lethargy; leucopenia, hypotension, pruritus,  hyperkalaemia or hypokalaemia, and hypernatraemia;  osteonecrosis of the jaw (see also MHRA/CHM  advice, p. 472), isolated cases of seizures, hallucina-  tions, haematuria, acute renal failure, deterioration of  renal disease, conjunctivitis and other ocular symp-  toms; atrial fibrillation, and reactivation of herpes  simplex and zoster also reported; also injection-site  reactions   • By slow intravenous infusion (via cannula in a rela-  tively large vein), see also Appendix 6  Hypercalcaemia of malignancy, according to serum  calcium concentration 15-60 mg in single infusion or  in divided doses over 2-4 days; max. 90 mg per  treatment course   Osteolytic lesions and bone pain in bone metastases  associated with breast cancer or multiple myeloma,  90 mg every 4 weeks (or every 3 weeks to coincide  with chemotherapy in breast cancer)   Paget’s disease of bone, 30 mg once a week for 6  weeks (total dose 180 mg) or 30 mg in first week then  60 mg every other week (total dose 210 mg); max.  total 360 mg (in divided doses of 60 mg) per treatment  course; may be repeated every 6 months  • CHILD not recommended   Calcium and vitamin D supplements Oral supplements are  advised to minimise potential risk of hypocalcaemia for those  with mainly lytic bone metastases or multiple myeloma at risk  of calcium or vitamin D deficiency (e.g. through malabsorption  or lack of exposure to sunlight) and in those with Paget’s  disease    Disodium pamidronate (Non-proprietary) (Ml  Concentrate for intravenous infusion, disodium  pamidronate 3 mg/mL, net price 5-mL vial = £27.50,  10-mL vial = £55.00; 6 mg/mL, 10-mL vial = £95.00;  9mg/mL, 10-mL vial =£165.00; 15mg/mL, 1-mL  vial = £29.83, 2-mL vial = £59.66, 4-mL vial = £1 19.32,  6-mL vial £170.46   Injection, powder for reconstitution, disodium pami-  dronate, for use as an infusion. Net price 1 5-mg vial =  £29.83; 30-mg vial = £59.66; 90-mg vial = £170.45 (all  with diluent)    Indications see under Dose  Cautions consider dental check-up before initiating  bisphosphonate (risk of osteonecrosis of the jaw, see  MHRA/CHM advice, p. 472); monitor renal function  and serum calcium, phosphate and magnesium; car-  diac disease (avoid fluid overload); interactions:  Appendix 1 (bisphosphonates)   Contra-indications hypocalcaemia; oral route  abnormalities of the oesophagus and other factors  which delay emptying (e.g. stricture or achalasia)  Renal impairment for treatment of osteoporosis,  avoid if eGFR less than 30mL/minute/1.73m 2 ; for  reduction of bone damage in bone metastases, if  eGFR 30-50 mL/minute/ 1.73 m 2 reduce intravenous  dose to 4 mg and infuse over 1 hour, reduce oral dose  to 50 mg on alternative days, if eGFR less than 30 mL/  minute/ 1.73 m 2 reduce intravenous dose to 2 mg and  infuse over 1 hour, reduce oral dose to 50 mg once  weekly   Side-effects hypocalcaemia, hypophosphataemia,  influenza-like symptoms (including fever, chills, and  muscle pain), bone pain; oesophageal reactions (see  below), diarrhoea, nausea, vomiting, gastritis, abdo-  minal pain, dyspepsia, pharyngitis; headache, asthe-  nia, rash; rarely anaemia, hypersensitivity reactions  (pruritus, bronchospasm and angioedema reported);  urticaria; injection-site reactions; very rarely osteo-  necrosis of the jaw (see MHRA/CHM advice, p. 472)  Oesophageal reactions Severe oesophageal reactions  reported with all oral bisphosphonates; patients should be  advised to stop tablets and seek medical attention for  symptoms of oesophageal irritation such as dysphagia, pain  on swallowing, retrosternal pain, or heartburn    • Reduction of bone damage in bone metastases in  breast cancer, by mouth, 50 mg daily, or by intra-  venous infusion, 6 mg every 3-4 weeks   • Hypercalcaemia of malignancy by intravenous infu-  sion, according to serum calcium concentration, 2-  4 mg in single infusion   • Treatment of postmenopausal osteoporosis, by  mouth, 150 mg once a month or by intravenous  injection over 15-30 seconds, 3 mg every 3 months   Counselling Tablets should be swallowed whole with plenty  of water while sitting or standing; to be taken on an empty  stomach at least 30 minutes ( Bondronat ® tablets, 50 mg) or  1 hour ( Bonviva ® tablets, 150 mg) before first food or drink  (other than water) of the day, or another oral medicine;  patient should stand or sit upright for at least 1 hour after  taking tablet   Tablets, f/c, ibandronic acid 50 mg, net price 28-tab  pack = £183.69. Counselling, administration  Concentrate for intravenous infusion, ibandronic  acid 1 mg/mL, net price 2-mL amp = £89.36, 6-mL  vial = £183.69   Tablets, f/c, ibandronic acid 150 mg, net price 1-tab  pack = £18.40, 3-tab pack = £55.21. Counselling,  administration   Injection, ibandronic acid 1 mg/mL, net price 3-mL  prefilled syringe = £68.64   Cautions oesophageal abnormalities and other factors  which delay transit or emptying (e.g. stricture or  achalasia — see also under Side-effects); correct  hypocalcaemia before starting, correct other distur-  bances of bone and mineral metabolism (e.g. vitamin-  D deficiency) at onset of treatment; consider dental  check-up before initiating bisphosphonate (risk of  osteonecrosis of the jaw, see MHRA/CHM advice,  p. 472); interactions: Appendix 1 (bisphosphonates)   Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2  Pregnancy avoid   Side-effects abdominal pain, dyspepsia, nausea,  diarrhoea, constipation, headache, musculoskeletal  pain; less commonly oesophagitis, oesophageal ulcer,  dysphagia, gastritis, duodenitis, uveitis; rarely glossi-  tis, oesophageal stricture; also reported gastroduo-  denal ulceration, hepatic disorders, Stevens- Johnson  syndrome, toxic epidermal necrolysis, hair loss,  osteonecrosis of the jaw (see MHRA/CHM advice,  p. 472)   Oesophageal reactions Patients should be advised to stop  taking the tablets and seek medical attention if they develop  symptoms of oesophageal irritation such as dysphagia, pain  on swallowing, retrosternal pain, or heartburn   • Paget’s disease of bone, 30 mg daily for 2 months; may  be repeated if necessary after at least 2 months   • Treatment of postmenopausal osteoporosis to reduce  risk of vertebral or hip fractures, 5 mg daily or 35 mg  once weekly   • Prevention of osteoporosis (including corticosteroid-  induced osteoporosis) in postmenopausal women,   • Treatment of osteoporosis in men at high risk of  fractures, 3 5 mg once weekly   Counselling Swallow tablets whole with full glass of water;  on rising, take on an empty stomach at least 30 minutes  before first food or drink of the day or, if taking at any other  time of the day, avoid food and drink for at least 2 hours  before or after risedronate (particularly avoid calcium-con-  taining products e.g. milk; also avoid iron and mineral  supplements and antacids); stand or sit upright for at least 30  minutes; do not take tablets at bedtime or before rising   Actonel® (Warner Chilcott) [MO  Tablets, f/c, risedronate sodium 5 mg (yellow), net  price 28-tab pack = £17.99; 30 mg (white), 28-tab pack  = £143.95. Counselling, administration, food and cal-  cium (see above)   Actonel Once a Week® (Warner Chilcott) (Ml  Tablets, f/c, orange, risedronate sodium 35 mg, net  price 4-tab pack = £19.12. Counselling, administra-  tion, food and calcium (see above)   ^With calcium carbonate and colecalciferol  For cautions, contra-indications, and side-effects of  calcium carbonate, see section 9.5. 1.1 and of colecal-  ciferol, see section 9.6.4   Actonel® Combi (Warner Chilcott) (Ml  Tablets, f/c, orange, risedronate sodium 35 mg  ( Actonel Once a Weekly,    Granules, effervescent, lemon flavour, calcium carb-  onate 2.5 g (calcium 1 g or Ca z+ 25 mmol) and cole-  calciferol 22 micrograms (880 units) /sachet, net price  24-sachet plus 4-tab pack = £19.12. Counselling,  administration, food and calcium (see above)   Dose treatment of postmenopausal osteoporosis to reduce risk  of vertebral or hip fractures, given in weekly cycles, 1 Actonel  Once a Week® tablet on the first day followed by 1 calcium and  colecalciferol sachet daily for 6 days   Counselling Tablets should be swallowed whole with plenty of  water while sitting or standing; to be taken on an empty stomach  at least 30 minutes before breakfast (or another oral medicine);  patient should stand or sit upright for at least 30 minutes after  taking tablet. Granules should be stirred into a glass of water and  after dissolution complete taken immediately   Cautions monitor renal and hepatic function and  white cell count; also monitor serum calcium and  phosphate periodically; renal dysfunction reported in  patients receiving concomitant NSAIDs; maintain  adequate fluid intake during treatment; consider  dental check-up before initiating bisphosphonate (risk  of osteonecrosis of the jaw, see MHRA/CHM advice,  p. 472); interactions: Appendix 1 (bisphosphonates)   Renal impairment use half normal dose if eGFR 10-  30mL/minute/1.73m 2 ; avoid if eGFR less than  1 0 mL /minute /1.73m 2   Side-effects nausea, diarrhoea; skin reactions; bron-  chospasm; very rarely osteonecrosis of the jaw (see  MHRA/CHM advice, p. 472)   • Osteolytic lesions, hypercalcaemia and bone pain  associated with skeletal metastases in patients with  breast cancer or multiple myeloma, by mouth, 1.6 g  daily in single or 2 divided doses increased if neces-  sary to a max. of 3.2 g daily   Counselling Avoid food for 1 hour before and after treat-  ment, particularly calcium-containing products e.g. milk; also  avoid iron and mineral supplements and antacids; maintain  adequate fluid intake   Bonefos® (Bayer Schering) (Ml  Capsules, yellow, sodium clodronate 400 mg, net  price 120-cap pack = £139.83. Counselling, food and  calcium   Tablets, f/c, scored, sodium clodronate 800 mg, net  price 60-tab pack = £146.43. Counselling, food and  calcium   Capsules, blue/ white, sodium clodronate 400 mg, net  price 30-cap pack = £34.96, 120-cap pack = £139.83.  Counselling, food and calcium   Tablets, f/c, scored, sodium clodronate 520 mg, net  price 60-tab pack = £152.59. Label: 10, patient infor-  mation leaflet, counselling, food and calcium  Dose 2 tablets daily in single or two divided doses; may be  increased to max. 4 tablets daily   Indications Paget’s disease of bone  Cautions correct disturbances of calcium metabolism  (e.g. vitamin D deficiency, hypocalcaemia) before  starting; avoid concomitant use of indometacin; con-  sider dental check-up before initiating bisphosphonate  (risk of osteonecrosis of the jaw, see MHRA/CHM  advice, p. 472); interactions: Appendix 1 (bisphos-  phonates)   Contra-indications juvenile Paget’s disease  Renal impairment use with caution and monitor renal  function regularly if eGFR 30-90 mL/minute/ 1.73 m 2 ;  avoid if eGFR less than 30 mL/minute/ 1.73 m 2  Pregnancy avoid   Breast-feeding avoid — no information available  Side-effects stomach pain, nausea, diarrhoea; rarely  asthenia, dizziness, headache and skin reactions; very  rarely osteonecrosis of the jaw (see MHRA/CHM  advice, p. 472)   • 400 mg daily as a single dose for 12 weeks; may be  repeated if necessary after 6 months  Counselling Avoid food for 2 hours before and after treat-  ment, particularly calcium-containing products e.g. milk; also  avoid antacids   Cautions correct disturbances of calcium metabolism  (e.g. vitamin D deficiency, hypocalcaemia) before  starting; monitor serum electrolytes, calcium, phos-  phate and magnesium; cardiac disease (avoid fluid  overload); consider dental check-up before initiating  bisphosphonate (risk of osteonecrosis of the jaw, see  MHRA/CHM advice, p. 472); interactions: Appendix  1 (bisphosphonates)   Renal function Renal impairment and renal failure have  been reported. Before each dose ensure patient is hydrated  and assess renal function. Continue to monitor renal function  in patients at risk, such as those with pre-existing renal  impairment, those of advanced age, those taking concomi-  tant nephrotoxic drugs or diuretics, or those who are dehy-  drated. Use with caution with concomitant medicines that  affect renal function   Renal impairment avoid if serum creatinine above  400 micromol/litre in tumour-induced hypercal-  caemia; in advanced malignancies involving bone, if  eGFR 50-60 mL/minute/ 1.73 m 2 reduce dose to  3.5 mg every 3-4 weeks, if eGFR 40-50 mL/minute/  1.73 m 2 reduce dose to 3.3 mg every 3-4 weeks, if  eGFR 30-40 mL/minute/ 1.73 m 2 reduce dose to 3 mg  every 3-4 weeks, avoid if eGFR less than 30 mL/  minute/ 1.73 m 2 (or if serum creatinine greater than  265 micromol/litre); if renal function deteriorates in  patients with bone metastases, withhold dose until  serum creatinine returns to within 10% of baseline  value; avoid in Paget’s disease, treatment of postme-  nopausal osteoporosis and osteoporosis in men if    eGFR less than 35 mL/minute/ 1.73 m 2 ; see also  Cautions above   Pregnancy avoid — toxicity in animal studies  Breast-feeding avoid — no information available  Side-effects hypophosphataemia, anaemia, influenza-  like symptoms including bone pain, myalgia, arthr-  algia, fever and rigors; gastro-intestinal disturbances;  atrial fibrillation; headache, dizziness, conjunctivitis,  renal impairment (rarely acute renal failure); less  commonly anorexia, taste disturbance, dry mouth,  stomatitis, chest pain, hypertension, hypotension,  dyspnoea, cough, paraesthesia, tremor, anxiety,  lethargy, sleep disturbance, blurred vision, weight  gain, pruritus, rash, sweating, muscle cramps, hae-  maturia, proteinuria, urinary frequency, hypersensi-  tivity reactions (including angioedema), asthenia,  peripheral oedema, thrombocytopenia, leucopenia,  hypomagnesaemia, hypokalaemia, also injection-site  reactions; rarely bradycardia, confusion, hyperkal-  aemia, hypematraemia, pancytopenia, osteonecrosis  of the jaw (see also MHRA/CHM advice, p. 472); very  rarely uveitis and episcleritis  Dose   Aclasta® (Novartis) T (Ml  Intravenous infusion, zoledronic acid 50micr-  ograms/mL, net price 100-mL bottle = £266.72  Dose treatment of Paget’s disease of bone, by intravenous infu-  sion, 5 mg as a single dose over at least 15 minutes  Note At least 500 mg elemental calcium twice daily (with vitamin  D, section 9.6.4) for at least 10 days is recommended following  infusion   Treatment of postmenopausal osteoporosis and osteoporosis in  men (including corticosteroid-induced osteoporosis), by intra-  venous infusion, 5 mg over at least 15 minutes once a year  Note In patients with a recent low-trauma hip fracture, the dose  should be given 2 or more weeks following hip fracture repair;  before first infusion give 50 000-125 000 units of vitamin D (sec-  tion 9.6.4)   Note The Scottish Medicines Consortium (p. 4) has advised (Feb-  ruary 2008) that in postmenopausal women Aclasta ® is accepted  for restricted use within the NHS Scotland for the treatment of  osteoporosis in those for whom oral treatment options for  osteoporosis are inappropriate and when initiated by a specialist   Concentrate for intravenous infusion, zoledronic  acid, 800 micrograms /mL, net price 5-mL (4-mg) vial  = £183.30   Dose reduction of bone damage in advanced malignancies  involving bone, by intravenous infusion, 4 mg over at least 15  minutes every 3-4 weeks; CHILD not recommended  Note Calcium 500 mg daily and vitamin D 400 units daily should  also be taken   Hypercalcaemia of malignancy, by intravenous infusion, 4 mg as a  single dose over at least 15 minutes; CHILD not recommended  Note The Scottish Medicines Consortium (p. 4) has advised  (May 2003) that for the prevention of skeletal related events  Zometa ® is accepted for restricted use within NHS Scotland  for the treatment of patients with breast cancer and multiple  myeloma if prescribed by an oncologist   Denosumab is a human monoclonal antibody that  inhibits osteoclast formation, function, and survival,  thereby decreasing bone resorption. It is licensed for  the treatment of postmenopausal osteoporosis in  women at increased risk of fractures and for the treat-  ment of bone loss associated with hormone ablation in  men with prostate cancer.   Denosumab for the prevention of  osteoporotic fractures in postmenopausal  women (October 2010)   Denosumab is recommended as a treatment option  for the primary prevention of osteoporotic fragility  fractures in postmenopausal women at increased  risk of fractures;   • who are unable to comply with the special  instructions for administering alendronate and  either risedronate or etidronate, or have an  intolerance of, or a contra-indication to, those  treatments and   • who comply with particular combinations of  bone mineral density measurement, age, and  independent risk factors for fracture, as indi-  cated in the full NICE guidance (available at   Denosumab is recommended as a treatment option  for the secondary prevention of osteoporotic fragility  fractures only in postmenopausal women at  increased risk of fractures who are unable to comply  with the special instructions for administering alen-  dronate and either risedronate or etidronate, or have  an intolerance of, or a contra-indication to, those  treatments.   Indications see notes above  Cautions correct hypocalcaemia and vitamin D defi-  ciency before starting (monitor plasma-calcium con-  centration during therapy); consider dental check-up  and carry out invasive procedures before initiating  treatment (risk of osteoneocrosis of the jaw)   Renal impairment increased risk of hypocalcaemia if  eGFR less than 30 mL/minute/ 1.73 m 2 — monitor  plasma-calcium concentration  Pregnancy avoid  Breast-feeding avoid   Side-effects constipation; urinary tract infection,  upper respiratory tract infection; pain in extremity,  sciatica; cataracts, rash; less commonly diverticulitis,  cellulitis (seek prompt medical attention), ear infec-  tion, eczema; rarely osteonecrosis of the jaw; very  rarely hypocalcaemia  Dose   • By subcutaneous injection, 60 mg every 6 months  Note Supplement with calcium and vitamin D   Strontium ranelate stimulates bone formation and  reduces bone resorption. It is licensed for the treatment  of postmenopausal osteoporosis. The Scottish Medi-  cines Consortium (p. 4) has advised (July 2005) that  treatment with strontium ranelate should be restricted  to those patients in whom bisphosphonates are contra-  indicated or not tolerated, and then only in women aged  over 75 years with a previous fracture and low bone  mineral density or in other women at equivalent risk.   Cautions predisposition to thromboembolism; inter-  feres with colorimetric measurements of calcium in  blood and urine; interactions: Appendix 1 (strontium  ranelate)   Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2   Side-effects nausea, diarrhoea; venous thromboem-  bolism; headache; dermatitis, eczema; very rarely  vomiting, abdominal pain, stomatitis, and hyper-  sensitivity reactions, including rash, pruritus, urticaria  and angioedema — see Severe Allergic Reactions,  below    Severe allergic reactions  Severe allergic reactions, including drug rash with  eosinophilia and systemic symptoms (DRESS), have  been reported in patients taking strontium ranelate.  DRESS starts with rash, fever, swollen glands, and  increased white cell count, and it can affect the liver,  kidneys and lungs; DRESS can also be fatal.   Patients should be advised to stop taking strontium  ranelate and consult their doctor immediately if skin  rash develops. Treatment with strontium ranelate  should not be restarted.   • 2 g once daily in water, preferably at bedtime  Counselling Avoid food for 2 hours before and after taking  granules, particularly calcium-containing products e.g. milk;  also preferably avoid concomitant antacids containing alu-  minium and magnesium hydroxides for 2 hours after taking  granules   Granules, yellow, strontium ranelate, 2g/sachet, net  price 28-sachets = £25.60. Label: 5, 13, counselling,  food and calcium   Bromocriptine and other  dopaminergic drugs  Drugs affecting gonadotrophins  Metyrapone and trilostane  Somatomedins   Bromocriptine is a stimulant of dopamine receptors in  the brain; it also inhibits release of prolactin by the  pituitary. Bromocriptine is used for the treatment of  galactorrhoea, and for the treatment of prolactinomas  (when it reduces both plasma prolactin concentration  and tumour size). Bromocriptine also inhibits the release  of growth hormone and is sometimes used in the treat-  ment of acromegaly, but somatostatin analogues (such  as octreotide, section 8. 3.4.3) are more effective.   Cabergoline has actions and uses similar to those of  bromocriptine, but its duration of action is longer. It has   similar side-effects to bromocriptine, however patients  intolerant of bromocriptine may be able to tolerate  cabergoline (and vice versa).   Quinagolide is a non-ergot dopamine D 2 agonist; it has  actions and uses similar to those of ergot-derived  dopamine agonists, but its side-effects differ slightly.    Cautions see notes below; also bromocriptine and  cabergoline should be used with caution in patients  with a history of peptic ulcer, particularly in acromegalic  patients. Treatment should be withdrawn if gastrointes-  tinal bleeding occurs. In hyperprolactinaemic patients,  the source of the hyperprolactinaemia should be estab-  lished (i.e. exclude pituitary tumour before treatment).  Bromocriptine and cabergoline should be used with  caution in patients with Raynaud’s syndrome and car-  diovascular disease (see also Contra-indications under  Bromocriptine, below). Monitor for fibrotic disease (see  Fibrotic Reactions, below). Caution is also advised in  patients with a history of serious mental disorders  (especially psychotic disorders) and in those with  acute porpyhria (see section 9.8.2). Tolerance may be  reduced by alcohol.    Contra-indications Bromocriptine and cabergoline  should not be used in patients with hypersensitivity to  ergot alkaloids. They are contra-indicated in those with  cardiac valvulopathy (exclude before treatment, see  Fibrotic Reactions, below). They should also be avoided  in pre-eclampsia (see also Contra-indications under  Bromocriptine, below).    Side-effects Nausea, constipation, and headache are  common side-effects of bromocriptine and cabergoline.  Paraesthesia has been reported rarely. Other reported  side-effects include hypotension (see also Hypotensive  Reactions, below), dyskinesia, pathological gambling,  increased libido, hypersexuality, leg cramps, allergic  skin reactions, alopecia, and peripheral oedema. Bromo-  criptine and cabergoline have been associated with  pleuritis, pleural effusion, cardiac valvulopathy, pericar-  dial effusion, constrictive pericarditis, and retroperito-  neal, pleural, and pulmonary fibrosis (see Fibrotic Reac-  tions).   Ergot-derived dopamine-receptor agonists, bromo-  criptine, cabergoline, lisuride [discontinued], and  pergolide have been associated with pulmonary,  retroperitoneal, and pericardial fibrotic reactions.  Exclude cardiac valvulopathy with echocardiogra-  phy before starting treatment with these ergot deri-  vatives for chronic endocrine disorders (excludes  suppression of lactation) or Parkinson’s disease; it  may also be appropriate to measure the erythrocyte  sedimentation rate and serum creatinine and to  obtain a chest X-ray. Patients should be monitored  for dyspnoea, persistent cough, chest pain, cardiac  failure, and abdominal pain or tenderness. If long-  term treatment is expected, then lung-function tests  may also be helpful. Patients taking cabergoline or  pergolide should be regularly monitored for cardiac  fibrosis, by echocardiography (within 3-6 months of  initiating treatment and subsequently at 6-12 month  intervals).   Sudden onset of sleep Excessive daytime sleepi-  ness and sudden onset of sleep can occur with  dopaminergic drugs.   Patients starting treatment with these drugs should  be warned of the possibility of these effects and of  the need to exercise caution when driving or oper-  ating machinery.   Patients who have suffered excessive sedation or  sudden onset of sleep should refrain from driving  or operating machines until those effects have  stopped recurring.   Hypotensive reactions Hypotensive reactions can  be disturbing in some patients during the first few  days of treatment with bromocriptine, cabergoline,  or quinagolide — monitor blood pressure for a few  days after starting treatment and following dosage  increases; particular care should be exercised when  driving or operating machinery.    Suppression of lactation Although bromocriptine  and cabergoline are licensed to suppress lactation, they  are not recommended for routine suppression (or for  the relief of symptoms of postpartum pain and engorge-  ment) that can be adequately treated with simple anal-  gesics and breast support. If a dopamine-receptor ago-  nist is required, cabergoline is preferred. Quinagolide is  not licensed for the suppression of lactation.   Cautions see notes above; also specialist evaluation —  monitor for pituitary enlargement, particularly during  pregnancy; monitor visual field to detect secondary  field loss in macroprolactinoma; contraceptive advice  if appropriate (oral contraceptives may increase pro-  lactin concentration); interactions: Appendix 1  (bromocriptine)   Contra-indications see notes above; also hyper-  tension in postpartum women or in puerperium (see  also below)   Postpartum or puerperium Should not be used postpar-  tum or in puerperium in women with high blood pressure,  coronary artery disease, or symptoms (or history) of serious  mental disorder; monitor blood pressure carefully (especially  during first few days) in postpartum women. Very rarely  hypertension, myocardial infarction, seizures or stroke (both  sometimes preceded by severe headache or visual distur-  bances), and mental disorders have been reported in post-  partum women given bromocriptine for lactation suppres-  sion — caution with antihypertensive therapy and avoid other  ergot alkaloids. Discontinue immediately if hypertension,  unremitting headache, or signs of CNS toxicity develop  Hepatic impairment dose reduction may be neces-  sary   Pregnancy see Cautions above  Breast-feeding suppresses lactation; avoid breast  feeding for about 5 days if lactation prevention fails  Side-effects see notes above; also drowsiness (see  also Driving, above), nasal congestion; less commonly  vomiting, postural hypotension, fatigue, dizziness, dry  mouth; also, particularly with high doses, confusion,  psychomotor excitation, hallucinations; rarely diarr-  hoea, gastro-intestinal bleeding, gastric ulcer, abdo-  minal pain, tachycardia, bradycardia, arrhythmia,  insomnia, psychosis, visual disturbances, tinnitus;    very rarely vasospasm of fingers and toes particularly  in patients with Raynaud’s syndrome, and effects like  neuroleptic malignant syndrome on withdrawal;  urinary incontinence, leucopenia, thrombocytopenia,  hyponatraemia, reversible hearing loss, increased  libido, and hypersexuality also reported  Dose   • Prevention or suppression of lactation (but see notes  above and under Cautions), 2.5 mg on day 1 (pre-  vention) or daily for 2-3 days (suppression); then   • Hypogonadism, galactorrhoea, infertility, initially 1-  1.25 mg at bedtime, increased gradually; usual dose   7.5 mg daily in divided doses, increased if necessary  to max. 30 mg daily, usual dose in infertility without  hyperprolactinaemia, 2.5 mg twice daily   • Acromegaly, initially 1-1.25 mg at bedtime, increase  gradually to 5 mg every 6 hours   • Prolactinoma, initially 1-1.25 mg at bedtime;  increased gradually to 5 mg every 6 hours (occasional  patients may require up to 30 mg daily)   Bromocriptine (Non-proprietary) (Ml  Tablets, bromocriptine (as mesilate) 2.5 mg, net price  30-tab pack = £22.92. Label: 10, 21, counselling,  driving, see notes above   1 mg, net price 100-tab pack = £9.90; 2.5 mg, 30-tab  pack = £5.78. Label: 10, 21, counselling, driving, see  notes above   Capsules, bromocriptine (as mesilate) 5 mg (blue/  white), net price 100-cap pack = £37.57; 10 mg  (white), 100-cap pack = £69.50. Label: 10, 21, coun-  selling, driving, see notes above   Indications see notes above and under Dose  Cautions see notes above; also monthly pregnancy  tests during the amenorrhoeic period; advise non-  hormonal contraception if pregnancy not desired (see  also Pregnancy, below); interactions: Appendix 1  (cabergoline)   Contra-indications see notes above; history of  puerperal psychosis; history of pulmonary, pericar-  dial, or retroperitoneal fibrotic disorders (see Fibrotic  Reactions in notes above); cardiac valvulopathy  Hepatic impairment reduce dose in severe hepatic  impairment   Pregnancy no evidence of harm; exclude pregnancy  before starting and discontinue 1 month before  intended conception (ovulatory cycles persist for 6  months) — discontinue if pregnancy occurs during  treatment (specialist advice needed)   Breast-feeding suppresses lactation; avoid breast-  feeding if lactation prevention fails  Side-effects see notes above; also cardiac valvulopa-  thy, drowsiness (see also Driving, above), dyspepsia,  gastritis, epigastric and abdominal pain, angina, syn-  cope, depression, contusion, hallucinations, breast  pain; rarely vomiting, palpitation, epistaxis, digital  vasospasm, hot flushes, transient hemianopia, muscle  weakness; also reported erythromelalgia   • Prevention of lactation (but see notes above and  under Contra-indications), during first day postpar-  tum, 1 mg as a single dose; suppression of established  lactation (but see notes above) 250 micrograms every  12 hours for 2 days; CHILD under 16 years, not  recommended   • Hyperprolactinaemic disorders, 500 micrograms  weekly (as a single dose or as 2 divided doses on  separate days) increased at monthly intervals in steps  of 500 micrograms until optimal therapeutic response  (usually 1 mg weekly, range 0.25-2 mg weekly) with  monthly monitoring of serum prolactin levels; reduce  initial dose and increase more gradually if patient  intolerant; over 1 mg weekly give as divided doses; up  to 4.5 mg weekly has been used in hyperprolactinae-  mic patients; CHILD under 16 years, not recommended   Danazol inhibits pituitary gonadotrophins; it combines  androgenic activity with antioestrogenic and anti-  progestogenic activity. It is licensed for the treatment  of endometriosis and for the relief of severe pain and  tenderness in benign fibrocystic breast disease where  other measures have proved unsatisfactory. It may also  be effective in the long-term management of hereditary  angioedema [unlicensed indication],   Cetrorelix and ganirelix are luteinising hormone  releasing hormone antagonists, which inhibit the release  of gonadotrophins (luteinising hormone and follicle-  stimulating hormone). They are used in the treatment  of infertility by assisted reproductive techniques.   Cabergoline (Non-proprietary) (Ml  Tablet, scored, cabergoline 500 micrograms, net price  8-tab pack = £34.03. Label: 10, 21, counselling, driv-  ing, see notes above   Indications see notes above and under Dose  Cautions see notes above; history of psychotic illness;  advise non-hormonal contraception if pregnancy not  desired; interactions: Appendix 1 (quinagolide)  Contra-indications hypersensitivity to quinagolide  (but not ergot alkaloids)   Breast-feeding suppresses lactation  Side-effects nausea, vomiting, anorexia, abdominal  pain, constipation or diarrhoea; syncope, hypotension  (see also notes above), oedema, flushing; nasal con-  gestion; headache, dizziness, fatigue, insomnia; rarely  sudden onset of sleep (see notes above); very rarely  psychosis  Dose   • Hyperprolactinaemia, 25 micrograms at bedtime for 3  days; increased at intervals of 3 days in steps of  25 micrograms to usual maintenance dose of 75-  150 micrograms daily; for doses higher than  300 micrograms daily increase in steps of 75-  150 micrograms at intervals of not less than 4 weeks;  CHILD not recommended   Norprolac® (Ferring) (Ml  Tablets, quinagolide (as hydrochloride) 75 micr-  ograms (white), net price 30-tab pack = £27.00; starter  pack of 3 x 25-microgram tabs (pink) with 3 x 50-  microgram tabs (blue) = £4.50. Label: 10, 21, coun-  selling, driving, see notes above    Indications adjunct in the treatment of female  infertility (under specialist supervision)   either 250 micrograms in the morning, starting on day  5 or 6 of ovarian stimulation with gonadotrophins (or  each evening starting on day 5 of ovarian stimulation);  continue throughout administration of gonadotrophin  including day of ovulation induction (or evening  before ovulation induction)  or 3 mg on day 7 of ovarian stimulation with gona-  dotrophins; if ovulation induction not possible on day  5 after 3-mg dose, additional 250 micrograms once  daily until day of ovulation induction   Cetrotide® (Merck Serono) (Ml  Injection, powder for reconstitution, cetrorelix (as  acetate), net price 250-micrograms vial = £22.61; 3-  mg vial = £158.26 (both with solvent)   Indications see notes above and under Dose  Cautions cardiac impairment (avoid if severe), elderly,  polycythaemia, epilepsy, diabetes mellitus, hyper-  tension, migraine, lipoprotein disorder, history of  thrombosis or thromboembolic disease; withdraw if  virilisation (may be irreversible on continued use);  non-hormonal contraceptive methods should be used,  if appropriate; interactions: Appendix 1 (danazol)  Contra-indications ensure that patients with amen-  orrhoea are not pregnant; thromboembolic disease;  undiagnosed genital bleeding; androgen-dependent  tumours; acute porphyria (section 9.8.2)    Pregnancy avoid; has weak androgenic effects and  virilisation of female fetus reported  Breast-feeding no data available but avoid because of  possible androgenic effects in infant  Side-effects nausea, dizziness, skin reactions includ-  ing rashes, photosensitivity and exfoliative dermatitis,  fever, backache, nervousness, mood changes, anxiety,  changes in libido, vertigo, fatigue, epigastric and  pleuritic pain, headache, weight gain; menstrual dis-  turbances, vaginal dryness and irritation, flushing and  reduction in breast size; musculo-skeletal spasm, joint  pain and swelling, hair loss; androgenic effects  including acne, oily skin, oedema, hirsutism, voice  changes and rarely clitoral hypertrophy (see also  Cautions); temporary alteration in lipoproteins and  other metabolic changes, insulin resistance; throm-  botic events; leucopenia, thrombocytopenia, eosino-  philia, reversible erythrocytosis or polycythaemia  reported; headache and visual disturbances may  indicate benign intracranial hypertension; rarely cho-  lestatic jaundice, pancreatitis, peliosis hepatis and  benign hepatic adenomata  Dose   Note In women of child-bearing potential, treatment should  start during menstruation, preferably on day 1    • Endometriosis, 200-800 mg daily in up to 4 divided  doses, adjusted to achieve amenorrhoea, usually for  3-6 months   • Severe pain and tenderness in benign fibrocystic  breast disease not responding to other treatment,   • Hereditary angioedema [unlicensed indication], initi-  ally 200 mg 2-3 times daily, then reduced according to  response   Danazol (Non-proprietary) [Ml  Capsules, danazol 100 mg, net price 28-cap pack =  £18.40, 60-cap pack = £17.04; 200 mg, 56-cap pack =  £ 66.20   Injection, ganirelix, 500 micrograms /mL, net price  0.5-mL prefilled syringe = £21.48   Administration of gonadorelin analogues produces an  initial phase of stimulation; continued administration is  followed by down-regulation of gonadotrophin-releas-  ing hormone receptors, thereby reducing the release of  gonadotrophins (follicle stimulating hormone and  luteinising hormone) which in turn leads to inhibition  of androgen and oestrogen production.   Gonadorelin analogues are used in the treatment of  endometriosis, precocious puberty, infertility, anaemia  due to uterine fibroids (together with iron supplementa-  tion), breast cancer (section 8.3.4. 1), prostate cancer  (section 8. 3.4.2) and before intra-uterine surgery. Use  of leuprorelin and triptorelin for 3 to 4 months before  surgery reduces the uterine volume, fibroid size and  associated bleeding. For women undergoing hyster-  ectomy or myomectomy, a vaginal procedure is made  more feasible following the use of a gonadorelin analo-  gue.   Cautions Non-hormonal, barrier methods of contra-  ception should be used during entire treatment period  with gonadorelin analogues; also use with caution in  patients with metabolic bone disease because decrease  in bone mineral density can occur.   Contra-indications Gonadorelin analogues are con-  tra-indicated for use longer than 6 months in the treat-  ment of endometriosis (do not repeat) and when there is  unexplained vaginal bleeding.    Danol® (Sanofi-Aventis) fMO  Capsules, danazol 100 mg (grey/white), net price 60-  cap pack = £16.38; 200 mg (pink/white), 60-cap pack  = £32.43    Pregnancy The use of gonadorelin analogues in  pregnancy is contra-indicated. Pregnancy should be  excluded before treatment; the first injection should be  given during menstruation or shortly afterwards or use  barrier contraception for 1 month beforehand.   Indications adjunct in the treatment of female  infertility (under specialist supervision)   Side-effects nausea, headache, malaise, injection-site  reactions; very rarely hypersensitivity reactions  including rash, facial oedema, and dyspnoea also  reported   • By subcutaneous injection preferably into the upper  leg (rotate injection sites to prevent lipoatrophy),   250 micrograms in the morning (or each afternoon)  starting on day 5 or day 6 of ovarian stimulation with  gonadotrophins; continue throughout administration  of gonadotrophins including day of ovulation induc-  tion (if administering in afternoon, give last dose in  afternoon before ovulation induction)   Side-effects Side-effects of the gonadorelin analogues  related to the inhibition of oestrogen production include  menopausal-like symptoms (e.g. hot flushes, increased  sweating, vaginal dryness, dyspareunia and loss of libi-  do) and a decrease in trabecular bone density; these  effects can be reduced by hormone replacement (e.g.  with an oestrogen and a progestogen or with tibolone).  Side-effects of gonadorelin analogues also include head-  ache (rarely migraine) and hypersensitivity reactions  including urticaria, pruritus, rash, asthma and anaphy-  laxis; when treating uterine fibroids, bleeding associated  with fibroid degeneration can occur; spray formulations  can cause irritation of the nasal mucosa including nose  bleeds; local reactions at injection site can occur; other  side-effects also reported with some gonadorelin analo-  gues include palpitation, hypertension, ovarian cysts  (may require withdrawal), changes in breast size,  musculoskeletal pain or weakness, visual disturbances,  paraesthesia, changes in scalp and body hair, oedema of  the face and extremities, weight changes, and mood  changes including depression.   Cautions see notes above; polycystic ovarian disease,  depression, hypertension, diabetes  Contra-indications see notes above; hormone-  dependent tumours  Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above; initially withdrawal  bleeding and subsequently breakthrough bleeding,  leucorrhoea; nausea, vomiting, constipation, diarr-  hoea; anxiety, memory and concentration distur-  bances, sleep disturbances, nervousness, dizziness,  drowsiness; breast tenderness, lactation; abdominal  pain; fatigue; increased thirst, changes in appetite;  acne, dry skin, splitting nails, dry eyes; altered blood  lipids, leucopenia, thrombocytopenia; hearing distur-  bances; reduced glucose tolerance  Dose   • Endometriosis, intranasally, 300 micrograms (one  150-microgram spray in each nostril) 3 times daily  (starting on days 1 or 2 of menstruation); max. dura-  tion of treatment 6 months (do not repeat)   • Pituitary desensitisation before induction of ovulation  by gonadotrophins for in vitro fertilisation (under  specialist supervision), by subcutaneous injection,  200-500 micrograms daily given as a single injection  (occasionally up to 500 micrograms twice daily may  be needed) starting in early follicular phase (day 1) or,  after exclusion of pregnancy, in midluteal phase (day  21) and continued until down-regulation achieved  (usually about 1-3 weeks) then maintained during  gonadotrophin administration (stopping gonadotro-  phin and buserelin on administration of chorionic  gonadotrophin at appropriate stage of follicular  development)   Intranasally, 150 micrograms (one spray in one nos-  tril) 4 times daily during waking hours (occasionally  up to 300 micrograms 4 times daily may be needed)  starting in early follicular phase (day 1) or, after  exclusion of pregnancy, in midluteal phase (day 21)  and continued until down-regulation achieved  (usually about 2-3 weeks) then maintained during  gonadotrophin administration (stopping gonadotro-  phin and buserelin on administration of chorionic  gonadotrophin at appropriate stage of follicular  development)   Counselling Avoid use of nasal decongestants before and  for at least 30 minutes after treatment   Sup recur® (Sanofi-Aventis) tMI  Nasal spray, buserelin (as acetate) 150 micrograms/  metered spray. Net price 2 x 100-dose pack (with  metered dose pumps) = £87.63. Counselling, nasal  decongestants   Injection, buserelin (as acetate) 1 mg/mL. Net price  5.5-mL vial = £13.76   Indications see under Dose; prostate cancer (section  8.34.2); early and advanced breast cancer (section  8.34.1)   Endometriosis, 3.6 mg every 28 days; max. duration  of treatment 6 months (do not repeat)   3.6 mg (may be repeated after 28 days if uterus is large  or to allow flexible surgical timing)   Before surgery in women who have anaemia due to  uterine fibroids, 3.6 mg every 28 days (with supple-  mentary iron); max. duration of treatment 3 months  Pituitary desensitisation before induction of ovulation  by gonadotrophins for in vitro fertilisation (under  specialist supervision), after exclusion of pregnancy,  3.6 mg to achieve pituitary down-regulation (usually  1-3 weeks) then gonadotrophin is administered  (stopping gonadotrophin on administration of  chorionic gonadotrophin at appropriate stage of fol-  licular development)   Cautions see notes above; monitor liver function;  family history of osteoporosis; chronic use of other  drugs which reduce bone density including alcohol  and tobacco; diabetes    Breast-feeding see notes above  Side-effects see notes above; breast tenderness;  nausea, vomiting, diarrhoea, anorexia; fever, chills;  sleep disturbances, dizziness, fatigue, leucopenia,  thrombocytopenia, altered blood lipids, pulmonary  embolism; spinal fracture, paralysis, hypotension and  worsening of depression also reported  Dose   Endometriosis, 3.75 mg as a single dose in first 5 days  of menstrual cycle then every month for max. 6  months (course not to be repeated)   Endometrial thinning before intra-uterine surgery,  3.75 mg as a single dose (given between days 3 and 5  of menstrual cycle) 5-6 weeks before surgery  Reduction of size of uterine fibroids and of associated  bleeding before surgery, 3.75 mg as a single dose  every month usually for 3-4 months (max. 6 months)   • By intramuscular injection (as Prostap® 3)  Endometriosis, 11.25 mg as a single dose in first 5  days of menstrual cycle then every 3 months for max.  6 months (course not to be repeated)   • Endometriosis, women over 18 years, 200 micr-  ograms twice daily as one spray in one nostril in the  morning and one spray in the other nostril in the  evening (starting on days 2-4 of menstruation), max.  duration of treatment 6 months (do not repeat)   • Pituitary desensitisation before induction of ovulation  by gonadotrophins for in vitro fertilisation (under  specialist supervision), 400 micrograms (one spray in  each nostril) twice daily starting in early follicular  phase (day 2) or, after exclusion of pregnancy, in  midluteal phase (day 21) and continued until down-  regulation achieved (usually within 4 weeks) then  maintained (usually for 8-12 days) during gonado-  trophin administration (stopping gonadotrophin and  nafarelin on administration of chorionic gonadotro-  phin at follicular maturity); discontinue if down-reg-  ulation not achieved within 12 weeks  Counselling Avoid use of nasal decongestants before and  for at least 30 minutes after treatment; repeat dose if sneez-  ing occurs during or immediately after administration   Synarel® (Pharmacia) (Ml  Nasal spray, nafarelin (as acetate) 200 micrograms/  metered spray. Net price 30-dose unit = £30.41; 60-  dose unit = £52.43. Label: 10, patient information  leaflet, counselling, see above   Indications endometriosis, precocious puberty,  reduction in size of uterine fibroids; advanced prostate  cancer (section 8. 3.4.2)   Breast-feeding see notes above  Side-effects see notes above; also gastro-intestinal  disturbances; in precocious puberty, withdrawal  bleeding may occur in the first month of treatment;  asthenia  Dose   Decapeptyl® SR (Ipsen) (Ml  Injection, (powder for suspension), m/r, triptorelin (as  acetate), net price 3-mg vial (with diluent) = £69.00  Dose by intramuscular injection, endometriosis and reduction in  size of uterine fibroids, 3 mg every 4 weeks starting during first 5  days of menstrual cycle; for uterine fibroids continue treatment for  at least 3 months; max. duration of treatment 6 months (not to be  repeated)   Injection, (powder for suspension), m/r, triptorelin (as  acetate), net price 11.25-mg vial (with diluent) =  £207.00   Dose by intramuscular injection, endometriosis, 11.25 mg every  3 months starting during first 5 days of menstrual cycle; max.  duration of treatment 6 months (not to be repeated)    Precocious puberty, 11.25 mg every 3 months; discontinue when  bone maturation consistent with age of 12 years in girls or 13-14  years in boys   Gonapeptyl Depot® (Ferring) (Ml  Injection, (powder for suspension), triptorelin (as  acetate), net price 3.75-mg prefilled syringe (with  prefilled syringe of vehicle) = £81.69  Dose by subcutaneous or deep intramuscular injection, endo-  metriosis and reduction in size of uterine fibroids, 3.75 mg every 4  weeks starting during first 5 days of menstrual cycle; max. dura-  tion of treatment 6 months (not to be repeated)   Precocious puberty, body-weight over 30 kg, initially 3.75 mg  every 2 weeks for 3 doses, then every 3-4 weeks; body-weight 20-  30 kg, initially 2.5 mg every 2 weeks for 3 doses, then every 3-4  weeks; body-weight under 20 kg, initially 1.875 mg every 2 weeks  for 3 doses, then every 3-4 weeks; discontinue when bone  maturation consistent with age over 12 years in girls or over 13  years in boys   Once any serious underlying cause for breast pain has  been ruled out, most women will respond to reassur-  ance and reduction in dietary fat; withdrawal of an oral  contraceptive or of hormone replacement therapy may  help to resolve the pain.   Mild, non-cyclical breast pain is treated with simple  analgesics (section 4.7.1); moderate to severe pain,  cyclical pain or symptoms that persist for longer than  6 months may require specific drug treatment.   Danazol (section 6.7.2) is licensed for the relief of  severe pain and tenderness in benign fibrocystic breast  disease which has not responded to other treatment.   Tamoxifen (section 8.3.4. 1) may be a useful adjunct in  the treatment of mastalgia [unlicensed indication] espe-  cially when symptoms can definitely be related to cyclic  oestrogen production; it may be given on the days of the  cycle when symptoms are predicted.   Treatment for breast pain should be reviewed after 6  months and continued if necessary. Symptoms recur in  about 50% of women within 2 years of withdrawal of  therapy but may be less severe.    Metyrapone is a competitive inhibitor of 1 1 [3-hydroxy-  lation in the adrenal cortex; the resulting inhibition of  cortisol (and to a lesser extent aldosterone) production  leads to an increase in ACTH production which, in turn,  leads to increased synthesis and release of cortisol  precursors. It may be used as a test of anterior pituitary  function.    Although most types of Cushing’s syndrome are treated  surgically, that which occasionally accompanies carci-  noma of the bronchus is not usually amenable to sur-  gery. Metyrapone has been found helpful in controlling  the symptoms of the disease; it is also used in other  forms of Cushing’s syndrome to prepare the patient for  surgery. The dosages used are either low, and tailored to  cortisol production, or high, in which case corticosteroid  replacement therapy is also needed.   Trilostane reversibly inhibits the enzyme system essen-  tial for the production of mineralocorticoids and gluco-    corticoids in the adrenal cortex, and may be useful in  Cushing’s syndrome and primary hyperaldosteronism.  Trilostane appears to be less effective than metyrapone  for Cushing’s syndrome (where it is tailored to cortico-  steroid production). It also has a minor role in post-  menopausal breast cancer that has relapsed following  initial oestrogen antagonist therapy (corticosteroid  replacement therapy is also required). Ketoconazole  (section 5.2.2) is also used by specialists for the manage-  ment of Cushing’s syndrome [unlicensed indication].   Cautions gross hypopituitarism (risk of precipitating  acute adrenal failure); hypertension on long-term  administration; hypothyroidism (delayed response);  many drugs interfere with diagnostic estimation of  steroids; avoid in acute porphyria (section 9.8.2)  Driving Drowsiness may affect the performance of skilled  tasks (e.g. driving)   Side-effects occasional nausea, vomiting, dizziness,  headache, hypotension, sedation; rarely abdominal  pain, allergic skin reactions, hypoadrenalism, hirsut-  ism  Dose   • Differential diagnosis of ACTH-dependent Cushing’s  syndrome, 750 mg every 4 hours for 6 doses; CHILD  15 mg/kg (minimum 250 mg) every 4 hours for 6  doses   • Resistant oedema due to increased aldosterone  secretion in cirrhosis, nephrotic syndrome, and con-  gestive heart failure (with glucocorticoid replacement  therapy) 3 g daily in divided doses   Metopirone® (Alliance) (Ml  Capsules, ivory, metyrapone 250 mg, net price 100-  tab pack = £38.88. Label: 21, counselling, driving   Cautions breast cancer (concurrent corticosteroid  replacement therapy needed, see under Dose), adr-  enal cortical hyperfunction (tailored to cortisol and  electrolytes, concurrent corticosteroid therapy may  be needed, see under Dose); interactions: Appendix 1  (trilostane)   Contra-indications children  Hepatic impairment use with caution  Renal impairment use with caution  Pregnancy avoid; interferes with placental sex horm-  one production; use non-hormonal method of  contraception  Breast-feeding avoid    Side-effects flushing, tingling and swelling of mouth,  rhinorrhoea, nausea, vomiting, diarrhoea, and rashes  reported; rarely granulocytopenia   • Adrenal cortical hyperfunction, 240 mg daily in  divided doses for at least 3 days then tailored  according to response with regular monitoring of  plasma electrolytes and circulating corticosteroids  (both mineralocorticoid and glucocorticoid replace-  ment therapy may be needed); usual dose: 120—   • Postmenopausal breast cancer (with glucocorticoid  replacement therapy) following relapse to initial oes-  trogen receptor antagonist therapy, initially 240 mg  daily increased every 3 days in steps of 240 mg to a  maintenance dose of 960 mg daily (720 mg daily if not  tolerated)   Modrenal® (Bioenvision) fMl  Capsules, trilostane 60 mg (pink/black), net price  100-cap pack = £49.50; 120 mg (pink/yellow), 100-  cap pack = £98.50. Label: 21    Somatomedins are a group of polypeptide hormones  structurally related to insulin and commonly known as  insulin-like growth factors (IGFs). Mecasermin, a  human insulin-like growth factor-I (rhIGF-I), is the prin-  cipal mediator of the somatotropic effects of human  growth hormone and is used to treat growth failure in  children and adolescents with severe primary insulin-  like growth factor-I deficiency.   Cautions correct hypothyroidism before initiating  treatment; diabetes mellitus (adjustment of antidia-  betic therapy may be necessary), monitor ECG before  and on termination of treatment (and during treat-  ment if ECG abnormal), papilloedema (see under  Side-effects), monitor for disorders of the epiphysis of  the hip (monitor for limping), monitor for signs of  tonsillar hypertrophy (snoring, sleep apnoea, and  chronic middle ear effusions)   Pregnancy avoid unless essential; contraception  advised in women of child-bearing potential   Side-effects headache, funduscopy for papilloedema  recommended if severe or recurrent headache, visual  problems, nausea and vomiting occur — if papilloede-  ma confirmed consider benign intracranial hyper-  tension (rare cases reported); cardiomegaly, ventri-  cular hypertrophy, tachycardia; convulsions, sleep  apnoea, night terrors, dizziness, nervousness; tonsillar  hypertrophy (see Cautions above); hypoglycaemia  (especially in first month, and in younger children),  hyperglycaemia, gynaecomastia; arthralgia, myalgia;  visual disturbance, impaired hearing; antibody for-  mation; injection-site reactions (rotate site)   • By subcutaneous injection, ADOLESCENT and CHILD  over 2 years, initially 40 micrograms/kg twice daily  for 1 week, if tolerated increase dose in steps of  40 micrograms/kg to max. 120 micrograms/kg twice  daily; discontinue if no response within 1 year  Counselling Dose should be administered just before or  after food; do not increase dose if a dose is missed  Note Reduce dose if hypoglycaemia occurs despite adequate  food intake; withhold injection if patient unable to eat   Injection, mecasermin 10 mg/mL, net price 4-mL vial  = £605.00. Counselling, administration    This chapter also includes advice on the drug man-  agement of the following:    For hormonal therapy of gynaecological disorders  see section 6.4.1 (including HRT), section 6.5.1 and  section 6.7.2.    Because of the complexity of dosage regimens in  obstetrics, in all cases detailed specialist literature  should be consulted.   Prostaglandins and oxytocics are used to induce abor-  tion or induce or augment labour and to minimise blood  loss from the placental site. They include oxytocin,  carbetocin, ergometrine, and the prostaglandins. All  induce uterine contractions with varying degrees of  pain according to the strength of contractions induced.   Induction of abortion Gemeprost, a prostaglandin  administered vaginally as pessaries, is suitable for the  medical induction of late therapeutic abortion; geme-  prost is also used to ripen the cervix before surgical  abortion, particularly in primigravidas. The prostaglan-  din misoprostol (section 7.1.2) is given by mouth or by  vaginal administration to induce medical abortion [unli-  censed indication]; intravaginal use ripens the cervix  before surgical abortion [unlicensed indication], Extra-  amniotic dinoprostone is rarely used nowadays.   Pre-treatment with mifepristone (section 7.1.2) can  facilitate the process of medical abortion. It sensitises  the uterus to subsequent administration of a prostaglan-  din and, therefore, abortion occurs in a shorter time and  with a lower dose of prostaglandin.   Induction and augmentation of labour Dino-  prostone is available as vaginal tablets, pessaries and    vaginal gels for the induction of labour. The intravenous  solution is rarely used; it is associated with more side-  effects.   Oxytocin ( Syntocinon ®) is administered by slow intra-  venous infusion, using an infusion pump, to induce or  augment labour, usually in conjunction with amniotomy.  Uterine activity must be monitored carefully and  hyperstimulation avoided. Large doses of oxytocin  may result in excessive fluid retention.   Misoprostol is given orally or vaginally for the induc-  tion of labour [unlicensed indication],    Prevention and treatment of haemorrhage Bleed-  ing due to incomplete abortion can be controlled with  ergometrine and oxytocin ( Syntometrine ®) given  intramuscularly, the dose is adjusted according to the  patient’s condition and blood loss. This is commonly  used before surgical evacuation of the uterus, particu-  larly when surgery is delayed. Oxytocin and ergo-  metrine combined are more effective in early pregnancy  than either drug alone.   Active management of the third stage of labour reduces  the risk of postpartum haemorrhage; oxytocin is given  by intramuscular injection [unlicensed] on delivery of  the anterior shoulder or, at the latest, immediately after  the baby is delivered. Alternatively, ergometrine  500 micrograms with oxytocin 5 units ( Syntometrine ®  1 mL) can be given by intramuscular injection in the  absence of hypertension; oxytocin alone causes less   In excessive uterine bleeding, any placental products  remaining in the uterus should be removed. Oxytocic  drugs are used to treat postpartum haemorrhage caused  by uterine atony; treatment options are as follows:   • oxytocin 5 units by slow intravenous injection (dose  may be repeated), followed in severe cases by intra-  venous infusion of oxytocin 40 units in 500 mL  infusion fluid (prolonged administration — see  Appendix 6) at a rate that controls uterine atony or  • ergometrine 250-500 micrograms by intramuscular  injection or   • ergometrine 500 micrograms with oxytocin 5 units  [Syntometrine® 1 mL) by intramuscular injection   Carboprost has an important role in severe postpartum  haemorrhage unresponsive to ergometrine and oxy-  tocin.   Misoprostol [unlicensed] can be used in postpartum  haemorrhage when oxytocin, ergometrine, and carbo-  prost are not available or are inappropriate.   Hepatic impairment manufacturer advises avoid  Renal impairment manufacturer advises avoid  Side-effects nausea, vomiting, abdominal pain,  metallic taste; flushing, hypotension, chest pain; dys-  pnoea; headache, tremor, dizziness; anaemia; back  pain; pruritus; feeling of warmth, chills; tachycardia  and sweating also reported  Dose   • By slow intravenous injection over 1 minute, a single  dose of 100 micrograms, as soon as possible after  delivery, preferably before removal of placenta   Indications postpartum haemorrhage due to uterine  atony in patients unresponsive to ergometrine and  oxytocin   Cautions history of glaucoma or raised intra-ocular  pressure, asthma, hypertension, hypotension, anae-  mia, jaundice, diabetes, epilepsy; uterine scars;  excessive dosage may cause uterine rupture; inter-  actions: Appendix 1 (prostaglandins)  Contra-indications untreated pelvic infection; cardiac  or pulmonary disease   Hepatic impairment manufacturer advises avoid  Renal impairment manufacturer advises avoid  Side-effects nausea, vomiting and diarrhoea, hyper-  thermia and flushing, bronchospasm; less frequent  effects include raised blood pressure, dyspnoea, and  pulmonary oedema; chills, headache, diaphoresis,  dizziness; cardiovascular collapse also reported;  erythema and pain at injection site reported  Dose   • By deep intramuscular injection, 250 micrograms  repeated if necessary at intervals of not less than 15  minutes; total dose should not exceed 2 mg (8 doses)   Hemabate® (Pharmacia) (Ml  Injection, carboprost as trometamol salt (trometha-  mine salt) 250 micrograms/mL, net price 1-mL amp =  £18.20 (hosp. only)   Cautions history of asthma, glaucoma and raised  intra-ocular pressure; hypertension; history of epi-  lepsy; uterine scarring; monitor uterine activity and  fetal status (particular care if history of uterine  hypertony); uterine rupture; see also notes above;  monitor for disseminated intravascular coagulation  after parturition; risk factors for disseminated intra-  vascular coagulation; effect of oxytocin enhanced  (care needed in monitoring uterine activity when used  in sequence); interactions: Appendix 1 (prosta-  glandins)   Contra-indications active cardiac, or pulmonary dis-  ease; placenta praevia or unexplained vaginal bleed-  ing during pregnancy, ruptured membranes, major  cephalopelvic disproportion or fetal malpresentation,  history of caesarean section or major uterine surgery,    untreated pelvic infection, fetal distress, grand multi-  paras and multiple pregnancy, history of difficult or  traumatic delivery; avoid extra-amniotic route in  cervicitis or vaginitis   Hepatic impairment manufacturers advise avoid  Renal impairment manufacturers advise avoid  Side-effects nausea, vomiting, diarrhoea; other side-  effects include uterine hypertonus, severe uterine  contractions, pulmonary or amniotic fluid embolism,  abruptio placenta, fetal distress, maternal hyper-  tension, bronchospasm, rapid cervical dilation, fever,  backache; uterine hypercontractility with or without  fetal bradycardia, low Apgar scores; cardiac arrest,  uterine rupture, stillbirth or neonatal death also  reported; vaginal symptoms (warmth, irritation, pain);  after intravenous administration — flushing, shivering,  headache, dizziness, temporary pyrexia and raised  white blood cell count; disseminated intravascular  coagulation reported; also local tissue reaction and  erythema after intravenous administration and pos-  sibility of infection after extra-amniotic administration  Dose   • See under preparations, below  Important Do not confuse dose of Prostin E2 ® vaginal gel  with that of Prostin E2 ® vaginal tablets — not bioequivalent.   Pessaries (within retrieval device), releasing dino-  prostone approx. 10 mg over 24 hours; net price 1-  pessary pack = £30.00   Dose by vagina, cervical ripening and induction of labour at  term, 1 pessary (in retrieval device) inserted high into posterior  fornix and removed when cervical ripening adequate; if oxytocin  necessary, remove 30 minutes before oxytocin infusion; remove if  cervical ripening inadequate after 24 hours (dose not to be  repeated)   Prostin E2® (Pharmacia) (Ml  Intravenous solution for dilution and use as an  infusion, dinoprostone 1 mg/mL, net price 0.75-mL  amp = £8.52; 10 mg/mL, 0.5-mL amp = £18.40 (both  hosp. only; rarely used, consult product literature for  dose and indications)   Extra-amniotic solution dinoprostone 10 mg/  mL, net price 0.5-mL amp (with diluent) = £18.40  (hosp. only; less commonly used nowadays, consult  product literature for dose and indications)   Vaginal gel, dinoprostone 400 micrograms/mL, net  price 2.5 mL (lmg) = £13.28; 800 micrograms/mL,  2.5 mL (2 mg) =£13.28   Dose by vagina, induction of labour, inserted high into posterior  fornix (avoid administration into cervical canal), 1 mg (unfavour-  able primigravida 2 mg), followed after 6 hours by 1-2 mg if  required; max. [gel] 3 mg (unfavourable primigravida 4 mg)   Dose by vagina, induction of labour, inserted high into posterior  fornix, 3 mg, followed after 6-8 hours by 3 mg if labour is not  established; max. 6 mg [vaginal tablets]   Indications see notes above  Cautions cardiac disease; hypertension; multiple  pregnancy; acute porphyria (section 9.8.2); interac-  tions: Appendix 1 (ergot alkaloids)  Contra-indications induction of labour, first and sec-  ond stages of labour, vascular disease, severe cardiac  disease, sepsis, severe hypertension, eclampsia    Hepatic impairment manufacturer advises caution in  mild or moderate impairment and avoid in severe  impairment   Renal impairment manufacturer advises caution in  mild or moderate impairment and avoid in severe  impairment   Side-effects nausea, vomiting, abdominal pain; chest  pain, arrhythmias (including bradycardia), palpitation,  hypertension, vasoconstriction; dyspnoea, pulmonary  oedema; headache, dizziness; tinnitus; rash; very  rarely myocardial infarction  Dose   Ergometrine (Non-proprietary) (Ml  Injection, ergometrine maleate 500 micrograms/mL,  net price 1-mL amp = 60p   Injection, ergometrine maleate 500 micrograms,  oxytocin 5units/mL, net price 1-mL amp = £1.35  Dose by intramuscular injection, 1 mL; by intravenous injection,  no longer recommended   Cautions obstructive airways disease, cardiovascular  insufficiency, raised intra-ocular pressure, cervicitis or  vaginitis; interactions: Appendix 1 (prostaglandins)  Important For warnings relating to use of gemeprost in a B  patient undergoing induction of abortion with mifepristone,  see under Mifepristone and Note below   Side-effects vaginal bleeding and uterine pain;  nausea, vomiting, or diarrhoea; headache, muscle  weakness, dizziness, flushing, chills, backache, dys-  pnoea, chest pain, palpitation and mild pyrexia;  uterine rupture reported (most commonly in multi-  paras or if history of uterine surgery or if given with  intravenous oxytocics); also reported severe hypo-  tension, coronary artery spasm and myocardial  infarction   • By vagina, cervical ripening prior to first trimester  surgical abortion, 1 mg inserted into posterior fomix 3  hours before surgery   • Second trimester abortion, 1 mg inserted into poster-  ior fomix every 3 hours for max. of 5 administrations;  second course may begin 24 hours after start of  treatment (if treatment fails pregnancy should be  terminated by another method)   Note If used in combination with mifepristone, carefully moni-  tor blood pressure and pulse for 3 hours   Gemeprost (Sanofi-Aventis) (Ml  Pessaries, gemeprost 1 mg, net price 5-pessary pack  = £215.00   Cautions induction or enhancement of labour — pre-  sence of borderline cephalopelvic disproportion  (avoid if significant), secondary uterine inertia, mild or  moderate pregnancy-induced hypertension or cardiac  disease, women over 35 years or with history of  lower-uterine segment caesarean section (see also  under Contra-indications below); risk factors for dis-  seminated intravascular coagulation; monitor for dis-  seminated intravascular coagulation after parturition;  avoid large infusion volumes and restrict fluid intake  by mouth (risk of hyponatraemia and water-intoxica-  tion — see also Appendix 6); effects enhanced by  concomitant prostaglandins (very careful monitoring  of uterine activity); caudal block anaesthesia (may  enhance hypertensive effects of sympathomimetic  vasopressors); see also interactions: Appendix 1  (oxytocin)   Contra-indications hypertonic uterine contractions,  fetal distress; any condition where spontaneous  labour or vaginal delivery inadvisable; avoid pro-  longed administration in oxytocin-resistant uterine  inertia, severe pre-eclamptic toxaemia, or severe  cardiovascular disease   Side-effects nausea, vomiting; arrhythmia; headache;  rarely disseminated intravascular coagulation, rash,  and anaphylactoid reactions (with dyspnoea, hypo-  tension, or shock); uterine spasm (may occur at low  doses), uterine hyperstimulation (usually with exces-  sive doses — may cause fetal distress, asphyxia, and  death, or may lead to hypertonicity, tetanic contrac-  tions, soft-tissue damage or uterine rupture); water  intoxication and hyponatraemia associated with high  doses with large infusion volumes of electrolyte-free  fluid (see also under Dose below); placental abruption  and amniotic fluid embolism also reported on over-  dose   • Induction of labour for medical reasons or stimulation  of labour in hypotonic uterine inertia, by intravenous  infusion (not to be started for at least 6 hours after  administration of vaginal prostaglandin), initially  0.001-0.004 units/minute, increased at intervals of at  least 30 minutes until a maximum of 3-4 contractions  occur every 10 minutes (0.01 units/minute is often  adequate) up to max. 0.02 units/minute; if regular  contractions not established after total of 5 units stop  induction attempt (may be repeated next day starting  again at 0.00 1-0.004 units/minute)   Important Careful monitoring of fetal heart rate and uterine  motility essential for dose titration (avoid intravenous  injection during labour); discontinue immediately in uterine  hyperactivity or fetal distress   • Caesarean section, by slow intravenous injection  immediately after delivery, 5 units   • Prevention of postpartum haemorrhage, after delivery  of placenta, by slow intravenous injection, 5 units (if  infusion used for induction or enhancement of labour,  increase rate during third stage and for next few  hours).   Note Can be given in a dose of 10 units by intramuscular  injection [unlicensed route] instead of oxytocin with ergo-  metrine ( Syntometrine ®), see notes above   • Treatment of postpartum haemorrhage, by slow  intravenous injection, 5 units (dose maybe repeated),  followed in severe cases by intravenous infusion of    40 units in 500 mL infusion fluid at a rate sufficient to  control uterine atony   • Incomplete, inevitable, or missed abortion, by slow  intravenous injection, 5 units followed if necessary by  intravenous infusion, 0.02-0.04 units/minute or faster  Important Prolonged intravenous administration at high doses  with large volume of fluid (which is possible in inevitable or  missed abortion or postpartum haemorrhage) may cause water  intoxication with hyponatraemia. To avoid: use electrolyte-  containing diluent (i.e. not glucose), increase oxytocin con-  centration to reduce fluid, restrict fluid intake by mouth;  monitor fluid and electrolytes.   Note Oxytocin doses in the BNF may differ from those in the  product literature   Injection, oxytocin, net price 5units/mL, 1-mL amp  = 76p; lOunits/mL, 1-mL amp = 86p   This section is not included in the BNF. For the manage-  ment of ductus arteriosus, see BNF for Children section  2.14.    Mifepristone, an antiprogestogenic steroid, sensitises  the myometrium to prostaglandin-induced contractions  and ripens the cervix. For termination of pregnancy, a  single dose of mifepristone is followed by administration  of a prostaglandin (gemeprost or misoprostol [unli-  censed]). Guidelines of the Royal College of Obstetri-  cians and Gynaecologists (September 2004) include the  following [unlicensed] regimens for inducing medical  abortion:    • For gestation up to 9 weeks, mifepristone 200 mg by  mouth followed 1-3 days later by misoprostol 800 micr-  ograms vaginally; in women at more than 7 weeks  gestation (49-63 days), if the abortion has not occurred  4 hours after misoprostol, a further dose of misoprostol  400 micrograms may be given vaginally or by mouth   • For gestation between 9 and 13 weeks, mifepristone  200 mg by mouth followed 36-48 hours later by miso-  prostol 800 micrograms vaginally followed if necessary  by a maximum of 4 further doses at 3-hourly intervals of  misoprostol 400 micrograms vaginally or by mouth   • For gestation between 13 and 24 weeks, mifepristone  200 mg by mouth followed 36-48 hours later by miso-  prostol 800 micrograms vaginally then a maximum of 4  further doses at 3-hourly intervals of misoprostol  400 micrograms by mouth   Indications see under dose  Cautions asthma (avoid if severe and uncontrolled);  haemorrhagic disorders and anticoagulant therapy;  prosthetic heart valve or history of endocarditis (see    section 5.1 table 2); risk factors for or existing cardi-  ovascular disease; adrenal suppression (may require  corticosteroid); interactions: Appendix 1 (mife-  pristone)   Important For warnings relating to use of gemeprost in a  patient undergoing induction of abortion with mifepristone,  see under Gemeprost   Contra-indications uncontrolled severe asthma; sus-  pected ectopic pregnancy (use other specific means of  termination); chronic adrenal failure; acute porphyria  (section 9.8.2)   Side-effects gastro-intestinal cramps; uterine con-  tractions, vaginal bleeding (sometimes severe) may  occur between administration of mifepristone and  surgery (and rarely abortion may occur before sur-  gery); less commonly hypersensitivity reactions  including rash and urticaria; rarely hypotension,  malaise, headache, fever, hot flushes, dizziness, and  chills; infections (including toxic shock syndrome)  also reported   • Medical termination of intra-uterine pregnancy of up  to 49 days gestation, by mouth, mifepristone 600 mg  as a single dose under medical supervision followed  36-48 hours later (unless abortion already complete)  by gemeprost 1 mg by vagina or misoprostol   400 micrograms by mouth [unlicensed]; alternative  regimen, mifepristone 200 mg by mouth as a single  dose followed 36-48 hours later (unless abortion  already complete) by gemeprost 1 mg by vagina;  observe for at least 3 hours (or until bleeding or pain  at acceptable level); follow-up visit within 2 weeks to  verify complete expulsion and to assess vaginal  bleeding   • Medical termination of intra-uterine pregnancy of 50-  63 days gestation, by mouth, mifepristone 600 mg  (200 mg also effective) as a single dose under medical  supervision, followed 36-48 hours later (unless abor-  tion already complete) by gemeprost 1 mg by vagina;  observe for at least 3 hours (or until bleeding or pain  at acceptable level); follow-up visit within 2 weeks to  verify complete expulsion and to assess vaginal  bleeding   • Cervical ripening before mechanical cervical dilata-  tion for termination of pregnancy of up to 84 days  gestation, by mouth, mifepristone 200 mg as a single  dose under medical supervision 36-48 hours before  procedure   • Termination of pregnancy of 13-24 weeks gestation  (in combination with a prostaglandin), by mouth,  mifepristone 600 mg (200 mg may be effective) as a  single dose under medical supervision followed 36-48  hours later by gemeprost 1 mg by vagina every 3  hours up to max. 5 mg or misoprostol (see above  [unlicensed]); if abortion does not occur, 24 hours  after start of treatment repeat course of gemeprost   1 mg by vagina up to max. 5 mg; follow-up visit after  appropriate interval to assess vaginal bleeding  recommended   Note Careful monitoring of blood pressure and pulse essen-  tial for 3 hours after administration of gemeprost pessary  (risk of profound hypotension)   • Labour induction in fetal death in utero where pros-  taglandin or oxytocin inappropriate, by mouth, mife-  pristone 600 mg daily as a single dose for 2 days under  medical supervision; if labour not started within 72  hours of first dose, another method should be used   Tablets, yellow, mifepristone 200 mg, net price 3-tab  pack = £52.66 (supplied to NHS hospitals and pre-  mises approved under Abortion Act 1967). Label: 10,  patient information leaflet    Tocolytic drugs postpone premature labour and they  are used with the aim of reducing harm to the child.  However, there is no satisfactory evidence that the use  of these drugs reduces mortality. The greatest benefit is  gained by using the delay to administer corticosteroid  therapy or to implement other measures which improve  perinatal health (including transfer to a unit with neo-  natal intensive care facility).    The oxytocin receptor antagonist, atosiban, is licensed  for the inhibition of uncomplicated premature labour  between 24 and 33 weeks of gestation. Atosiban may be  preferable to a beta 2 agonist because it has fewer side-  effects.    The dihydropyridine calcium-channel blocker nife-  dipine (section 2.6.2) also has fewer side-effects than  a beta 2 agonist. Nifedipine [unlicensed indication] can  be given initially in a dose of 20 mg followed by 10-  20 mg 3-4 times daily adjusted according to uterine  activity.    A beta 2 agonist (ritodrine, salbutamol, or terbutaline)  is used for inhibiting uncomplicated premature labour  between 24 and 33 weeks of gestation and it may permit  a delay in delivery of at least 48 hours. Prolonged  therapy should be avoided since risk to the mother  increases after 48 hours and there is a lack of evidence  of benefit from further treatment; maintenance treat-  ment is therefore not recommended.   Indometacin (section 10.1.1), a cyclo-oxygenase inhi-  bitor, also inhibits labour [unlicensed indication] and it  can be useful in situations where a beta 2 agonist is not  appropriate; however, there are concerns about neo-  natal complications such as transient impairment of  renal function and premature closure of ductus arter-  iosus.   Cautions monitor blood loss after delivery; intra-  uterine growth restriction; abnormal placental site  Contra-indications eclampsia and severe pre-  eclampsia, intra-uterine infection, intra-uterine fetal  death, antepartum haemorrhage (requiring immediate  delivery), placenta praevia, abruptio placenta, intra-  uterine growth restriction with abnormal fetal heart  rate, premature rupture of membranes after 30 weeks’  gestation   Hepatic impairment no information available  Renal impairment no information available  Side-effects nausea, vomiting, tachycardia, hypo-  tension, headache, dizziness, hot flushes, hyperglyc-  aemia, injection-site reaction; less commonly pruritus,  rash, fever, insomnia   • By intravenous injection, initially 6.75 mg over 1  minute, then by intravenous infusion 18 mg/hour for  3 hours, then 6 mg/hour for up to 45 hours; max.  duration of treatment 48 hours   Injection, atosiban (as acetate) 7.5mg/mL, net price  0.9-mL (6.75-mg) vial = £18.41  Concentrate for intravenous infusion, atosiban (as  acetate) 7.5 mg/mL, net price 5-mL vial = £52.82   Cautions Beta 2 agonists should be used with caution in  patients with suspected cardiovascular disease (such  patients should be assessed by a cardiologist before  initiating therapy — see also Contra-indications, below),  hypertension, mild to moderate pre-eclampsia, hyper-  thyroidism, and hypokalaemia (particular risk with  potassium-depleting diuretics — see also Hypokalaemia,  p. 176). It is important to monitor pulse rate (should not  exceed 140 beats per minute), ECG (discontinue treat-  ment if signs of myocardial ischaemia develop), and the  patient’s fluid and electrolyte status (avoid over-hydra-  tion — discontinue drug immediately and initiate diuretic  therapy if pulmonary oedema occurs). Beta 2 agonists  should also be used with caution in diabetes — monitor  blood glucose (risk of hyperglycaemia and ketoacidosis,  especially with intravenous beta 2 agonists).   Contra-indications Beta 2 agonists are contra-indi-  cated in cardiac disease and in patients with significant   B risk factors for myocardial ischaemia; they should also  be avoided in antepartum haemorrhage, intra-uterine  infection, intra-uterine fetal death, placenta praevia,  abruptio placenta, threatened miscarriage, cord com-  pression, and eclampsia or severe pre-eclampsia.   Side-effects Side-effects of the beta 2 agonists include  nausea, vomiting, pulmonary oedema (see Cautions  above and under Ritodrine dose), palpitation, tachy-  cardia, arrhythmias, myocardial ischaemia, peripheral  vasodilation, headache, tremor, hyperglycaemia, hypo-  kalaemia (see Cautions), muscle cramps and tension,  and hypersensitivity reactions (including angioedema,  urticaria, rash, bronchospasm, hypotension, and col-  lapse).   Cautions see notes above; interactions: Appendix 1  (sympathomimetics and sympathomimetics, beta 2 )  Contra-indications see notes above  Side-effects see notes above; also reported flushing,  sweating; salivary gland enlargement; leucopenia and  agranulocytosis on prolonged administration (several  weeks); liver function abnormalities (including  increased transaminases and hepatitis)   • By intravenous infusion (important: minimum fluid  volume, see below), initially 50 micrograms/minute,  increased gradually according to response by  50 micrograms/minute every 10 minutes until con-  tractions stop or maternal heart rate reaches 140  beats per minute; continue for 12-48 hours after    contractions cease (usual rate 150-350 micrograms/  minute); max. rate 350 micrograms/minute; or by  intramuscular injection, 10 mg every 3-8 hours con-  tinued for 12-48 hours after contractions have ceased;  then by mouth (but see notes above), 10 mg 30  minutes before termination of intravenous infusion,  repeated every 2 hours for 24 hours, followed by 10-  20 mg every 4-6 hours, max. oral dose 120 mg daily  Important Manufacturer states that although fatal pulm-  onary oedema associated with ritodrine infusion is almost  certainly multifactorial in origin, evidence suggests that fluid  overload may be the most important single factor. The  volume of infusion should therefore be kept to a minimum;  for further guidance see Appendix 6. For specific guidance  on infusion rates, consult product literature   Tab lets yellow, scored, ritodrine hydrochloride  10 mg, net price 90-tab pack = £30.40  Injection, ritodrine hydrochloride 10 mg/mL, net  price 5-mL amp = £3.55   Cautions see notes above; interactions: Appendix 1  (sympathomimetics, beta 2 )   • By intravenous infusion, initially 10 micrograms/  minute, rate increased gradually according to  response at 10-minute intervals until contractions  diminish then increase rate slowly until contractions  cease (max. rate 45 micrograms/minute); maintain  rate for 1 hour after contractions have stopped, then  gradually reduce by 50% every 6 hours; then by  mouth (but see notes above), 4 mg every 6-8 hours   Cautions see notes above; interactions: Appendix 1  (sympathomimetics, beta 2 )   • By intravenous infusion, 5 micrograms/minute for 20  minutes, increased every 20 minutes in steps of   2.5 micrograms/minute until contractions have  ceased (more than 10 micrograms/minute should  seldom be given — 20 micrograms /minute should not  be exceeded), continue for 1 hour then decrease every  20 minutes in steps of 2.5 micrograms /minute to  lowest dose that maintains suppression, continue at  this level for 12 hours then by mouth (but see notes  above), 5 mg every 8 hours for as long as is desirable  to prolong pregnancy (or alternatively follow the  intravenous infusion by subcutaneous injection  250 micrograms every 6 hours for a few days then by  mouth as above)   Symptoms are often restricted to the vulva, but infec-  tions almost invariably involve the vagina which should  also be treated. Applications to the vulva alone are likely  to give only symptomatic relief without cure.   Aqueous medicated douches may disturb normal vagi-  nal acidity and bacterial flora.   Topical anaesthetic agents give only symptomatic relief  and may cause sensitivity reactions. They are indicated  only in cases of pruritus where specific local causes  have been excluded.   Systemic drugs are required in the treatment of infec-  tions such as gonorrhoea and syphilis (section 5.1).   A cream containing an oestrogen may be applied on a  short-term basis to improve the vaginal epithelium in  menopausal atrophic vaginitis. It is important to bear  in mind that topical oestrogens should be used in the  smallest effective amount to minimise systemic effects.  Modified-release vaginal tablets and an impregnated  vaginal ring are now also available.   The risk of endometrial hyperplasia and carcinoma is  increased when systemic oestrogens are administered  alone for prolonged periods (section 6.4. 1.1). The endo-  metrial safety of long-term or repeated use of topical  vaginal oestrogens is uncertain; treatment should be  reviewed at least annually, with special consideration  given to any symptoms of endometrial hyperplasia or  carcinoma.   Topical oestrogens are also used in postmenopausal  women before vaginal surgery for prolapse when there  is epithelial atrophy.   For a general comment on hormone replacement ther-  apy, including the role of topical oestrogens, see section  6.4.1. 1.   Breast-feeding avoid; adverse effects on lactation;  see also Combined Hormonal Contraceptives, section  7.3.1   Side-effects see notes above; see also Oestrogens for  HRT (section 6.4. 1.1); local irritation   Gynest® (Marlborough) (MO  Intravaginal cream, estriol 0.01%, net price 80 g with  applicator = £4.67   attempts to reduce or discontinue should be made at 3-6 month   Excipients include cetyl alcohol, polysorbates, stearyl alcohol  Condoms effect on latex condoms and diaphragms not yet known  Dose insert 1 applicator-dose daily for 2-3 weeks, then reduce to  twice a week (discontinue every 2-3 months for 4 weeks to assess  need for further treatment); vaginal surgery, 1 applicator-dose  daily for 2 weeks before surgery, resuming 2 weeks after surgery   Vagifem® (Novo Nordisk) (Ml  Vaginal tablets, f/c, estradiol 10 micrograms in dis-  posable applicators, net price 24-applicator pack =  £16.72; estradiol 25 micrograms in disposable appli-  cators, 15-applicator pack = £9.50   Condoms no evidence of damage to latex condoms and diaphragms  Dose insert 1 vaginal tablet daily for 2 weeks then reduce to 1  tablet twice weekly; initiate therapy with 10 microgram vaginal  tablets, increased after 3 months to 25 microgram vaginal tablet if  response inadequate    ^Vaginal ring  Estring® (Pharmacia) (Ml  Vaginal ring, releasing estradiol approx. 7.5 micr-  ograms/24 hours, net price 1-ring pack = £31.42.  Label: 10, patient information leaflet  Dose for postmenopausal urogenital conditions (not suitable for  vasomotor symptoms or osteoporosis prophylaxis), to be inserted  into upper third of vagina and worn continuously; replace after 3  months; max. duration of continuous treatment 2 years   Indications see notes above  Cautions see notes above; see also Oestrogens for  HRT (section 6.4. 1.1); interrupt treatment periodically  to assess need for continued treatment  Contra-indications see notes above; see also Oestro-  gens for HRT (section 6.4. 1.1)   Replens MD® and Sylk® are acidic, non-hormonal  vaginal moisturisers; Replens MD® provides a high  moisture content for up to 3 days.    Effective specific treatments are available for the com-  mon vaginal infections.   Candidal vulvitis can be treated locally with cream, but  is almost invariably associated with vaginal infection  which should also be treated. Vaginal candidiasis is  treated primarily with antifungal pessaries or cream  inserted high into the vagina (including during men-  struation). Single-dose preparations offer an advantage  when compliance is a problem. Local irritation may  occur on application of vaginal antifungal products.   Imidazole drugs (clotrimazole, econazole, fenticona-  zole, and miconazole) are effective against Candida in  short courses of 1 to 14 days according to the prepara-  tion used; treatment can be repeated if initial course fails  to control symptoms or if symptoms recur. Vaginal  applications may be supplemented with antifungal  cream for vulvitis and to treat other superficial sites of  infection.   Oral treatment of vaginal infection with fluconazole or  itraconazole (section 5.2.1) is also effective; oral keto-  conazole has been associated with fatal hepatotoxicity  (see section 5.2.2).   B Vulvovaginal candidiasis in pregnancy Vulvova-  ginal candidiasis is common during pregnancy and can  be treated with vaginal application of an imidazole (such  as clotrimazole), and a topical imidazole cream for  vulvitis. Pregnant women need a longer duration of  treatment, usually about 7 days, to clear the infection.  Oral antifungal treatment should be avoided during  pregnancy.   Recurrent vulvovaginal candidiasis Recurrence of  vulvovaginal candidiasis is particularly likely if there are  predisposing factors such as antibacterial therapy,  pregnancy, diabetes mellitus and possibly oral contra-  ceptive use. Reservoirs of infection may also lead to  recontamination and should be treated; these include  other skin sites such as the digits, nail beds, and umbi-  licus as well as the gastro-intestinal tract and the  bladder. The partner may also be the source of re-  infection and, if symptomatic, should be treated with  cream at the same time.   Treatment against Candida may need to be extended for  6 months in recurrent vulvovaginal candidiasis. Some  recommended regimens [all unlicensed] include:   • initially, fluconazole (section 5.2.1) by mouth  150 mg every 72 hours for 3 doses, then 150 mg  once every week for 6 months;   • initially, vaginal application of a topical imidazole  for 10-14 days, then clotrimazole vaginally 500-mg  pessary once every week for 6 months;   • initially, vaginal application of a topical imidazole  for 10-14 days, then itraconazole (section 5.2.1) by  mouth 50-100 mg daily for 6 months.   Cream (topical), clotrimazole 1%, net price 20 g =  £1.52 50g = £4.12   Dose apply to anogenital area 2-3 times daily  Pessary, clotrimazole 500 mg, net price 1 pessary  with applicator = £3.13   Dose insert 1 pessary at night as a single dose; can be repeated  once if necessary   Cream (topical), clotrimazole 1%, net price 20 g =  £2.14; 50 g = £3.50   Excipients include benzyl alcohol, cetostearyl alcohol, polysorbates  Condoms damages latex condoms and diaphragms  Dose apply to anogenital area 2-3 times daily  Thrush Cream (topical), clotrimazole 2%, net price  20 g = £3.99   Excipients include benzyl alcohol, cetostearyl alcohol, polysorbates  Condoms damages latex condoms and diaphragms  Dose apply to anogenital area 2-3 times daily  Intravaginal cream (10% FC®) f^l, clotrimazole  10%, net price 5-g applicator pack = £4.50   Dose insert 5 g at night as a single dose; can be repeated once if   Cream Combi, clotrimazole 10% vaginal cream and  2% topical cream, net price 5-g vaginal cream (with  applicator) and 10-g topical cream = £6.81   Excipients include benzyl alcohol, cetostearyl alcohol, polysorbates  Condoms damages latex condoms and diaphragms  Dose see under individual components  Pessaries, clotrimazole 100 mg, net price 6 pessaries  with applicator = £3.63; 200 mg, 3 pessaries with  applicator = £3.63   Dose insert 200 mg for 3 nights or 100 mg for 6 nights; course   Pessary, clotrimazole 500 mg, net price 1 pessary  with applicator = £2.00   Dose insert 1 pessary at night as a single dose; can be repeated   Combi, clotrimazole 500-mg pessary and cream  (topical) 2%, net price 1 pessary and 10-g cream =  £5.21   Intravaginal cream, miconazole nitrate 2%, net price  78 g with applicators = £4.33   Dose insert 5-g applicatorful once daily for 10-14 days or twice   daily for 7 days; course can be repeated once if necessary; topical,    Ovule (= vaginal capsule) ( Gyno-Daktarin 1®),  miconazole nitrate 1.2 g in a fatty basis, net price 1  ovule = £2.94   Gyno-Pevaryl® (Janssen-Cilag) (Ml  Cream, econazole nitrate 1%, net price 15 g = £1.32;  30 g = £3.02   night for at least 14 nights; course can be repeated once if   Note Applicator available separately from Marlborough  Pessaries, econazole nitrate 150 mg, net price 3  pessaries = £2.78   Pessary ( Gyno-Pevaryl 1®), econazole nitrate  150 mg, formulated for single-dose therapy, net price  1 pessary with applicator = £2.95   Dose ADULT and CHILD over 16 years, insert 1 pessary at night as   Gynoxin® (Recordati) (Ml  Intravaginal cream, fenticonazole nitrate 2%, net  price 30 g with applicator = £3.74   Condoms damages latex condoms and diaphragms  Dose insert 5-g applicatorful intravaginally twice daily for 3 days  Vaginal capsule, fenticonazole nitrate 200 mg, net  price 3 vaginal capsules = £2.42   Nizoral® Qanssen-Cilag) (Ml  Cream (topical), ketoconazole 2%, net price 30 g =  £3.40   Excipients include polysorbates, propylene glycol, stearyl alcohol  Condoms effect on latex condoms and diaphragms not yet known  Dose apply to anogenital area once or twice daily   Trichomonal infections commonly involve the lower  urinary tract as well as the genital system and need  systemic treatment with metronidazole or tinidazole  (section 5.1.11).   Bacterial infections with Gram-negative organisms are  particularly common in association with gynaecological  operations and trauma. Metronidazole is effective  against certain Gram-negative organisms, especially  Bacteroides spp. and can be used prophylactically in  gynaecological surgery.   Vaginal preparations intended to restore normal acidity  may prevent recurrence of vaginal infections and permit  the re-establishment of the normal vaginal flora.    The antiviral drugs aciclovir, famciclovir, and valaciclo-  vir can be used in the treatment of genital infection due  to herpes simplex virus, the HSV type 2 being a major  cause of genital ulceration; they have a beneficial effect  on virus shedding and healing, generally giving relief  from pain and other symptoms. See section 5.3.2. 1 for  systemic preparations, and section 13.10.3 for topical  preparations.   Cream, clindamycin 2% (as phosphate), net price 40-g  pack with 7 applicators = £10.86   Condoms damages latex condoms and diaphragms  Side-effects irritation, cervicitis, and vaginitis; poorly absorbed  into the blood — low risk of systemic effects, see section 5.1.6  Dose bacterial vaginosis, insert 5-g applicatorful at night for 3-7  nights   Cautions not recommended during menstruation; some absorp-  tion may occur, see section 5.1.11 for systemic effects  Side-effects local effects including irritation, candidiasis, abnor-  mal discharge, pelvic discomfort   Dose prevention of bacterial vaginosis, ADULT over 18 years  insert contents of 1 tube at night for 2-3 nights after menstruation   Combined hormonal contraceptives  Progestogen-only contraceptives  Spermicidal contraceptives  Contraceptive devices  Emergency contraception   The Fraser Guidelines 1 should be followed when pre-  scribing contraception for women under 16 years. The  UK Medical Eligibility Criteria for Contraceptive Use  (available at www.fsrh.org) is published by the Faculty of  Sexual and Reproductive Healthcare; it categorises the  risks of using contraceptive methods with pre-existing  medical conditions.   Hormonal contraception is the most effective method  of fertility control, but can have major and minor side-  effects, especially for certain groups of women.  Intra-uterine devices are a highly effective method of  contraception but may produce undesirable local side-  effects. They may be used in women of all ages irre-   1. See Department of Health Guidance (July 2004): Best  practice guidance for doctors and other health profes-  sionals on the provision of advice and treatment to young  people under 16 on contraception, sexual and reproductive  health. Available at www.dh.gov.uk    spective of parity, but are less appropriate for those with  an increased risk of pelvic inflammatory disease.   Barrier methods alone (condoms, diaphragms, and  caps) are less effective but can be reliable for well-  motivated couples if used in conjunction with a sper-  micide. Occasionally sensitivity reactions occur. A  female condom ( Femidom ®) is also available; it is  prelubricated but does not contain a spermicide.   Oral contraceptives containing an oestrogen and a  progestogen (‘combined oral contraceptives’) are effec-  tive preparations for general use. Advantages of com-  bined oral contraceptives include:   Combined oral contraceptives containing a fixed  amount of an oestrogen and a progestogen in each  active tablet are termed ‘monophasic’; those with vary-  ing amounts of the two hormones are termed ‘phasic’. A  transdermal patch and a vaginal ring, both containing an  oestrogen with a progestogen, are also available.   B Choice The majority of combined oral contraceptives  contain ethinylestradiol as the oestrogen component;  mestranol and estradiol valerate are also used. The  ethinylestradiol content of combined oral contra-  ceptives ranges from 20 to 40 micrograms. Generally a  preparation with the lowest oestrogen and progestogen  content which gives good cycle control and minimal  side-effects in the individual woman is chosen.   • Low strength preparations (containing ethinylestra-  diol 20 micrograms) are particularly appropriate for  women with risk factors for circulatory disease,  provided a combined oral contraceptive is other-  wise suitable. It is recommended that the combined  oral contraceptive is not continued beyond 50 years  of age since more suitable alternatives exist.   • Standard strength preparations (containing ethiny-  lestradiol 30 or 35 micrograms or in 30-40 micr-  ogram phased preparations) are appropriate for  standard use — but see Risk of Venous Thromboem-  bolism below. Phased preparations are generally  reserved for women who either do not have with-  drawal bleeding or who have breakthrough bleeding  with monophasic products.   The progestogens desogestrel, drospirenone, and gesto-  dene (in combination with ethinylestradiol) may be  considered for women who have side-effects (such as  acne, headache, depression, weight gain, breast symp-  toms, and breakthrough bleeding) with other progesto-  gens. However, women should be advised that  desogestrel and gestodene have also been associated  with an increased risk of venous thromboembolism.  Drospirenone, a derivative of spironolactone, has anti-  androgenic and anti-mineralocorticoid activity; it should   be used with care if an increased plasma-potassium  concentration might be hazardous.   The progestogen norelgestromin is combined with ethi-  nylestradiol in a transdermal patch ( Evra ®).   The vaginal contraceptive ring contains the progestogen  etonogestrel combined with ethinylestradiol  (NuvaRing®).   Risk of venous thromboembolism There is an  increased risk of venous thromboembolic disease (par-  ticularly during the first year) in users of oral contra-  ceptives, but this risk is considerably smaller than that  associated with pregnancy (about 60 cases of venous  thromboembolic disease per 100 000 pregnancies). In  all cases the risk of venous thromboembolism increases  with age and in the presence of other risk factors for  venous thromboembolism, such as obesity.   The incidence of venous thromboembolism in healthy,  non-pregnant women who are not taking an oral contra-  ceptive is about 5-10 cases per 100 000 women per  year. For those using combined oral contraceptives  containing second-generation progestogens, such as  levonorgestrel, this incidence is about 15 per 100 000  women per year of use. The risk of venous thromboem-  bolism with transdermal patches may be slightly  increased compared with combined oral contraceptives  that contain levonorgestrel. Some studies have reported  a greater risk of venous thromboembolism in women  using combined oral contraceptives containing the  third-generation progestogens desogestrel and gesto-  dene; the incidence in these women is about 25 per  100 000 women per year of use. The absolute risk of  venous thromboembolism in women using combined  oral contraceptives containing these third-generation  progestogens is very small and well below the risk  associated with pregnancy. The risk of venous throm-  boembolism in women using a combined oral contra-  ceptive containing drospirenone may be between that  associated with combined oral contraceptives contain-  ing second-generation progestogens and those contain-  ing third-generation progestogens. The risk of venous  thromboembolism associated with vaginal ring use  compared to the risk with other combined hormonal  contraceptives is unknown.   Provided that women are informed of the relative risks  of venous thromboembolism and accept them, the  choice of oral contraceptive is for the woman together  with the prescriber jointly to make in light of her  individual medical history and any contra-indications.    Travel Women taking oral contraceptives or using the  patch or vaginal ring are at an increased risk of deep-  vein thrombosis during travel involving long periods of  immobility (over 5 hours). The risk may be reduced by  appropriate exercise during the journey and possibly by  wearing graduated compression hosiery.    Missed pill The critical time for loss of contraceptive  protection is when a pill is omitted at the beginning or  end of a cycle (which lengthens the pill-free interval).   If a woman forgets to take a pill, it should be taken as  soon as she remembers, and the next one taken at the  normal time (even if this means taking 2 pills together).  A missed pill is one that is 24 or more hours late; for  women taking Qlaira®, see below. If a woman misses  only one pill, she should take an active pill as soon as    she remembers and then resume normal pill-taking. No  additional precautions are necessary.   If a woman misses 2 or more pills (especially from the  first 7 in a packet), she may not be protected. She should  take an active pill as soon as she remembers and then  resume normal pill-taking. In addition, she must either  abstain from sex or use an additional method of contra-  ception such as a condom for the next 7 days. If these 7  days run beyond the end of the packet, the next packet  should be started at once, omitting the pill-free interval  (or, in the case of everyday (ED) pills, omitting the 7  inactive tablets).   A missed pill for a woman taking QIaira® is one that is  12 hours or more late; for information on how to  manage missed pills in women taking QIaira ®, refer to  product literature.   Emergency contraception (section 7.3.5) is recom-  mended if 2 or more combined oral contraceptive  tablets are missed from the first 7 tablets in a packet  and unprotected intercourse has occurred since finish-  ing the last packet.   Note The Faculty of Sexual and Reproductive Healthcare  offers 2 different types of missed pill advice depending on  the ethinylestradiol content of the contraceptive pill. The  missed pill information above offers the same advice regardless  of the ethinylestradiol content of the contraceptive pill; it is a  simplified, more cautious version of advice issued by the  Faculty of Sexual and Reproductive Healthcare.   Delayed application or detached patch If a patch  is partly detached for less than 24 hours, reapply to the  same site or replace with a new patch immediately; no  additional contraception is needed and the next patch  should be applied on the usual ‘change day’. If a patch  remains detached for more than 24 hours or if the user is  not aware when the patch became detached, then stop  the current contraceptive cycle and start a new cycle by  applying a new patch, giving a new ‘Day 1’; an addi-  tional non-hormonal contraceptive must be used con-  currently for the first 7 days of the new cycle.   If application of a new patch at the start of a new cycle is  delayed, contraceptive protection is lost. A new patch  should be applied as soon as remembered giving a new  ‘Day T; additional non-hormonal methods of contra-  ception should be used for the first 7 days of the new  cycle. If intercourse has occurred during this extended  patch-free interval, a possibility of fertilisation should be  considered. If application of a patch in the middle of the  cycle is delayed (i.e. the patch is not changed on day 8 or  day 15):   • for up to 48 hours, apply a new patch immediately;  next patch ‘change day’ remains the same and no  additional contraception is required;   • for more than 48 hours, contraceptive protection  may have been lost. Stop the current cycle and start  a new 4-week cycle immediately by applying a new  patch giving a new ‘Day T; additional non-hormo-  nal contraception should be used for the first 7 days  of the new cycle.   If the patch is not removed at the end of the cycle (day  22), remove it as soon as possible and start the next  cycle on the usual ‘change day’, the day after day 28; no  additional contraception is required.   Expulsion, delayed insertion or removal, or bro-  ken vaginal ring If the vaginal ring is expelled for less  than 3 hours, rinse the ring with cool water and reinsert  immediately; no additional contraception is needed.    If the ring remains outside the vagina for more than 3  hours or if the user does not know when the ring was  expelled, contraceptive protection may be reduced:   • If ring expelled during week 1 or 2 of cycle, rinse  ring with cool water and reinsert; use additional  precautions (barrier methods) for next 7 days;   • If ring expelled during week 3 of cycle, either insert  a new ring to start a new cycle or allow a withdrawal  bleed and insert a new ring no later than 7 days after  ring was expelled; latter option only available if ring  was used continuously for at least 7 days before  expulsion.   If insertion of a new ring at the start of a new cycle is  delayed, contraceptive protection is lost. A new ring  should be inserted as soon as possible; additional pre-  cautions (barrier methods) should be used for the first 7  days of the new cycle. If intercourse occurred during the  extended ring-free interval, pregnancy should be con-  sidered.    If the ring breaks during use, remove it and insert a new  ring immediately; additional precautions (barrier meth-  ods) should be used for the first 7 days of the new cycle.    Diarrhoea and vomiting Vomiting and persistent,  severe diarrhoea can interfere with the absorption of  combined oral contraceptives. If vomiting occurs within  2 hours of taking a combined oral contraceptive another  pill should be taken as soon as possible. In cases of  persistent vomiting or severe diarrhoea lasting more  than 24 hours, additional precautions should be used  during and for 7 days (9 days for QIaira®) after recovery  (see also under Missed pill, above). If the vomiting and  diarrhoea occurs during the last 7 tablets, the next pill-  free interval should be omitted (in the case of ED tablets  the inactive ones should be omitted).    Interactions The effectiveness of combined oral  contraceptives, progestogen-only oral contraceptives  (section 7.3.2. 1), contraceptive patches, and vaginal  rings can be considerably reduced by interaction with  drugs that induce hepatic enzyme activity (e.g. carba-  mazepine, eslicarbazepine, modafinil, nelfinavir,  nevirapine, oxcarbazepine, phenytoin, phenobarbi-  tal, primidone, ritonavir, St John’s Wort, topiramate,  and, above all, rifabutin and rifampicin). A condom  together with a long-acting method, such as an inject-  able contraceptive, may be more suitable for patients  with HIV infection or at risk of HIV infection; advice on  the possibility of interaction with antiretroviral drugs  should be sought from HIV specialists.   For a short course of an enzyme-inducing drug, the dose  of combined oral contraceptives should be adjusted to  provide ethinylestradiol 50 micrograms or more daily  [unlicensed use]; furthermore, additional contraceptive  precautions should be taken whilst taking the enzyme-  inducing drug and for 4 weeks after stopping it. Addi-  tional contraceptive precautions are also required for  women using contraceptive patches and vaginal rings  whilst taking the enzyme-inducing drug and for 4 weeks  after stopping. If concomitant administration runs    No additional contraception is required if removal of the  ring is delayed by up to 1 week (4 weeks of continuous  use). The 7-day ring-free interval should be observed  and subsequently a new ring should be inserted. Contra-  ceptive protection may be reduced with continuous use  of the ring for more than 4 weeks — pregnancy should be  ruled out before inserting a new ring.    beyond the 3 weeks of patch or vaginal ring use, a new  treatment cycle should be started immediately without a  patch-free or ring-free break.   Women requiring a long-term course of an enzyme-  inducing drug should be encouraged to consider a  contraceptive method that is unaffected by the interact-  ing drug. In women unable to use an alternative method  of contraception (for rifampicin and rifabutin see also  below), a regimen of combined oral contraceptives  should be taken which provides a daily intake of ethi-  nylestradiol 50 micrograms or more [unlicensed use];  ‘tricycling’ (i.e. taking 3 or 4 packets of monophasic  tablets without a break followed by a short tablet-free  interval of 4 days) may be recommended. Rifampicin  and rifabutin are such potent enzyme-inducing drugs  that an alternative method of contraception (such as an  IUD) is always recommended. Since enzyme activity  does not return to normal for several weeks after stop-  ping an enzyme-inducing drug, appropriate contracep-  tive measures are required for 4 to 8 weeks after stop-  ping. Contraceptive patches and vaginal rings are not  recommended for women taking enzyme-inducing  drugs over a long period.   In the past there have been concerns that some anti-  bacterials that do not induce liver enzymes (e.g ampi-  cillin, doxycycline) reduce the efficacy of combined oral  contraceptives by impairing the bacterial flora respon-  sible for recycling ethinylestradiol from the large bowel.  However, there is a lack of evidence to support this  interaction. Current recommendations are that no addi-  tional contraceptive precautions are required when  combined oral contraceptives are used with antibac-  terials that do not induce liver enzymes, unless diarr-  hoea or vomiting occur (see above).   B it is also currently recommended that no additional  contraceptive precautions are required when contra-  ceptive patches or vaginal rings are used with antibac-  terials that do not induce liver enzymes.   Surgery Oestrogen-containing contraceptives should  preferably be discontinued (and adequate alternative  contraceptive arrangements made) 4 weeks before  major elective surgery and all surgery to the legs or  surgery which involves prolonged immobilisation of a  lower limb; they should normally be recommenced at  the first menses occurring at least 2 weeks after full  mobilisation. A progestogen-only contraceptive may be  offered as an alternative and the oestrogen-containing  contraceptive restarted after mobilisation, as above.  When discontinuation of an oestrogen-containing con-  traceptive is not possible, e.g. after trauma or if a patient  admitted for an elective procedure is still on an oestro-  gen-containing contraceptive, thromboprophylaxis  (with unfractionated or low molecular weight heparin  and graduated compression hosiery) is advised. These  recommendations do not apply to minor surgery with  short duration of anaesthesia, e.g. laparoscopic sterilisa-  tion or tooth extraction, or to women using oestrogen-  free hormonal contraceptives.   Reason to stop immediately Combined hormonal  contraceptives or hormone replacement therapy (HRT)  should be stopped (pending investigation and treat-  ment), if any of the following occur:   • sudden severe chest pain (even if not radiating to left  arm);    • unexplained swelling or severe pain in calf of one leg;   • serious neurological effects including unusual severe,  prolonged headache especially if first time or getting  progressively worse or sudden partial or complete loss  of vision or sudden disturbance of hearing or other  perceptual disorders or dysphasia or bad fainting attack  or collapse or first unexplained epileptic seizure or  weakness, motor disturbances, very marked numbness  suddenly affecting one side or one part of body;   • detection of a risk factor which contra-indicates treat-  ment (see Cautions and Contra-indications under Com-  bined Hormonal Contraceptives below or under Oestro-  gens for HRT (section 6.4. 1.1)).   Cautions see notes above; risk factors for venous  thromboembolism (see below and also notes above),  arterial disease and migraine, see below; personal or  family history of hypertriglyceridaemia (increased risk  of pancreatitis); hyperprolactinaemia (seek specialist  advice); history of severe depression especially if  induced by hormonal contraceptive; undiagnosed  breast mass; gene mutations associated with breast  cancer (e.g. BRCA 1); sickle-cell disease; inflamm-  atory bowel disease including Crohn’s disease;  reduced efficacy of contraceptive patch in women  with body-weight > 90 kg; active trophoblastic dis-  ease (until return to normal of urine- and plasma-  gonadotrophin concentration) — seek specialist  advice; interactions: see above and Appendix 1  (oestrogens, progestogens)   Risk factors for venous thromboembolism See also  notes above. Use with caution if any of following factors  present but avoid if two or more factors present:   • family history of venous thromboembolism in first-  degree relative aged under 45 years (avoid contracep-  tive containing desogestrel or gestodene, or avoid if  known prothrombotic coagulation abnormality e.g. fac-  tor V Leiden or antiphospholipid antibodies (including  lupus anticoagulant));   • obesity — body mass index > 30 kg/m 2 (avoid if body  mass index > 35 kg/m 2 unless no suitable alternative);   • long-term immobilisation e.g. in a wheelchair (avoid if  confined to bed or leg in plaster cast);   Risk factors for arterial disease Use with caution if any  one of following factors present but avoid if two or more  factors present:   • family history of arterial disease in first degree relative  aged under 45 years (avoid if atherogenic lipid profile);   140 mmHg or diastolic 90 mmHg (avoid if blood pres-  sure above systolic 160 mmHg or diastolic 95mmHg)\   • obesity (avoid if body mass index >35 kg/m 2 unless no  suitable alternative);    • migraine without aura (avoid if migraine with aura  (focal symptoms), or severe migraine frequently lasting  over 72 hours despite treatment, or migraine treated  with ergot derivatives).   Migraine Women should report any increase in headache  frequency or onset of focal symptoms (discontinue imme-  diately and refer urgently to neurology expert if focal neu-  rological symptoms not typical of aura persist for more than  1 hour — see also Reason To Stop Immediately in notes  above)   Contra-indications see notes above; personal history  of venous or arterial thrombosis, severe or multiple  risk factors for arterial disease or for venous throm-  boembolism (see above), heart disease associated  with pulmonary hypertension or risk of embolus;  sclerosing treatment for varicose veins; migraine with  aura (see also above); transient cerebral ischaemic  attacks without headaches; systemic lupus erythe-  matosus with (or unknown) antiphospholipid anti-  bodies; acute porphyria (section 9.8.2); gallstones;  history of haemolytic uraemic syndrome or history  during pregnancy of pruritus, cholestatic jaundice,  chorea, pemphigoid gestationis; history of breast  cancer but can be used after 5 years if no evidence of  disease and non-hormonal methods unacceptable;  undiagnosed vaginal bleeding   Hepatic impairment avoid in active liver disease  including disorders of hepatic excretion (e.g. Dubin-  Johnson or Rotor syndromes), infective hepatitis  (until liver function returns to normal), and liver  tumours   Breast-feeding avoid until weaning or for 6 months  after birth (adverse effects on lactation)   Side-effects see notes above; also nausea, vomiting,  abdominal cramps, changes in body-weight, liver  impairment, hepatic tumours; fluid retention,  thrombosis (more common when factor V Leiden  present or in blood groups A, B, and AB; see also  notes above), hypertension, changes in lipid metab-  olism; headache, depression, chorea, nervousness,  irritability; changes in libido, breast tenderness,  enlargement, and secretion; reduced menstrual loss,  ‘spotting’ in early cycles, absence of withdrawal  bleeding, amenorrhoea after discontinuation, changes  in vaginal discharge, cervical erosion; contact lenses  may irritate, visual disturbances; leg cramps; skin  reactions, chloasma, photosensitivity; rarely gall-  stones and systemic lupus erythematosus  Breast cancer There is a small increase in the risk of having  breast cancer diagnosed in women taking the combined oral  contraceptive pill; this relative risk may be due to an earlier  diagnosis. In users of combined oral contraceptive pills the  cancers are more likely to be localised to the breast. The  most important factor for diagnosing breast cancer appears  to be the age at which the contraceptive is stopped rather  than the duration of use; any increase in the rate of diagnosis  diminishes gradually during the 10 years after stopping and  disappears by 10 years   Cervical cancer Use of combined oral contraceptives for 5  years or longer is associated with a small increased risk of  cervical cancer; the risk diminishes after stopping and dis-  appears by about 10 years. The risk of cervical cancer with  transdermal patches and vaginal rings is not yet known  Note The possible small increase in the risk of breast cancer  and cervical cancer should be weighed against the protective  effect against cancers of the ovary and endometrium   • By mouth, each tablet should be taken at approxi-  mately same time each day; if delayed, contraceptive  protection may be lost (see missed pill)   21 -day combined (monophasic) preparations, 1  tablet daily for 2 1 days; subsequent courses repeated  after a 7-day interval (during which withdrawal    bleeding occurs); first course usually started on day 1  of cycle — if starting on day 4 of cycle or later, addi-  tional precautions (barrier methods) necessary during  first 7 days   Every day (ED) combined (monophasic) prepara-  tions, 1 active tablet starting on day 1 of cycle (see  also under preparations below) — if starting on day 4  of cycle or later, additional precautions (barrier  methods) necessary during first 7 days; withdrawal  bleeding occurs when inactive tablets being taken;  subsequent courses repeated without interval  Phasic preparations, see under individual prepara-  tions below   Changing to combined preparation containing differ-  ent progestogen 21-day combined preparations: continue  current pack until last tablet and start first tablet of new  brand the next day. If a 7-day break is taken before starting  new brand, additional precautions (barrier methods) should  be used during first 7 days (9 days for Qlaira ®) of taking the  new brand   Every Day (ED) combined preparations: start the new brand  (first tablet of a 21 -day preparation or the first active tablet  of an ED preparation) the day after taking the last active  tablet of previous brand (omitting the inactive tablets)  Changing from progestogen-only tablet Start on day 1 of  menstruation or any day if amenorrhoea present and  pregnancy has been excluded   Secondary amenorrhoea (exclude pregnancy) Start any  day, additional precautions (barrier methods) necessary  during first 7 days (9 days for Qlaira ®)   After childbirth (not breast-feeding) Start 3 weeks after  birth (increased risk of thrombosis if started earlier); later  than 3 weeks postpartum additional precautions (barrier  methods) necessary for first 7 days (9 days for Qlaira ®)  After abortion or miscarriage Start same day    • By transdermal application, apply first patch on day 1  of cycle, change patch on days 8 and 15; remove third  patch on day 22 and apply new patch after 7-day  patch-free interval to start subsequent contraceptive  cycle   Note If first patch applied later than day 1, additional  precautions (abstinence or barrier methods) should be  used for the next 7 days   Changing from combined oral contraception Apply  patch on the first day of withdrawal bleeding; if no with-  drawal bleeding within 5 days of taking last active tablet, rule  out pregnancy before applying first patch. Unless patch is  applied on first day of withdrawal bleeding, additional pre-  cautions (barrier methods) should be used concurrently for  first 7 days   Changing from progestogen-only method From an  implant, apply first patch on the day implant removed;  from an injection, apply first patch when next injection due;  from oral progestogen, first patch may be started on any day  after stopping pill. For all methods additional precautions  (barrier methods) should be used concurrently for first 7  days   After childbirth (not breast-feeding) Start 4 weeks after  birth; if started later than 4 weeks after birth additional  precautions (barrier methods) should be used for first 7 days  After abortion or miscarriage Before 20 weeks’ gestation  start immediately; no additional contraception required if  started immediately. After 20 weeks’ gestation start on day  21 after abortion or on the first day of first spontaneous  menstruation; additional precautions (barrier methods)  should be used for first 7 days after applying the patch   • By vagina, insert ring into vagina on day 1 of cycle and  leave in for 3 weeks; remove ring on day 22; subse-  quent courses repeated after 7-day ring-free interval  (during which withdrawal bleeding occurs)   Note If first ring inserted later than day 1, additional pre-  cautions (barrier methods) should be used for the next 7 days  Changing from combined hormonal contraception  Insert ring at the latest on the day after the usual tablet-  free, patch-free, or placebo-tablet interval. If previous con-   Changing from progestogen-only method From an  implant or intra-uterine progestogen-only device, insert  ring on the day implant or intra-uterine progestogen-only  device removed; from an injection, insert ring when next  injection due; from oral preparation, first ring may be  inserted on any day after stopping pill. For all methods  additional precautions (barrier methods) should be used  concurrently for first 7 days  After first trimester abortion Start immediately  After childbirth (not breast-feeding) or second trime-  ster abortion Start 4 weeks afterbirth or abortion; if started  later than 4 weeks after birth or abortion, additional pre-  cautions (barrier methods) should be used for first 7 days   For information on these preparations, see Combined  Oral Contraceptives table, below   Patches, self-adhesive (releasing ethinylestradiol  approx. 33.9 micrograms/24 hours and norelgestro-  min approx. 203 micrograms/24 hours); net price 9-  patch pack = £16.70. Counselling, administration  Dose 1 patch to be applied once weekly for three weeks, fol-  lowed by a 7-day patch-free interval; subsequent courses repeated  after 7-day patch-free interval (during which withdrawal bleeding  occurs); for starting routines see under Dose above  Note Adhesives or bandages should not be used to hold patch in  place. If patch no longer sticky do not reapply but use a new  patch.   The Scottish Medicines Consortium has advised (September  2003) that Evra ® patches should be restricted for use in women  who are likely to comply poorly with combined oral contra-  ceptives   1. Dose 1 tablet daily for 21 days starting on day 1 of cycle; subsequent courses repeated after 7-day tablet-free interval (during  which withdrawal bleeding occurs); for starting routines see under Dose above   2. Caution use with care if increased plasma-potassium concentration might be hazardous; renal impairment avoid if eGFR less  than 30 mL/minute/ 1.73 m 1 2    1. Dose 1 tablet daily for 28 days, starting on day 1 of cycle with first active tablet (withdrawal bleeding occurs when inactive  tablets being taken); subsequent courses repeated without interval; for starting routines see under Dose above   2. Dose 1 tablet daily for 21 days starting on day 1 of cycle; subsequent courses repeated after 7-day tablet-free interval (during  which withdrawal bleeding occurs); for starting routines see under Dose above   ^Ethinylestradiol with Etonogestrel  See Risk of Venous Thromboembolism in notes above  before prescribing    contraceptive course without a break (or in the case of  ED tablets omitting the inactive ones).   After childbirth Start any time after 3 weeks postpar-  tum (increased risk of breakthrough bleeding if started  earlier).   15 micrograms/24 hours and etonogestrel approx.  120 micrograms/24 hours, net price 3-ring pack =  £27.00. Counselling, administration  Dose 1 ring to be inserted into the vagina, removed on day 22;  subsequent courses repeated after 7-day ring-free interval (during  which withdrawal bleeding occurs); for starting routines see under  Dose above   Counselling The presence of the ring should be checked regularly.  In case of expulsion see Expulsion, Delayed Insertion or Removal,  or Broken Vaginal Ring, p. 495   Oral progestogen-only preparations may offer a suitable  alternative when oestrogens are contra-indicated  9 (including those patients with venous thrombosis or a  past history or predisposition to venous thrombosis),  but may have a higher failure rate than combined  preparations. They are suitable for older women, for  heavy smokers, and for those with hypertension, valv-  ular heart disease, diabetes mellitus, and migraine. Men-  strual irregularities (oligomenorrhoea, menorrhagia) are  more common but tend to resolve on long-term treat-  ment.   Interactions Effectiveness of oral progestogen-only  preparations is not affected by antibacterials that do not  induce liver enzymes. The efficacy of oral progestogen-  only preparations is, however, reduced by enzyme-indu-  cing drugs and an additional or alternative contracep-  tive method is recommended during treatment with an  enzyme-inducing drug and for at least 4 weeks after-  wards — see p. 495 and Appendix 1 (progestogens).   Surgery All progestogen-only contraceptives (includ-  ing those given by injection) are suitable for use as an  alternative to combined oral contraceptives before  major elective surgery, before all surgery to the legs,  or before surgery which involves prolonged immobilisa-  tion of a lower limb.   Starting routine One tablet daily, on a continuous  basis, starting on day 1 of cycle and taken at the same  time each day (if delayed by longer than 3 hours (12  hours for Cerazette®) contraceptive protection may be  lost). Additional contraceptive precautions are not  necessary when initiating treatment.   Changing from a combined oral contraceptive Start on  the day following completion of the combined oral   Missed pill The following advice is now recom-  mended by family planning organisations:   ‘If you forget a pill, take it as soon as you remember and  carry on with the next pill at the right time. If the pill was  more than 3 hours (12 hours for Cerazette ®) overdue you are  not protected. Continue normal pill-taking but you must also  use another method, such as the condom, for the next 2  days.’   The Faculty of Sexual and Reproductive Healthcare  recommends emergency contraception (see p. 505) if  one or more progestogen-only contraceptive tablets are  missed or taken more than 3 hours (12 hours for  Cerazette ®) late and unprotected intercourse has  occurred before 2 further tablets have been correctly  taken.   Diarrhoea and vomiting Vomiting and persistent,  severe diarrhoea can interfere with the absorption of  oral progestogen-only contraceptives. If vomiting  occurs within 2 hours of taking an oral progestogen-  only contraceptive, another pill should be taken as soon  as possible. If a replacement pill is not taken within 3  hours (12 hours for Cerazette®) of the normal time for  taking the progestogen-only pill, or in cases of persistent  vomiting or very severe diarrhoea, additional precau-  tions should be used during illness and for 2 days after  recovery (see also under Missed pill above).   Cautions arterial disease; sex-steroid dependent can-  cer; past ectopic pregnancy; malabsorption syn-  dromes; active trophoblastic disease (until return to  normal of urine- and plasma-gonadotrophin concen-  tration) — seek specialist advice; systemic lupus  erythematosus with positive (or unknown) anti-  phospholipid antibodies; functional ovarian cysts;  history of jaundice in pregnancy; interactions: see  notes above and Appendix 1 (progestogens)   Other conditions The product literature advises caution in  patients with history of thromboembolism, hypertension,  diabetes mellitus and migraine; evidence for caution in these  conditions is unsatisfactory   Contra-indications undiagnosed vaginal bleeding;  severe arterial disease; acute porphyria (section  9.8.2); history of breast cancer but can be used after 5  years if no evidence of disease and non-hormonal  contraceptive methods unacceptable   Hepatic impairment caution in severe liver disease  and recurrent cholestatic jaundice; avoid in liver  tumour   Breast-feeding progestogen-only contraceptives do  not affect lactation; see also After Childbirth above   Side-effects menstrual irregularities (see also notes  above); nausea, vomiting, headache, dizziness, breast  discomfort, depression, skin disorders, disturbance of  appetite, weight changes, changes in libido  Breast cancer There is a small increase in the risk of having  breast cancer diagnosed in women using, or who have    recently used, a progestogen-only contraceptive pill; this  relative risk may be due to an earlier diagnosis. The most  important risk factor appears to be the age at which the  contraceptive is stopped rather than the duration of use; the  risk disappears gradually during the 10 years after stopping  and there is no excess risk by 10 years. A possible small  increase in the risk of breast cancer should be weighed  against the benefits  Dose   • 1 tablet daily at same time each day, starting on day 1  of cycle then continuously; if administration delayed  for 3 hours (12 hours for Cerazette ®) or more it should  be regarded as a ‘missed pill’, see notes above   Tablets, f/c, desogestrel 75 micrograms, net price 3 x  28-tab pack = £8.68   The Scottish Medicines Consortium has advised (September  2003) that Cerazette ® should be restricted for use in women  who cannot tolerate oestrogen-containing contraceptives or  in whom such preparations are contra-indicated   Femulen® (Pharmacia) (Ml  Tablets, etynodiol diacetate 500 micrograms, net  price 3 x 28-tab pack = £3.31   Tablets, norethisterone 350 micrograms, net price 3 x  28-tab pack = £1.66   Tablets, norethisterone 350 micrograms, net price 3 x  28-tab pack = £2.10   Medroxyprogesterone acetate ( Depo-Provera ®) is a  long-acting progestogen given by intramuscular injec-  tion; it is as effective as the combined oral preparations  but because of its prolonged action it should never be  given without full counselling backed by the patient  information leaflet. It may be used as a short-term or  long-term contraceptive for women who have been  counselled about the likelihood of menstrual distur-  bance and the potential for a delay in return to full  fertility. Delayed return of fertility and irregular cycles  may occur after discontinuation of treatment but there is  no evidence of permanent infertility. Heavy bleeding has  been reported in patients given medroxyprogesterone  acetate in the immediate puerperium; delaying the first  injection until 6 weeks after birth may minimise  bleeding problems. If the woman is not breast-feeding,  the first injection may be given within 5 days  postpartum (she should be warned that the risk of  heavy or prolonged bleeding may be increased). The  manufacturer advises that in women who are breast-  feeding, the first dose should be delayed until 6 weeks  after birth; however, evidence suggests no harmful  effect to infant if given earlier. The benefits of using  medroxyprogesterone acetate in breast-feeding women  outweigh any risks.   Reduction in bone mineral density and, rarely, osteo-  porosis and osteoporotic fractures have also been  reported with medroxyprogesterone acetate. The reduc-  tion in bone mineral density occurs in the first 2-3 years  of use and then stabilises. See also below.    • In adolescents, medroxyprogesterone acetate  (. Depo-Provera ®) should be used only when  other methods of contraception are inappropri-  ate;   • in all women, the benefits of using medroxy-  progesterone acetate beyond 2 years should be  evaluated against the risks;   • in women with risk factors for osteoporosis, a  method of contraception other than medroxy-  progesterone acetate should be considered.    Norethisterone enantate ( Noristerat ®) is a long-acting  progestogen given as an oily injection which provides  contraception for 8 weeks; it is used as short-term  interim contraception e.g. before vasectomy becomes  effective.    Nexplanon® is a highly effective long-acting contra-  ceptive, consisting of an etonogestrel-releasing  implant that is inserted subdermally into the lower  surface of the upper arm and provides contraception for  up to 3 years. The manufacturer advises that in heavier  women, blood etonogestrel concentrations are lower  and therefore the implant may not provide effective  contraception during the third year; they advise that  earlier replacement may be considered in such  patients — however, evidence to support this recom-  mendation is lacking. Local reactions such as bruising  and itching can occur at the insertion site. The  contraceptive effect of etonogestrel is rapidly reversed  on removal of the implant. The doctor or nurse  administering (or removing) the system should be fully  trained in the technique and should provide full  counselling reinforced by the patient information  leaflet.   Implanon®, also an etonogestrel-releasing implant, has  been discontinued (October 2010), but some women  may have the implant in place until 2013.   The cautions, contra-indications, and side-effects of oral  progestogen-only contraceptives apply to parenteral  progestogen-only contraceptives, except that parenteral  preparations reliably inhibit ovulation and therefore  protect against ectopic pregnancy and functional  ovarian cysts.    Interactions Effectiveness of parenteral progestogen-  only contraceptives is not affected by antibacterials that  do not induce liver enzymes. However, effectiveness of  norethisterone and etonogestrel (but not depot  medroxyprogesterone acetate) may be reduced by  enzyme-inducing drugs; additional contraceptive pre-  cautions should be taken whilst taking the enzyme-  inducing drug and for 4 weeks after stopping it or an  alternative contraceptive method should be considered  if long-term use of the enzyme-inducing drug is con-  templated.   Cautions see notes above and under preparations;  possible risk of breast cancer, see oral progestogen-  only contraceptives (section 7.3.2. 1); history during  pregnancy of pruritus or of deterioration of oto-    sclerosis, disturbances of lipid metabolism; interac-  tions: see notes above and Appendix 1 (progestogens)  Counselling Full counselling backed by patient information  leaflet required before administration   Contra-indications see notes above; history of breast  cancer but can be used after 5 years if no evidence of  disease and non-hormonal contraceptive methods  unacceptable   Pregnancy not known to be harmful; for Implanon®  or Nexplanon® if pregnancy occurs remove implant   Breast-feeding progestogen-only contraceptives do  not affect lactation; see also notes above and under  preparations   Side-effects see notes above; injection-site reactions  Cervical cancer Use of injectable progestogen-only contra-  ceptives may be associated with a small increased risk of  cervical cancer, similar to that seen with combined oral  contraceptives, see p. 496. The risk of cervical cancer with  other progestogen-only contraceptives is not yet known.   Depo-Provera® (Pfizer) (Ml  Injection (aqueous suspension), medroxyprogester-  one acetate 150mg/mL, net price 1-mL prefilled  syringe = £6.01, 1-mL vial = £6.01. Counselling, see  patient information leaflet   Dose by deep intramuscular injection, 150 mg within first 5 days  of cycle or within first 5 days after parturition (delay until 6 weeks  after parturition if breast-feeding): for long-term contraception,  repeated every 12 weeks (if interval greater than 12 weeks and 5  days, rule out pregnancy before next injection and advise patient  to use additional contraceptive measures (e.g. barrier) for 14 days  after the injection)   Noristerat® (Bayer Schering) (Ml  Injection (oily), norethisterone enantate 200mg/mL,  net price 1-mL amp = £3.38. Counselling, see patient  information leaflet   Dose by deep intramuscular injection given very slowly into  gluteal muscle, short-term contraception, 200 mg within first 5  days of cycle or immediately after parturition (duration 8 weeks);  may be repeated once after 8 weeks (withhold breast-feeding for  neonates with severe or persistent jaundice requiring medical  treatment)   Dose by subdermal implantation, no hormonal contraceptive  use in previous month, 1 implant inserted during first 5 days of  cycle; postpartum, 1 implant inserted 21-28 days after delivery; in  breast-feeding mothers, 1 implant inserted after 28 days post-  partum; abortion or miscarriage in the second trimester, 1 implant  inserted 21-28 days after abortion or miscarriage; abortion or  miscarriage in first trimester, 1 implant inserted within 5 days;  changing from other hormonal contraceptive, consult product  literature; remove implant within 3 years of insertion    replacement therapy. This may therefore be a contra-  ceptive method of choice for women who have  excessively heavy menses.   The effects of the progestogen-only intra-uterine system  are mainly local and hormonal including prevention of  endometrial proliferation, thickening of cervical mucus,  and suppression of ovulation in some women (in some  cycles). In addition to the progestogenic activity, the  intra-uterine system itself may contribute slightly to the  contraceptive effect. Return of fertility after removal is  rapid and appears to be complete.   Advantages of the progestogen-only intra-uterine sys-  tem over copper intra-uterine devices are that there  may be an improvement in any dysmenorrhoea and a  reduction in blood loss; there is also evidence that the  frequency of pelvic inflammatory disease may be  reduced (particularly in the youngest age groups who  are most at risk).   In primary menorrhagia, menstrual bleeding is reduced  significantly within 3-6 months of inserting the proges-  togen-only intra-uterine system, probably because it  prevents endometrial proliferation. Another treatment  should be considered if menorrhagia does not improve  within this time (section 6.4. 1.2).   Cautions and contra-indications Generally the  cautions and contra-indications for the progestogen-  only intra-uterine system are as for standard intra-  uterine devices (section 7.3.4), but the risk of ectopic  pregnancy is considerably smaller. Although the proges-  togen-only intra-uterine system produces little systemic  progestogenic activity, it is usually avoided for 5 years  after any evidence of breast cancer. However, the sys-  tem can be considered for a woman in long-term remis-  sion from breast cancer who has menorrhagia and  requires effective contraception. Since levonorgestrel  is released close to the site of the main contraceptive  action (on cervical mucus and endometrium) progesto-  genic side-effects and interactions are less likely; in  particular, enzyme-inducing drugs are unlikely to sig-  nificantly reduce the contraceptive effect of the proges-  togen-only intra-uterine system and additional contra-  ceptive precautions are not required.   Side-effects Initially, changes in the pattern and  duration of menstrual bleeding (spotting or prolonged  bleeding) are common; endometrial disorders should be  ruled out before insertion and the patient should be fully  counselled (and provided with a patient information  leaflet). Improvement in progestogenic side-effects,  such as mastalgia and in the bleeding pattern usually  occurs a few months after insertion and bleeding may  often become very light or absent. Functional ovarian  cysts (usually asymptomatic) can occur and usually  resolve spontaneously (ultrasound monitoring recom-  mended).    The progestogen-only intra-uterine system, Mirena ® ,  releases levonorgestrel directly into the uterine cavity.  It is licensed for use as a contraceptive, for the  treatment of primary menorrhagia and for the preven-  tion of endometrial hyperplasia during oestrogen   Indications see under preparation  Cautions see notes above; history of depression;  advanced uterine atrophy; systemic lupus erythe-  matosus with positive (or unknown) antiphospholipid  antibodies; not suitable for emergency contraception;  interactions: see notes above and Appendix 1 (pro-  gestogens)    Contra-indications see notes above  Hepatic impairment see Oral Progestogen-only  Contraceptives, section 7.3.2. 1  Pregnancy avoid; if pregnancy occurs remove system  Breast-feeding progestogen-only contraceptives do  not affect lactation   Side-effects see notes above; also abdominal pain;  peripheral oedema; depression (sometimes severe),  nervousness; salpingitis and pelvic inflammatory dis-  ease; pelvic pain, back pain; rarely hirsutism, hair loss,  pruritus, migraine, rash  Dose    Mirena® (Bayer Schering) (Ml  Intra-uterine system, T-shaped plastic frame  (impregnated with barium sulphate and with threads  attached to base) with polydimethylsiloxane reservoir  releasing levonorgestrel 20 micrograms/24 hours, net  price = £85.66. Counselling, see patient information  leaflet   Dose contraception and menorrhagia, insert into uterine cavity  within 7 days of onset of menstruation or any time if replacement,  or any time if reasonably certain woman is not pregnant and there  is no risk of conception (additional precautions (e.g. barrier  methods) necessary for next 7 days), or immediately after first-  trimester termination by curettage; postpartum insertions should  be delayed until at least 4 weeks after delivery; effective for 5  years.   Prevention of endometrial hyperplasia during oestrogen replace-  ment therapy, insert during last days of menstruation or with-  drawal bleeding or any time if amenorrhoeic; effective for 4 years  Note When system is removed (and not immediately replaced), if  pregnancy is not desired, remove during the first few days of the  onset of menstruation, otherwise additional contraceptive measures  should be used for at least 7 days before removal   Spermicidal contraceptives are useful additional safe-  guards but do not give adequate protection if used alone  unless fertility is already significantly diminished (sec-  tion 6.4. 1.1). They have two components: a spermicide  and a vehicle which itself may have some inhibiting  effect on sperm activity. They are suitable for use with  barrier methods, such as diaphragms or caps; however,  spermicidal contraceptives are not generally recom-  mended for use with condoms, as there is no evidence  of any additional protection compared with non-sper-  micidal lubricants.   Spermicidal contraceptives are not suitable for use in  those with or at high risk of sexually transmitted infec-  tions (including HIV); high frequency use of the spermi-  cide nonoxinol ‘9’ has been associated with genital  lesions, which may increase the risk of acquiring these  infections.    Products such as petroleum jelly [Vaseline®), baby  oil and oil-based vaginal and rectal preparations are  likely to damage condoms and contraceptive  diaphragms made from latex rubber, and may  render them less effective as a barrier method of  contraception and as a protection from sexually  transmitted infections (including HIV).   Condoms no evidence of harm to latex condoms and diaphragms  Breast-feeding present in milk in animal studies   The intra-uterine device (IUD) is a suitable contracep-  tive for women of all ages irrespective of parity; how-  ever, it is less appropriate for those with an increased  risk of pelvic inflammatory disease (see below). The  most effective intra-uterine devices have at least  380 mm 2 of copper and have banded copper on the  arms.    Smaller devices have been introduced to minimise side-  effects; these consist of a plastic carrier wound with  copper wire or fitted with copper bands; some also have  a central core of silver to prevent fragmentation of the  copper. Fertility declines with age and therefore a cop-  per intra-uterine device which is fitted in a woman over  the age of 40, may remain in the uterus until meno-  pause.    A frameless, copper-bearing intra-uterine device  ( GyneFix ®) is also available. It consists of a knotted,  polypropylene thread with 6 copper sleeves; the device  is anchored in the uterus by inserting the knot into the  uterine fundus. The intra-uterine devices Multiload®  Cu250 and Multiload® Cu250 Short (Organon) have  been discontinued, but some women may have the  devices in place until 2011.   The timing and technique of fitting an intra-uterine  device are critical for its subsequent performance. The  healthcare professional inserting (or removing) the  device should be fully trained in the technique and  should provide full counselling backed, where avail-  able, by the patient information leaflet. Devices should  not be fitted during the heavy days of the period; they  are best fitted after the end of menstruation and before  the calculated time of implantation. The main excess  risk of infection occurs in the first 20 days after insertion  and is believed to be related to existing carriage of a  sexually transmitted infection. Women are considered  to be at a higher risk of sexually transmitted infections if:   • have had more than one partner in the past year or   In these women, pre-insertion screening (for chlamydia  and, depending on sexual history and local prevalence  of disease, Neisseria gonorrhoeae) should be per-  formed. If results are unavailable at the time of fitting  an intra-uterine device for emergency contraception,  appropriate prophylactic antibacterial cover should be  given. The woman should be advised to attend as an  emergency if she experiences sustained pain during the  next 20 days.    An intra-uterine device should not be removed in mid-  cycle unless an additional contraceptive was used for    the previous 7 days. If removal is essential post-coital  contraception should be considered.   If an intra-uterine device fails and the woman wishes to  continue to full-term the device should be removed in  the first trimester if possible.   Cautions see notes above; also anaemia, menorrhagia  (progestogen intra-uterine system might be prefer-  able, section 7.3. 2. 3), endometriosis, severe primary  dysmenorrhoea, history of pelvic inflammatory dis-  ease, diabetes, fertility problems, nulliparity and  young age, severely scarred uterus (including after  endometrial resection) or severe cervical stenosis;  drug- or disease-induced immunosuppression (risk of  infection — avoid if marked immunosuppression); epi-  lepsy (risk of seizure at time of insertion); increased  risk of expulsion if inserted before uterine involution;  gynaecological examination before insertion, 6-8  weeks after then annually but counsel women to see  doctor promptly in case of significant symptoms,  especially pain; anticoagulant therapy (avoid if possi-  ble)   Contra-indications severe anaemia, recent sexually  transmitted infection (if not fully investigated and  treated), unexplained uterine bleeding, distorted or  small uterine cavity, genital malignancy, active tro-  phoblastic disease (until return to normal of urine-  and plasma-gonadotrophin concentration), pelvic  inflammatory disease, established or marked immu-  nosuppression; copper devices: copper allergy,   Pregnancy remove device; if pregnancy occurs,  increased likelihood that it may be ectopic  Breast-feeding not known to be harmful  Side-effects uterine or cervical perforation, displace-  ment, expulsion; pelvic infection may be exacerbated,  menorrhagia, dysmenorrhoea, allergy; on insertion :  pain (alleviated by NSAID such as ibuprofen 30 min-  utes before insertion) and bleeding, occasionally epi-  leptic seizure and vasovagal attack   Cu-Safe® T300 (Williams) M  Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier, surface area approx. 300 mm 2 ,  impregnated with barium sulphate for radio-opacity, mono-  filament thread attached to base of vertical stem; preloaded  in inserter, net price = £9.11   For uterine length over 5 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier, surface area approx. 300 mm 2 ,  impregnated with barium sulphate for radio-opacity, mono-  filament thread attached to base of vertical stem; preloaded  in inserter, net price = £9.47   For uterine length over 5 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier with copper sleeve on each arm,  total surface area approx. 380 mm 2 , impregnated with bar-  ium sulphate for radio-opacity, monofilament thread  attached to base of vertical stem; preloaded in inserter, net  price = £10.06   For uterine length over 6 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, 6 copper sleeves with surface area of  330 mm 2 on polypropylene thread, net price = £26.64  Suitable for all uterine sizes; replacement every 5 years   Intra-uterine device, copper wire, wound on vertical stem of  U-shaped plastic carrier, surface area approx. 375 mm 2 ,  impregnated with barium sulphate for radio-opacity, mono-  filament thread attached to base of vertical stem; preloaded  in inserter, net price = £8.52   For uterine length over 7 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier with copper sleeves fitted flush on to  distal portion of each horizontal arm, total surface area  approx. 380 mm 2 , impregnated with barium sulphate for  radio-opacity, thread attached to base of vertical stem; easy-  loading system, no capsule, net price = £12.46  For minimum uterine length 5 cm; replacement every 5 years (see  also notes above)   Intra-uterine device, as Load ® 375, with copper surface  area approx. 375 mm 2 and vertical stem length 3.5 cm, net  price = £9.24   For uterine length 6-9 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  U-shaped plastic carrier, surface area approx. 375 mm 2 ,  impregnated with barium sulphate for radio-opacity, mono-  filament thread attached to base of vertical stem; preloaded  in inserter, net price = £8.80   For uterine length over 6-9 cm; replacement every 5 years (see  also notes above)   Multi-Safe® 375 Short Stem (Williams) Ml  Intra-uterine device, copper wire, wound on vertical stem of  U-shaped plastic carrier, surface area approx. 375 mm 2 ,  impregnated with barium sulphate for radio-opacity, mono-  filament thread attached to base of vertical stem; preloaded  in inserter, net price = £8.80   For uterine length 5-7 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier, surface area approx. 380 mm 2 ,  impregnated with barium sulphate for radio-opacity, threads  attached to base of vertical stem, net price = £13.80  For uterine length 6.5-9 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, copper wire with silver core, wound on  vertical stem of T-shaped plastic carrier, surface area approx.  380 mm 2 , impregnated with barium sulphate for radio-opa-  city, threads attached to base of vertical stem, net price =  £12.97   For uterine length 6.5-9 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier with copper collar on the distal  portion of each arm, total surface area approx. 380 mm 2 ,  impregnated with barium sulphate for radio-opacity, threads  attached to base of vertical stem, quick-loading system, net  price = £10.29; also available with a capsule loading device  ( T-Safe ® 380A Capped M), net price = £10.29  For uterine length 6.5-9 cm; replacement every 10 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier, with copper sleeves fitted flush on  to distal portion of each horizontal arm, total surface area  approx. 380 mm 2 , impregnated with barium sulphate for    radio-opacity, thread attached to base of vertical stem; easy-  loading system, no capsule, net price = £12.46  For uterine length 6.5-9 cm; replacement every 10 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier, surface area approx. 380 mm 2 ,  impregnated with barium sulphate for radio-opacity, thread  attached to base of vertical stem; net price = £11.22  For uterine length 5-7 cm; replacement every 5 years (see also  notes above)   Intra-uterine device, copper wire, wound on vertical stem of  T-shaped plastic carrier, surface area approx. 380 mm 2 ,  impregnated with barium sulphate for radio-opacity, thread  attached to base of vertical stem; net price = £11.22  For uterine length 6.5-9 cm; replacement every 5 years (see also  notes above)   Opaque rubber, sizes 1 (50 mm), 2 (55 mm), 3 (60 mm), 4  (65 mm), 5 (75 mm), net price = £6.85   Opaque rubber, sizes 22 to 3 1 mm (rising in steps of 3 mm),  net price = £8.46   Opaque rubber, sizes 1 to 3 (42, 48, and 54 mm), net price =  £7.26   Silicone, sizes 22, 26, and 30 mm, net price = £15.00  Brands include FemCap ®   Transparent rubber with flat metal spring, sizes 55-95 mm  (rising in steps of 5 mm), net price = £5.78  Brands include Reflexions ®   Opaque rubber with coiled metal spring, sizes 60-100 mm  (rising in steps of 5 mm), net price = £6.79   Opaque rubber with arcing spring, sizes 60-95 mm (rising in  steps of 5 mm), net price = £7.72   Silicone with coiled metal spring, sizes 60-90 mm (rising in  steps of 5 mm), net price = £8.35  Brands include Milex Omniflex ®   Silicone with arcing spring, sizes 60-90 mm (rising in steps of   Hormonal emergency contraceptives include levonor-  gestrel and ulipristal; either drug should be taken as  soon as possible after unprotected intercourse to  increase efficacy.   Levonorgestrel is effective if taken within 72 hours (3  days) of unprotected intercourse and may also be used    between 72 and 120 hours after unprotected intercourse  [unlicensed use], but efficacy decreases with time. Uli-  pristal, a progesterone receptor modulator, is effective if  taken within 120 hours (5 days) of unprotected inter-  course.   Levonorgestrel is less effective than insertion of an  intra-uterine device (see below). Ulipristal is as effective  as levonorgestrel, but its efficacy compared to an intra-  uterine device is not yet known.   If vomiting occurs within 2 hours of taking levonor-  gestrel or within 3 hours of taking ulipristal, a replace-  ment dose should be given. If an antiemetic is required  domperidone is preferred.   • that a barrier method of contraception needs to be  used until the next period;   • the need to return promptly if any lower abdominal  pain occurs because this could signify an ectopic  pregnancy (and also in 3 to 4 weeks if the subse-  quent menstrual bleed is abnormally light, heavy or  brief, or is absent, or if she is otherwise concerned).   Interactions The effectiveness of levonorgestrel, and  possibly ulipristal, is reduced in women taking enzyme-  inducing drugs (and possibly for 4 weeks after stopping);  a copper intra-uterine device can be offered instead or  the dose of levonorgestrel should be increased to a total  of 3 mg taken as a single dose [unlicensed dose — advise  women accordingly]. There is no need to increase the  dose for emergency contraception if the patient is taking  antibacterials that are not enzyme inducers.   Cautions see notes above; past ectopic pregnancy;  severe malabsorption syndromes; active trophoblastic  disease (until return to normal of urine- and plasma-  gonadotrophin concentration) — seek specialist  advice; interactions: see notes above and Appendix  1 (progestogens)   Side-effects menstrual irregularities (see also notes  above), nausea, low abdominal pain, fatigue, head-  ache, dizziness, breast tenderness, vomiting   • 1.5 mg as a single dose as soon as possible after coitus  (preferably within 12 hours but no later than after 72  hours)   1. Can be sold to women over 16 years; when supplying  emergency contraception to the public, pharmacists should  refer to guidance issued by the Royal Pharmaceutical  Society of Great Britain   Levonelle® 1500 (Bayer Schering) (Ml  Tablets, levonorgestrel 1.5 mg, net price 1-tab pack =  £5.20   Indications emergency contraception  Cautions see notes above; uncontrolled severe  asthma; effectiveness of combined hormonal and  progestogen-only contraceptives may be reduced —  additional precautions (barrier methods) required;  repeated use within a menstrual cycle; interactions:  see notes above and Appendix 1 (ulipristal)   Hepatic impairment manufacturer advises avoid in  severe impairment — no information available  Pregnancy limited information available  Breast-feeding manufacturer advises avoid for at  least 36 hours — no information available  Side-effects gastro-intestinal disturbances (including  nausea, vomiting, diarrhoea, and abdominal pain);  dizziness, fatigue, headache; menstrual irregularities  (see notes above); back pain, muscle spasms; less  commonly tremor, hot flushes, uterine spasm, breast  tenderness, dry mouth, blurred vision, pruritus, and  rash  Dose   • 30 mg as a single dose as soon as possible after coitus,  but no later than after 120 hours   ellaOne® (HRA Pharma) T iMl  Tablets, ulipristal acetate 30 mg, net price 1-tab pack  = £16.95   B Insertion of an intra-uterine device is more effective  than oral levonorgestrel for emergency contraception. A  copper intra-uterine contraceptive device (section 7.3.4)  can be inserted up to 120 hours (5 days) after unpro-  tected intercourse; sexually transmitted infections  should be tested for and insertion of the device should  usually be covered by antibacterial prophylaxis (e.g.  azithromycin 1 g as a single dose). If intercourse has  occurred more than 5 days previously, the device can  still be inserted up to 5 days after the earliest likely  calculated ovulation (i.e. within the minimum period  before implantation), regardless of the number of epi-  sodes of unprotected intercourse earlier in the cycle.   Chronic retention is painless and often long-standing.  Catheterisation is unnecessary unless there is deteriora-  tion of renal function. After the cause has initially been  established and treated, drugs may be required to  increase detrusor muscle tone.   Benign prostatic hyperplasia is treated either surgically  or medically with alpha-blockers (see below). Dutaste-  ride and finasteride (section 6.4.2) are alternatives to  alpha-blockers, particularly in men with a significantly  enlarged prostate.   The alpha! -selective alpha blockers, alfuzosin, doxazo-  sin, indoramin, prazosin, tamsulosin and terazosin  relax smooth muscle in benign prostatic hyperplasia  producing an increase in urinary flow-rate and an  improvement in obstructive symptoms.   Cautions Since alpha! -selective alpha blockers reduce  blood pressure, patients receiving antihypertensive  treatment may require reduced dosage and specialist  supervision. Caution is required in the elderly and in  patients undergoing cataract surgery (risk of intra-  operative floppy iris syndrome). For interactions, see  Appendix 1 (alpha-blockers).   Contra-indications Alpha-blockers should be avoided  in patients with a history of postural hypotension and  micturition syncope.   Side-effects Side-effects of alphaj -selective alpha  blockers include drowsiness, hypotension (notably pos-  tural hypotension), syncope, asthenia, dizziness, depres-  sion, headache, dry mouth, gastro-intestinal distur-  bances, oedema, blurred vision, intra-operative floppy  iris syndrome (most strongly associated with tamsulo-  sin), rhinitis, erectile disorders (including priapism),  tachycardia, and palpitations. Hypersensitivity reactions  including rash, pruritus and angioedema have also been  reported.   For drugs used in the treatment of urinary-tract infec-  tions see section 5.1.13.   Driving May affect performance of skilled tasks e.g. driving  Contra-indications see notes above  Hepatic impairment initial dose 2.5 mg once daily,  adjusted according to response to 2.5 mg twice daily  in mild to moderate impairment — avoid if severe;  avoid modified-release preparations  Renal impairment initial dose 2.5 mg twice daily and  adjust according to response; manufacturers advise  use modified-release preparations with caution in  severe impairment as limited experience  Side-effects see notes above; also less commonly  flushes and chest pain; also reported liver damage  and cholestasis   • 2.5 mg 3 times daily, max. 10 mg daily; ELDERLY initially  2.5 mg twice daily   First dose effect First dose may cause collapse due to  hypotensive effect (therefore should be taken on retiring to  bed). Patient should be warned to lie down if symptoms such  as dizziness, fatigue or sweating develop, and to remain lying  down until they abate completely   Alfuzosin hydrochloride (Non-proprietary) [Ml  Tablets, f/c, alfuzosin hydrochloride 2.5 mg, net price  60-tab pack = £20.37. Counselling, initial dose, driv-  ing, see above   Xatral® (Sanofi-Aventis) (Ml  Tablets, f/c, alfuzosin hydrochloride 2.5 mg, net price  60-tab pack = £20.37. Counselling, initial dose, driv-  ing, see above   Tablets, m/r, yellow/white, alfuzosin hydrochloride  10 mg, net price 30-tab pack = £12.51. Label: 21, 25,  counselling, initial dose, driving, see above  Dose benign prostatic hyperplasia 10 mg once daily  Acute urinary retention associated with benign prostatic hyper-  plasia in men over 65 years, 10 mg once daily for 2-3 days during  catheterisation and for one day after removal; max. 4 days   Vasran® XL (Ranbaxy) (M  Tablets, m/r, alfuzosin hydrochloride 10 mg, net price  30-tab pack = £11.48. Label: 21, 25, counselling,  initial dose, driving, see above  Dose benign prostatic hyperplasia 10 mg once daily   Xatral® XL (Sanofi-Aventis) (5°M1  Tablets, m/r, yellow/white, alfuzosin hydrochloride  10 mg, net price 10-tab pack = £4.17, 30-tab pack =  £12.51. Label: 21, 25, counselling, initial dose, driving,  see above   Dose benign prostatic hyperplasia 10 mg once daily  Acute urinary retention associated with benign prostatic hyper-  plasia in men over 65 years, 10 mg once daily for 2-3 days during  catheterisation and for one day after removal; max. 4 days   • Initially 1 mg daily; dose may be doubled at intervals  of 1-2 weeks according to response, up to max. 8 mg  daily; usual maintenance 2-4 mg daily   Cautions see notes above and section 2.5.4  Contra-indications see notes above and section 2.5.4   Hepatic impairment section 2.5.4  Renal impairment section 2.5.4  Side-effects see notes above and section 2.5.4   • 20 mg twice daily; increased if necessary by 20 mg  every 2 weeks to max. 100 mg daily in divided doses;  ELDERLY, 20 mg at night may be adequate   Cautions see notes above and section 2.5.4  Contra-indications see notes above and section 2.5.4  Hepatic impairment section 2.5.4  Renal impairment section 2.5.4  Side-effects see notes above and section 2.5.4  Dose   • Initially 500 micrograms twice daily for 3-7 days,  subsequently adjusted according to response; usual  maintenance (and max.) 2 mg twice daily; ELDERLY  initiate with lowest possible dose   First dose effect First dose may cause collapse due to  hypotensive effect (therefore should be taken on retiring to  bed). Patient should be warned to lie down if symptoms such  as dizziness, fatigue or sweating develop, and to remain lying  down until they abate completely    Indications benign prostatic hyperplasia  Cautions see notes above  Driving May affect performance of skilled tasks e.g. driving  Contra-indications see notes above  Hepatic impairment avoid in severe impairment  Renal impairment use with caution if eGFR less than  10 mL/minute/ 1.73 m 2  Side-effects see notes above  Dose   tamsulosin hydrochloride (Non-proprietary) 1M1  Capsules, m/r, tamsulosin hydrochloride 400 micr-  ograms, net price 30-cap pack = £4.62. Label: 25,  counselling, driving   Brands include Bazetham ® MR, Contiflo ® XL, Diffundox ® XL,  Pinexel ® PR, Stronazon ® MR, Tabphyn ® MR  1. Tamsulosin hydrochloride 400 microgram capsules can be  sold to the public for the treatment of functional symptoms  of benign prostatic hyperplasia in men aged 45-75 years to  be taken for up to 6 weeks before clinical assessment by a  doctor; a proprietary brand Flomax Relief ® MR is on sale to  the public    Flomaxtra® XL (Astellas) [Ml  Tablets, m/r, tamsulosin hydrochloride 400 micr-  ograms, net price 30-tab pack = £10.47. Label: 25,  counselling, driving   Capsules, m/r, brown/orange, tamsulosin hydro-  chloride 400 micrograms, dutasteride 500 micr-  ograms, net price 30-cap pack = £19.80. Label: 25,  counselling, driving   • Initially 1 mg at bedtime; if necessary dose may be  doubled at intervals of 1-2 weeks according to  response, up to max. 10 mg once daily; usual main-  tenance 5-10 mg daily   First dose effect First dose may cause collapse due to  hypotensive effect (therefore should be taken on retiring to  bed). Patient should be warned to lie down if symptoms such  as dizziness, fatigue or sweating develop, and to remain lying  down until they abate completely   Terazosin (Non-proprietary) (Ml  Tablets, terazosin (as hydrochloride) 2 mg, net price  28-tab pack = £2.16; 5 mg, 28-tab pack = £2.58; 10 mg,  28-tab pack = £7.88. Counselling, initial dose, driving   Tablets, terazosin (as hydrochloride) 2 mg (yellow)  net price, 28-tab pack = £2.29; 5 mg (tan), 28-tab pack  = £4.29; 10 mg (blue), 28-tab pack = £8.57; starter  pack (for benign prostatic hyperplasia) of 7 x 1-mg  tab with 14 x 2-mg tab and 7 x 5-mg tab = £10.97.  Label: 3, counselling, see dose above   B The parasympathomimetic bethanechol increases  detrusor muscle contraction. However, it has only a  limited role in the relief of urinary retention; its use  has been superseded by catheterisation.   Distigmine inhibits the breakdown of acetylcholine. It  may help patients with an upper motor neurone neuro-  genic bladder.   Cautions autonomic neuropathy (use lower initial  dose); interactions: Appendix 1 (parasympatho-  mimetics)   Contra-indications peptic ulcer; intestinal or urinary  obstruction; conditions where increased motility of  the urinary or gastro-intestinal tract could be harmful;  cardiovascular disorders (including recent myocardial  infarction, bradycardia, and heart block); hypotension;  obstructive airways disease; epilepsy; parkinsonism;  hyperthyroidism   Side-effects nausea, vomiting, diarrhoea, abdominal  pain, increased salivation, eructation; flushing, hypo-  tension, bradycardia; bronchoconstriction, rhinorr-  hoea; headache; increased lacrimation; increased  sweating   • 10-25 mg 3-4 times daily half an hour before food   Tablets, scored, bethanechol chloride 10 mg, net price  100-tab pack = £5.07; 25 mg, 100-tab pack = £6.48.  Label: 22   Cautions peptic ulcer; conditions where increased  motility of the urinary or gastro-intestinal tract could  be harmful; oesophagitis; cardiovascular disease;  bronchospasm; epilepsy; parkinsonism; interactions:  Appendix 1 (parasympathomimetics)   Side-effects abdominal pain, diarrhoea, increased  salivation; bradycardia, A V block, hypotension; dys-  pnoea; muscle twitching; increased lacrimation, mio-  sis; increased sweating   • Urinary retention, 5 mg daily, half an hour before  breakfast   • Neurogenic bladder, 5 mg daily or on alternate days,  half an hour before breakfast   Ubretid® (Sanofi-Aventis) (Ml  Tablets, scored, distigmine bromide 5 mg, net price  30-tab pack = £41.22. Label: 22   Incontinence in adults which arises from detrusor  instability is managed by combining drug therapy with  conservative methods for managing urge incontinence  such as pelvic floor exercises and bladder training;  stress incontinence is generally managed by non-drug  methods. Duloxetine, an inhibitor of serotonin and  noradrenaline re-uptake can be added and is licensed  for the treatment of moderate to severe stress incont-  inence in women; it may be more effective when used as  an adjunct to pelvic floor exercises.   Antimuscarinic drugs reduce symptoms of urgency and  urge incontinence and increase bladder capacity. Oxy-  butynin also has a direct relaxant effect on urinary  smooth muscle. Side-effects limit the use of oxybutynin,  but they may be reduced by starting at a lower dose. A  modified-release preparation of oxybutynin is effective  and has fewer side-effects; a transdermal patch is also  available. The efficacy and side-effects of tolterodine  are comparable to those of modified-release oxybuty-  nin. Flavoxate has less marked side-effects but it is also  less effective. Darifenacin, fesoterodine, propiverine,    solifenacin, and trospium are newer antimuscarinic  drugs licensed for urinary frequency, urgency, and  incontinence. The need for continuing antimuscarinic  drug therapy should be reviewed every 4-6 weeks until  symptoms stabilise, and then every 6-12 months.   The Scottish Medicines Consortium (p. 4) has advised  (June 2008) that fesoterodine ( Toviaz ®) is accepted for  restricted use within NHS Scotland as a second-line  treatment for overactive bladder syndrome.   Propantheline and tricyclic antidepressants were used  for urge incontinence but they are little used now  because of their side-effects. The use of imipramine is  limited by its potential to cause cardiac side-effects.  Purified bovine collagen implant ( Contigen ®, Bard) is  indicated for urinary incontinence caused by intrinsic  sphincter deficiency (poor or non-functioning bladder  outlet mechanism). The implant should be inserted only  by surgeons or physicians trained in the technique for  injection of the implant.   Cautions Antimuscarinic drugs should be used with  caution in the elderly (especially if frail), in those with  autonomic neuropathy, and in those susceptible to  angle-closure glaucoma. They should also be used  with caution in hiatus hernia with reflux oesophagitis.  Antimuscarinics can worsen hyperthyroidism, coronary  artery disease, congestive heart failure, hypertension,  prostatic hyperplasia, arrhythmias, and tachycardia. For  interactions, see Appendix 1 (antimuscarinics).   Contra-indications Antimuscarinic drugs should be  avoided in patients with myasthenia gravis, significant  bladder outflow obstruction or urinary retention, severe  ulcerative colitis, toxic megacolon, and in gastrointes-  tinal obstruction or intestinal atony.   Side-effects Side-effects of antimuscarinic drugs  include dry mouth, gastrointestinal disturbances  including constipation, flatulence, taste disturbances,  blurred vision, dry eyes, drowsiness, dizziness, fatigue,  difficulty in micturition (less commonly urinary reten-  tion), palpitation, and skin reactions (including dry skin,  rash, and photosensitivity); also headache, diarrhoea,  angioedema, arrhythmias, and tachycardia. Central ner-  vous system stimulation, such as restlessness, disorien-  tation, hallucination, and convulsion may occur; chil-  dren are at higher risk of these effects. Antimuscarinic  drugs can reduce sweating, leading to heat sensations  and fainting in hot environments or in patients with  fever, and very rarely may precipitate angle-closure  glaucoma.   • ADULT over 18 years, 7.5 mg once daily, increased if  necessary after 2 weeks to 15 mg once daily   Tablets, m/r, darifenacin (as hydrobromide) 7.5 mg  (white), net price 28-tab pack = £20.90; 15 mg (peach),  28-tab pack = £20.90. Label: 3, 25    Indications moderate to severe stress urinary incont-  inence in women; major depressive disorder (section  4.3.4); diabetic neuropathy (section 4.3.4); generalised  anxiety disorder (section 4.3.4)   Cautions elderly; cardiac disease; hypertension (avoid  if uncontrolled); history of mania; history of seizures;  raised intra-ocular pressure, susceptibility to angle-  closure glaucoma; bleeding disorders or concomitant  use of drugs that increase risk of bleeding; interac-  tions: Appendix 1 (duloxetine)   Withdrawal Nausea, vomiting, headache, anxiety, dizziness,  paraesthesia, sleep disturbances, and tremor are the most  common features of abrupt withdrawal or marked reduction  of the dose; dose should be reduced over at least 1-2 weeks  Hepatic impairment manufacturer advises avoid  Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2    Pregnancy toxicity in animal studies — avoid in  patients with stress urinary incontinence; risk of  neonatal withdrawal symptoms if used near term   Side-effects nausea, vomiting, dyspepsia, constipa-  tion, diarrhoea, abdominal pain, weight changes,  decreased appetite, flatulence, dry mouth; palpitation,  hot flush; insomnia, abnormal dreams, paraesthesia,  drowsiness, anxiety, headache, dizziness, fatigue,  weakness, tremor, nervousness, anorexia; sexual  dysfunction; visual disturbances; sweating, pruritus;  less commonly gastritis, halitosis, hepatitis, bruxism,  tachycardia, hypertension, postural hypotension,  syncope, raised cholesterol, vertigo, taste disturbance,  cold extremities, impaired temperature regulation,  impaired attention, movement disorders, muscle  twitching, musculoskeletal pain, thirst, stomatitis,  hypothyroidism, urinary disorders, and photosensit-  ivity; rarely mania; very rarely angle-closure glauc-  oma; also reported supraventricular arrhythmia, chest  pain, hallucinations, suicidal behaviour (see Suicidal  Behaviour and Antidepressant Therapy, p. 233), sei-  zures, hypersensitivity reactions including urticaria,  angioedema, rash (including Stevens-Johnson  syndrome) and anaphylaxis, hyponatraemia (see  Hyponatraemia and Antidepressant Therapy, p. 233)    • ADULT over 18 years, 40 mg twice daily, assess for  benefit and tolerability after 2-4 weeks  Note Initial dose of 20 mg twice daily for 2 weeks can  minimise side-effects   Capsules, duloxetine (as hydrochloride) 20 mg (blue),  net price 28-cap pack = £18.48, 56-cap pack = £30.80;  40 mg (orange /blue), 56-cap pack = £36.96. Label: 2   Section 4.3.4 (major depressive episode, generalised  anxiety disorder, and diabetic neuropathy)   Cautions see notes above; gastro-oesophageal reflux  Contra-indications see notes above  Hepatic impairment manufacturer advises increase  dose cautiously; max. 4 mg daily in moderate  impairment; avoid in severe impairment; consult  product literature before concomitant use of cyto-  chrome P450 enzyme inhibitors  Renal impairment increase dose cautiously if eGFR  30-80 mL/minute/ 1.73m 2 ; max. 4 mg daily if eGFR  less than 30 mL/minute/ 1.73 m 2 ; consult product lit-  erature before concomitant use of cytochrome P450  enzyme inhibitors   Side-effects see notes above; also insomnia; less  commonly nasal dryness, pharyngolaryngeal pain,  cough, and vertigo   • ADULT over 18 years, 4 mg once daily, increased if  necessary to max. 8 mg once daily  Note Max. 4 mg daily with concomitant atazanavir, clarithro-   B mycin, indinavir, itraconazole, ketoconazole, nelfinavir, ritona-  vir, saquinavir, or telithromycin; in patients with hepatic or  renal impairment, consult product literature before concomi-  tant use with amprenavir, aprepitant, atazanavir, clarithro-  mycin, diltiazem, erythromycin, fluconazole, fosamprenavir,  indinavir, itraconazole, ketoconazole, nelfinavir, ritonavir,  saquinavir, telithromycin, verapamil, or grapefruit juice   Tablets, m/r, f/c, fesoterodine fumarate 4 mg (light  blue), net price 28-tab pack = £25.78; 8 mg (blue), 28-  tab pack = £25.78. Label: 3, 25   Indications urinary frequency and incontinence, dys-  uria, urgency; bladder spasms due to catheterisation,  cytoscopy, or surgery   Side-effects see notes above; also vertigo, eosino-  philia, leucopenia, urticaria, erythema, and pruritus   • ADULT and CHILD over 12 years, 200 mg 3 times daily   Urispas 200® (Recordati) M  Tablets, f/c, flavoxate hydrochloride 200 mg, net  price 90-tab pack = £11.67   Indications urinary frequency, urgency and incont-  inence, neurogenic bladder instability, and nocturnal  enuresis associated with overactive bladder   Side-effects see notes above; also less commonly  anorexia, facial flushing; rarely night terrors; appli-  cation site reactions with patches ; also reported cog-  nitive impairment   • ADULT and CHILD over 12 years, initially 5 mg 2-3 times  daily, increased if necessary to max. 5 mg 4 times  daily; ELDERLY initially 2.5-3 mg twice daily, increased  to 5 mg twice daily according to response and toler-  ance; CHILD 5-12 years, neurogenic bladder instability,  2.5-3 mg twice daily, increased to 5 mg 2-3 times  daily; CHILD under 5 years, see BNF for Children ;  CHILD 7-18 years, nocturnal enuresis associated with  overactive bladder, 2.5-3 mg twice daily increased to  5 mg 2-3 times daily (last dose before bedtime)   Oxybutynin Hydrochloride (Non-proprietary) (Ml  Tablets, oxybutynin hydrochloride 2.5 mg, net price  56-tab pack = £6.58; 3 mg, 56-tab pack = £9.15; 5 mg,  56-tab pack = £5.53, 84-tab pack = £12.50. Label: 3   Cystrin® (Sanofi-Aventis) (Ml  Tablets, oxybutynin hydrochloride 3 mg, net price 56-  tab pack = £9.15; 5 mg (scored), 84-tab pack = £21.99.  Label: 3   Ditropan® (Sanofi-Aventis) (Ml  Tablets, both blue, scored, oxybutynin hydrochloride  2.5 mg, net price 84-tab pack = £6.59; 5 mg, 84-tab  pack = £12.82. Label: 3   Elixir, oxybutynin hydrochloride 2.5 mg/5 mL, net  price 150-mL pack = £6.88. Label: 3   Lyrinel® XL Oanssen-Cilag) (M  Tablets, m/r, oxybutynin hydrochloride 5 mg (yel-  low), net price 30-tab pack = £10.81; 10 mg (pink), 30-  tab pack = £21.62. Label: 3, 25   Dose initially 5 mg once daily, adjusted according to response in  steps of 5 mg at weekly intervals; max. 20 mg once daily; CHILD  over 6 years, neurogenic bladder instability, initially 5 mg once  daily, adjusted according to response in steps of 5 mg at weekly  intervals; max. 15 mg once daily   Note Patients taking immediate-release oxybutynin may be trans-  ferred to the nearest equivalent daily dose of Lyrinel ® XL   Patches, self-adhesive, oxybutynin 36 mg (releasing  oxybutynin approx. 3.9 mg/24 hours), net price 8-  patch pack = £27.20. Label: 3, counselling, adminis-  tration   Dose ADULT over 18 years, urinary frequency, urgency and  incontinence, apply 1 patch twice weekly to clean, dry, unbroken  skin on abdomen, hip or buttock, remove after every 3-4 days and   Note The Scottish Medicines Consortium has advised (July  2005) that Kent era® should be restricted for use in patients  who benefit from oral oxybutynin but cannot tolerate its  side-effects   • Initially 1 5 mg 3 times daily at least one hour before  food and 30 mg at bedtime, subsequently adjusted  according to response (max. 120 mg daily)    already taking itraconazole, ketoconazole, nelfinavir,  or ritonavir; avoid in severe impairment  Renal impairment max. 5 mg daily if eGFR less than  30 mL/minute/ 1.73 m 2 ; avoid if eGFR less than  30 mL/minute/ 1.73 m 2 in those already taking itra-  conazole, ketoconazole, nelfinavir, or ritonavir  Pregnancy manufacturer advises caution — no infor-  mation available   • ADULT over 18 years, 5 mg daily, increased if necessary  to 10 mg once daily   Note Max. 5 mg daily with concomitant itraconazole, keto-  conazole, nelfinavir, or ritonavir   Tablets, f/c, solifenacin succinate 5 mg (yellow), net  price 30-tab pack = £27.62; 10 mg (pink), 30-tab pack  = £35.91. Label: 3   Renal impairment doses above 30 mg daily should be  used with caution if eGFR less than 30 mL/minute/  1.73 m 2   • ADULT over 18 years, 15 mg 1-3 times daily, increased  if necessary to max. 15 mg 4 times daily   Detrunorm® (Amdipharm) (Ml  Tablets, pink, s/c, propiverine hydrochloride 15 mg,  net price 56-tab pack = £18.00. Label: 3   Detrunorm® XL (Amdipharm) (Ml  Capsules, orange/white, m/r, propiverine hydro-  chloride 30 mg, net price 28-cap pack = £24.45.  Label: 3, 25   Dose ADULT over 18 years, urinary frequency, urgency, and  incontinence, 30 mg once daily   Hepatic impairment max. 5 mg daily in moderate  impairment; avoid in moderate impairment in those   Cautions see notes above; history of QT-interval pro-  longation; concomitant use with other drugs known to  prolong QT interval    Renal impairment reduce dose to 1 mg twice daily if  eGFR less than 30mL/minute/1.73m 2 ; avoid  Detrusitol® XL if eGFR less than 30 mL/minute/  1.73 m 2    Side-effects see notes above; also chest pain, per-  ipheral oedema; sinusitis, bronchitis; paraesthesia,  fatigue, vertigo, weight gain; flushing also reported    • Urinary frequency, urgency, and incontinence, ADULT  over 18 years, 2 mg twice daily; reduce to 1 mg twice  daily if necessary to minimise side-effects; CHILD 2-18  years, see BNF for Children   • Nocturnal enuresis associated with overactive  bladder, CHILD 7-18 years, see BNF for Children   Tablets, f/c, tolterodine tartrate 1 mg, net price 56-tab  pack = £29.03; 2 mg, 56-tab pack = £30.56. Label: 3    4 Modified release  Detrusitol® XL (Pharmacia) (Ml  Capsules, blue, m/r, tolterodine tartrate 4 mg, net  price 28-cap pack = £25.78. Label: 3, 25  Dose urinary frequency, urgency and incontinence, ADULT over  18 years, 4 mg once daily   Hepatic impairment manufacturer advises caution in  mild to moderate impairment; avoid in severe  impairment   Renal impairment use with caution; reduce dose to  20 mg once daily or 20 mg on alternate days if eGFR  10-30 mL/minute/ 1.73m 2 ; avoid Regurin® XL   Side-effects see notes above; rarely chest pain, dys-  pnoea, and asthenia; very rarely myalgia and arthr-  algia   • ADULT and CHILD over 12 years, 20 mg twice daily  before food   Trospium chloride (Non-proprietary) (Ml  Tablets, f/c, trospium chloride 20 mg, net price 60-tab  pack = £18.20. Label: 23  Brands include Flotros ®   Regurin® (Speciality European) (Ml  Tablets, brown-yellow, f/c, trospium chloride 20 mg,  net price 60-tab pack = £26.00. Label: 23   Regurin® XL (Speciality European) Ml  Capsules, orange/white, m/r, trospium chloride  60 mg, net price 28-cap pack = £23.05. Label: 23, 25  Dose ADULT over 18 years, 60 mg once daily   B Nocturnal enuresis is common in young children, but  persists in as many as 5% by 10 years of age. Treatment  is not appropriate in children under 5 years and it is  usually not needed in those aged under 7 years and in  cases where the child and parents are not anxious about  the bedwetting; however, children over 10 years usually  require prompt treatment. An enuresis alarm should be  first-line treatment for well-motivated, well-supported  children aged over 7 years because alarms have a lower  relapse rate than drug treatment when discontinued.  Use of an alarm can be combined with drug therapy if  either method alone is unsuccessful.   Drug therapy is not usually appropriate for children  under 7 years of age; it can be used when alternative  measures have failed, preferably on a short-term basis,  for example to cover periods away from home, or if the  child and family are anxious about the condition.  Desmopressin (section 6.5.2), an analogue of vaso-  pressin, is used for nocturnal enuresis; it is given by oral  or by sublingual administration. Particular care is  needed to avoid fluid overload. Treatment should not  be continued for longer than 3 months without inter-  rupting treatment for 1 week for full re-assessment.  Desmopressin should not be given intranasally for  nocturnal enuresis due to an increased incidence of  side-effects.   Tricyclic antidepressants (section 4.3.1) such as imipra-  mine, and rarely amitriptyline and nortriptyline, are  used but behavioural disturbances can occur and  relapse is common after withdrawal. Treatment should  not normally exceed 3 months unless a full physical  examination is made and the child is fully re-assessed;  toxicity following overdosage with tricyclics is of parti-  cular concern.    Nocturnal enuresis associated with daytime symptoms  (overactive bladder) can be managed by antimuscarinic  drugs (see Urinary incontinence, p. 508), with the addi-  tion of desmopressin if necessary.    The acute pain of ureteric colic may be relieved with  pethidine (section 4.7.2). Diclofenac by injection or as  suppositories (section 10.1.1) is also effective and com-  pares favourably with pethidine; other non-steroidal  anti-inflammatory drugs are occasionally given by injec-  tion.    Lidocaine gel is a useful topical application in urethral  pain or to relieve the discomfort of catheterisation  (section 15.2).   Alkalinisation of urine can be undertaken with potas-  sium citrate. The alkalinising action may relieve the  discomfort of cystitis caused by lower urinary tract  infections. Sodium bicarbonate is used as a urinary  alkalinising agent in some metabolic and renal disorders  (section 9.2.1. 3).   Indications relief of discomfort in mild urinary-tract  infections; alkalinisation of urine  Cautions cardiac disease; elderly; interactions:   Oral solution, potassium citrate 30%, citric acid  monohydrate 5% in a suitable vehicle with a lemon  flavour. Extemporaneous preparations should be  recently prepared according to the following formula:  potassium citrate 3 g, citric acid monohydrate 500 mg,  syrup 2.5 mL, quillaia tincture 0.1 mL, lemon spirit  0.05 mL, double-strength chloroform water 3mL,  water to 10 mL. Contains about 28 mmol K + /10mL.  Label: 27   Dose 10 mL 3 times daily well diluted with water  Proprietary brands of potassium citrate are on sale to the public  for the relief of discomfort in mild urinary-tract infections   Indications relief of discomfort in mild urinary-tract  infections; alkalinisation of urine  Cautions cardiac disease; patients on sodium-  restricted diet; elderly; avoid prolonged use; interac-  tions: Appendix 1 (antacids)   • 3 g in water every 2 hours until urinary pH exceeds 7;  maintenance of alkaline urine 5-10 g daily   Cautions cardiac disease; hypertension; patients on a  sodium-restricted diet; elderly; interactions: Appen-  dix 1 (sodium citrate)   Side-effects mild diuresis  Note Proprietary brands of sodium citrate are on sale to the  public for the relief of discomfort in mild urinary-tract  infections    Instillation of epirubicin (section 8.1.2) is used for  treatment and prophylaxis of certain forms of superficial  bladder cancer; instillation of doxorubicin (section  8.1.2) is also used for some papillary tumours.   Instillation of BCG (Bacillus Calmette-Guerin), a live  attenuated strain derived from Mycobacterium bovis  (section 8.2.4), is licensed for the treatment of primary  or recurrent bladder carcinoma in-situ and for the pre-  vention of recurrence following transurethral resection.   Interstitial cystitis Dimethyl sulfoxide may be used  for symptomatic relief in patients with interstitial cystitis  (Hunner’s ulcer). 50 mL of a 50% solution ( Rimso-50 ® —  available from ‘special-order’ manufacturers or specia-  list importing companies, p. 988) is instilled into the  bladder, retained for 15 minutes, and voided by the  patient. Treatment is repeated at intervals of 2 weeks.  Bladder spasm and hypersensitivity reactions may  occur and long-term use requires ophthalmic, renal,  and hepatic assessment at intervals of 6 months.  Interactions: see Appendix 1 (dimethyl sulfoxide).   A terpene mixture ( Rowatinex ®) is claimed to be of  benefit in urolithiasis for the expulsion of calculi.   Capsules, yellow, e/c, anethol 4 mg, bomeol 10 mg,  camphene 15 mg, cineole 3 mg, fenchone 4 mg,  pinene 31 mg, net price 50 = £7.35. Label: 25  Dose 1-2 capsules 3-4 times daily before food; CHILD not  recommended   Aqueous chlorhexidine (section 13.1 1.2) can be used in  the management of common infections of the bladder  but it is ineffective against most Pseudomonas spp.  Solutions containing chlorhexidine 1 in 5000 (0.02%)  are used but they may irritate the mucosa and cause  burning and haematuria (in which case they should be  discontinued); sterile sodium chloride solution 0.9%  (physiological saline) is usually adequate and is pre-  ferred as a mechanical irrigant.   Continuous bladder irrigation with amphotericin  50 micrograms/mL (section 5.2.3) may be of value in  mycotic infections.   Dissolution of blood clots Clot retention is usually  treated by irrigation with sterile sodium chloride solu-  tion 0.9% but sterile sodium citrate solution for  bladder irrigation 3% may also be helpful.   Bladder cancer Bladder instillations of doxorubicin  (section 8.1.2), mitomycin (section 8.1.2), and thiotepa  (section 8.1.1) are used for recurrent superficial bladder  tumours. Such instillations reduce systemic side-effects;  adverse effects on the bladder (e.g. micturition disorders  and reduction in bladder capacity) may occur.   sodium citrate 3%, dilute hydrochloric acid 0.2%, in  purified water, freshly boiled and cooled, and steri-  lised   There is a high risk of fluid absorption from the irrigant  used in endoscopic surgery within the urinary tract; if  this occurs in excess, hypervolaemia, haemolysis, and  renal failure may result. Glycine irrigation solution  1.5% is the irrigant of choice for transurethral resection  of the prostate gland and bladder tumours; sterile sod-  ium chloride solution 0.9% (physiological saline) is  used for percutaneous renal surgery.   Glycine Irrigation Solution (Non-proprietary)  Irrigation solution, glycine 1.5% in water for injec-  tions   The deposition which occurs in catheterised patients is  usually chiefly composed of phosphate and to minimise  this the catheter (if latex) should be changed at least as  often as every 6 weeks. If the catheter is to be left for  longer periods a silicone catheter should be used  together with the appropriate use of catheter mainte-  nance solutions. Repeated blockage usually indicates  that the catheter needs to be changed.   Brands include OptiFlo S®, 50- and 100-mL sachets =  £3.20; Uriflex S®, 100-mL sachet = £2.40; Uriflex  SP®, with integral drug additive port, 100-mL sachet  = £2.40; Uro-Tainer Sodium Chloride®, 50- and 100-  mL sachets = £3.25; Uro-Tainer M® , with integral  drug additive port, 50- and 100-mL sachets = £2.90   Citric acid 3.23%, magnesium oxide 0.38%, sodium  bicarbonate 0.7%, disodium edetate 0.01%. Brands  include OptiFlo G®, 50- and 100-mL sachets = £3.40;  Uriflex G®, 100-mL sachet = £2.40; Uro-Tainer ®  Twin Suby G, 2 x 30-mL = £4.46   Citric acid 6%, gluconolactone 0.6%, magnesium  carbonate 2.8%, disodium edetate 0.01%. Brands  include OptiFlo R®, 50- and 100-mL sachets = £3.40;  Uriflex R®, 100-mL sachet = £2.40; Uro-Tainer -®  Twin Solutio R, 2 x 30-mL = £4.46   Reasons for failure to produce a satisfactory erection  include psychogenic, vascular, neurogenic, and endo-  crine abnormalities', impotence can also be drug-   B induced. Intracavernosal injection or urethral applica-  tion of vasoactive drugs under careful medical super-  vision is used for both diagnostic and therapeutic pur-  poses.   Erectile disorders may also be treated with drugs given  by mouth which increase the blood flow to the penis.  Drugs should be used with caution if the penis is  deformed (e.g. in angulation, cavemosal fibrosis, and  Peyronie’s disease).   Priapism If priapism occurs with alprostadil, treatment  should not be delayed more than 6 hours and is as  follows:   Initial therapy by penile aspiration — using aseptic tech-  nique a 19-21 gauge butterfly needle inserted into the  corpus cavernosum and 20-50 mL of blood aspirated; if  necessary the procedure may be repeated on the oppo-  site side.   If initial aspiration is unsuccessful a second 1 9-2 1 gauge  butterfly needle can be inserted into the opposite cor-  pus cavernosum and sterile physiological saline intro-  duced through the first needle and drained through the  second.   If aspiration and lavage of corpora are unsuccessful,  cautious intracavernosal injection of a sympathomi-  metic (section 2.7.2) with action on alpha-adrenergic  receptors, continuously monitoring blood pressure and  pulse ( extreme caution: coronary heart disease, hyper-  tension, cerebral ischaemia or if taking antidepressant)  as follows:   • intracavernosal injections of phenylephrine 100-  200 micrograms (0.5-1 mL of a 200 microgram/  mL solution) every 5-10 minutes; max. total dose  1 mg [unlicensed indication] [ important : if suitable   strength of phenylephrine injection not available  may be specially prepared by diluting 0.1 mL of  the phenylephrine 1% (lOmg/mL) injection (sec-  tion 2.7.2) to 5mLwith sodium chloride 0.9%];  alternatively   • intracavernosal injections of adrenaline 10-20 micr-  ograms (0.5-1 mL of a 20 microgram/mL solution)  every 5-10 minutes; max. total dose 100 micr-  ograms [unlicensed indication] [important: if suita-  ble strength of adrenaline not available may be  specially prepared by diluting 0.1 mL of the adrena-  line 1 in 1000 (1 mg/mL, section 3.4.3) injection to  5 mL with sodium chloride 0.9%];  alternatively   • intracavernosal injection of metaraminol ( caution :  has been associated with fatal hypertensive crises );  metaraminol lmg (0.1 mL of 10 mg/mL met-  araminol injection, section 2.7.2) is diluted to  50 mL with sodium chloride injection 0.9% and  given carefully by slow injection into the corpora  in 5-mL injections every 15 minutes [unlicensed  indication].   If necessary the sympathomimetic injections can be  followed by further aspiration of blood through the  same butterfly needle.   If sympathomimetics unsuccessful, urgent surgical  referral for management (possibly including shunt pro-  cedure).   Prescribing on the NHS Drug treatments for erectile  dysfunction may only be prescribed on the NHS under  certain circumstances (see individual preparations). The  Department of Health (England) has recommended that  treatment should also be available from specialist ser-  vices (commissioned by Health Authorities and Primary  Care Groups, and operating under local agreement)  when the condition is causing severe distress; specialist  centres should use form FP10(HP) or form HBP in  Scotland or form WP10HP in Wales and endorse them  ‘SLS’ if the treatment is to be dispensed in the commu-  nity. The following criteria should be considered when  assessing distress:   • a marked effect on mood, behaviour, social and  environmental awareness;   Alprostadil (prostaglandin EJ is given by intracavemo-  sal injection or intraurethral application for the manage-  ment of erectile dysfunction (after exclusion of treatable  medical causes); it is also used as a diagnostic test.    regularly to detect signs of penile fibrosis (consider  discontinuation if angulation, cavernosal fibrosis or  Peyronie’s disease develop); interactions; Appendix 1  (prostaglandins)   Contra-indications predisposition to prolonged erec-  tion (as in sickle cell anaemia, multiple myeloma or  leukaemia); not for use with other agents for erectile  dysfunction, in patients with penile implants or when  sexual activity medically inadvisable; urethral appli-  cation also contra-indicated in urethral stricture,  severe hypospadia, severe curvature, balanitis,  urethritis   Side-effects hypotension, hypertension; dizziness,  headache; penile pain, other localised pain (buttocks,  leg, testicular, abdominal); influenza-like syndrome;  urethral burning, urethral bleeding; injection site  reactions including penile fibrosis, penile oedema,  penile rash, haematoma, haemosiderin deposits; less  commonly nausea, dry mouth, vasodilatation, syn-  cope, supraventricular extrasystole, rapid pulse,  asthenia, leg cramps, pelvic pain, scrotal or testicular  oedema, scrotal erythema, testicular thickening, mic-  turation difficulties, haematuria, mydriasis, and  sweating; local reactions including penile warmth,  pruritus, irritation, penile numbness or sensitivity,  balantitis, phimosis, priapism (see section 7.4.5 and  under Cautions), abnormal ejaculation; rarely vertigo,  urinary-tract infection, and hypersensitivity reactions  (including rash, erythema, urticaria, and anaphylaxis)  Dose    24 hours; usual dose 5-20 micrograms; max. 60 micrograms; max.  frequency of injection not more than 3 times per week with at  least 24 hour interval between injections  Note The first dose must be given by medically trained personnel;  self-administration may only be undertaken after proper training  Aid to diagnosis, 10-20 micrograms as a single dose (where  evidence of neurological dysfunction, initially 5 micrograms and  max. 10 micrograms) — consult product literature for details   1 Viridal® Duo (UCB Pharma) ® (Ml  Starter Pack (hosp. only), contents as for Continua-  tion Pack below plus Duoject applicator, 10-micr-  ogram starter pack = £20.13, 20-microgram starter  pack = £24.54, 40-microgram starter pack = £29.83;  Continuation Pack, 2 double-chamber cartridges  (containing alprostadil and diluent), 2 needles, swabs,  10-microgram continuation pack = £16.55, 20-micr-  ogram continuation pack = £21.39, 40-microgram  continuation pack = £27.22; replacement Duoject®  applicators available from UCB Pharma  Dose by direct intracavernosal injection, ADULT over 18 years,  erectile dysfunction, initially 5 micrograms (2.5 micrograms in  neurogenic erectile dysfunction) increasing in steps of 2.5-  5 micrograms to obtain dose suitable for producing erection not  lasting more than 1 hour; usual range 10-20 micrograms; max.  40 micrograms; max. frequency of injection not more than 2-3  times per week with at least 24 hour interval between injections;  reduce dose if erection lasts longer than 2 hours  Note The first dose must be given by medically trained personnel;  self-administration may only be undertaken after proper training   ^averject® (Pharmacia) ® (Ml  Injection, powder for reconstitution, alprostadil, net  price 5-microgram vial = £7.73; 10-microgram vial =  £9.24; 20-microgram vial = £1 1.94; 40-microgram vial  = £21.58 (all with diluent-filled syringe, needles and  swabs)   Caverject® Dual Chamber, double-chamber car-  tridges (containing alprostadil and diluent), net price  10-microgram cartridge (for doses 2.5-10 micr-  ograms) = £7.35; 20-microgram cartridge (for doses  5-20 micrograms) = £9.50 (both with needles)   Dose by direct intracavernosal injection, ADULT over 18 years,  erectile dysfunction, first dose 2.5 micrograms, second dose  5 micrograms (if some response to first dose) or 7.5 micrograms (if  no response to first dose), increasing in steps of 5-10 micrograms  to obtain dose suitable for producing erection lasting not more  than 1 hour (neurological dysfunction, first dose 1.25 micrograms,  second dose 2.5 micrograms, third dose 5 micrograms, increasing  in steps of 5-10 micrograms to obtain suitable dose); if no  response to dose then next higher dose can be given within 1 hour,  if there is a response the next dose should not be given for at least   • have diabetes, multiple sclerosis, Parkinson’s disease,  poliomyelitis, prostate cancer, severe pelvic injury, single  gene neurological disease, spina bifida, or spinal cord  injury;   • have had radical pelvic surgery, prostatectomy (including  transurethral resection of the prostate), or kidney trans-  plant;   • were receiving Caverject ® , Erecnos ® , MUSE ® , Viagra ® ,  or Viridal ® for erectile dysfunction, at the expense of the  NHS, on 14 September 1998;   • are suffering severe distress as a result of impotence  (prescribed in specialist centres only, see notes above).    ^USE® (Meda) (M (M  Urethral application, alprostadil, net price 125-  microgram single-use applicator = £9.89, 250-micr-  ogram single-use applicator = £11.30, 500-microgram  single-use applicator = £11.30, 1-mg single-use  applicator = £10.89 (all strengths also available in  packs of 6 applicators)   Condoms no evidence of harm to latex condoms and diaphragms  Dose by direct urethral application, ADULT over 18 years, erectile  dysfunction, initially 250 micrograms adjusted according to  response (usual range 0.125-1 mg); max. 2 doses in 24 hours and  7 doses in 7 days)   Note During initiation of treatment MUSE ® should be used under  medical supervision; self-administration may only be undertaken  after proper training   Sildenafil, tadalafil and vardenafil are phosphodi-  esterase type-5 inhibitors licensed for the treatment of  erectile dysfunction; they are not recommended for use  with other treatments for erectile dysfunction. The  patient should be assessed appropriately before pre-  scribing sildenafil, tadalafil or vardenafil. Since these  drugs are given by mouth there is a potential for drug  interactions.   Cautions Sildenafil, tadalafil, and vardenafil should be  used with caution in cardiovascular disease, left ventri-  cular outflow obstruction, anatomical deformation of  the penis (e.g. angulation, cavernosal fibrosis, Peyronie’s  disease), and in those with a predisposition to priapism  (e.g. in sickle-cell disease, multiple myeloma, or leuk-  aemia). Concomitant treatment with a phosphodi-  esterase type-5 inhibitor and an alpha-blocker (section  2.5.4 and section 7.4.1) can increase the risk of postural  hypotension — initiate treatment with a phosphodi-  esterase type-5 inhibitor (at a low dose) only once the    patient is stable on the alpha-blocker; see also interac-  tions: Appendix 1 (sildenafil, tadalafil, vardenafil).   Contra-indications Sildenafil, tadalafil, and vardenafil  are contra-indicated in patients receiving nitrates, in  patients in whom vasodilation or sexual activity are  inadvisable, or in patients with a previous history of  non-arteritic anterior ischaemic optic neuropathy In the  absence of information, manufacturers contra-indicate  these drugs in hypotension (avoid if systolic blood  pressure below 90mmHg), recent stroke, unstable  angina, and myocardial infarction.   Side-effects The side-effects of sildenafil, tadalafil,  and vardenafil include dyspepsia, nausea, vomiting,  headache (including migraine), flushing, dizziness, myal-  gia, back pain, visual disturbances (non-arteritic anterior  ischaemic optic neuropathy has been reported — stop  drug if sudden visual impairment occurs), and nasal  congestion. Less common side-effects include painful  red eyes, palpitation, tachycardia, hypotension, hyper-  tension, epistaxis. Other side-effects reported rarely  include syncope, hypersensitivity reactions (including  rash, facial oedema, and Stevens- Johnson syndrome),  and priapism. Serious cardiovascular events (including  arrhythmia, unstable angina, and myocardial infarction),  seizures, sudden hearing loss (discontinue drug and  seek medical advice), and retinal vascular occlusion  have also been reported.   Contra-indications see notes above; also hereditary  degenerative retinal disorders  Hepatic impairment initial dose 25 mg; manufacturer  advises avoid in severe impairment  Renal impairment initial dose 25 mg if eGFR less than  30 mL/minute/ 1.73 m 2   Side-effects see notes above; also less commonly  chest pain, drowsiness, hypoaesthesia, vertigo, tinni-  tus, dry mouth, fatigue; rarely cerebrovascular acci-  dent and atrial fibrillation   • ADULT over 18 years initially 50 mg approx. 1 hour  before sexual activity, subsequent doses adjusted  according to response to 25-100 mg as a single dose  as needed; max. 1 dose in 24 hours (max. single dose  100 mg)   Note Onset of effect may be delayed if taken with food   • have diabetes, multiple sclerosis, Parkinson’s disease,  poliomyelitis, prostate cancer, severe pelvic injury, single  gene neurological disease, spina bifida, or spinal cord  injury;   • have had radical pelvic surgery, prostatectomy (including  transurethral resection of the prostate), or kidney trans-  plant;   • were receiving Caverjecl ® , Erecnos ® , MUSE ® , Viagra ® ,  or Viridal ® for erectile dysfunction, at the expense of the  NHS, on 14 September 1998;   Tablets, all blue, f/c, sildenafil (as citrate), 25 mg, net  price 4-tab pack = £16.59, 8-tab pack = £33.19; 50 mg,  4-tab pack = £19.34, 8-tab pack = £38.67; 100 mg, 4-  tab pack = £23.50, 8-tab pack = £46.99   Contra-indications see notes above; also moderate  heart failure, uncontrolled arrhythmias, uncontrolled  hypertension   Renal impairment max. dose 10 mg if eGFR less than  30 mL/minute/ 1.73 m 2 (avoid regular once-daily  dosing)   Side-effects see notes above; also increased sweating,  abdominal pain, and transient amnesia reported   • ADULT over 18 years, initially 10 mg at least 30 minutes  before sexual activity, subsequent doses adjusted  according to response, up to 20 mg as a single dose;  max. 1 dose in 24 hours (but daily dose of 10-20 mg  not recommended); for patients who anticipate sexual  activity at least twice weekly, 5 mg once daily can be  taken, reduced to 2.5 mg once daily according to  response   Note Effect of intermittent dosing may persist for longer  than 24 hours   Tablets, f/c, tadalafil 2.5 mg (orange), net price 28-tab  pack = £54.99; 5 mg (light yellow), 28-tab pack =  £54.99; 10 mg (light yellow), 4-tab pack = £26.99;   20 mg (yellow), 4-tab pack = £26.99; 8-tab pack =  £53.98   Indications erectile dysfunction  Cautions see notes above; also elderly; bleeding dis-  orders or active peptic ulceration; susceptibility to  prolongation of QT interval (including concomitant  use of drugs which prolong QT interval); interac-  tions: Appendix 1 (vardenafil)   Contra-indications see notes above; also hereditary  degenerative retinal disorders  Hepatic impairment initial dose 5 mg in mild to  moderate impairment, increased subsequently  according to response (max. 10 mg in moderate  impairment); manufacturer advises avoid in severe  impairment   Renal impairment initial dose 5 mg if eGFR less than  30 mL/minute/ 1 .73 m 2   Side-effects see notes above; also less commonly  drowsiness, dyspnoea, increased lacrimation, photo-  sensitivity; rarely anxiety, transient amnesia, hyper-  tonia, and raised intra-ocular pressure   • ADULT over 18 years, initially 10 mg (patients on alpha-  blocker therapy 5 mg) approx. 25-60 minutes before  sexual activity, subsequent doses adjusted according  to response up to max. 20 mg as a single dose; max. 1  dose in 24 hours   Note Onset of effect may be delayed if taken with high-fat  meal    ‘Levitra* * (Bayer Schering) ® (Ml  Tablets, all orange, f/c, vardenafil (as hydrochloride  trihydrate) 5 mg, net price 4-tab pack = £7.56, 8-tab  pack = £15.12; 10 mg, 4-tab pack = £14.08, 8-tab pack  = £28.16; 20 mg, 4-tab pack = £23.48, 8-tab pack =  £46.96   Although not licensed the smooth muscle relaxant  papaverine has also been given by intracavernosal  injection for erectile dysfunction. Patients with neurolo-  gical or psychogenic impotence are more sensitive to  the effect of papaverine than those with vascular  abnormalities. Phentolamine is added if the response  is inadequate [unlicensed indication].   Persistence of the erection for longer than 4 hours is an  emergency, see advice in section 7.4.5.   • have diabetes, multiple sclerosis, Parkinson’s disease,  poliomyelitis, prostate cancer, severe pelvic injury, single  gene neurological disease, spina bifida, or spinal cord  injury;   • have had radical pelvic surgery, prostatectomy (including  transurethral resection of the prostate), or kidney trans-  plant;   • were receiving Caverject ® , Erecnos ® , MUSE ® , Viagra ® ,  or Viridal® for erectile dysfunction, at the expense of the  NHS, on 14 September 1998;   • are suffering severe distress as a result of impotence  (prescribed in specialist centres only, see notes above).    The chemotherapy of cancer is complex and should be  confined to specialists in oncology. Cytotoxic drugs  have both anti-cancer activity and the potential to  damage normal tissue; most cytotoxic drugs are terato-  genic. Chemotherapy may be given with a curative  intent or it may aim to prolong life or to palliate  symptoms. In an increasing number of cases chemo-  therapy may be combined with radiotherapy or surgery  or both as either neoadjuvant treatment (initial chemo-  therapy aimed at shrinking the primary tumour, thereby  rendering local therapy less destructive or more effec-  tive) or as adjuvant treatment (which follows definitive  treatment of the primary disease, when the risk of sub-  clinical metastatic disease is known to be high). All  cytotoxic drugs cause side-effects and a balance has  to be struck between likely benefit and acceptable  toxicity.   • Reconstitution should be carried out in desig-  nated pharmacy areas;   • Protective clothing (including gloves, gowns,  and masks) should be worn;   • The eyes should be protected and means of first  aid should be specified;   • Pregnant staff should avoid exposure to cyto-  toxic drugs (all females of child-bearing age  should be informed of the reproductive hazard);   • Use local procedures for dealing with spillages  and safe disposal of waste material, including  syringes, containers, and absorbent material;    Combinations of cytotoxic drugs, as continuous or  pulsed cycles of treatment, are frequently more toxic  than single drugs but have the advantage in certain  tumours of enhanced response, reduced development  of drug resistance and increased survival. However for  some tumours, single-agent chemotherapy remains the  treatment of choice.   Cytotoxic drugs fall into a number of classes, each with  characteristic antitumour activity, sites of action, and    toxicity. A knowledge of sites of metabolism and excre-  tion is important because impaired drug handling as a  result of disease is not uncommon and may result in  enhanced toxicity    Intrathecal chemotherapy  A Health Service Circular (HSC 2008/001) provides  guidance on the introduction of safe practice in NHS  Trusts where intrathecal chemotherapy is adminis-  tered; written local guidance covering all aspects of  national guidance should be available. Support for  training programmes is also available.   Department of Health  PO Box 777  London SE1 6XH  Fax: 01623 724524   It is also available from the Department of Health  website (www.dh.gov.uk)    Safe systems for cytotoxic medicines NHS cancer  networks have been established across the UK to bring  together all stakeholders in all sectors of care, to work  collaboratively to plan and deliver high quality cancer  services for a given population. NHS cancer networks  have websites containing information on local chemo-  therapy services and treatment (see  www.cancer.nhs.uk/networks.htm).   • cytotoxic drugs for the treatment of cancer should  be given as part of a wider pathway of care coordi-  nated by a multidisciplinary team;   • cytotoxic drugs should be prescribed, dispensed,  and administered only in the context of a written  protocol or treatment plan;   • injectable cytotoxic drugs should only be dispensed  if they are prepared for administration   • oral cytotoxic medicines should be dispensed with  clear directions for use   The National Patient Safety Agency has advised  (January 2008) that the prescribing and use of oral  cytotoxic medicines should be carried out to the  same standard as parenteral cytotoxic therapy. Stan-  dards to be followed to achieve this include:   • non-specialists who prescribe or administer on-  going oral cytotoxic medication should have  access to written protocols and treatment  plans, including guidance on the monitoring  and treatment of toxicity   • staff dispensing oral cytotoxic medicines should  confirm that the prescribed dose is appropriate  for the patient. Patients should have written  information that includes details of the intended  oral anti-cancer regimen, the treatment plan,  and arrangements for monitoring, taken from  the original protocol from the initiating hospital.  Staff dispensing oral cytotoxic medicines should  also have access to this information, and to  advice from an experienced cancer pharmacist  in the initiating hospital   Doses of cytotoxic drugs are determined using a  variety of different methods including body-surface  area or body-weight. Alternatively, doses may be  fixed. Doses may be further adjusted following con-  sideration of a patient’s neutrophil count, renal and  hepatic function, and history of previous adverse  effects to the cytotoxic drug. Doses may also differ  depending on whether a drug is used alone or in  combination.   Because of the complexity of dosage regimens in the  treatment of malignant disease, dose statements  have been omitted from some of the drug entries  in this chapter. However, even where dose state-  ments have been provided, detailed specialist litera-  ture, individual hospital chemotherapy protocols, or  local cancer networks (www.cancer.nhs.uk/  networks.htm) should be consulted prior to pre-  scribing, dispensing, or administering cytotoxic  drugs.   Prescriptions should not be repeated except on the  instructions of a specialist.   Side-effects common to most cytotoxic drugs are dis-  cussed below whilst side-effects characteristic of a par-  ticular drug or class of drugs (e.g. neurotoxicity with  vinca alkaloids) are mentioned in the appropriate sec-  tions. Manufacturers’ product literature, hospital-trust  protocols, and cancer-network protocols should be con-  sulted for full details of side-effects associated with  individual drugs and specific chemotherapy regimes.    Many side-effects of cytotoxic drugs often do not occur  at the time of administration, but days or weeks later. It  is therefore important that patients and healthcare pro-  fessionals can identify symptoms that cause concern  and can contact an expert for advice. Toxicides should  be accurately recorded using a recognised scoring sys-  tem such as the Common Toxicity Criteria for Adverse  Events (CTCAE) developed by the National Cancer  Institute.   Extravasation of intravenous drugs A number of  cytotoxic drugs will cause severe local tissue necrosis if  leakage into the extravascular compartment occurs. To  reduce the risk of extravasation injury it is recom-  mended that cytotoxic drugs are administered by appro-  priately trained staff. For information on the prevention  and management of extravasation injury, see section  10.3.    Oral mucositis A sore mouth is a common complica-  tion of cancer chemotherapy; it is most often associated  with fluorouracil, methotrexate, and the anthracyclines.  It is best to prevent the complication. Good oral hygiene  (rinsing the mouth frequently and effective brushing of  the teeth with a soft brush 2-3 times daily) is probably  beneficial. For fluorouracil, sucking ice chips during  short infusions of the drug is also helpful.   Once a sore mouth has developed, treatment is much  less effective. Saline mouthwashes should be used but  there is no good evidence to support the use of anti-  septic or anti-inflammatory mouthwashes. In general,  mucositis is self-limiting but with poor oral hygiene it  can be a focus for blood-borne infection.    Tumour lysis syndrome Tumour lysis syndrome  occurs secondary to spontaneous or treatment-related  rapid destruction of malignant cells. Patients at risk of  tumour lysis syndrome include those with non-  Hodgkin’s lymphoma (especially if high grade and  bulky disease), Burkitt’s lymphoma, acute lymphoblastic  leukaemia and acute myeloid leukaemia (particularly if  high white blood cell counts or bulky disease), and  occasionally those with solid tumours. Pre-existing  hyperuricaemia, dehydration, and renal impairment  are also predisposing factors. Features include hyper-  kalaemia, hyperuricaemia (see below), and hyper-  phosphataemia with hypocalcaemia; renal damage and  arrhythmias can follow. Early identification of patients at  risk, and initiation of prophylaxis or therapy for tumour  lysis syndrome, is essential.   Hyperuricaemia Hyperuricaemia, which may be pre-  sent in high-grade lymphoma and leukaemia, can be  markedly worsened by chemotherapy and is associated  with acute renal failure. Allopurinol (section 10.1.4)  should be started 24 hours before treating such tumours  and patients should be adequately hydrated. The dose of  mercaptopurine or azathioprine should be reduced if  allopurinol needs to be given concomitantly (see Appen-  dix 1).   Rasburicase (section 10.1.4), a recombinant urate oxi-  dase, is licensed for hyperuricaemia in patients with  haematological malignancy, for details, see p. 657. It  rapidly reduces plasma uric acid and may be of parti-  cular value in preventing complications following treat-  ment of leukaemias or bulky lymphomas.   Nausea and vomiting Nausea and vomiting cause  considerable distress to many patients who receive   B chemotherapy and to a lesser extent abdominal radio-  therapy, and may lead to refusal of further treatment;  prophylaxis of nausea and vomiting is therefore extre-  mely important. Symptoms may be acute (occurring  within 24 hours of treatment), delayed (first occurring  more than 24 hours after treatment), or anticipatory  (occurring prior to subsequent doses). Delayed and  anticipatory symptoms are more difficult to control  than acute symptoms and require different manage-  ment.   Patients vary in their susceptibility to drug-induced  nausea and vomiting; those affected more often include  women, patients under 50 years of age, anxious patients,  and those who experience motion sickness. Susceptibil-  ity also increases with repeated exposure to the cyto-  toxic drug.   Drugs may be divided according to their emetogenic  potential and some examples are given below, but the  symptoms vary according to the dose, to other drugs  administered and to individual susceptibility.   Mildly emetogenic treatment — fluorouracil, etoposide,  methotrexate (less than 100 mg/m 2 ), the vinca alka-  loids, and abdominal radiotherapy.   Moderately emetogenic treatment — the taxanes, doxo-  rubicin, intermediate and low doses of cyclophosph-  amide, mitoxantrone, and high doses of methotrexate  (0. 1-1.2 g/m 2 ).   Highly emetogenic treatment — cisplatin, dacarbazine,  and high doses of cyclophosphamide.   Prevention of acute symptoms. For patients at low risk  of emesis , pretreatment with domperidone or with    metoclopramide, continued for up to 24 hours after  chemotherapy, is often effective (section 4.6). If meto-  clopramide or domperidone are not sufficiently effec-  tive, additional drugs such as dexamethasone (6-10 mg  by mouth) or lorazepam (1-2 mg by mouth) may be  used.   For patients at high risk of emesis or when other treat-  ment is inadequate, a specific (5HT 3 ) serotonin antago-  nist (section 4.6), usually given by mouth, is often highly  effective, particularly when used with dexamethasone;  adding the neurokinin receptor antagonist, aprepitant  (section 4.6) can improve control of cisplatin-related  nausea and vomiting.   Prevention of delayed symptoms. Dexamethasone,  given by mouth, is the drug of choice for preventing  delayed symptoms; it is used alone or with metoclo-  pramide or prochlorperazine. The 5HT 3 antagonists  may be less effective for delayed symptoms.  Prevention of anticipatory symptoms. Good symp-  tom control is the best way to prevent anticipatory  symptoms. Lorazepam can be helpful for its amnesic,  sedative, and anxiolytic effects.   Bone-marrow suppression All cytotoxic drugs  except vincristine and bleomycin cause bone-marrow  depression. This commonly occurs 7 to 10 days after  administration, but is delayed for certain drugs, such as  carmustine, lomustine, and melphalan. Peripheral blood  counts must be checked before each treatment, and  doses should be reduced or therapy delayed if bone-  marrow has not recovered.   Fever in a neutropenic patient (neutrophil count less  than 1.0 x 10 9 /litre) requires immediate broad-spec-  trum antibacterial therapy. Appropriate bacteriological  investigations should be conducted as soon as possible.  All patients should initially be investigated and treated  under the supervision of the appropriate oncology or  haematology specialist.   In selected patients, the duration and the severity of  neutropenia can be reduced by the use of amifostine,  p. 522 or recombinant human granulocyte-colony sti-  mulating factors, section 9.1.6.   Symptomatic anaemia is usually treated with red blood  cell transfusions. For guidance on the use of erythro-  poietins in patients with cancer, see MHRA/CHM  advice (p. 582) and NICE guidance (p. 583).   For advice on the use of live vaccines in individuals with  impaired immune response, see section 14.1.   Alopecia Reversible hair loss is a common complica-  tion, although it varies in degree between drugs and  individual patients. No pharmacological methods of  preventing this are available.   Reproductive function Most cytotoxic drugs are  teratogenic and should not be administered during  pregnancy, especially during the first trimester. Consid-  erable caution is necessary if a pregnant woman pre-  sents with cancer requiring chemotherapy, and specia-  list advice should always be sought.   Contraceptive advice should be offered where appro-  priate before cytotoxic therapy begins (and should cover  the duration of contraception required after therapy has  ended). Regimens that do not contain an alkylating drug  may have less effect on fertility, but those with an  alkylating drug carry the risk of causing permanent    male sterility (there is no effect on potency). Pre-treat-  ment counselling and consideration of sperm storage  may be appropriate. Women are less severely affected,  though the span of reproductive life may be shortened  by the onset of a premature menopause. No increase in  fetal abnormalities or abortion-rate has been recorded  in patients who remain fertile after cytotoxic chemo-  therapy.   Thromboembolism Venous thromboembolism can  be a complication of cancer itself, but chemotherapy  increases the risk.    Cardioxane® (Novartis) ▼ (Ml  Intravenous infusion, powder for reconstitution,  dexrazoxane (as hydrochloride), net price 500-mg vial  = £156.57   Dose prevention of anthracycline-induced cardiotoxicity, ADULT  over 18 years, by intravenous infusion (30 minutes prior to  anthracycline administration), 20 times the doxorubicin-equiva-  lent dose or 10 times the epirubicin-equivalent dose   Savene® (SpePharm) T (Ml  Intravenous infusion, powder for reconstitution,  dexrazoxane (as hydrochloride), net price 10 x 500-  mg vials (with diluent) = £6750.00  Dose anthracycline extravasation, ADULT over 18 years, by  intravenous infusion, 1 g/m 2 (max. 2g) daily for 2 days, then  500 mg/m 2 for 1 day   Note Local coolants such as ice packs should be removed at least  15 minutes before administration   Anthracycline-induced cardiotoxicity The anthra-  cycline cytotoxic drugs are associated with dose-  related, cumulative, and potentially life-threatening car-  diotoxic side-effects.   Dexrazoxane, an iron chelator, is licensed for the pre-  vention of chronic cumulative cardiotoxicity caused by  doxorubicin or epirubicin treatment in advanced or  metastatic cancer patients who have previously  received anthracycline therapy. Patients receiving dex-  razoxane should still be monitored for cardiac toxicity.  The myelosuppressive effects of dexrazoxane may be  additive to those of chemotherapy.   Anthracycline extravasation Dexrazoxane is  licensed for the treatment of anthracycline extravasa-  tion. The first dose should be given as soon as possible  and within six hours after the injury. For further infor-  mation on the prevention and management of extra-  vasation injury, see section 10.3.   Local guidelines for the management of extravasa-  tion should be followed or specialist advice sought.   Folinic acid (given as calcium folinate) is used to  counteract the folate-antagonist action of methotrexate  and thus speed recovery from methotrexate-induced  mucositis or myelosuppression (‘folinic acid rescue’).   Folinic acid is also used in the management of metho-  trexate overdose, together with other measures to main-  tain fluid and electrolyte balance, and to manage pos-  sible renal failure.    Folinic acid does not counteract the antibacterial activ-  ity of folate antagonists such as trimethoprim.    When folinic acid and fluorouracil are used together in  metastatic colorectal cancer the response-rate improves  compared to that with fluorouracil alone.    The calcium salt of levofolinic acid, a single isomer of  folinic acid, is also used for rescue therapy following  methotrexate administration, for cases of methotrexate  overdose, and for use with fluorouracil for colorectal  cancer. The dose of calcium levofolinate is generally half  that of calcium folinate.   The disodium salts of folinic acid and levofolinic acid  are also used for rescue therapy following methotrexate  therapy, and for use with fluorouracil for colorectal  cancer.    Indications see notes above and under preparations  Cautions see notes above; monitor full blood count  Hepatic impairment monitor liver function  Renal impairment use with caution — risk of accu-  mulation; manufacturer of Cardioxane® advises  reduce dose by 50% if creatinine clearance less than  40 mL/minute   Pregnancy avoid unless essential (toxicity in animal  studies); ensure effective contraception during and for  at least 3 months after treatment in men and women  Breast-feeding discontinue breast-feeding  Side-effects nausea, vomiting, dyspepsia, abdominal  pain, diarrhoea, stomatitis, dry mouth, anorexia;  dyspnoea; dizziness, syncope, asthenia, paraesthesia,  tremor, fatigue, drowsiness; pyrexia; vaginal  haemorrhage; myalgia; blood disorders (including  anaemia, leucopenia, neutropenia, and thrombocyto-  penia); alopecia, pruritus; peripheral oedema, injec-  tion-site reactions including phlebitis  Dose    Palifermin, a human keratinocyte growth factor, is  licensed for the management of oral mucositis in  patients with haematological malignancies receiving  myeloablative radiochemotherapy with autologous hae-  matopoietic stem-cell support.   Indications see notes above  Cautions avoid simultaneous administration of  methotrexate; not indicated for pernicious anaemia or  other megaloblastic anaemias caused by vitamin B 12  deficiency; interactions: Appendix 1 (folates)  Contra-indications intrathecal injection  Pregnancy not known to be harmful; benefit out-  weighs risk   Side-effects rarely pyrexia after parenteral use;  insomnia, agitation, and depression after high doses   Calcium Folinate (Non-proprietary) [Ml  Tablets, scored, folinic acid (as calcium salt) 15 mg,  net price 10-tab pack = £39.20, 30-tab pack = £85.74  Brands include Refolinon ®   Note Not all strengths and pack sizes are available from all  manufacturers   Injection, folinic acid (as calcium salt) 3mg/mL, net  price 1-mL amp = £4.00, 10-mL amp = £4.62; 7.5 mg/  mL, net price 2-mL amp = £7.80; 10 mg/mL, net price  5-mL vial = £19.41, 10-mL vial = £35.09, 30-mL vial =  £94.69, 3 5-mL vial = £90.98  Brands include Refolinon ®   Note Not all strengths and pack sizes are available from all  manufacturers   Injection, powder for reconstitution, folinic acid (as  calcium salt), net price 15-mg vial = £4.46; 30-mg vial  = £8.36  Dose   Note Doses expressed as folinic acid  Prevention of methotrexate-induced adverse effects, usually  started 12-24 hours after start of methotrexate infusion, by  intramuscular injection, or by intravenous injection, or by intra-  venous infusion, 15 mg, repeated every 6 hours for 24 hours (may  be continued by mouth); consult local treatment protocol for  further information   Suspected methotrexate overdosage, by intravenous injection or  by intravenous infusion (at a max. rate of 160 mg/minute), initial  dose equal to or exceeding dose of methotrexate; consult poisons  information service (p. 32) for advice on continuing management  Adjunct to fluorouracil in colorectal cancer, consult product  literature   Levofolinic Acid (Non-proprietary) LmD  Injection, levofolinic acid (as disodium salt) 50 mg/  mL, net price 1-mL vial = £24.70, 4-mL vial = £80.40  Dose as an antidote to methotrexate, by intravenous injection or  infusion, consult product literature  Adjunct to fluorouracil in colorectal cancer, consult product  literature   Side-effects oral paraesthesia, taste disturbance,  thickening and discoloration of tongue; fever;  oedema; arthralgia; rash, pruritus, erythema, skin  hyperpigmentation   • By intravenous injection, 60 micrograms /kg once  daily for 3 doses (third dose given 24-48 hours before  myeloablative therapy) then 3 further doses at least 24  hours after myeloablative therapy, and more than 4  days after most recent palifermin injection, starting on  same day as (but after) stem-cell infusion; CHILD not  recommended   Injection, folinic acid (as disodium salt) 50 mg/mL,  net price 2-mL vial = £35.09, 8-mL vial = £126.25, 18-  mL vial = £284.07   Amifostine is licensed for the reduction of risk of  infection associated with cisplatin- and cyclophosph-  amide-induced neutropenia in advanced ovarian carci-  noma, and for the reduction of nephrotoxicity caused by  cisplatin use in advanced solid tumours of non-germ-  cell origin. Amifostine is also licensed for protection  against xerostomia during radiotherapy for head and  neck cancer.   Contra-indications see Folinic acid  Pregnancy see Folinic acid  Breast-feeding see Folinic acid  Side-effects see Folinic acid   M Calcium levofolinate  Calcium Levofolinate (Non-proprietary) (Ml  Injection, levofolinic acid (as calcium salt) 10 mg/mL,  net price 17. 5-mL vial = £84.63   Injection, levofolinic acid (as calcium salt) 10 mg/mL,  net price 2. 5-mL vial = £11.62, 17.5-mL vial = £81.33  Dose   Note Doses expressed as levofolinic acid  Prevention of methotrexate-induced adverse effects, (usually  started 12-24 hours after beginning of methotrexate infusion), by  intramuscular injection, or by intravenous injection or by intra-  venous infusion, usually 7.5 mg every 6 hours for 10 doses  Suspected methotrexate overdosage, by intravenous injection or  by intravenous infusion (at a max. rate of 160 mg/minute), initial  dose at least 50% of the dose of methotrexate; consult poisons  information sendee (p. 32) for advice on continuing management  Adjunct to fluorouracil in colorectal cancer, consult product  literature    Other drugs for the reduction of risk of infection asso-  ciated with neutropenia include granulocyte-colony sti-  mulating factors (section 9.1.6).   Cautions ensure adequate hydration before treatment;  infuse with patient supine and monitor arterial blood  pressure (interrupt infusion if blood pressure  decreases significantly, consult product literature);  during chemotherapy interrupt antihypertensive  therapy 24 hours before treatment with amifostine  and monitor closely; during radiotherapy monitor  closely if concomitant antihypertensive therapy;  monitor serum-calcium concentration in patients at  risk of hypocalcaemia; patients at risk of renal  impairment; caution in handling — risk of cutaneous  reactions   Hepatic impairment avoid — no information available  Renal impairment avoid — no information available  Pregnancy toxicity in animal studies; avoid  Breast-feeding avoid — no information available  Side-effects nausea, vomiting, hiccups; hypotension  (managed by infusion of sodium chloride 0.9% and    postural management), hypertension, flushing,  arrhythmias (including rarely atrial fibrillation,  supraventricular tachycardia); sneezing; drowsiness,  dizziness, syncope; hypocalcaemia; rarely chest pain,  apnoea, seizures, serious skin reactions (including  Stevens-Johnson syndrome, toxic epidermal necro-  lysis, and very rarely exfoliative and bullous  dermatitis, toxicoderma), and renal failure; very rarely  myocardial infarction, laryngeal oedema, and respir-  atory arrest  Dose   • Reduction of neutropenia-related risk of infection due  to cyclophosphamide and cisplatin treatment in  patients with advanced ovarian carcinoma, by intra-  venous infusion over 15 minutes, ADULT under 70  years, 910 mg/m 2 started within 30 minutes before  chemotherapy (reduced to 740 mg/m 2 for subsequent  cycles if full dose could not be given first time due to  hypotension lasting more than 5 minutes after inter-  ruption, consult product literature)   • Reduction of nephrotoxicity associated with cisplatin  in patients with advanced solid tumours of non-germ-  cell origin, consult product literature   • Prevention of xerostomia during radiotherapy for  head and neck cancer, consult product literature   Ethyol® (Genopharm) (Ml  Intravenous infusion, powder for reconstitution,  amifostine, net price 500-mg vial = £225.00   Haemorrhagic cystitis is a common manifestation of  urothelial toxicity which occurs with the oxazaphos-  phorines, cyclophosphamide and ifosfamide; it is caused  by the metabolite acrolein. Mesna reacts specifically  with this metabolite in the urinary tract, preventing  toxicity. Mesna is used routinely (preferably by mouth)  in patients receiving ifosfamide, and in patients receiv-  ing cyclophosphamide by the intravenous route at a  high dose (e.g. more than 2 g) or in those who experi-  enced urothelial toxicity when given cyclophosphamide  previously.   Cautions false positive urinary ketones; false positive  or false negative urinary erythrocytes   Side-effects nausea, vomiting, colic, diarrhoea, fati-  gue, headache, limb and joint pains, depression, irrit-  ability, rash, hypotension and tachycardia; rarely  hypersensitivity reactions (more common in patients  with auto-immune disorders)   Tablets, f/c, mesna 400 mg, net price 10-tab pack =  £42.90; 600 mg, 10-tab pack = £61.10    Injection, mesna lOOmg/mL, net price 4-mL amp =  £3.95; 10-mL amp = £9.77   Note For oral administration contents of ampoule are taken in a  flavoured drink such as orange juice or cola which may be stored  in a refrigerator for up to 24 hours in a sealed container   Extensive experience is available with these drugs,  which are among the most widely used in cancer  chemotherapy. They act by damaging DNA, thus inter-  fering with cell replication. In addition to the side-effects  common to many cytotoxic drugs (section 8.1), there  are two problems associated with prolonged usage.  Firstly, gametogenesis is often severely affected (section  8. 1). Secondly, prolonged use of these drugs, particularly  when combined with extensive irradiation, is associated  with a marked increase in the incidence of acute non-  lymphocytic leukaemia.   Cyclophosphamide is used mainly in combination with  other agents for treating a wide range of malignancies,  including some leukaemias, lymphomas, and solid  tumours. It is given by mouth or intravenously; it is  inactive until metabolised by the liver. A urinary meta-  bolite of cyclophosphamide, acrolein, can cause hae-  morrhagic cystitis; this is a rare but serious complica-  tion; increased fluid intake for 24-48 hours after  intravenous injection, can prevent this complication.  When high-dose therapy (e.g. more than 2g intrave-  nously) is used or when the patient is considered to be at  high risk of cystitis (e.g. because of pelvic irradiation)  mesna (given initially intravenously then by mouth) can  also help prevent cystitis — see under Urothelial Toxicity  (section 8.1).   Ifosfamide is related to cyclophosphamide and is given  intravenously; mesna (section 8.1) is routinely given  with it to reduce urothelial toxicity.   Chlorambucil is used either alone or in combination  therapy for some lymphomas and chronic leukaemias. It  is given by mouth. Side-effects, apart from bone-marrow  suppression, are uncommon. However, patients occa-  sionally develop severe widespread rashes which can  progress to Stevens-Johnson syndrome or to toxic epi-  dermal necrolysis. If a rash occurs further chlorambucil  is contra-indicated and cyclophosphamide is substi-  tuted.   Melphalan is licensed for the treatment of multiple  myeloma, polycythaemia vera, childhood neuroblasto-  ma, advanced ovarian adenocarcinoma, and advanced  breast cancer. However, in practice, melphalan is rarely  used for ovarian adenocarcinoma; it is no longer used  for advanced breast cancer. Melphalan is also licensed  for regional arterial perfusion in localised malignant  melanoma of the extremities and localised soft-tissue  sarcoma of the extremities. Interstitial pneumonitis and  life-threatening pulmonary fibrosis are rarely associated  with melphalan.   Busulfan is given by mouth to treat chronic myeloid  leukaemia. Busulfan given by mouth or intravenously,  followed by cyclophosphamide, is also licensed as con-  ditioning treatment before haematopoietic stem-cell  transplantation in adults and children. Frequent blood  tests are necessary because excessive myelosuppres-  sion may result in irreversible bone-marrow aplasia.  Rarely, progressive pulmonary fibrosis is associated    with busulfan. Skin hyperpigmentation is a common  side-effect of oral therapy.   Lomustine is a lipid-soluble nitrosourea and is given by  mouth. It is used mainly to treat Hodgkin’s disease  resistant to conventional therapy, malignant melanoma  and certain solid tumours. Bone-marrow toxicity is  delayed, and the drug is therefore given at intervals of  4 to 6 weeks. Permanent bone-marrow damage can  occur with prolonged use. Nausea and vomiting are  common and moderately severe.   Bendamustine given intravenously is licensed for the  treatment of chronic lymphocytic leukaemia, non-  Hodgkin’s lymphoma, and for the treatment of multiple  myeloma.   Carmustine given intravenously has similar activity to  lomustine; it is given to patients with multiple myeloma,  non-Hodgkin’s lymphomas, and brain tumours. Cumu-  lative renal damage and delayed pulmonary fibrosis  may occur with intravenous use. Carmustine implants  are licensed for intralesional use in adults for the treat-  ment of recurrent glioblastoma multiforme as an  adjunct to surgery. Carmustine implants are also  licensed for high-grade malignant glioma as adjunctive  treatment to surgery and radiotherapy.   NICE guidance (carmustine implants and  temozolomide for the treatment of newly  diagnosed high-grade glioma)   Estramustine is a combination of an oestrogen and  chlormethine used predominantly in prostate cancer.  It is given by mouth and has both an antimitotic effect  and (by reducing testosterone concentration) a hormo-  nal effect.   Treosulfan is given by mouth or by intravenous or  intraperitoneal administration and is used to treat  ovarian cancer. Skin pigmentation is a common side-  effect and allergic alveolitis, pulmonary fibrosis and  haemorrhagic cystitis occur rarely.    Thiotepa is usually used as an intracavitary drug for the  treatment of malignant effusions or bladder cancer  (section 7.4.4). It is also occasionally used to treat breast  cancer, but requires parenteral administration.    Mitobronitol is occasionally used to treat chronic  myeloid leukaemia; it is available on a named-patient  basis from specialist importing companies, see p. 988.   Contra-indications jaundice; severe bone marrow  suppression, low leucocyte or platelet count; major  surgery less than 30 days before start of treatment   Hepatic impairment consider a 30% dose reduction  in moderate impairment; avoid in severe impairment   Renal impairment no information available on use in  patients with creatinine clearance less than 10 mL/  minute    treatment in men or women, and for 6 months after  treatment in men; see also Reproductive function,  p. 520   Side-effects see section 8.1; also anorexia, diarrhoea,  constipation, haemorrhage, hypotension, hyper-  tension, palpitation, angina, arrhythmias, respiratory  dysfunction, insomnia, pain, chills, malaise, infection,  pyrexia, amenorrhoea, dehydration, electrolyte dis-  turbances (including hypokalaemia); less commonly  pericardial effusion; rarely acute circulatory failure,  drowsiness, voice changes, sweating; very rarely taste  disturbance, tachycardia, myocardial infarction, car-  diac failure, pulmonary fibrosis, paraesthesia, periph-  eral neuropathy, neurological disorders, ataxia, anti-  cholinergic syndrome, encephalitis, phlebitis, multiple  organ failure, haemolysis; also reported secondary  tumours, Stevens- Johnson syndrome, toxic epidermal  necrolysis   Injection, powder for reconstitution, bendamustine  hydrochloride, net price 25-mg vial = £69.45; 100-mg  vial = £275.81   Cautions see section 8.1 and notes above; monitor  cardiac function; previous radiation therapy; avoid in  acute porphyria (but see section 9.8.2); interactions:  Appendix 1 (busulfan)   Pregnancy avoid (teratogenic in animals)-, manufac-  turers advise effective contraception during and for 6  months after treatment in men or women; see also  Reproductive Function, p. 520   Side-effects see section 8.1 and notes above; also  hepatotoxicity (including hepatic veno-occlusive dis-  ease, hyperbilirubinaemia, jaundice and fibrosis);  cardiac tamponade in thalassaemia; pneumonia; skin  hyperpigmentation   • Chronic myeloid leukaemia, induction of remission,  by mouth, 60 micrograms /kg daily (max. 4 mg);  maintenance, usually 0.5-2 mg daily   • Conditioning treatment before haematopoietic stem-  cell transplantation, by mouth or by intravenous  infusion, consult product literature   Concentrate for intravenous infusion, busulfan  6mg/mL, net price 10-mL vial = £201.25   Indications see notes above  Cautions see section 8.1 and notes above; avoid in  acute porphyria (but see section 9.8.2); interactions:  Appendix 1 (carmustine)   Cautions see section 8.1 and notes above; history of  epilepsy and children with nephrotic syndrome  (increased risk of seizures); avoid in acute porphyria  (but see section 9.8.2)   Tablets, f/c, brown, chlorambucil 2 mg, net price 25-  tab pack = £8.36   Cautions see section 8.1 and notes above; previous or  concurrent mediastinal irradiation — risk of cardio-  toxicity; diabetes mellitus; avoid in acute porphyria  (but see section 9.8.2); interactions: Appendix 1  (cyclophosphamide)   Renal impairment reduce dose if serum creatinine  concentration greater than 120micromol/litre   Pregnancy avoid (manufacturer advises effective  contraception during and for at least 3 months after  treatment in men or women); see also Reproductive  Function, p. 520   Breast-feeding discontinue breast-feeding during and  for 36 hours after stopping treatment   Side-effects see section 8.1 and notes above; also  anorexia; pancreatitis; cardiotoxicity at high doses;  interstitial pulmonary fibrosis; inappropriate secretion  of anti-diuretic hormone, disturbances of carbohy-  drate metabolism; urothelial toxicity; pigmentation of  palms, nails, and soles: rarely hepatotoxicity and renal  dysfunction   Cyclophosphamide (Non-proprietary) (Ml  Tablets, s/c, cyclophosphamide (anhydrous) 50 mg,  net price 100 = £20.20. Label: 25, 27  Injection, powder for reconstitution, cyclophosph-  amide, net price 500-mg vial = £5.66; 1-g vial = £10.66   Indications prostate cancer  Cautions see section 8.1; congestive heart failure;  diabetes; hypertension; epilepsy; hypercalcaemia;    avoid in acute porphyria (but see section 9.8.2);  interactions: Appendix 1 (estramustine)   Hepatic impairment manufacturer advises caution  and regular liver function tests; avoid in severe  impairment   Side-effects see section 8.1; also diarrhoea; conges-  tive heart failure, ischaemic heart disease, myocardial  infarction; oedema (rarely angioneurotic) impotence,  gynaecomastia; altered liver function  Dose   • 0. 14-1.4 g daily in divided doses (usual initial dose  560-840 mg daily)   Counselling Each dose should be taken not less than 1 hour  before or 2 hours after meals and should not be taken with  dairy products   Estracyt® (Pharmacia) (Ml  Capsules, estramustine phosphate 140 mg (as  disodium salt), net price 100-cap pack = £171.28.  Label: 23, counselling, see above    Cautions see section 8.1 and notes above; ensure  satisfactory electrolyte balance and renal function  before each course (risk of tubular dysfunction, Fan-  coni’s syndrome or diabetes insipidus if renal toxicity  not treated promptly); diabetes mellitus; avoid in  acute porphyria (but see section 9.8.2); interactions:  Appendix 1 (ifosfamide)   Hepatic impairment avoid  Renal impairment avoid if serum creatinine concen-  tration greater than 120micromol/litre  Pregnancy avoid (teratogenic and carcinogenic in  animals ); manufacturer advises adequate contra-  ception during and for at least 6 months after treat-  ment in men or women; see also Reproductive  Function, p. 520   Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above; also  drowsiness, confusion, disorientation, restlessness,  psychosis; urothelial toxicity, renal toxicity (see Cau-  tions above); less commonly severe encephalopathy;  rarely diarrhoea, constipation, convulsions, anorexia,  very rarely jaundice, thrombophlebitis, syndrome of  inappropriate antidiuretic hormone secretion; acute  pancreatitis, arrhythmias, and heart failure also  reported   Ifosfamide (Non-proprietary) [Ml  Injection, powder for reconstitution, ifosfamide, net  price 1-g vial = £43.53; 2-g vial = £88.62 (hosp. only)    Pregnancy avoid (manufacturer advises effective  contraception during and for at least 6 months after  treatment in men or women); see also Reproductive  Function, p. 520   Capsules, blue/clear, lomustine 40 mg, net price 20-  cap pack = £455.62   Note The brand name CCNU 9 has been used for lomustine  capsules   • By mouth, multiple myeloma, dose may vary  according to regimen; typical dose 150 micrograms/  kg daily for 4 days, repeated every 6 weeks  Polycythaemia vera, initially, 6- 10 mg daily reduced  after 5-7 days to 2-4 mg daily until satisfactory   Tablets, melphalan 2 mg, net price 25 = £13.75  Injection, powder for reconstitution, melphalan  50 mg (as hydrochloride), net price 50-mg vial (with  solvent-diluent) = £33.13   Indications see notes above and section 7.4.4  Cautions see section 8.1; avoid in acute porphyria (but  see section 9.8.2); interactions: Appendix 1 (thiotepa)  Pregnancy avoid (teratogenic and embryotoxic in  animals)', see also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1   Injection, powder for reconstitution, thiotepa, net  price 15-mg vial = £5.20   Injection, powder for reconstitution, thiotepa, net  price 15-mg vial = £123.00; 100-mg vial = £736.00   Injection, powder for reconstitution, treosulfan, net  price 1 g = £39.44; 5 g = £152.41 (both in infusion  bottle with transfer needle)   Drugs in this group are widely used. Many cytotoxic  antibiotics act as radiomimetics and simultaneous use of  radiotherapy should be avoided as it may result in  markedly enhanced toxicity.   Daunorubicin, doxorubicin, epirubicin and ida-  rubicin are anthracycline antibiotics. Mitoxantrone is  an anthracycline derivative.   Doxorubicin is used to treat the acute leukaemias,  Hodgkin’s and non-Hodgkin’s lymphomas, paediatric  malignancies, and some solid tumours including breast  cancer. It is given by injection into a fast-running infu-  sion, commonly at 21 -day intervals. Extravasation can  cause severe tissue necrosis. Doxorubicin is largely  excreted in the bile and an elevated bilirubin concentra-  tion is an indication for reducing the dose. Diarrhoea,  dehydration, and red coloration of the urine can com-  monly occur, and renal damage has been reported.  Supraventricular tachycardia related to drug adminis-  tration is an uncommon complication. Higher cumula-  tive doses are associated with cardiomyopathy and it is  usual to limit total cumulative doses to 450 mg/m 2  because symptomatic and potentially fatal heart failure  is common above this dose. Patients should be assessed  before treatment by echocardiography; the elderly, and  those with cardiac disease, hypertension, or who have  received myocardial irradiation, should be treated cau-  tiously. Cardiac monitoring may assist in determining  safe dosage. Some evidence suggests that weekly low-  dose administration may be less cardiotoxic. Doxorubi-  cin is also given by bladder instillation for the treatment  of transitional cell carcinoma, papillary bladder tumours  and carcinoma in-situ.   Liposomal formulations of doxorubicin for intravenous  use are also available. They may reduce the incidence of  cardiotoxicity and lower the potential for local necrosis,  but infusion reactions, sometimes severe, may occur.  Hand-foot syndrome (painful, macular reddening skin  eruptions) occurs commonly with liposomal doxorubi-  cin and may be dose limiting. It can occur after 2-3  treatment cycles and may be prevented by cooling  hands and feet and avoiding socks, gloves, or tight-  fitting footwear for 4-7 days after treatment.   NICE guidance (paclitaxel, pegylated liposo-  mal doxorubicin and topotecan for second-line  or subsequent treatment of advanced ovarian  cancer)    Epirubicin is structurally related to doxorubicin and  clinical trials suggest that it is as effective in the treat-  ment of breast cancer. A maximum cumulative dose of  0.9-1 g/m 2 is recommended to help avoid cardiotoxi-  city. Like doxorubicin it is given intravenously and by  bladder instillation. Hyperpigmentation of skin, nails,  and oral mucosa, and red coloration of the urine, may  occur.   Idarubicin has general properties similar to those of  doxorubicin; it is mostly used in the treatment of hae-  matological malignancies. Diarrhoea, abdominal pain,  haemorrhage, cardiac disorders, rash, and red pigmen-  tation of the urine are commonly reported. Skin and nail  hyperpigmentation have been reported less frequently.  Idarubicin is given intravenously and it may also be  given by mouth.   Daunorubicin also has general properties similar to  those of doxorubicin. It should be given by intravenous  infusion and is indicated for acute leukaemias. A lipo-  somal formulation for intravenous use is licensed for  AIDS-related Kaposi’s sarcoma.    Mitoxantrone is structurally related to doxorubicin; it is  used for metastatic breast cancer. Mitoxantrone is also  licensed for treatment of non-Hodgkin’s lymphoma,  adult acute non-lymphocytic leukaemia, and non-  resectable primary hepatocellular carcinoma. It is  given intravenously and is well tolerated, but myelosup-  pression and dose-related cardiotoxicity occur; cardiac  examinations are recommended after a cumulative dose  of 160 mg/m 2 .   Bleomycin is given intravenously or intramuscularly to  treat metastatic germ cell cancer and, in some regimens,  non-Hodgkin’s lymphoma. It causes little bone-marrow  suppression but dermatological toxicity is common and  increased pigmentation particularly affecting the flex-  ures and subcutaneous sclerotic plaques may occur.  Mucositis is also relatively common and an association  with Raynaud’s phenomenon is reported. Hypersensi-  tivity reactions manifest by chills and fevers commonly  occur a few hours after drug administration and may be  prevented by simultaneous administration of a cortico-  steroid, for example hydrocortisone intravenously. The  principal problem associated with the use of bleomycin  is progressive pulmonary fibrosis. This is dose-related,  occurring more commonly at cumulative doses greater  than 300 000 units (see Bleomycin, below) and in the  elderly. Basal lung crepitations or suspicious chest X-ray  changes are an indication to stop therapy with this drug.  Patients who have received extensive treatment with  bleomycin (e.g. cumulative dose more than  100 000 units — see Bleomycin below) may be at risk of  developing respiratory failure if a general anaesthetic is  given with high inspired oxygen concentrations. Anaes-  thetists should be warned of this.   Dactinomycin is principally used to treat paediatric  cancers; it is given intravenously. Its side-effects are  similar to those of doxorubicin, except that cardiac  toxicity is not a problem.   Mitomycin is given intravenously to treat upper gastro-  intestinal and breast cancers and by bladder instillation  for superficial bladder tumours. It causes delayed bone-    marrow toxicity and therefore it is usually administered  at 6-weekly intervals. Prolonged use may result in  permanent bone-marrow damage. It may also cause  lung fibrosis and renal damage.   Renal impairment reduce dose by half if serum-  creatinine 177-354 micromol/litre; reduce dose  further if serum-creatinine greater than 354 micr-  omol/litre   Bleomycin (Non-proprietary) (Ml  Injection, powder for reconstitution, bleomycin (as  sulphate), net price 15 000-unit vial = £15.56  Note To conform to the European Pharmacopoeia vials pre-  viously labelled as containing ‘15 units’ of bleomycin are now  labelled as containing 15 000 units. The amount of bleomycin in  the vial has not changed.   Renal impairment reduce dose by 25% if serum  creatinine 105-265 micromol/litre and by 50% if  serum creatinine greater than 265 micromol/litre   Daunorubicin (Non-proprietary) fMO  Injection, powder for reconstitution, daunorubicin (as  hydrochloride), net price 20-mg vial = £55.00  Note The brand name Cerubidin ® was formerly used.   DaunoXome® (Gilead) (Ml  Concentrate for intravenous infusion, daunorubicin  encapsulated in liposomes. For dilution before use, net  price 50-mg vial = £137.67  For advanced AIDS-related Kaposi’s sarcoma   Contra-indications see notes above; ; severe myo-  cardial insufficiency, recent myocardial infarction,  severe arrhythmias; previous treatment with maxi-  mum cumulative doses of doxorubicin or other  anthracyclines; intravesical use in urinary infections,  bladder inflammation, and in urethral stenosis with  catheterisation difficulties   Hepatic impairment reduce dose according to bili-  rubin concentration; avoid in severe impairment  Pregnancy avoid (teratogenic and toxic in animal  studies); manufacturer of liposomal product advises  effective contraception during and for at least 6  months after treatment in men or women; see also  Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above   Doxorubicin (Non-proprietary) (Ml  Injection, powder for reconstitution, doxorubicin  hydrochloride, net price 10-mg vial = £18.72; 50-mg  vial = £96.86   B Injection, doxorubicin hydrochloride 2mg/mL, net  price 5-mL vial = £20.60, 25-mL vial = £103.00, 100-  mL vial = £275.00   Concentrate for intravenous infusion, pegylated  doxorubicin hydrochloride 2 mg/mL encapsulated in  liposomes. For dilution before use, net price 10-mL  vial = £360.23, 25-mL vial = £712.49  For AIDS-related Kaposi’s sarcoma in patients with low CD4  count and extensive mucocutaneous or visceral disease, for  advanced ovarian cancer when platinum-based chemotherapy  has failed, for progressive multiple myeloma (in combination with  bortezomib) in patients who have received at least one prior  therapy and who have undergone or are unsuitable for bone-  marrow transplantation, and as monotherapy for metastatic  breast cancer in patients with increased cardiac risk   Myocet® (Cephalon) ▼ (MO  Injection, powder for reconstitution, doxorubicin  hydrochloride (as doxorubicin-citrate complex)  encapsulated in liposomes, net price 50-mg vial (with  vials of liposomes and buffer) = £455.68  For use with cyclophosphamide for metastatic breast cancer   Epirubicin (Non-proprietary) (Ml  Injection, epirubicin hydrochloride 2 mg/mL, net  price 5-mL vial = £18.31, 25-mL vial = £92.13, 50-mL  vial = £95.54, 100-mL vial = £306.20   Injection, epirubicin hydrochloride 2 mg/mL, net  price 5-mL vial = £19.31, 25-mL vial = £96.54, 100-mL  vial = £386.16   Indications acute leukaemias (see notes above);  advanced breast cancer after failure of first-line  chemotherapy (not including anthracyclines)  Cautions see section 8.1 and notes above; caution in  handling — irritant to tissues; interactions: Appendix  1 (idarubicin)   recent myocardial infarction; severe arrhythmias  Hepatic impairment reduce dose according to serum-  bilirubin concentration; avoid in severe impairment  Renal impairment reduce dose; avoid in severe  impairment   • By mouth, acute non-lymphocytic leukaemia, mono-  therapy, 30 mg/m 2 daily for 3 days or in combination  therapy, 15-30 mg/m 2 daily for 3 days  Advanced breast cancer, monotherapy, 45 mg/m 2 as a  single dose or 15 mg/m 2 daily for 3 consecutive days;  repeat every 3-4 weeks   Note Max. cumulative dose by mouth (for all indications)  400 mg/m 2   Zavedos® (Pharmacia) (Ml  Capsules, idarubicin hydrochloride, 5 mg (red), net  price 1-cap pack = £41.47; 10 mg (red/white), 1-cap  pack = £69.12. Label: 25  Injection, powder for reconstitution, idarubicin  hydrochloride, net price 5-mg vial = £87.36; 10-mg  vial = £174.72   Mitomycin C Kyowa® (Kyowa Hakko) (Ml  Injection, powder for reconstitution, mitomycin, net  price 2-mg vial = £5.89; 10-mg vial = £19.37; 20-mg  vial = £36.94; 40-mg vial = £73.88 (hosp. only)   Hepatic impairment manufacturer advises use with  caution in severe impairment; manufacturer advises  avoid if serum bilirubin concentration 60 micromol/  litre or greater   Pregnancy avoid; manufacturer advises effective  contraception during and for at least 6 months after  treatment in men or women; see also Reproductive  Function, p. 520   Side-effects see section 8.1 and notes above, ano-  rexia, diarrhoea, abdominal pain, gastro-intestinal  bleeding, constipation, dyspnoea, drowsiness, confu-  sion, paraesthesia, anxiety, amenorrhoea, and transi-  ent blue-green discoloration of urine and blue disco-  loration of skin and nails also reported   Mitoxantrone (Non-proprietary) (§MI  Concentrate for intravenous infusion, mitoxantrone  (as hydrochloride) 2mg/mL, net price 10-mL vial =  £100.00   Concentrate for intravenous infusion, mitoxantrone  (as hydrochloride) 2mg/mL, net price 10-mL vial =  £121.85, 12.5-mL vial = £152.33, 15-mL vial = £203.04    bination therapy for adjuvant treatment of advanced  colon cancer following surgery, for monotherapy or  combination therapy of metastatic colorectal cancer,  and for first-line treatment of advanced gastric cancer  in combination with a platinum-based regimen. Cape-  citabine is also licensed for second-line treatment of  locally advanced or metastatic breast cancer either in  combination with docetaxel (where previous therapy  included an anthracycline) or alone (after failure of a  taxane and anthracycline regimen or where further  anthracycline treatment is not indicated). For the role  of capecitabine in the treatment of breast cancer, see  section 8.3.4. 1.   Capecitabine and oxaliplatin in the adjuvant  treatment of stage III (Dukes’ C) colon cancer  (April 2006)   Capecitabine alone or oxaliplatin combined with  fluorouracil and folinic acid are options for adjuvant  treatment following surgery for stage III (Dukes’ C)  colon cancer.   Capecitabine and tegafur with uracil for  metastatic colorectal cancer (May 2003)  Capecitabine or tegafur with uracil (in combination  with folinic acid) is an option for the first-line treat-  ment of metastatic colorectal cancer.    Antimetabolites are incorporated into new nuclear  material or combine irreversibly with cellular enzymes,  preventing normal cellular division.   Methotrexate inhibits the enzyme dihydrofolate reduc-  tase, essential for the synthesis of purines and pyrimi-  dines. It is given by mouth, intravenously, intramuscu-  larly, or intrathecally.   Methotrexate is used as maintenance therapy for child-  hood acute lymphoblastic leukaemia. Other uses  include choriocarcinoma, non-Hodgkin’s lymphoma,  and a number of solid tumours. Intrathecal metho-  trexate is used in the CNS prophylaxis of childhood  acute lymphoblastic leukaemia, and as a therapy for  established meningeal cancer or lymphoma.  Methotrexate causes myelosuppression, mucositis, and  rarely pneumonitis. It is contra-indicated in significant  renal impairment because it is excreted primarily by the  kidney. It is also contra-indicated in patients with severe  hepatic impairment. It should also be avoided in the  presence of significant pleural effusion or ascites  because it can accumulate in these fluids, and its sub-  sequent return to the circulation may cause myelosup-  pression. Systemic toxicity may follow intrathecal  administration and blood counts should be carefully  monitored.   Folinic acid (section 8.1) following methotrexate admin-  istration helps to prevent methotrexate-induced muco-  sitis or myelosuppression.   Capecitabine, which is metabolised to fluorouracil, is  given by mouth. It is licensed as monotherapy or com-    Cytarabine acts by interfering with pyrimidine synth-  esis. It is given subcutaneously, intravenously, or  intrathecally. Its predominant use is in the induction of  remission of acute myeloblastic leukaemia. It is a potent  myelosuppressant and requires careful haematological  monitoring. A liposomal formulation of cytarabine for  intrathecal use is licensed for lymphomatous meningitis.  Fludarabine is licensed for the initial treatment of  advanced B-cell chronic lymphocytic leukaemia (CLL)  or after first-line treatment in patients with sufficient  bone-marrow reserves; it is usually given by mouth, but  can be given by intravenous injection or infusion. Flu-  darabine is well tolerated but it does cause myelosup-  pression, which may be cumulative. Immunosuppres-  sion is also common (see panel on cladribine and  fludarabine below), and co-trimoxazole is used to pre-  vent pneumocystis infection. Immune-mediated haemo-  lytic anaemia, thrombocytopenia, and neutropenia are  less common side-effects.   The Scottish Medicines Consortium (p. 4) has advised  (October 2006) that fludarabine is accepted for  restricted use for the treatment of B-cell chronic  lymphocytic leukaemia (CLL) in patients with sufficient  bone marrow reserves. First-line treatment should only  be initiated in patients with advanced disease, Rai stages  III/IV (Binet stage C), or Rai stages I/II (Binet stage A/  B) where the patient has disease-related symptoms or  evidence of progressive disease.   Fludarabine monotherapy for the first-line  treatment of chronic lymphocytic leukaemia  (February 2007)   Fludarabine monotherapy, is not recommended for  the first-line treatment of chronic lymphocytic leuk-    Cladribine is given by intravenous infusion for the  treatment of hairy cell leukaemia. It is also given for  chronic lymphocytic leukaemia in patients who have  failed to respond to standard regimens containing an  alkylating agent. Cladribine produces severe myelosup-  pression, with neutropenia, anaemia, and thrombocyto-  penia; haemolytic anaemia has also been reported. High  doses of cladribine have been associated with acute  renal failure and severe neurotoxicity.    Cladribine and fludarabine have a potent and  prolonged immunosuppresive effect. Patients trea-  ted with cladribine or fludarabine are more prone to  serious bacterial, opportunistic fungal, and viral  infections, and prophylactic therapy is recom-  mended in those at risk. To prevent potentially  fatal transfusion-related graft-versus-host reaction,  only irradiated blood products should be adminis-  tered. Prescribes should consult specialist literature  when using highly immunosuppressive drugs.    Clofarabine is licensed for the treatment of acute  lymphoblastic leukaemia in patients aged 1 to 21  years who have relapsed or are refractory after receiv-  ing at least two previous regimens. It is given by intra-  venous infusion.   Nelarabine is licensed for the treatment of T-cell acute  lymphoblastic leukaemia and T-cell lymphoblastic  lymphoma in patients who have relapsed or who are  refractory after receiving at least two previous regi-  mens. It is given by intravenous infusion. Neurotoxicity  is common with nelarabine and close monitoring for  neurological adverse events is strongly recommended —  discontinue if neurotoxicity occurs.   The Scottish Medicines Consortium (p. 4) has advised  (March 2008) that the use of nelarabine (Atriance®)  within NHS Scotland is restricted to bridging treatment  before stem cell transplantation.   Gemcitabine is used intravenously; it is given alone for  elderly patients or for palliative treatment, or with cis-  platin as first-line treatment for locally advanced or  metastatic non-small cell lung cancer. It is also used in  the treatment of locally advanced or metastatic pan-  creatic cancer (see NICE guidance below). Combined  with cisplatin, gemcitabine is also licensed for the treat-  ment of advanced bladder cancer. Combined with car-  boplatin, gemcitabine is licensed for the treatment of  locally advanced or metastatic epithelial ovarian cancer  which has relapsed after a recurrence-free interval of at  least 6 months following previous platinum-based ther-  apy. Combined with paclitaxel, gemcitabine is also  licensed for the treatment of metastatic breast cancer  which has relapsed after previous chemotherapy includ-  ing an anthracycline (see NICE guidance below). Gem-  citabine is generally well tolerated but it can cause mild  gastro-intestinal side-effects, musculoskeletal pain,  influenza-like symptoms and rashes; renal impairment  and pulmonary toxicity have also been reported.  Haemolytic uraemic syndrome has been reported rarely  and gemcitabine should be discontinued if signs of  microangiopathic haemolytic anaemia occur.   The Scottish Medicines Consortium has advised  (November 2006) that gemcitabine is accepted for  restricted use for the treatment of metastatic breast  cancer, which has relapsed following previous chemo-  therapy including an anthracycline (unless contra-indi-  cated).   Gemcitabine, in combination with paclitaxel, is an  option for the treatment of metastatic breast cancer  only when docetaxel monotherapy or docetaxel plus  capecitabine are also considered appropriate.   Gemcitabine is an option for first-line chemotherapy  for patients with advanced or metastatic adenocar-  cinoma of the pancreas and a Karnofsky score of at  least 50 [Karnofsky score is a measure of the ability  to perform ordinary tasks].   Gemcitabine is not recommended for patients who  can have potentially curative surgery. There is insuf-  ficient evidence about its use for second-line treat-  ment of pancreatic adenocarcinoma.    Fluorouracil is usually given intravenously because  absorption following oral administration is unpredict-  able. It is used to treat a number of solid tumours,  including gastro-intestinal tract cancers and breast can-  cer. It is commonly used with folinic acid in advanced  colorectal cancer. It may also be used topically for  certain malignant and pre-malignant skin lesions. Toxi-  city is unusual, but may include myelosuppression,  mucositis, and rarely a cerebellar syndrome. On pro-  longed infusion, a desquamative hand-foot syndrome  may occur.   Pemetrexed inhibits thymidylate transferase and other  folate-dependent enzymes. It is licensed for use with  cisplatin for the treatment of unresectable malignant  pleural mesothelioma which has not previously been  treated with chemotherapy (see NICE guidance, below).  Pemetrexed is also licensed for use with cisplatin for the  first-line treatment of locally advanced or metastatic  non-small cell lung cancer other than predominantly  squamous cell histology (see NICE guidance, below),  and as monotherapy for its second-line treatment (but  see NICE guidance, below). It is also licensed as mono-  therapy for maintenance treatment in locally advanced  or metastatic non-small cell lung cancer other than  predominantly squamous cell histology that has not  progressed immediately following combination therapy  of a platinum compound with either gemcitabine, pacli-  taxel, or docetaxel. Pemetrexed is given by intravenous  infusion.   The Scottish Medicines Consortium (p. 4) has advised  (July 2005) that pemetrexed ( Alimta ®) in combination  with cisplatin is accepted for restricted use within NHS  Scotland for previously untreated patients with stage  III/IV unresectable malignant pleural mesothelioma.   The Scottish Medicines Consortium (p. 4) has advised  (January 2010) that pemetrexed [Alimta®) is accepted  for restricted use within NHS Scotland in combination  with cisplatin for the first-line treatment of locally  advanced or metastatic non-small cell lung cancer other  than predominantly squamous cell histology; it is  restricted to patients in whom the histology of the  tumour has been confirmed as adenocarcinoma or large  cell carcinoma.    The Scottish Medicines Consortium (p. 4) has advised  (August 2008) that pemetrexed ( Alimta ®) is accepted  for restricted use within NHS Scotland as monotherapy  for the second-line treatment of locally advanced or  metastatic non-small cell lung cancer without predomi-  nantly squamous cell histology; it is restricted for use in  patients with good performance status who would  otherwise be eligible for docetaxel treatment.   Pemetrexed for the treatment of malignant  pleural mesothelioma (January 2008)  Pemetrexed is an option for the treatment of malig-  nant pleural mesothelioma only in patients who have  a WHO performance status of 0 or 1 [WHO perfor-  mance status is a measure of the ability to perform  ordinary tasks], who are considered to have  advanced disease and for whom surgical resection  is considered inappropriate.   Pemetrexed for the first-line treatment of  non-small cell lung cancer (September  2009)   Pemetrexed, in combination with cisplatin, is an  option for the first-line treatment of locally advanced  or metastatic non-small cell lung cancer only if the  histology of the tumour has been confirmed as  adenocarcinoma or large-cell carcinoma.   Pemetrexed for the treatment of non-small  cell lung cancer (August 2007)   Pemetrexed is not recommended for the treatment  of locally advanced or metastatic non-small cell lung  cancer which has previously been treated with  chemotherapy.   Pemetrexed for the treatment of non-small  cell lung cancer (June 2010)   Pemetrexed is an option for the maintenance treat-  ment of locally advanced or metastatic non-small  cell lung cancer other than predominantly squamous  cell histology that has not progressed immediately  following combination therapy of a platinum com-  pound with either gemcitabine, paclitaxel, or doce-  taxel.    Raltitrexed, a thymidylate synthase inhibitor, is given  intravenously for palliation of advanced colorectal can-  cer when fluorouracil and folinic acid cannot be used. It  is probably of similar efficacy to fluorouracil. Raltitrexed  is generally well tolerated, but can cause marked mye-  losuppression and gastro-intestinal side-effects.    Mercaptopurine is used as maintenance therapy for the  acute leukaemias and in the management of ulcerative  colitis and Crohn’s disease (section 1.5.3). Azathioprine,    which is metabolised to mercaptopurine, is generally  used as an immunosuppressant (section 8.2.1 and sec-  tion 10.1.3). The dose of both drugs should be reduced if  the patient is receiving allopurinol since it interferes  with their metabolism.   Tegafur (in combination with uracil) is given by mouth,  together with calcium folinate, in the management of  metastatic colorectal cancer. Tegafur is a prodrug of  fluorouracil; uracil inhibits the degradation of fluoro-  uracil. Tegafur (with uracil) has been shown to be of  similar efficacy as a combination of fluorouracil and  folinic acid for metastatic colorectal cancer. For NICE  guidance on capecitabine and tegafur with uracil for  metastatic colorectal cancer, see above.   Tioguanine is given by mouth for the treatment of acute  leukaemias and chronic myeloid leukaemia. It can be  given at various stages of treatment in short-term  cycles. Tioguanine has a lower incidence of gastro-  intestinal side-effects than mercaptopurine. Long-term  therapy is no longer recommended because of the high  risk of liver toxicity; treatment with tioguanine should  be discontinued if liver toxicity develops.   Azacitidine is a pyrimidine analogue that is given by  subcutaneous injection. It is used in the treatment of  intermediate-2 and high-risk myelodysplastic syn-  dromes, chronic myelomonocytic leukaemia, and  acute myeloid leukaemia, in adults who are not eligible  for haemotopoietic stem cell transplantation.    Cautions see section 8.1; history of severe congestive  heart failure, unstable cardiac or pulmonary disease;  monitor for bleeding   Hepatic impairment caution in severe impairment  Renal impairment delay next treatment cycle if  serum-creatinine or blood urea nitrogen greater than  twice baseline value and above the upper level of  normal until values return to normal or baseline, and  then reduce dose by 50% on the next treatment cycle.  Reduce dose by 50% on the next treatment cycle if  serum-bicarbonate concentration less than 20 mmol/  litre    Pregnancy avoid (toxicity in animal studies); manu-  facturer advises effective contraception during and for  3 months after treatment in men or women; see also  Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also gastro-intestinal  disturbances (including diarrhoea, constipation,  abdominal pain, and dyspepsia), anorexia; hyper-  tension, hypotension; dyspnoea, pneumonia; anxiety,  insomnia, dizziness, headache, drowsiness; haema-  turia; hypokalaemia; arthralgia, myalgia; injection-site  reactions, rash, haematoma; haemorrhage (including  cerebral haemorrhage); less commonly hypersensi-  tivity reactions (including anaphylactic reactions);  hepatic coma and renal failure also reported   Renal impairment reduce starting dose of 1.25 g/m 2  to 75% if creatinine clearance 30-50 mL/minute;  avoid if creatinine clearance less than 30 mL/minute  Pregnancy avoid (teratogenic in animal studies); see  also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; hand-foot (desquama-  tive) syndrome; diarrhoea  Dose   • Stage III colon cancer, adjuvant following surgery,  monotherapy, ADULT over 18 years 1.25 g/m 2 twice  daily for 14 days, subsequent courses repeated after a  7-day interval; recommended duration of treatment 6  months   • Stage III colon cancer, adjuvant following surgery, in  combination therapy, ADULT over 18 years 0.8-1 g/m 2  twice daily for 14 days, subsequent courses repeated  after a 7-day interval; recommended duration of  treatment 6 months   • Metastatic colorectal cancer, monotherapy, ADULT  over 18 years 1.25 g/m 2 twice daily for 14 days,  subsequent courses repeated after a 7-day interval   • Metastatic colorectal cancer, in combination therapy,  ADULT over 18 years 0.8-1 g/m 2 twice daily for 14  days, subsequent courses repeated after a 7-day  interval   B tinum-based regimen, ADULT over 18 years 0.8-1 g/m 2  twice daily for 14 days, subsequent courses repeated  after a 7-day interval or 625 mg/m 2 twice daily given  continuously   • Locally advanced or metastatic breast cancer,  monotherapy or in combination with docetaxel, ADULT  over 18 years 1.25 g/m 2 twice daily for 14 days,  subsequent courses repeated after a 7-day interval  Note Adjust dose according to tolerability — consult product  literature   Tablets, f/c, peach, capecitabine 150 mg, net price  60-tab pack = £40.02; 500 mg, 120-tab pack =  £265.55. Label: 21   Renal impairment regular monitoring recommended  Pregnancy avoid (teratogenic in animal studies);  manufacturer advises that men should not father  children during and for 6 months after treatment; see  also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above; also  constipation, diarrhoea, abdominal pain, flatulence;  oedema, tachycardia; cough, dyspnoea; dizziness,    insomnia, anxiety, headache; chills, asthenia, malaise;  myalgia, arthralgia; sweating, rash, pruritus, and  purpura   Concentrate for intravenous infusion, cladribine  1 mg/mL. For dilution and use as an infusion, net  price 10-mL vial = £159.70   For hairy cell leukaemia and for B-cell chronic lymphocytic  leukaemia in patients who have failed to respond to standard  regimens containing an alkylating agent   Injection (for subcutaneous use only — no dilution  required), cladribine 2 mg/mL, net price 5-mL vial =  £165.00   Hepatic impairment manufacturer advises caution in  mild to moderate impairment; avoid in severe  impairment   Renal impairment manufacturer advises caution in  mild to moderate impairment; avoid in severe  impairment   Side-effects see section 8.1; also diarrhoea, abdo-  minal pain, jaundice; tachycardia, flushing, hypo-  tension, pericardial effusion, oedema, haematoma;  dyspnoea, cough; anxiety, agitation, dizziness, drow-  siness, headache, paraesthesia, peripheral neuropathy,  restlessness; haematuria; arthralgia, myalgia; rash,  pruritus, hand-foot (desquamative) syndrome, sweat-  ing; pancreatitis also reported   Evoltra® (Genzyme) ▼ (S  Concentrate for intravenous infusion, clofarabine  1 mg/mL, net price 20-mL vial = £1153.20   Cytarabine (Non-proprietary) [Ml  Injection (for intravenous, subcutaneous, or intrathe-  cal use), cytarabine 20 mg/mL, net price 5-mL vial =  £4.00   Injection (for intravenous or subcutaneous use),  cytarabine 20 mg/mL, net price 5-mL vial = £3.90, 25-  mL vial = £19.50; 100 mg/mL, 1-mL vial = £4.00, 5-  mL vial = £20.00, 10-mL vial = £39.00, 20-mL vial =  £77.50   Note The Scottish Medicines Consortium (p. 4) has advised  (July 2007) that liposomal cytarabine suspension  (DepoCyte®) is not recommended for use within NHS  Scotland for the intrathecal treatment of lymphomatous  meningitis   Injection, fluorouracil (as sodium salt) 25 mg/mL, net  price 10-mL vial = £3.20, 20-mL vial = £6.40, 100-mL  vial = £32.00; 50 mg/mL, 10-mL vial = £6.40, 20-mL  vial = £12.80, 50-mL vial = £32.00, 100-mL vial =  £64.00   Cautions see section 8.1 and notes above; monitor for  signs of haemolysis; monitor for neurological toxicity;  worsening of existing and increased susceptibility to  skin cancer; interactions: Appendix 1 (fludarabine)   Renal impairment reduce dose by up to 50% if  creatinine clearance 30-70 mL/minute; avoid if  creatinine clearance less than 30 mL/minute   Pregnancy avoid (embryotoxic and teratogenic in  animal studies); manufacturer advises effective  contraception during and for at least 6 months after  treatment in men or women; see also Reproductive  Function, p. 520   Side-effects see section 8.1 and notes above; also  diarrhoea, anorexia; oedema; pneumonia, cough;  peripheral neuropathy, visual disturbances; chills,  fever, malaise, weakness; rash  Dose   • By mouth, ADULT 40 mg/m 2 for 5 days every 28 days  usually for 6 cycles   Fludarabine (Non-proprietary) (Ml  Injection, powder for reconstitution, fludarabine  phosphate, net price 50-mg vial = £140.40   Tablets, f/c, pink, fludarabine phosphate 10 mg, net  price 15-tab pack = £268.12, 20-tab pack = £350.70  Injection, powder for reconstitution, fludarabine  phosphate, net price 50-mg vial = £147.07   Indications see notes above; pre-malignant and  malignant skin lesions (section 13.8.1)   Hepatic impairment manufacturer advises caution  Renal impairment manufacturer advises caution  Pregnancy avoid (teratogenic in animal studies);  manufacturer advises effective contraception during  treatment; men must avoid fathering a child during  and for 6 months after treatment; see also Repro-  ductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above   Gemcitabine (Non-proprietary) (Ml  Injection, powder for reconstitution, gemcitabine (as  hydrochloride), net price 200-mg vial = £32.00, 1-g  vial = £162.00, 1.5-g vial = £213.93, 2-g vial = £324.00   Injection, powder for reconstitution, gemcitabine (as  hydrochloride), net price 200-mg vial = £32.55; 1-g  vial = £162.76   Indications acute leukaemias and chronic myeloid  leukaemia; inflammatory bowel disease [unlicensed  indication] (section 1.5.3)   Tablets, yellow, scored, mercaptopurine 50 mg, net  price 25-tab pack = £22.54   Indications see notes above and under Dose; Crohn’s  disease [unlicensed indication] (section 1.5.3); rheu-  matoid arthritis (section 10.1.3); psoriasis (section  13.5.3)   Cautions see section 8.1, notes above and section  10.1.3; interactions: Appendix 1 (methotrexate)    Renal impairment reduce dose; risk of nephrotoxicty  at high doses; avoid in severe impairment   Pregnancy avoid (teratogenic; fertility may be reduced  during therapy but this may be reversible); manufac-  turer advises effective contraception during and for at  least 3 months after treatment in men or women; see  also Reproductive Function, p. 520    • By intravenous injection or infusion, or by intra-arte-  rial infusion, or by intramuscular injection, or  intrathecal administration, consult product literature   Methotrexate (Non-proprietary) £mD  Injection, methotrexate (as sodium salt) 2.5mg/mL,  net price 2-mL vial = £1.68; 25mg/mL, 2-mL vial =  £3.00, 20-mL vial = £30.00  Injection, methotrexate lOOmg/mL (not for  intrathecal use), net price 10-mL vial = £78.33, 50-mL  vial = £380.07   B Cautions see section 8.1 and notes above; previous or  concurrent intrathecal chemotherapy or craniospinal  irradiation (increased risk of neurotoxicity)   Driving May affect performance of skilled tasks (e.g. driving)  Pregnancy avoid (toxicity in animal studies); manu-  facturer advises effective contraception during and for  at least 3 months after treatment in men and women;  see also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also abdominal pain,  constipation, taste disturbance, anorexia, diarrhoea;  hypotension, oedema; pleural effusion, wheezing,  dyspnoea, cough; confusion, seizures, amnesia,  drowsiness, peripheral neurological disorders,  hypoaesthesia, paraesthesia, ataxia, demyelination,  tremor, dizziness, headache, asthenia, fatigue; pyrexia;  electrolyte disturbances; blurred vision; muscle  weakness, myalgia, arthralgia; benign and malignant  tumours also reported   Indications see notes above  Cautions see section 8.1 and notes above; history of  cardiovascular disease; diabetes; prophylactic folic  acid and vitamin B 12 supplementation required (con-  sult product literature); concomitant nephrotoxic  drugs including non-steroidal anti-inflammatory   Pregnancy avoid (toxicity in animal studies); manu-  facturer advises effective contraception during treat-  ment; men must avoid fathering a child during and for  6 months after treatment; see also Reproductive  Function, p. 520   Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also gastro-intestinal  disturbances; oedema; neuropathy; dehydration;  conjunctivitis, increased lacrimation; skin disorders;  less commonly colitis, arrhythmias, and interstitial  pneumonitis; rarely hepatitis; peripheral ischaemia  and acute renal failure also reported   Injection, powder for reconstitution, pemetrexed (as  disodium), net price 100-mg vial = £160.00; 500-mg  vial = £800.00   Hepatic impairment caution in mild to moderate  impairment; avoid if severe  Renal impairment reduce dose and increase dosing  interval if creatinine clearance less than 65 mL/min-  ute (consult product literature); avoid if creatinine  clearance less than 25 mL/minute  Pregnancy pregnancy must be excluded before treat-  ment; ensure effective contraception during and for at  least 6 months after treatment in men or women; see  also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above   Hepatic impairment manufacturer advises monitor  liver function in mild to moderate impairment and  avoid in severe impairment  Renal impairment use with caution  Pregnancy avoid; manufacturer advises effective  contraception during and for 3 months after treatment  in men or women; see also Reproductive Function,  p. 520   • ADULT, tegafur 300 mg/m 2 (with uracil 672 mg/m 2 )  daily in 3 divided doses for 28 days; subsequent  courses repeated after 7-day interval; for dose  adjustment due to toxicity, consult product literature    Uftoral® (Merck Serono) (5°M1  Capsules, tegafur 100 mg, uracil 224 mg, net price 36-  cap pack = £96.12, 120-cap pack = £320.40. Label: 23   Indications see notes above  Cautions see section 8.1 and notes above; monitor  liver function weekly — discontinue if liver toxicity  develops; interactions: Appendix 1 (tioguanine)  Hepatic impairment reduce dose  Renal impairment reduce dose  Pregnancy avoid (teratogenicity reported when men  receiving tioguanine have fathered children); ensure  effective contraception during treatment in men or  women; see also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also stomatitis and  hepatotoxicity; rarely intestinal necrosis and perfora-  tion  Dose   The vinca alkaloids, vinblastine, vincristine, and vin-  desine, are used to treat a variety of cancers including  leukaemias, lymphomas, and some solid tumours (e.g.  breast and lung cancer). Vinorelbine is a semi-synthetic  vinca alkaloid; it is given intravenously or orally for the  treatment of advanced breast cancer and for advanced  non-small cell lung cancer. For the role of vinorelbine in  the treatment of breast cancer, see section 8. 3. 4.1.  Vinflunine is licensed as monotherapy for the treat-  ment of advanced or metastatic transitional cell carci-  noma of the urothelial tract after failure of a platinum-  containing regimen.   Neurotoxicity, usually as peripheral or autonomic neuro-  pathy, occurs with all vinca alkaloids and is a limiting  side-effect of vincristine; it occurs less often with vin-  desine, vinblastine, vinorelbine, and vinflunine. Patients  with neurotoxicity commonly have peripheral paraes-  thesia, loss of deep tendon reflexes, abdominal pain, and  constipation; ototoxicity has been reported. If symp-  toms of neurotoxicity are severe, doses should be  reduced. Motor weakness can also occur, and increasing  motor weakness calls for dose reduction or discontinua-  tion of these drugs. Recovery from neurotoxic effects is  usually slow but complete.   Myelosuppression is a dose-limiting side-effect of vin-  blastine, vindesine, vinorelbine, and vinflunine; vincrist-  ine causes negligible myelosuppression. The vinca alka-  loids cause severe local irritation and care must be  taken to avoid extravasation. Severe bronchospasm  has been reported following administration of the  vinca alkaloids (more commonly when used in combi-  nation with mitomycin-C).   Vinblastine, vincristine, vindesine, vinflunine, and  vinorelbine injections are for intravenous adminis-  tration only. Inadvertent intrathecal administration  can cause severe neurotoxicity, which is usually  fatal.   The National Patient Safety Agency has advised  (August 2008) that adult and teenage patients trea-  ted in an adult or adolescent unit should receive  their vinca alkaloid dose in a 50 mL minibag. Teen-  agers and children treated in a child unit may receive  their vinca alkaloid dose in a syringe.    Etoposide may be given orally or by slow intravenous  infusion, the oral dose being double the intravenous  dose. A preparation containing etoposide phosphate  can be given by intravenous injection or infusion. Etopo-  side is usually given daily for 3-5 days and courses  should not be repeated more frequently than at intervals  of 21 days. It has particularly useful activity in small cell  carcinoma of the bronchus, the lymphomas, and testi-  cular cancer.   Etoposide (Non-proprietary) (Ml  Concentrate for intravenous infusion, etoposide  20mg/mL, net price 5-mLvial = £12.15, 10-mL vial =  £29.00, 25-mL vial = £60.75  Brands include Eposin ®    Etopophos® (Bristol-Myers Squibb) (Ml  Injection, powder for reconstitution, etoposide (as  phosphate), net price 100-mg vial = £26.17 (hosp.  only)   Vepesid® (Bristol-Myers Squibb) (Ml  Capsules, both pink, etoposide 50 mg, net price 20 =  £99.82; 100 mg, 10-cap pack = £87.23 (hosp. only).  Label: 23   Cautions see section 8.1 and notes above; caution in  handling; interactions: Appendix 1 (vinblastine)   Pregnancy avoid (teratogenicity and fetal loss in ani-  mal studies); see also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above; also  rarely inappropriate secretion of antidiuretic horm-  one; diarrhoea, intestinal necrosis, paralytic ileus,  seizures, urinary retention, muscle wasting, and eye  disorders also reported; irritant to tissues   Vincristine (Non-proprietary) IMl  Injection, vincristine sulphate 1 mg/mL, net price 1-  mL vial = £13.47; 2-mL vial = £26.66; 5-mL vial =  £44.16   Injection, vincristine sulphate 1 mg/mL, net price 1-  mL vial = £14.18; 2-mL vial = £28.05    Indications see notes above  Cautions see section 8.1 and notes above; neuro-  muscular disease; caution in handling  Contra-indications see section 8.1 and notes above  Important Intrathecal injection contra-indicated  Hepatic impairment dose reduction may be neces-  sary   Cautions see section 8.1 and notes above; cardiovas-  cular disease; QT-interval prolongation (avoid hypo-  kalaemia or concomitant use of drugs that prolong  QT-interval); interactions: Appendix 1 (vinflunine)  Contra-indications see notes above  Important Intrathecal injection contra-indicated  Hepatic impairment reduce dose — consult product  literature   Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above; also  anorexia, diarrhoea, dyspepsia; tachycardia, hyper-  tension, hypotension, thrombosis; oedema; insomnia,  fatigue; dehydration; cutaneous reactions, sweating;  less commonly increased weight, myocardial infarc-  tion, renal failure; also reported QT-interval prolon-  gation, inappropriate anti-diuretic hormone secretion,  blurred vision   Concentrate for intravenous infusion, vinflunine (as  ditartrate) 25 mg/mL, net price 2-mL vial = £212.50,  10-mL vial = £1062.50   Cautions see section 8.1 and notes above; ischaemic  heart disease; caution in handling; interactions:  Appendix 1 (vinorelbine)   Contra-indications see section 8.1 and notes above;  with capsules previous significant surgical resection  of stomach or small bowel, long-term oxygen therapy,  concurrent radiotherapy if treating the liver  Important Intrathecal injection contra-indicated   Hepatic impairment reduce oral dose in moderate  impairment, avoid oral use in severe impairment;  reduce intravenous dose in severe impairment; con-  sult product literature   Pregnancy avoid unless essential (teratogenicity, and  fetal loss in animal studies); manufacturer advises  effective contraception during and for 3 months after  treatment; men must avoid fathering a child during  and for 3 months after treatment; see also Repro-  ductive Function, p. 520   • By mouth, 60 mg/m 2 once weekly for 3 weeks,  increased if tolerated to 80 mg/m 2 once weekly; max.  160 mg once weekly   Vinorelbine (Non-proprietary) (Mi  Concentrate for intravenous infusion, vinorelbine  (as tartrate) 10 mg/mL, net price 1-mL vial = £29.00,  5-mL vial = £139.00   Concentrate for intravenous infusion, vinorelbine  (as tartrate) 10 mg/mL, net price 1-mL vial = £29.75;  5-mL vial = £139.98   Capsules, vinorelbine (as tartrate) 20 mg (brown), net  price 1-cap pack = £43.98; 30 mg (pink), 1-cap pack =  £65.98; 80 mg (yellow), 1-cap pack = £175.92.   Amsacrine has an action and toxic effects similar to  those of doxorubicin (section 8.1.2) and is given intra-  venously. It is occasionally used in acute myeloid leuk-  aemia. Side-effects include myelosuppression and  mucositis; electrolytes should be monitored as fatal  arrhythmias have occurred in association with hypokal-  aemia.    Side-effects see section 8.1; diarrhoea, leucocyte  activation syndrome (unexplained fever, dyspnoea,  weight gain, pulmonary infiltrates, pleural or pericar-  dial effusions, with or without leucocytosis — treat  with high dose corticosteroids, consult product lit-  erature); hyperglycaemia, hypokalaemia, QT interval  prolongation, atrial fibrillation, atrial flutter,  haemorrhage, pleuritic pain, musculoskeletal pain,  paraesthesia, fatigue; less commonly abdominal pain,  tachycardia, vasculitis, hypotension, oedema, pneu-  monitis, seizures, renal failure, blurred vision, and rash   Concentrate for intravenous infusion, amsacrine  5 mg (as lactate)/mL, when reconstituted by mixing  two solutions, net price 1.5-mL (75-mg) amp with  13.5-mL diluent vial = £54.08 (hosp. only)   Arsenic trioxide is licensed for acute promyelocytic  leukaemia in patients who have relapsed or failed to  respond to previous treatment with a retinoid and  chemotherapy.   Cautions see section 8.1; correct electrolyte abnorm-  alities before treatment; ECG required before and  during treatment — consult product literature; avoid  concomitant administration with drugs causing QT  interval prolongation, hypokalaemia, and hypo-  magnesaemia; previous treatment with anthracyclines  (increased risk of QT interval prolongation); interac-  tions: Appendix 1 (arsenic trioxide)   Hepatic impairment manufacturer advises caution —  limited information available  Renal impairment manufacturer advises caution —  limited information available  Pregnancy avoid (teratogenic and embryotoxic in  animal studies); manufacturer advises effective  contraception during treatment in men and women;  see also Reproductive function, p. 520  Breast-feeding discontinue breast-feeding    Bevacizumab is a monoclonal antibody that inhibits  vascular endothelial growth factor. It is licensed for the  treatment of metastatic colorectal cancer in combina-  tion with fluoropyrimidine-based chemotherapy (but  see NICE guidance below). It is also licensed for first-  line treatment of metastatic breast cancer in combina-  tion with paclitaxel, or docetaxel, and also for advanced  or metastatic renal cell carcinoma in combination with  interferon alfa-2a (but see NICE Guidance, p. 545).  Bevacizumab, in combination with platinum-based  chemotherapy, is licensed for first-line treatment of  unresectable advanced, metastatic or recurrent non-  small cell lung cancer other than predominantly squa-  mous cell histology. Bevacizumab is given by intra-  venous infusion.    MHRA/CHM advice  Bevacizumab and sunitinib: risk of  osteonecrosis of the jaw (January 2011)  Treatment with bevacizumab or sunitinib may be a  risk factor for the development of osteonecrosis of  the jaw.   Patients treated with bevacizumab or sunitinib, who  have previously received bisphosphonates, or are  treated concurrently with bisphosphonates, may be  particularly at risk.   Dental examination and appropriate preventive den-  tistry should be considered before treatment with  bevacizumab or sunitinib.   If possible, invasive dental procedures should be  avoided in patients treated with bevacizumab or  sunitinib who have previously received, or who are  currently receiving, intravenous bisphosphonates.   Bevacizumab and cetuximab for the  treatment of metastatic colorectal cancer  (January 2007)   • Bevacizumab in combination with fluorouracil  plus folinic acid, with or without irinotecan, is  not recommended for the first-line treatment of  metastatic colorectal cancer;   • Cetuximab in combination with irinotecan is not  recommended for the second-line or subsequent  treatment of metastatic colorectal cancer after  the failure of an irinotecan-containing chemo-  therapy regimen.   Cautions see section 8.1; intra-abdominal inflamma-  tion (risk of gastro-intestinal perforation); increased  risk of fistulas (discontinue permanently if tracheo-  oesophageal or grade 4 fistula develops); withhold  treatment for elective surgery and avoid for at least 28  days after major surgery or until wound fully healed;  history of hypertension (increased risk of proteinur-  ia — discontinue if nephrotic syndrome); uncontrolled  hypertension; monitor blood pressure; history of  arterial thromboembolism; history of cardiovascular  disease (increased risk of cardiovascular events  especially in the elderly); monitor for congestive heart  failure; increased risk of haemorrhage (especially  tumour-associated haemorrhage); monitor for rever-  sible posterior leucoencephalopathy syndrome (pre-  senting as seizures, headache, altered mental status,  visual disturbance or cortical blindness, with or  without hypertension); untreated CNS metastases;  consider dental check-up before initiating treatment  (risk of osteonecrosis of the jaw, see MHRA/CHM  advice, above)   Breast-feeding manufacturer advises avoid breast-  feeding during and for at least 6 months after treat-  ment   Side-effects see section 8.1; gastro-intestinal per-  foration, intestinal obstruction, abdominal pain,  diarrhoea, constipation, taste disturbances; mucocu-  taneous bleeding, haemorrhage, hypoxia, arterial  thromboembolism, congestive heart failure, syncope,  supraventricular tachycardia, hypertension (see also  Cautions); dyspnoea, rhinitis; anorexia, drowsiness,  headache, peripheral neuropathy, asthenia, lethargy;  pyrexia; proteinuria; dehydration; eye disorders; fis-  tulas, pulmonary hypertension, impaired wound  healing, osteonecrosis of the jaw (see MHRA/CHM  advice, above), hand-foot syndrome, exfoliative  dermatitis, dry skin, skin discoloration, and hyper-  sensitivity reactions (including flushing, rash, hypo-  tension, chest pain, and rigors) also reported   Concentrate for intravenous infusion, bevacizumab  25mg/mL, net price 4-ml (100-mg) vial = £242.66,  16-ml (400-mg) vial = £924.40   Bexarotene is an agonist at the retinoid X receptor,  which is involved in the regulation of cell differentiation  and proliferation. It is associated with little myelosup-  pression or immunosuppression. Bexarotene can cause  regression of cutaneous T-cell lymphoma. The main  adverse effects are hyperlipidaemia, hypothyroidism,  leucopenia, headache, rash, and pruritus.   The Scottish Medicines Consortium (p. 4) has advised  (November 2002) that bexarotene is recommended for  restricted use as a second-line treatment for patients  with advanced cutaneous T-cell lymphoma.    Indications skin manifestations of cutaneous T-cell  lymphoma refractory to previous systemic treatment   Cautions see section 8.1 and notes above; hyperlipid-  aemia (avoid if uncontrolled), hypothyroidism (avoid if  uncontrolled); hypersensitivity to retinoids; avoid in  acute porphyria (section 9.8.2); interactions: Appen-  dix 1 (bexarotene)   Pregnancy avoid; manufacturer advises effective  contraception during and for at least 1 month after  treatment in men or women; see also Reproductive  Function, p. 520   • Initially 300 mg/m 2 daily as a single dose with a meal;  adjust dose according to response   Targretin® (Cephalon) (Ml  Capsules, bexarotene 75 mg in a liquid suspension,  net price 100-cap pack = £937.50   Bortezomib, a proteasome inhibitor, is licensed as  monotherapy for the treatment of multiple myeloma  that has progressed despite the use of at least one  therapy, and where the patient has already had, or is  unable to have, bone-marrow transplantation. It is also  licensed for use in combination with melphalan and  prednisolone for the treatment of previously untreated  multiple myeloma in patients who are not eligible for  high-dose chemotherapy with bone marrow transplan-  tation. Bortezomib is given by intravenous injection.   Bortezomib monotherapy is an option for the treat-  ment of progressive multiple myeloma in patients  who are at first relapse having received one prior  therapy and who have undergone, or are unsuitable  for, bone-marrow transplantation, under the follow-  ing circumstances:   • the response to bortezomib is measured using  serum M protein after a maximum of four cycles  of treatment, and treatment is continued only in  patients who have a reduction in serum M  protein of 50% or more (where serum M protein  is not measurable, an appropriate alternative  biochemical measure of response should be  used) and   • the manufacturer rebates the full cost of borte-  zomib if there is an inadequate response (as  defined above) after four cycles of treatment.    zoster infection; history of seizures; amyloidosis; risk  of neuropathy — consult product literature; monitor  blood-glucose concentration in patients on oral anti-  diabetics; interactions: Appendix 1 (bortezomib)  Contra-indications acute diffuse infiltrative pulm-  onary disease; pericardial disease  Hepatic impairment manufacturer advises caution in  mild to moderate impairment — consider dose reduc-  tion; avoid in severe impairment  Renal impairment no information available for  creatinine clearance less than 20mL/minute/1.73 m 2  Pregnancy manufacturer advises effective contra-  ception during and for 3 months after treatment in  men or women — toxicity in animal studies; see also  Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also gastro-intestinal  disturbances including constipation (cases of ileus  reported), taste disturbance, dry mouth, decreased  appetite; postural hypotension, hypertension, hae-  matoma, phlebitis, chest pain, oedema; dyspnoea,  cough; confusion, depression, insomnia, anxiety, per-  ipheral neuropathy, paraesthesia, headache, dizziness,  tremor, asthenia, fatigue; reactivation of herpes zoster  infection, influenza-like symptoms; renal impairment,  dysuria; dehydration, hypokalaemia, hyperglycaemia;  muscle cramps, arthralgia, bone pain; blurred vision,  eye pain; epistaxis; urticaria, pruritus, erythema, dry  skin, eczema, rash, increased sweating; less com-  monly syncope, seizures; reversible posterior leu-  coencephalopathy syndrome (discontinue treatment),  toxic epidermal necrolysis, Sweet’s syndrome, and  vasculitic rash also reported    Velcade® (Janssen-Cilag) T (Ml  Injection, powder for reconstitution, bortezomib (as  mannitol boronic ester), net price 3.5-mg vial =  £762.38   Cetuximab is licensed for the treatment of metastatic  colorectal cancer in patients with tumours expressing  epidermal growth factor receptor, as combination ther-  apy, or as monotherapy if oxaliplatin- and irinotecan-  based therapy has failed or if irinotecan is not tolerated  (but see NICE guidance below, and under Bevacizumab  on p. 537). Cetuximab is also licensed, in combination  with radiotherapy, for the treatment of locally advanced  squamous cell cancer of the head and neck and in  combination with platinum-based chemotherapy for  recurrent or metastatic squamous cell cancer of the  head and neck (but see NICE guidance below).  Cetuximab is given by intravenous infusion. Patients  must receive an antihistamine and a corticosteroid  before infusion. Resuscitation facilities should be avail-  able and treatment should be initiated by a specialist.   The Scottish Medicines Consortium (p. 4) has advised  (January 2010) that cetuximab ( Erbitux ®) is accepted  for restricted use within NHS Scotland, in combination  with chemotherapy, for metastatic colorectal cancer in  patients with tumours expressing epidermal growth  factor; it is restricted to patients with non-resectable  metastases confined to the liver, who have not  previously received chemotherapy.   Cetuximab for the treatment of locally  advanced squamous cell cancer of the head  and neck (June 2008)   Cetuximab in combination with radiotherapy is an  option for the treatment of locally advanced squa-  mous cell cancer of the head and neck in patients  who have a Kamofsky performance status of 90% or  greater and when all forms of platinum-based che-  moradiotherapy treatment are contra-indicated.   Cetuximab for the treatment of recurrent or  metastatic squamous cell cancer of the head  and neck (June 2009)   Cetuximab in combination with platinum-based  chemotherapy is not recommended for the treat-  ment of recurrent or metastatic squamous cell can-  cer of the head and neck.   Cetuximab for the first-line treatment of  metastatic colorectal cancer (August 2009)  Cetuximab in combination with fluorouracil, folinic  acid and oxaliplatin is an option for the first-line  treatment of metastatic colorectal cancer under the  following circumstances:   • the primary tumour has been resected or is  potentially operable;   • the metastatic disease is confined to the liver  and is unresectable; and   • the patient is fit to undergo surgery to resect the  primary colorectal tumour and to undergo liver  surgery if the metastases become resectable  after treatment with cetuximab.   In patients unable to tolerate oxaliplatin, or in whom  oxaliplatin is contra-indicated, cetuximab in combi-  nation with fluorouracil, folinic acid and irinotecan  can be used as an alternative.   In addition, the manufacturer is required to rebate  16% of the amount of cetuximab used per patient  when used in combination with fluorouracil, folinic  acid, and oxaliplatin.   Patients who meet the above criteria should receive  cetuximab for no more than 16 weeks. At 16 weeks,  cetuximab should be stopped and the patient should  be assessed for resection of liver metastases.   Contra-indications KRAS mutated colorectal  tumours (avoid if KRAS tumour status unknown)   Breast-feeding avoid breast-feeding during and for 2  months after treatment — no information available   Side-effects infusion-related reactions including dys-  pnoea, dizziness, chills, fever, and hypersensitivity  reactions (possibly delayed onset) such as rash, urti-    caria, bronchospasm, hypotension, hypertension, and  shock; nausea, vomiting, diarrhoea; headache; skin  reactions including acne, pruritus, dry skin, desqua-  mation, hypertrichosis, and nail disorders; con-  junctivitis; hypomagnesaemia, hypocalcaemia   Erbitux® (Merck Serono) (Ml  Intravenous infusion, cetuximab 5mg/mL, net price  20-mL vial = £178.10, 100-mL vial = £890.50   Crisantaspase is the enzyme asparaginase produced  by Erwinia chrysanthemi. It is given intramuscularly,  intravenously, or subcutaneously almost exclusively in  acute lymphoblastic leukaemia. Facilities for the man-  agement of anaphylaxis should be available.   Side-effects see section 8.1; also liver dysfunction,  pancreatitis, diarrhoea; coagulation disorders;  lethargy, drowsiness, confusion, dizziness, neurotoxi-  city, convulsions, headache; less commonly changes  in blood lipids, anaphylaxis, hyperglycaemia; rarely  CNS depression; very rarely myalgia; abdominal pain  and hypertension also reported   Carmustine implants and temozolomide for  the treatment of newly diagnosed high-  grade glioma (June 2007)   Temozolomide is an option for the treatment of  newly diagnosed glioblastoma multiforme in  patients with a WHO performance status of 0 or 1.  Carmustine implants are an option for the treatment  of newly diagnosed high-grade (Grade 3 or 4) glioma  only for patients in whom at least 90% of the tumour  has been resected.   Hepatic impairment dose reduction may be required  in combined renal and hepatic impairment; avoid in  severe impairment   Renal impairment dose reduction may be required in  combined renal and hepatic impairment; avoid in  severe impairment   Pregnancy avoid (carcinogenic and teratogenic in  animal studies); ensure effective contraception during  and for at least 6 months after treatment in men or  women; see also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above; rarely  liver necrosis due to hepatic vein thrombosis; irritant  to skin and tissues   Dacarbazine (Non-proprietary) (Ml  Injection, powder for reconstitution, dacarbazine (as  citrate), net price 100-mg vial = £5.05; 200-mg vial =  £7.16; 500-mg vial =£16.50; 600-mg vial = £22.50; 1-g  vial = £31.80   Dacarbazine is used to treat metastatic melanoma and,  in combination therapy, soft tissue sarcomas. It is also a  component of a commonly used combination for  Hodgkin’s disease (ABVD — doxorubicin [previously  Adriamycin®], bleomycin, vinblastine, and dacarb-  azine). It is given intravenously. The predominant  side-effects are myelosuppression and severe nausea  and vomiting.   Temozolomide is structurally related to dacarbazine. It  is given by mouth and is licensed for the treatment of  newly diagnosed glioblastoma multiforme in adults (in  combination with radiotherapy) and subsequently as  monotherapy. It is also licensed for second-line treat-  ment of malignant glioma in adults and children over 3  years.   Temozolomide for the treatment of recurrent  malignant glioma (brain cancer) (April 2001)  Temozolomide may be considered for the treatment  of recurrent malignant glioma, which has not  responded to first-line chemotherapy.   Pregnancy avoid (teratogenic and embryotoxic in  animal studies); manufacturer advises adequate  contraception during treatment; men should avoid  fathering a child during and for at least 6 months after  treatment; see also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1  Dose   Temozolomide (Non-proprietary) (Ml  Capsules, temozolomide 5 mg, net price 5-cap pack =  £13.58; 20 mg, 5-cap pack = £54.30; 100 mg, 5-cap  pack = £271.52; 140 mg, 5-cap pack = £380.18;   180 mg, 5-cap pack = £488.74; 250 mg, 5-cap pack =  £678.80. Label: 23, 25  Brands include Temomedac®   Capsules, temozolomide 5 mg (green/white), net  price 5-cap pack = £16.29; 20 mg (yellow/white), 5-  cap pack = £65.16; 100 mg (pink/ white), 5-cap pack =  £325.80; 140 mg (blue/white), 5-cap pack = £456.12;  180 mg (orange/white), 5-cap pack = £586.44; 250 mg  (white), 5-cap pack = £814.50. Label: 23, 25   Hydroxycarbamide is an orally active drug used mainly  in the treatment of chronic myeloid leukaemia. It is also  licensed for the treatment of cancer of the cervix in  conjunction with radiotherapy. It is occasionally used for  polycythaemia (the usual treatment is venesection).  Myelosuppression, nausea, and skin reactions are the  most common toxic effects.   Cautions see section 8.1 and notes above; interac-  tions: Appendix 1 (hydroxycarbamide)   Hepatic impairment use with caution  Renal impairment use with caution  Pregnancy avoid (teratogenic in animal studies);  manufacturer advises effective contraception before  and during treatment; see also Reproductive Func-  tion, p. 520   Capsules, pink/green, hydroxycarbamide 500 mg,  net price 100-cap pack = £10.47   Mitotane is licensed for the symptomatic treatment of  advanced or inoperable adrenocortical carcinoma. It  selectively inhibits the activity of the adrenal cortex,  necessitating corticosteroid replacement therapy (sec-  tion 6.3.1); the dose of glucocorticoid should be  increased in case of shock, trauma, or infection.  Gastro-intestinal side-effects such as anorexia, nausea,  and vomiting, and endocrine side-effects, such as hypo-  gonadism and thyroid disorders, are very common with  mitotane; neurotoxicity occurs in many patients.   Driving CNS effects may affect performance of skilled tasks  (e.g. driving)   Counselling Warn patient to contact doctor immediately if  injury, infection, or illness occurs (because of risk of acute  adrenal insufficiency)   Side-effects see section 8.1 and notes above; also  gastro-intestinal disturbances (including nausea,  vomiting, diarrhoea, epigastric discomfort), anorexia,  liver disorders; hypercholesterolaemia, hypertrigly-  ceridaemia; ataxia, confusion, asthenia, myasthenia,  paraesthesia, drowsiness, neuropathy, cognitive  impairment, movement disorder, dizziness, headache;  gynaecomastia; prolonged bleeding time, leucopenia,  thrombocytopenia, anaemia; rash; rarely hypersali-  vation, hypertension, postural hypotension, flushing,  pyrexia, haematuria, proteinuria, haemorrhagic cyst-  itis, hypouricaemia, visual disturbances, and ocular  disorders    • ADULT over 18 years, initially 2-3 g daily, (up to 6g  daily in severe illness) in 2-3 divided doses, adjusted  according to plasma-mitotane concentration; reduce  dose or interrupt treatment if signs of toxicity; dis-  continue if inadequate response after 3 months  Note Plasma-mitotane concentration for optimum response  14-20 mg/litre    Lysodren® (HRA Pharma) (Ml  Tablets, scored, mitotane 500 mg, net price 100-tab  pack = £590.97. Label: 2, 10, 21, counselling, driving,  adrenal suppression   Panitumumab is a monoclonal antibody that binds to  the epidermal growth factor receptor (EGFR). It is  indicated as monotherapy for the treatment of EGFR  expressing metastatic colorectal cancer with non-  mutated KRAS gene after failure of fluoropyrimidine-,  oxaliplatin-, and irinotecan-containing chemotherapy  regimens. Panitumumab is given by intravenous infu-  sion.   Indications see notes above  Cautions monitor for dermatological reactions (may  require temporary or permanent discontinuation —  consult product literature); pulmonary disease — dis-  continue if pneumonitis or lung infiltrates occur;  monitor for hypomagnesaemia and hypocalcaemia  Contra-indications interstitial pulmonary disease  Pregnancy avoid (toxicity in animal studies); manu-  facturer advises effective contraception during and for  6 months after treatment; see also Reproductive  Function, p. 520   Breast-feeding manufacturer advises avoid breast-  feeding during and for 3 months after treatment  Side-effects see section 8.1; also infusion-related  reactions including hypertension, hypotension,  tachycardia, and severe hypersensitivity reactions  (possibly delayed onset); diarrhoea, abdominal pain,  constipation, dry mouth and nose; dyspnoea, cough,    embolism; fatigue, dizziness, headache; hypo-  magnesaemia, hypocalcaemia, hypokalaemia, dehy-  dration; ocular disorders (including conjunctivitis,  increased lacrimation, dry eyes, ocular hyperaemia);  skin reactions (including rash, erythema, pruritus, dry  skin, acne, hand-foot syndrome and exfoliation),  mucosal inflammation, hypertrichosis, and nail dis-  orders   Concentrate for intravenous infusion, panitumumab  20 mg/mL, net price 5-mL vial = £379.29, 20-mL vial  = £1517.16   Pentostatin is active in hairy cell leukaemia. It is given  intravenously on alternate weeks and can induce pro-  longed complete remission. It can cause myelosuppres-  sion, immunosuppression, and a number of other side-  effects that may be severe. Treatment should be with-  held in patients who develop a severe rash, and withheld  or discontinued in patients showing signs of neurotoxi-  city. Its use should be confined to specialist centres.   Pregnancy avoid (teratogenic in animal studies);  manufacturer advises that men should not father  children during and for 6 months after treatment; see  also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above   Carboplatin is widely used in the treatment of  advanced ovarian cancer and lung cancer (particularly  the small cell type). It is given intravenously. The dose  of carboplatin is determined according to renal function  rather than body surface area. Carboplatin can be given  on an outpatient basis and is better tolerated than cis-  platin; nausea and vomiting are reduced in severity and  nephrotoxicity, neurotoxicity, and ototoxicity are much  less of a problem than with cisplatin. It is, however,  more myelosuppressive than cisplatin.   Cisplatin is used alone or in combination for the  treatment of testicular, lung, cervical, bladder, head  and neck, and ovarian cancer (but carboplatin is pre-  ferred for ovarian cancer). It is given intravenously.  Cisplatin requires intensive intravenous hydration and  treatment may be complicated by severe nausea and  vomiting. Cisplatin is toxic, causing nephrotoxicity  (monitoring of renal function is essential), ototoxicity,  peripheral neuropathy, hypomagnesaemia and myelo-  suppression. It is, however, increasingly given in a day-  care setting.    Oxaliplatin is licensed in combination with fluorouracil  and folinic acid, for the treatment of metastatic color-  ectal cancer and as adjuvant treatment of colon cancer  after resection of the primary tumour; it is given by  intravenous infusion. Neurotoxic side-effects (including  sensory peripheral neuropathy) are dose limiting. Other  side-effects include gastro-intestinal disturbances, oto-  toxicity, and myelosuppression. If unexplained respir-  atory symptoms occur, oxaliplatin should be discontin-  ued until investigations exclude interstitial lung disease  and pulmonary fibrosis.   A combination of fluorouracil and folinic acid with  either irinotecan or oxaliplatin are options for first-  line treatment for advanced colorectal cancer.  Irinotecan alone or fluorouracil and folinic acid with  oxaliplatin are options for patients who require  further treatment subsequently.   Raltitrexed is not recommended for the treatment of  advanced colorectal cancer. Its use should be con-  fined to clinical studies.    NICE guidance (capecitabine and oxaliplatin in  the adjuvant treatment of stage III (Dukes’ C)  colon cancer)   Paclitaxel for ovarian cancer (January 2003)  Either paclitaxel in combination with a platinum  compound (cisplatin or carboplatin) or a platinum  compound alone are alternatives for the first-line  treatment of ovarian cancer (usually following sur-  gery).   Paclitaxel, pegylated liposomal doxorubicin,  and topotecan for second-line or  subsequent treatment of advanced ovarian  cancer (May 2005)   Paclitaxel, combined with a platinum compound  (carboplatin or cisplatin), is an option for advanced  cancer that relapses 6 months or more after com-  pleting initial platinum-based chemotherapy. Pacli-  taxel alone is an option for advanced ovarian cancer  that does not respond to, or relapses within 6  months of completing initial platinum-based chemo-  therapy.   Pegylated liposomal doxorubicin is an option for  advanced ovarian cancer that does not respond to,  or relapses within 12 months of completing initial  platinum-based chemotherapy.   Paclitaxel alone or pegylated liposomal doxorubicin  are options for advanced ovarian cancer in patients  who are allergic to platinum compounds. Topotecan  alone is an option only for advanced ovarian cancer  that does not respond to, or relapses within 6  months of completing initial platinum-based chemo-  therapy or in those allergic to platinum compounds  and for whom paclitaxel alone or pegylated liposo-  mal doxorubicin are inappropriate.   Renal impairment reduce dose and monitor haema-  tological parameters and renal function; avoid if  creatinine clearance less than 20 mL/minute  Pregnancy avoid (teratogenic and embryotoxic in  animal studies); see also Reproductive Function,  p. 520   Carboplatin (Non-proprietary) (5°M1  Injection, carboplatin lOmg/mL, net price 5-mL vial  = £22.04, 15-mL vial = £56.92, 45-mL vial = £168.85,  60-mL vial = £260.00   Cisplatin (Non-proprietary) [Ml  Injection, cisplatin 1 mg/mL, net price 10-mL vial =  £5.85, 50-mL vial = £24.50, 100-mL vial = £50.22  Injection, powder for reconstitution, cisplatin, net  price 50-mg vial = £17.00   Cautions see section 8.1 and notes above; interac-  tions: Appendix 1 (platinum compounds)   Renal impairment manufacturer advises avoid if  creatinine clearance less than 30 mL/minute   Pregnancy manufacturer advises avoid — toxicity in  animal studies; effective contraception required dur-  ing and for 4 months after treatment in women and 6  months after treatment in men; see also Reproductive  Function, p. 520   Oxaliplatin (Non-proprietary) (S  Injection, powder for reconstitution, oxaliplatin, net  price 50-mg vial = £150.00, 100-mg vial= £299.50   Eloxatin® (Sanofi-Aventis) (Ml  Concentrate for intravenous infusion, oxaliplatin  5 mg/mL, net price 10-mL vial = £158.57, 20-mL vial  = £317.13, 40-mL vial = £634.26   Porfimer sodium and temoporfin are used in the  photodynamic treatment of various tumours. The    drugs accumulate in malignant tissue and are activated  by laser light to produce a cytotoxic effect.   Porfimer sodium is licensed for photodynamic therapy  of non-small cell lung cancer and obstructing oeso-  phageal cancer. Temoporfin is licensed for photody-  namic therapy of advanced head and neck cancer.   Cautions see section 8.1; avoid exposure of skin and  eyes to direct sunlight or bright indoor light for at least  30 days   Contra-indications see section 8.1; tracheo-oeso-  phageal or broncho-oesophageal fistula; acute por-  phyria (section 9.8.2)   Injection, powder for reconstitution, porfimer sod-  ium, net price 15-mg vial = £154.00; 75-mg vial =  £770.00   Indications advanced head and neck squamous cell  carcinoma refractory to, or unsuitable for, other  treatments   Cautions see section 8.1; avoid exposure of skin and  eyes to direct sunlight or bright indoor light for at least  15 days after administration; avoid prolonged expo-  sure of injection site arm to direct sunlight for 6  months after administration, if extravasation occurs  protect area from light for at least 3 months; inter-  actions: Appendix 1 (temoporfin)  Contra-indications see section 8.1; acute porphyria  (section 9.8.2) or other diseases exacerbated by light;  elective surgery or ophthalmic slit-lamp examination  for 30 days after administration; concomitant photo-  sensitising treatment   Pregnancy toxicity in animal studies — manufacturer  advises avoid pregnancy for at least 3 months after  treatment; see also Reproductive Function, p. 520  Breast-feeding manufacturer advises avoid breast-  feeding for at least 1 month after treatment — no  information available    Side-effects see section 8.1; also constipation, dys-  phagia; haemorrhage, oedema; giddiness, trismus,  facial pain; injection site pain, blistering, scarring,  erythema, skin necrosis, hyperpigmentation, photo-  sensitivity (see Cautions above; sunscreens ineffec-  tive)   Injection, temoporfin 1 mg/mL, net price 1-mL vial =  £900.00, 3-mL vial = £1800.00, 6-mL vial = £3400.00   Procarbazine is most often used in Hodgkin’s disease. It  is given by mouth. Toxic effects include nausea, mye-  losuppression, and a hypersensitivity rash preventing  further use of this drug. It is a mild monoamine-oxidase  inhibitor and dietary restriction is rarely considered  necessary. Alcohol ingestion may cause a disulfiram-  like reaction.   Cautions see section 8.1 and notes above; cardiovas-  cular or cerebrovascular disease; phaeochromo-  cytoma; epilepsy; interactions: Appendix 1 (pro-  carbazine)   Hepatic impairment caution in mild to moderate  impairment; avoid in severe impairment   Renal impairment caution in mild to moderate  impairment; avoid in severe impairment   Procarbazine (Non-proprietary) (Ml  Capsules, procarbazine (as hydrochloride) 50 mg, net  price 50-cap pack = £199.60. Label: 4   Dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapa-  tinib, nilotinib, pazopanib, sorafenib, sunitinib, and tem-  sirolimus are protein kinase inhibitors.   Dasatinib, a tyrosine kinase inhibitor, is licensed for the  treatment of chronic myeloid leukaemia in those who  have resistance to or intolerance of previous therapy,  including imatinib. It is also licensed for acute lympho-  blastic leukaemia (Philadelphia chromosome positive)  in those who have resistance to or intolerance of pre-  vious therapy.   The Scottish Medicines Consortium (p. 4) has advised  (April 2007) that the use of dasatinib (Spry cel®) in NHS  Scotland is restricted to patients in the chronic phase of  chronic myeloid leukaemia.   Erlotinib, a tyrosine kinase inhibitor, is licensed in  combination with gemcitabine for the treatment of  metastatic pancreatic cancer. It is also licensed for the  treatment of locally advanced or metastatic non-small  cell lung cancer after failure of previous chemotherapy  and as monotherapy for maintenance treatment of  locally advanced or metastatic non-small cell lung can-  cer with stable disease after four cycles of platinum-  based chemotherapy.   The Scottish Medicines Consortium (p. 4) has advised  (May 2006) that erlotinib ( Tarceva ®) is accepted for  restricted use within NHS Scotland for the treatment of  locally advanced or metastatic non-small cell lung  cancer, after failure of at least one chemotherapy  regimen. Erlotinib is restricted to use in patients who  would otherwise be eligible for treatment with docetaxel  monotherapy.   Erlotinib is recommended, as an alternative to doc-  etaxel, as second-line treatment for locally advanced  or metastatic non-small-cell lung cancer after failure  of previous chemotherapy, on the basis that it is  provided by the manufacturer at an overall treat-  ment cost equal to that of docetaxel. Erlotinib is not  recommended in patients for whom docetaxel is  unsuitable or as third-line treatment after docetaxel.    Everolimus, a protein kinase inhibitor, is licensed for  the treatment of advanced renal cell carcinoma when  the disease has progressed despite treatment with vas-  cular endothelial growth factor-targeted therapy.   Gefitinib, a tyrosine kinase inhibitor, is licensed for the  treatment of locally advanced or metastatic non-small  cell lung cancer with activating mutations of epidermal  growth factor receptor.   Imatinib, a tyrosine kinase inhibitor, is licensed for the  treatment of newly diagnosed chronic myeloid leuk-  aemia where bone marrow transplantation is not con-  sidered first-line treatment, and for chronic myeloid  leukaemia in chronic phase after failure of interferon  alfa, or in accelerated phase, or in blast crisis (see NICE  guidance below). It is also licensed for the treatment of  c-kit (CD1 17)-positive unresectable or metastatic malig-  nant gastro-intestinal stromal tumours (GIST), and as  adjuvant treatment following resection of c-kit (CD1 17)-  positive GIST, in patients at significant risk of relapse.  Imatinib is licensed for the treatment of newly diag-  nosed acute lymphoblastic leukaemia in combination  with other chemotherapy, and as monotherapy for  relapsed or refractory acute lymphoblastic leukaemia.  Imatinib is also licensed for the treatment of unresect-  able dermatofibrosarcoma protuberans and for patients  with recurrent or metastatic dermatofibrosarcoma pro-  tuberans who cannot have surgery.   Imatinib is also licensed for the treatment of myelodys-  plastic/myeloproliferative diseases associated with pla-  telet-derived growth factor receptor gene rearrange-  ment and for the treatment of advanced  hypereosinophilic syndrome and chronic eosinophilic  leukaemia.   The Scottish Medicines Consortium (p. 4) has advised  (March 2002) that imatinib ( Glivec ®) should be used for  chronic myeloid leukaemia only under specialist super-  vision in accordance with British Society of Haematol-  ogy guidelines (November 2001).   Imatinib is recommended as first-line treatment for  Philadelphia-chromosome-positive chronic myeloid  leukaemia in the chronic phase and as an option for  patients presenting in the accelerated phase or with  blast crisis, provided that imatinib has not been used  previously.   Where imatinib has failed to stop disease progres-  sion from chronic phase to accelerated phase or to  blast crisis, continued use is recommended only as  part of further clinical study.   Imatinib for the adjuvant treatment of  gastro-intestinal stromal tumours (August  2010)   Imatinib is not recommended for the adjuvant treat-  ment of gastro-intestinal stromal tumours after sur-  gery.   Sorafenib for the treatment of advanced  hepatocellular carcinoma (May 2010)  Sorafenib is not recommended for the treatment of  advanced hepatocellular carcinoma in patients for  whom surgical or locoregional therapies have failed  or are unsuitable.   Imatinib for the treatment of unresectable  and/or metastatic gastro-intestinal stromal  tumours (October 2004)   Imatinib 400 mg daily is recommended as first-line  management of KIT (CD117)-positive unresectable  or metastatic, or both, gastro-intestinal stromal  tumours. Continued therapy is recommended only  if a response to initial treatment [as defined by  Southwest Oncology Group criteria available at  www.nice.org.uk/TA86] is achieved within 12  weeks. Patients who have responded should be  assessed at 12-week intervals. Discontinue if tumour  ceases to respond.   Imatinib for the treatment of unresectable  and/or metastatic gastro-intestinal stromal  tumours (November 2010)   Imatinib 600 mg daily or 800 mg daily is not recom-  mended for unresectable or metastatic, or both,  gastro-intestinal stromal tumours whose disease  has progressed after treatment with imatinib  400 mg daily.    Lapatinib, a tyrosine kinase inhibitor, is licensed for the  treatment of advanced or metastatic breast cancer in  patients with tumours that overexpress human epider-  mal growth factor receptor-2 (HER2). It is indicated, in  combination with capecitabine, for patients who have  had previous treatment with an anthracycline, a taxane,  and trastuzumab, or for postmenopausal women in  combination with an aromatase inhibitor section 8.3.4. 1.   Nilotinib, a tyrosine kinase inhibitor, is licensed for the  treatment of chronic myeloid leukaemia in those who  have resistance to or intolerance of previous therapy,  including imatinib.   The Scottish Medicines Consortium (p. 4) has advised  (February 2008) that nilotinib ( Tasigna ®) is accepted  for restricted use within NHS Scotland for the treatment  of chronic-phase chronic myeloid leukaemia in adults  resistant to or intolerant of at least one previous therapy,  including imatinib.   Pazopanib, a tyrosine kinase inhibitor, is licensed for the  treatment of advanced renal cell carcinoma, as first-line  treatment and for the treatment of patients who have  had previous treatment with cytokine therapy for  advanced disease.   Sorafenib, an inhibitor of multiple kinases, is licensed  for the treatment of advanced renal cell carcinoma  when treatment with interferon alfa or interleukin-2  has failed or is contra-indicated (but see NICE Guidance  below). It is also licensed for the treatment of hepato-  cellular carcinoma.    Sunitinib, a tyrosine kinase inhibitor, is licensed for the  treatment of advanced or metastatic renal cell carci-  noma (but see NICE Guidance, below). It is also licensed  for the treatment of unresectable or metastatic malig-  nant gastro-intestinal stromal tumours, after failure of  imatinib.   Sunitinib is recommended as first-line treatment for  advanced or metastatic renal cell carcinoma in  patients who are suitable for immunotherapy and  have an Eastern Cooperative Oncology Group per-  formance status of 0 or 1.   Sunitinib for the treatment of gastro-  intestinal stromal tumours (September  2009)   Sunitinib is recommended as an option for treatment  in patients with unresectable or metastatic gastro-  intestinal tumours if imatinib treatment has failed  because of resistance or intolerance, and the cost of  sunitinib for the first treatment cycle is met by the  manufacturer.   Bevacizumab (first-line), sorafenib (first-  and second-line), sunitinib (second-line) and  temsirolimus (first-line) for the treatment of  advanced or metastatic renal cell carcinoma  (August 2009)   Bevacizumab, sorafenib, and temsirolimus are not  recommended as first-line treatments for people  with advanced or metastatic renal cell carcinoma.  Sorafenib and sunitinib are not recommended as  second-line treatments for people with advanced  or metastatic renal cell carcinoma.   Temsirolimus is a protein kinase inhibitor licensed for  the first-line treatment of advanced renal cell carcinoma  (see NICE Guidance above), and for the treatment of  relapsed or refractory mantle cell lymphoma. Hyper-  sensitivity reactions, including some life-threatening  and rare fatal reactions, are associated with temsiroli-  mus therapy, usually during administration of the first  dose. Symptoms include flushing, chest pain, dyspnoea,  apnoea, hypotension, loss of consciousness, and  anaphylaxis. Where possible, patients should receive  an intravenous dose of antihistamine 30 minutes before  starting the temsirolimus infusion. The infusion may  have to be stopped temporarily for the treatment of  infusion-related effects — consult product literature for  appropriate management. If adverse reactions are not  managed with dose delays, a dose reduction should be  considered — consult product literature.   Cautions see section 8.1; susceptibility to QT-interval  prolongation (correct hypokalaemia or hypomagnes-  aemia before starting treatment); interactions:  Appendix 1 (dasatinib)   Side-effects see section 8.1; also diarrhoea, anorexia,  weight changes, abdominal pain, taste disturbance,  constipation, dyspepsia, colitis, gastritis; arrhythmias,  congestive heart failure, hypertension, chest pain,  flushing, haemorrhage (including gastro-intestinal and  CNS haemorrhage), palpitation; dyspnoea, pulmonary  hypertension, cough, oedema (more common in  patients over 65 years old), pleural effusion; depres-  sion, dizziness, headache, insomnia, neuropathy;  influenza-like symptoms; musculoskeletal pain; visual  disturbances; tinnitus; acne, dry skin, sweating, pru-  ritus, dermatitis, urticaria; less commonly pancreatitis,  hepatitis, cholestasis, cholecystitis, oesophagitis,  hypotension, transient ischaemic attack, thrombo-  phlebitis, syncope, asthma, seizures, amnesia, tremor,  drowsiness, gynaecomastia, irregular menstruation,  urinary frequency, proteinuria, hypocalcaemia, rhab-  domyolysis, hypersensitivity reactions (including  erythema nodosum), photosensitivity, and pigmenta-  tion and nail disorders; rarely cor pulmonale;  thrombosis and interstitial lung disease also reported  Dose   • Chronic phase chronic myeloid leukaemia, ADULT over  18 years 100 mg once daily, increased if necessary to  max. 140 mg once daily   • Accelerated and blast phase chronic myeloid leuk-  aemia, acute lymphoblastic leukaemia, ADULT over 18  years 140 mg once daily, increased if necessary to  max. 180 mg once daily    Sprycel® (Bristol-Myers Squibb) T (S  Tablets, f/c, dasatinib (as monohydrate) 20 mg, net  price 60-tab pack = £1252.48; 50 mg, 60-tab pack =  £2504.96; 70 mg, 60-tab pack = £2504.96; 100 mg, 30-  tab pack = £2504.96. Label: 25   Cautions see section 8.1; pre-existing liver disease or  concomitant use with hepatotoxic drugs — monitor  liver function; dose adjustment may be necessary if  smoking started or stopped during treatment; inter-  actions: Appendix 1 (erlotinib)   Hepatic impairment manufacturer advises caution in  mild to moderate impairment; avoid in severe  impairment    Side-effects see section 8.1 and notes above; also  diarrhoea, abdominal pain, dyspepsia, flatulence;  anorexia, depression, neuropathy, headache; fatigue,  rigor; conjunctivitis; pruritus, dry skin; less commonly  gastro-intestinal perforation, interstitial lung dis-  ease — discontinue if unexplained symptoms such as  dyspnoea, cough or fever occur; eyelash changes;  rarely hepatic failure; very rarely corneal perforation  or ulceration, Stevens-Johnson syndrome, and toxic  epidermal necrolysis   • Pancreatic cancer, 100 mg once daily in combination  with gemcitabine   Tablets, f/c, white-yellow, erlotinib (as hydrochloride)  25 mg, net price 30-tab pack = £378.33; 100 mg, 30-  tab pack = £1324.14; 150 mg, 30-tab pack = £1631.53.  Label: 23   Cautions see section 8.1; monitor blood-glucose con-  centration before treatment and periodically there-  after; reduce dose or discontinue if severe side-effects  occur — consult product literature; interactions:  Appendix 1 (everolimus)   Pneumonitis Non-infectious pneumonitis reported. Patients  should be advised to seek urgent medical advice if new or  worsening respiratory symptoms occur   Side-effects see section 8.1; also diarrhoea, dry  mouth, abdominal pain, dysphagia, anorexia, taste  disturbance; chest pain, hypertension, hyperlipid-  aemia, hypercholesterolaemia, peripheral oedema;  pneumonitis (including interstitial lung disease);  asthenia, fatigue, headache, insomnia; increased sus-  ceptibility to infections (including pneumonia, asper-  gillosis, and candidiasis); hyperglycaemia, dehydra-  tion; eyelid oedema; epistaxis; skin and nail disorders  (including hand-foot syndrome); less commonly con-  gestive heart failure and impaired wound healing;  hepatitis B reactivation and haemorrhage also  reported  Dose   Afinitor® (Novartis) ▼ Ml  Tablets, white-yellow, everolimus, 5 mg, net price 30-  tab pack = £2250.00; 10 mg, 30-tab pack = £2970.00.  Label: 25, counselling, pneumonitis   Indications see notes above  Cautions monitor liver function — consider disconti-  nuing if severe changes in liver function occur;  monitor for worsening of dyspnoea, cough and  fever — discontinue if interstitial lung disease con-  firmed; patients should seek immediate medical  advice if they experience any ocular symptoms;  interactions: Appendix 1 (gefitinib)    Hepatic impairment manufacturer advises caution in  moderate to severe impairment due to cirrhosis  Renal impairment manufacturer advises caution if  creatinine clearance less than 20 mL/minute  Pregnancy manufacturer advises avoid unless essen-  tial — toxicity in animal studies; see also Reproductive  Function, p. 520   Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also anorexia, diarrhoea,  dry mouth; epistaxis, interstitial lung disease — dis-  continue if confirmed; asthenia; pyrexia; haematuria,  proteinuria; dry eye, conjunctivitis, blepharitis; nail  disorder, skin reactions (including dry skin, rash, acne,  and pruritus); less commonly pancreatitis, corneal  erosion; rarely hepatitis, toxic epidermal necrolysis  Dose   Iressa® (AstraZeneca) T (Ml  Tablets, f/c, brown, gefitinib 250 mg, net price 30-tab  pack = £2167.71   Cautions see section 8.1; cardiac disease; monitor for  fluid retention; monitor liver function; interactions:  Appendix 1 (imatinib)   Renal impairment max. starting dose 400 mg daily if  creatinine clearance less than 60 mL/minute; reduce  dose further if not tolerated   Side-effects see section 8.1; also abdominal pain,  appetite changes, constipation, diarrhoea, flatulence,  gastro-oesophageal reflux, taste disturbance, weight  changes, dry mouth; oedema (including pulmonary  oedema, pleural effusion, and ascites), flushing,  haemorrhage; cough, dyspnoea; dizziness, headache,  insomnia, hypoaesthesia, paraesthesia, fatigue; influ-  enza-like symptoms; cramps, arthralgia; visual dis-  turbances, increased lacrimation, conjunctivitis, dry  eyes; epistaxis; dry skin, sweating, rash, pruritus,  photosensitivity; less commonly gastric ulceration,  pancreatitis, hepatic dysfunction (rarely hepatic fail-  ure, hepatic necrosis), dysphagia, heart failure,  tachycardia, palpitation, syncope, hypertension,  hypotension, cold extremities, cough, acute respir-  atory failure, depression, drowsiness, anxiety, periph-  eral neuropathy, tremor, migraine, impaired memory,  vertigo, gynaecomastia, menorrhagia, irregular men-  struation, sexual dysfunction, electrolyte distur-  bances, renal failure, urinary frequency, gout, tinnitus,  hearing loss; skin hyperpigmentation; rarely intestinal  obstruction, gastro-intestinal perforation, inflamm-  atory bowel disease, arrhythmia, atrial fibrillation,  myocardial infarction, angina, pulmonary fibrosis,  pulmonary hypertension, increased intracranial pres-  sure, convulsions, confusion, haemolytic anaemia,  rhabdomyolysis, myopathy, aseptic necrosis of bone,  cataract, glaucoma, angioedema, exfoliative  dermatitis, and Stevens- Johnson syndrome   • Chronic phase chronic myeloid leukaemia, ADULT  400 mg once daily, increased if necessary to max.  800 mg daily (in 2 divided doses); CHILD (chronic and  advanced phase) 2-18 years 340 mg/m 2 (max.   800 mg) daily (in 1-2 divided doses), increased to  570 mg/m 2 (max. 800 mg) daily if necessary (consult  product literature)   • Accelerated phase and blast crisis chronic myeloid  leukaemia, ADULT 600 mg once daily, increased if  necessary to max. 800 mg daily (in 2 divided doses)   • Dermatofibrosarcoma protuberans, ADULT 800 mg  daily in 2 divided doses   • Advanced hypereosinophilic syndrome and chronic  eosinophilic leukaemia, ADULT 100-400 mg once daily   Tablets, f/c, imatinib (as mesilate) 100 mg (yellow-  brown, scored), net price 60-tab pack = £802.04;   400 mg (yellow), 30-tab pack = £1604.08. Label: 21, 27  Counselling Tablets may be dispersed in water or apple juice    Cautions see section 8.1; low gastric pH (reduced  absorption); susceptibility to QT-interval prolongation  (including concomitant use of drugs that prolong QT-  interval and electrolyte disturbances); monitor left  ventricular function; monitor for pulmonary toxicity;  monitor liver function before treatment and at  monthly intervals; interactions: Appendix 1 (lapati-  nib)   Side-effects see section 8. 1 ; anorexia, diarrhoea (treat  promptly), decreased left ventricular ejection fraction,  cardiac failure (fatal cases reported), malaise, rash,  nail disorders, hyperbilirubinaemia, hepatotoxicity  (discontinue permanently if severe); less commonly  interstitial lung disease; respiratory failure (including  fatal cases) also reported    • In combination with capecitabine, ADULT over 18  years, 1.25 g once daily   • In combination with an aromatase inhibitor, ADULT  over 18 years, 1.5 g once daily   Counselling Always take at the same time in relation to food:  either one hour before or one hour after food. Patients should  report unexpected changes in bowel habit   Tablets, yellow, f/c, lapatinib 250 mg, net price 70-tab  pack = £804.30, 84 tab-pack = £965.16. Counselling,  administration   Indications see notes above  Cautions see section 8.1; history of pancreatitis; sus-  ceptibility to QT-interval prolongation (including  electrolyte disturbances, concomitant use of drugs  that prolong QT interval); interactions: Appendix 1  (nilotinib)   Side-effects see section 8.1; also abdominal pain,  constipation, diarrhoea, dyspepsia, flatulence, ano-  rexia, weight changes; palpitation, QT-interval pro-  longation, hypertension, oedema, flushing; dyspnoea,  cough, dysphonia; headache, fatigue, asthenia, dizzi-  ness, paraesthesia, insomnia, vertigo; hypomagnes-  aemia, hyperkalaemia, blood glucose changes; bone  pain, arthralgia, muscle spasm; urticaria, erythema,  hyperhidrosis, dry skin, rash, pruritus; less commonly  hepatitis, pancreatitis, dry mouth, chest pain, cardiac  failure, arrhythmias, pericardial effusion, coronary  artery disease, cardiomegaly, cardiac murmur,  bradycardia, hypertensive crisis, haemorrhage, mel-  aena, haematoma, pleural effusion, interstitial lung  disease, migraine, hypoaesthesia, hyperaesthesia,  depression, anxiety, tremor, influenza-like symptoms,  hyperthyroidism, breast pain, gynaecomastia, erectile  dysfunction, dysuria, urinary frequency, hypokal-  aemia, hyponatraemia, hypocalcaemia, hypopho-  sphataemia, dehydration, decreased visual acuity,  conjunctivitis, dry eyes, epistaxis, and ecchymosis   Cautions see section 8.1; monitor liver function before  treatment and at least monthly for the first 4  months — consult product literature; control blood  pressure before initiating and monitor blood pressure  throughout treatment (consider dose reduction or  interruption if hypertension uncontrolled despite anti-  hypertensive therapy); susceptibility to QT-interval  prolongation (including electrolyte disturbances,  concomitant use of drugs that prolong QT-interval);  patients at risk of myocardial infarction, ischaemic  stroke or transient ischaemic attack, cardiac disease;  increased risk of haemorrhage; increased risk of gas-  tro-intestinal perforation or fistulas; discontinue  treatment 7 days before elective surgery and restart  only if adequate wound healing; monitor thyroid  function; monitor for proteinuria; interactions:  Appendix 1 (pazopanib)   Contra-indications cerebral or clinically significant  gastro-intestinal haemorrhage or haemoptysis in the  past 6 months   Hepatic impairment use with caution in mild impair-  ment; reduce dose to 200 mg once daily in moderate  impairment; avoid in severe impairment  Renal impairment use with caution if creatinine  clearance less than 30 mL/minute — no information  available   Pregnancy avoid unless potential benefit outweighs  risk — toxicity in animal studies; effective contra-  ception advised during treatment; see also Repro-  ductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also abdominal pain,  dyspepsia, diarrhoea, weight loss, anorexia, taste  disturbance, flatulence, hepatic dysfunction, hyperbi-  lirubinaemia, hypertension, flushing, chest pain,  oedema, epistaxis, voice changes, headache, dizzi-  ness, malaise, paraesthesia, hypothyroidism, protei-  nuria (discontinue if grade 4), blood disorders  (including thrombocytopenia), muscle spasm, myal-  gia, sweating, skin reactions, dry skin, hair and skin  discoloration; less commonly hepatic failure, gastro-  intestinal perforation, peritonitis, pancreatitis, fistula,  cardiac dysfunction, transient ischaemic attack,  stroke, myocardial infarction, myocardial ischaemia,  bradycardia, haemorrhage, hypertensive crisis, QT-  interval prolongation, pulmonary embolism, periph-  eral neuropathy, menstrual disturbances  Dose   • ADULT over 18 years, 800 mg once daily; adjust dose in  steps of 200 mg according to tolerability (max. 800 mg  daily)   Tablets, f/c, pazopanib (as hydrochloride) 200 mg  (pink), net price 30-tab pack = £560.50; 400 mg  (white), 30-tab pack = £1121.00. Label: 23, 25   Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also diarrhoea, consti-  pation, dyspepsia, dysphagia, anorexia, hypertension,  haemorrhage, flushing, hoarseness, fatigue, asthenia,  depression, peripheral neuropathy, fever, erectile  dysfunction, renal failure, hypophosphataemia, arthr-  algia, myalgia, tinnitus, rash, pruritus, erythema, dry  skin, desquamation, acne, hand-foot skin reaction; less  commonly gastro-intestinal perforations, myocardial  infarction, congestive heart failure, hypertensive cri-  sis, reversible posterior leucoencephalopathy, thyroid  dysfunction, and Stevens- Johnson syndrome  Dose   Nexavar® (Bayer Schering) ▼ (Ml  Tablets, f/c, red, sorafenib (as tosylate) 200 mg, net  price 112-tab pack = £2980.47 Label: 23   Indications see notes above  Cautions see section 8.1; cardiovascular disease —  discontinue if congestive heart failure develops; sus-  ceptibility to QT-interval prolongation; hypertension;  increased risk of bleeding; monitor for thyroid dys-  function; consider dental check-up before initiating  treatment (risk of osteonecrosis of the jaw, see  MHRA/CHM advice, p. 537); interactions: Appendix  1 (sunitinib)   Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk — toxicity in animal studies;  effective contraception required during treatment; see  also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1; also abdominal pain,  diarrhoea, constipation, anorexia, taste disturbance,  dehydration; hypertension, oedema; dyspnoea,  cough; fatigue, dizziness, headache, insomnia, per-  ipheral neuropathy, paraesthesia; hypothyroidism;  arthralgia, myalgia; increased lacrimation; epistaxis;  skin, hair, and urine discoloration, hand-foot  syndrome, dry skin, and rash; gastro-intestinal per-  foration, fistula formation (interrupt treatment if  occurs) pancreatitis, osteonecrosis of the jaw (see  MHRA/CHM advice, p. 537), hepatic failure, protei-  nuria ( rarely nephrotic syndrome) and seizures  reported  Dose   • 50 mg daily for 4 weeks, followed by a 2-week treat-  ment-free period to complete 6-week cycle; adjust  dose in steps of 12.5 mg according to tolerability; dose  range 25-75 mg daily   Capsules, sunitinib (as malate) 12.5 mg (orange), net  price 28-cap pack = £784.70; 25 mg (caramel/  orange), 28-cap pack = £1569.40; 50 mg (caramel),  28-cap pack = £3138.80. Label: 14   Cautions see notes above; monitor respiratory func-  tion; monitor blood lipids; interactions: Appendix 1  (temsirolimus)   Hepatic impairment use with caution; in renal cell  carcinoma, reduce dose in severe impairment (con-  sult product literature); in mantle cell lymphoma,  avoid in moderate or severe impairment   Pregnancy manufacturer advises avoid (toxicity in  animal studies); ensure effective contraception during  treatment in men and women; see also Reproductive  Function, p. 520   Side-effects see section 8.1; also abdominal pain,  diarrhoea, anorexia, taste disturbance, gastro-intes-  tinal haemorrhage, bowel perforation, dysphagia;  hypertension, oedema, thrombosis, thrombophlebitis;  cough, dyspnoea, chest pain, interstitial lung disease,  hypersensitivity reactions (see notes above); insom-  nia, anxiety, depression, drowsiness, paraesthesia,  dizziness, asthenia; increased susceptibility to infec-    tion (including urinary-tract infection and pneu-  monia), pyrexia; hyperglycaemia; renal failure; hypo-  phosphataemia, hypokalaemia,  hypercholesterolaemia, hyperlipidaemia; myalgia,  arthralgia; eye disorders; rhinitis, epistaxis; skin dis-  orders (including rash and acne), folliculitis, impaired  wound healing; less commonly intracerebral bleeding    Paclitaxel is a member of the taxane group of drugs. It  is given by intravenous infusion. Paclitaxel given with  carboplatin or cisplatin is used for the treatment of  ovarian cancer (see NICE guidance p. 542); the combi-  nation is also considered appropriate for women whose  ovarian cancer is initially considered inoperable. Pacli-  taxel is also licensed for the secondary treatment of  metastatic breast cancer. There is limited evidence to  support its use in non-small cell lung cancer. Routine  premedication with a corticosteroid, an antihistamine  and a histamine H 2 -receptor antagonist is recom-  mended to prevent severe hypersensitivity reactions;  hypersensitivity reactions may occur rarely despite pre-  medication, although more commonly only bradycardia  or asymptomatic hypotension occur.    Other side-effects of paclitaxel include myelosuppres-  sion, peripheral neuropathy, and cardiac conduction  defects with arrhythmias (which are nearly always  asymptomatic). It also causes alopecia and muscle  pain; nausea and vomiting is mild to moderate.   Docetaxel is licensed for use in locally advanced or  metastatic breast cancer and non-small cell lung cancer  resistant to other cytotoxic drugs or for initial chemo-  therapy in combination with other cytotoxic drugs. It is  also licensed for hormone-resistant prostate cancer, for  use with other cytotoxic drugs for gastric adenocarci-  noma and head and neck cancer, and for adjuvant  treatment of operable node-positive and operable  node-negative breast cancer. Its side-effects are similar  to those of paclitaxel but persistent fluid retention  (commonly as leg oedema that worsens during treat-  ment) can be resistant to treatment; hypersensitivity  reactions also occur. Pretreatment with dexamethasone  by mouth is recommended for reducing fluid retention  and hypersensitivity reactions.   For the role of taxanes in the treatment of breast cancer,  see section 8.3.4. 1.    The Scottish Medicines Consortium (p. 4) has advised  that docetaxel ( Taxotere ®) in combination with cis-  platin and 5-fluorouracil is accepted for restricted use  within NHS Scotland for the induction treatment of  patients with unresectable (May 2007) and resectable  (June 2008) locally advanced squamous cell carcinoma  of the head and neck.    NICE guidance (paclitaxel, pegylated liposo-  mal doxorubicin and topotecan for second-line  or subsequent treatment of advanced ovarian  cancer)   Docetaxel for the treatment of hormone-  refractory metastatic prostate cancer (June  2006)   Docetaxel is an option for hormone-refractory meta-  static prostate cancer and a Kamofsky score of at  least 60% [Kamofsky score is a measure of the  ability to perform ordinary tasks].   Indications adjuvant treatment of operable node-  positive and operable node-negative breast cancer, in  combination with doxorubicin and cyclophosph-  amide; with doxorubicin for initial chemotherapy of  locally advanced or metastatic breast cancer; mono-  therapy for locally advanced or metastatic breast  cancer where cytotoxic chemotherapy with an  anthracycline or an alkylating drug has failed; with  capecitabine for locally advanced or metastatic breast  cancer where cytotoxic chemotherapy with an  anthracycline has failed; with trastuzumab for initial  chemotherapy of metastatic breast cancer which  overexpresses human epidermal growth factor-2;  locally advanced or metastatic non-small cell lung  cancer where first-line chemotherapy has failed; with  cisplatin for unresectable, locally advanced or meta-  static non-small cell lung cancer; with prednisolone  for hormone-refractory metastatic prostate cancer;  with cisplatin and fluorouracil for initial treatment of  metastatic gastric adenocarcinoma, including adeno-  carcinoma of the gastro-oesophageal junction; with  cisplatin and fluorouracil for induction treatment of  locally advanced squamous cell carcinoma of the  head and neck   Pregnancy avoid (toxicity and reduced fertility in  animal studies); manufacturer advises effective  contraception during and for at least 3 months after  treatment; see also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above   Docetaxel (Non-proprietary) (Ml  Infusion, docetaxel lOmg/mL, net price 2-mL vial =  £162.75, 8-mL vial = £534.75, 16-mL vial = £1069.50   Taxotere® (Sanofi-Aventis) Ml  Infusion, docetaxel 20mg/mL, net price 1-mL vial =  £162.75, 4-mL vial = £534.75, 8-mL vial = £1069.50  (hosp. only)   Indications ovarian cancer (advanced or residual dis-  ease following laparotomy) in combination with cis-  platin; metastatic ovarian cancer where platinum-  containing therapy has failed; locally advanced or  metastatic breast cancer (in combination with other  cytotoxics or alone if other cytotoxics have failed or  are inappropriate); adjuvant treatment of node-posi-  tive breast cancer following treatment with anthra-    cycline and cyclophosphamide; non-small cell lung  cancer (in combination with cisplatin) when surgery  or radiotherapy not appropriate; advanced AIDS-  related Kaposi’s sarcoma where liposomal anthracy-  cline therapy has failed   Cautions see section 8.1 and notes above; avoid in  acute porphyria (but see section 9.8.2); interactions:  Appendix 1 (paclitaxel)   Contra-indications see section 8.1 and notes above  Hepatic impairment avoid in severe impairment  Pregnancy avoid (toxicity in animal studies); ensure  effective contraception during and for at least 6  months after treatment in men or women; see also  Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above   Paclitaxel (Non-proprietary) (Ml  Infusion, paclitaxel 6mg/mL, net price 5-mL vial =  £66.85, 16.7-mL vial = £200.35, 25-mL vial = £300.52,  50-mL vial = £601.03   Excipients include polyoxyl castor oil (risk of anaphylaxis, see Excipi-  ents, p. 2)   Abraxane® (Abraxis) (Ml  Intravenous infusion, powder for reconstitution,  paclitaxel, net price 100-mg vial = £246.00   Taxol® (Bristol-Myers Squibb) (Ml  Infusion, paclitaxel 6mg/mL, net price 5-mL vial =  £116.05, 16.7-mL vial = £347.82, 25-mL vial =  £521.73, 50-mL vial = £1043.46 (hosp. only)   Excipients include polyoxyl castor oil (risk of anaphylaxis, see Excipi-  ents, p. 2)   Irinotecan and topotecan inhibit topoisomerase I, an  enzyme involved in DNA replication.   Irinotecan is licensed for metastatic colorectal cancer  in combination with fluorouracil and folinic acid or as  monotherapy when treatment containing fluorouracil  has failed. It is also licensed in combination with cetux-  imab for the treatment of epidermal growth factor  receptor-expressing metastatic colorectal cancer after  failure of chemotherapy that has included irinotecan.  Irinotecan is also licensed in combination with 5-fluoro-  uracil, folinic acid and bevacizumab for the first-line  treatment of metastatic carcinoma of the colon or  rectum. Irinotecan is also licensed in combination with  capecitabine with or without bevacizumab for the first-  line treatment of metastatic colorectal carcinoma. Iri-  notecan is given by intravenous infusion.    Topotecan is given by intravenous infusion or orally in  relapsed small-cell lung cancer when retreatment with  the first-line regimen is considered inappropriate. Topo-  tecan injection is also licensed for metastatic ovarian  cancer when first-line or subsequent treatment has  failed. Topotecan injection is licensed in combination  with cisplatin for treatment of recurrent carcinoma of  the cervix, after radiotherapy, and for patients with  stage IVB disease.   In addition to dose-limiting myelosuppression, side-  effects of irinotecan and topotecan include gastro-intes-   The Scottish Medicines Consortium (p. 4) has advised  (November 2007) that topotecan ( Hycamtin ®) is  accepted for restricted use in combination with cisplatin  for treatment of recurrent carcinoma of the cervix after  radiotherapy and for stage IVB disease; it is restricted to  patients who have not previously received cisplatin  treatment.   The Scottish Medicines Consortium (p. 4) has advised  (March 2009) that use of topotecan capsules within NHS  Scotland is restricted to patients in whom standard  intravenous chemotherapy is inappropriate and who  would otherwise receive best supportive care.   Topotecan for the treatment of recurrent and  stage IVB cervical cancer (October 2009)  Topotecan in combination with cisplatin is recom-  mended as a treatment option for recurrent or stage  IVB cervical cancer in patients who have not pre-  viously received cisplatin.   Topotecan for the treatment of relapsed  small-cell lung cancer (November 2009)   Oral topotecan is recommended as an option for  treatment in patients with relapsed small-cell lung  cancer only if re-treatment with the first-line regi-  men is not considered appropriate, and the combi-  nation of cyclophosphamide, doxorubicin and vin-  cristine is contra-indicated. Intravenous topotecan is  not recommended for people with relapsed small-  cell lung cancer.    NICE guidance (paclitaxel, pegylated liposo-  mal doxorubicin and topotecan for second-line  or subsequent treatment of advanced ovarian  cancer)    Side-effects see section 8.1 and notes above; also  acute cholinergic syndrome (with early diarrhoea) and  delayed diarrhoea (consult product literature); less  commonly interstitial pulmonary disease   Irinotecan (Non-proprietary) (Ml  Infusion, irinotecan hydrochloride 20mg/mL, net  price 2-mL vial = £49.03, 5-mL vial = £120.25, 15-mL  vial = £370.50, 25-mL vial = £601.25   Infusion, irinotecan hydrochloride 20mg/mL, net  price 2-mL vial = £53.00; 5-mL vial = £130.00; 15-mL  vial = £390.00   Indications see notes above  Cautions see section 8.1 and notes above  Contra-indications see section 8.1 and notes above  Hepatic impairment avoid in severe impairment  Renal impairment reduce dose; avoid infusion if  creatinine clearance less than 20 mL/minute; avoid  oral route if creatinine clearance less than 60 mL/  minute   Pregnancy avoid (teratogenicity and fetal loss in ani-  mal studies); see also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1 and notes above   Capsules, topotecan (as hydrochloride) 250 micr-  ograms (white), net price 10-cap pack = £75.00; 1 mg  (pink), 10-cap pack = £300.00. Label: 25    Intravenous infusion, powder for reconstitution,  topotecan (as hydrochloride), net price 1-mg vial =  £97.65; 4-mg vial = £290.62   Trabectedin is licensed for the treatment of advanced  soft tissue sarcoma when treatment with anthracyclines  and ifosfamide has failed or is contra-indicated and in  combination with pegylated liposomal doxorubicin for  the treatment of relapsed platinum-sensitive ovarian  cancer.   Contra-indications see section 8.1 and notes above;  also chronic inflammatory bowel disease, bowel  obstruction   Hepatic impairment monitor closely for neutropenia  if plasma-bilirubin concentration 1.5-3 times upper  limit of normal range (consult product literature);  avoid if plasma-bilirubin concentration greater than 3  times upper limit of normal range  Renal impairment manufacturer advises avoid — no  information available   Pregnancy avoid (teratogenic and toxic in animal  studies); manufacturer advises effective contraception  during and for at least 3 months after treatment; see  also Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding    Trabectedin is given by intravenous infusion. A cortico-  steroid, such as dexamethasone by intravenous infusion,  should be given 30 minutes before therapy for its anti-  emetic and hepatoprotective effects.   Trabectedin for the treatment of advanced  soft tissue sarcoma (February 2010)  Trabectedin is an option for advanced soft tissue  sarcoma when treatment with anthracyclines and  ifosfamide has failed, is inappropriate or is not  tolerated. The cost of trabectedin for treatment  after the fifth cycle is met by the manufacturer.    monitor haematological and hepatic parameters  weekly during first 2 cycles and at least once between  treatments in subsequent cycles; concomitant use  with hepatotoxic drugs (avoid alcohol)   Hepatic impairment manufacturer advises caution in  impairment — consider dose reduction; avoid in  patients with raised bilirubin  Renal impairment avoid monotherapy if creatinine  clearance less than 30 mL/minute; avoid combination  regimens if creatinine clearance less than 60 mL/  minute   Pregnancy effective contraception recommended  during and for at least 3 months after treatment in  women and at least 5 months after treatment in men;  see also Reproductive Function, p. 520  Breast-feeding manufacturer advises avoid breast-  feeding during and for 3 months after treatment  Side-effects see section 8.1; also abdominal pain,  constipation, diarrhoea, dyspepsia, taste disturbance,  hepatobiliary disorders; hypotension, oedema, flush-  ing; dyspnoea, cough; headache, insomnia, peripheral  neuropathy, paraesthesia, dizziness, anorexia, asthe-  nia, fatigue; pyrexia; hypokalaemia, dehydration,  increased blood creatine phosphokinase; myalgia,  arthralgia, back pain   Yondelis® (Pharma Mar) ▼ (Ml  Injection, powder for reconstitution, trabectedin, net  price 250-microgram vial = £363.00; 1-mg vial =  £1366.00   Trastuzumab is licensed for the treatment of early  breast cancer which overexpresses human epidermal  growth factor receptor-2 (HER2).   B Trastuzumab is also licensed, in combination with pacli-  taxel or docetaxel, for metastatic breast cancer in  patients with HER2-positive tumours who have not  received chemotherapy for metastatic breast cancer  and in whom anthracycline treatment is inappropriate.  Trastuzumab is also licensed, in combination with an  aromatase inhibitor, for metastatic breast cancer in  postmenopausal patients with hormone-receptor posi-  tive HER2-positive tumours not previously treated with  trastuzumab.   Trastuzumab is also licensed as monotherapy for meta-  static breast cancer in patients with tumours that over-  express HER2 who have received at least 2 chemother-  apy regimens including, where appropriate, an  anthracycline and a taxane; women with oestrogen-  receptor-positive breast cancer should also have  received hormonal therapy.   Trastuzumab is also licensed, in combination with cape-  citabine or fluorouracil and cisplatin, for metastatic  gastric cancer in patients with HER2-positive tumours  who have not received treatment for metastatic gastric  cancer.   Trastuzumab is given by intravenous infusion. Resusci-  tation facilities should be available and treatment should  be initiated by a specialist. See section 8.3.4. 1 for the  role of trastuzumab in the treatment of breast cancer.   Use with anthracyclines Concomitant use of tras-  tuzumab with anthracyclines (section 8.1.2) is asso-  ciated with cardiotoxicity. The use of anthracyclines  even after stopping trastuzumab can increase the risk    of cardiotoxicity and if possible should be avoided for up  to 24 weeks. If an anthracycline needs to be used,  cardiac function should be monitored closely.   Trastuzumab for the treatment of HER2-  positive metastatic gastric cancer  (November 2010)   Trastuzumab in combination with cisplatin and  capecitabine or fluorouracil is recommended for  human epidermal growth factor receptor-2-positive  metastatic adenocarcinoma of the stomach or gas-  tro-oesophageal junction in patients who:   • have tumours expressing high levels of HER2 as  defined by a positive immunohistochemistry  score of 3.   Indications see notes above and product literature  Cautions see section 8.1 and notes above; sympto-  matic heart failure, history of hypertension, coronary  artery disease, uncontrolled arrhythmias  Cardiotoxicity Monitor cardiac function before and during  treatment — for details of monitoring and managing cardio-  toxicity, consult product literature  Contra-indications see section 8.1 and notes above;  severe dyspnoea at rest   Pregnancy avoid unless potential benefit outweighs  risk; oligohydramnios and anhydramnios reported  Breast-feeding avoid breast-feeding during treatment  and for six months afterwards  Side-effects see section 8.1; also infusion-related  side-effects including chills, fever, hypersensitivity  reactions such as anaphylaxis, urticaria, and angio-  edema; gastro-intestinal symptoms; cardiotoxicity  (see also above), chest pain, hypotension; pulmonary  events (possibly delayed onset); headache, taste dis-  turbance, anxiety, malaise, depression, insomnia,  drowsiness, dizziness, paraesthesia, tremor, asthenia,  peripheral neuropathy, hypertonia; mastitis, urinary-  tract infection; ecchymosis, oedema, weight loss;  arthralgia, myalgia, arthritis, bone pain, leg cramps;  rash, pruritus, sweating, dry skin, alopecia, acne, nail  disorders   Tretinoin is licensed for the induction of remission in  acute promyelocytic leukaemia. It is used in previously  untreated patients as well as in those who have relapsed  after standard chemotherapy or who are refractory to it.   Cautions exclude pregnancy before starting treat-  ment; monitor haematological and coagulation pro-  file, liver function, serum calcium and plasma lipids    before and during treatment; increased risk of  thromboembolism during first month of treatment;  interactions: Appendix 1 (retinoids)   Hepatic impairment reduce dose to 25 mg/m 2  Renal impairment reduce dose to 25 mg/m 2  Pregnancy teratogenic; effective contraception must  be used for at least 1 month before oral treatment,  during treatment and for at least 1 month after stop-  ping (oral progestogen-only contraceptives not con-  sidered effective)   Side-effects retinoic acid syndrome (fever, dyspnoea,  acute respiratory distress, pulmonary infiltrates,  pleural effusion, hyperleukocytosis, hypotension,  oedema, weight gain, hepatic, renal and multi-organ  failure) requires immediate treatment — consult pro-  duct literature; gastro-intestinal disturbances, pan-  creatitis; arrhythmias, flushing, oedema; headache,  benign intracranial hypertension (mainly in children —  consider dose reduction if intractable headache in  children), shivering, dizziness, confusion, anxiety,  depression, insomnia, paraesthesia, visual and hear-  ing disturbances; raised liver enzymes, serum creat-  inine and lipids; bone and chest pain, alopecia,  erythema, rash, pruritus, sweating, dry skin and  mucous membranes, cheilitis; thromboembolism,  hypercalcaemia, and genital ulceration reported  Dose   • ADULT and CHILD 45 mg/m 2 daily in 2 divided doses,  max. duration of treatment 90 days (consult product  literature for details of concomitant chemotherapy)   Immunosuppressants are used to suppress rejection in  organ transplant recipients and to treat a variety of  chronic inflammatory and autoimmune diseases. Solid  organ transplant patients are usually maintained on a  corticosteroid combined with a calcineurin inhibitor  (ciclosporin or tacrolimus), or with an antiproliferative  drug (azathioprine or mycophenolate mofetil), or with  both. Specialist management is required and other  immunomodulators may be used to initiate treatment  or to treat rejection.   Different formulations of the same immunosuppres-  sant may vary in bioavailability and to avoid reduced  effect or excessive side-effects, it is important not to  change formulation except on the advice of a trans-  plant specialist.    Impaired immune responsiveness Modification of  tissue reactions caused by corticosteroids and other  immunosuppressants may result in the rapid spread of  infection. Corticosteroids may suppress clinical signs of  infection and allow diseases such as septicaemia or  tuberculosis to reach an advanced stage before being  recognised — important: for advice on measles expo-  sure, see section 14.5.1, and chickenpox (varicella)  exposure, see section 14.5.2. For advice on the use of  live vaccines in individuals with impaired immune  response, see section 14.1. For general comments and  warnings relating to corticosteroids and immuno-  suppressants, see section 6.3.2.   Pregnancy Transplant patients immunosuppressed  with azathioprine should not discontinue it on becoming  pregnant. However, there have been reports of prema-  ture birth and low birth-weight following exposure to  azathioprine, particularly in combination with corticos-  teroids. Spontaneous abortion has been reported follow-  ing maternal or paternal exposure. Azathioprine is ter-  atogenic in animal studies.   There is less experience of ciclosporin in pregnancy but  it does not appear to be any more harmful than aza-  thioprine. The use of these drugs during pregnancy  needs to be supervised in specialist units.   Azathioprine is widely used for transplant recipients  and it is also used to treat a number of auto-immune  conditions, usually when corticosteroid therapy alone  provides inadequate control. It is metabolised to  mercaptopurine, and doses should be reduced when  allopurinol is given concurrently.   Blood tests and monitoring for signs of myelosuppres-  sion are essential in long-term treatment with azathio-  prine. The enzyme thiopurine methyltransferase  (TPMT) metabolises azathioprine; the risk of myelosup-  pression is increased in those with reduced activity of  the enzyme, particularly in the few individuals who are  deficient for TPMT activity. Consider measuring TPMT  activity before starting azathioprine therapy. Patients  with deficient TPMT activity should not receive azathio-  prine; those with reduced TPMT activity may be treated  under specialist supervision.   Mycophenolate mofetil is metabolised to mycophe-  nolic acid which has a more selective mode of action  than azathioprine. It is licensed for the prophylaxis of  acute rejection in renal, hepatic or cardiac transplanta-  tion when used in combination with ciclosporin and  corticosteroids. There is evidence that compared with  similar regimens incorporating azathioprine, mycophe-  nolate mofetil reduces the risk of acute rejection epi-  sodes; the risk of opportunistic infections (particularly  due to tissue-invasive cytomegalovirus) and the occur-  rence of blood disorders such as leucopenia may be  higher. Cases of pure red cell aplasia have been reported  with mycophenolate mofetil; dose reduction or discon-  tinuation of mycophenolate mofetil should be consid-  ered under specialist supervision.    Indications see notes above; inflammatory bowel  disease [unlicensed indication] (section 1.5.3); rheu-  matoid arthritis (section 10.1.3); severe refractory  eczema [unlicensed indication] (section 13.5.3)  Cautions see notes above; monitor for toxicity  throughout treatment; monitor full blood count  weekly (more frequently with higher doses or if severe  hepatic or renal impairment) for first 4 weeks (man-  ufacturer advises weekly monitoring for 8 weeks but  evidence of practical value unsatisfactory), thereafter  reduce frequency of monitoring to at least every 3  months; reduce dose in elderly; interactions:  Appendix 1 (azathioprine)   Bone marrow suppression Patients should be warned to  report immediately any signs or symptoms of bone marrow  suppression e.g. inexplicable bruising or bleeding, infection   Renal impairment reduce dose; see also Cautions  Pregnancy treatment should not generally be initiated  during pregnancy; see also p. 553  Breast-feeding present in milk in low concentration;  no evidence of harm in small studies — use if potential  benefit outweighs risk   Side-effects hypersensitivity reactions (including  malaise, dizziness, vomiting, diarrhoea, fever, rigors,  myalgia, arthralgia, rash, hypotension and interstitial  nephritis — calling for immediate withdrawal); dose-  related bone marrow suppression (see also Cautions);  liver impairment, cholestatic jaundice, hair loss and  increased susceptibility to infections and colitis in  patients also receiving corticosteroids; nausea; rarely  pancreatitis, pneumonitis, hepatic veno-occlusive  disease, lymphoma   • By mouth, or (if oral administration not possible —  intravenous solution very irritant, see below) by  intravenous injection over at least 1 minute (followed  by 50 mL sodium chloride intravenous infusion), or by  intravenous infusion   Autoimmune conditions, 1-3 mg/kg daily, adjusted  according to response (consider withdrawal if no  improvement within 3 months)   Suppression of transplant rejection, 1-2.5 mg/kg daily  adjusted according to response  Note Azathioprine doses in BNF may differ from those in  product literature   Note Intravenous injection is alkaline and very irritant,  intravenous route should therefore be used only if oral  route not feasible, see also Appendix 6    Azathioprine (Non-proprietary) (Ml  Tablets, azathioprine 25 mg, net price 28-tab pack =  £6.67; 50 mg, 56-tab pack = £5.56. Label: 21  Brands include Azamune ®   Tablets, both f/c, azathioprine 25 mg (orange), net  price 100-tab pack = £10.99; 50 mg (yellow), 100-tab  pack = £7.99. Label: 21    Indications prophylaxis of acute renal, cardiac, or  hepatic transplant rejection (in combination with  ciclosporin and corticosteroids) under specialist  supervision   Cautions full blood counts every week for 4 weeks  then twice a month for 2 months then every month in  the first year (consider interrupting treatment if neu-  tropenia develops); exclude pregnancy before starting  treatment; elderly (increased risk of infection, gastro-  intestinal haemorrhage and pulmonary oedema);  children (higher incidence of side-effects may call for  temporary reduction of dose or interruption); active  serious gastro-intestinal disease (risk of haemorrhage,  ulceration and perforation); delayed graft function;  increased susceptibility to skin cancer (avoid expo-  sure to strong sunlight); interactions: Appendix 1  (mycophenolate)   Bone marrow suppression Patients should be warned to  report immediately any signs or symptoms of bone marrow  suppression e.g. infection or inexplicable bruising or bleed-  ing   Renal impairment no data available in cardiac or  hepatic transplant patients with renal impairment   Pregnancy avoid — congenital malformations  reported; effective contraception required before  treatment, during treatment, and for 6 weeks after  discontinuation of treatment   Side-effects taste disturbance, gingival hyperplasia,  nausea, constipation, flatulence, anorexia, weight  loss, vomiting, abdominal pain, gastro-intestinal  inflammation, ulceration, and bleeding, hepatitis,  jaundice, pancreatitis, stomatitis, oedema, tachy-  cardia, hypertension, hypotension, vasodilatation,  cough, dyspnoea, insomnia, agitation, confusion,  depression, anxiety, convulsions, paraesthesia,  myasthenic syndrome, tremor, dizziness, headache,  influenza-like syndrome, infections, hyperglycaemia,  renal impairment, malignancy (particularly of the  skin), blood disorders (including leucopenia, anae-  mia, thrombocytopenia, pancytopenia, and red cell  aplasia — see notes above), disturbances of electro-  lytes and blood lipids, arthralgia, alopecia, acne,  skin hypertrophy, and rash; also reported intestinal  villous atrophy, progressive multifocal leucoence-  phalopathy, interstitial lung disease, pulmonary  fibrosis  Dose   • Renal transplantation, by mouth, 1 g twice daily  starting within 72 hours of transplantation or by  intravenous infusion, 1 g twice daily starting within 24  hours of transplantation for max. 14 days (then  transfer to oral therapy); CHILD and ADOLESCENT 2-18  years, by mouth 600 mg/m 2 twice daily (max. 2g  daily)   Note Tablets and capsules not appropriate for dose titration  in children with body surface area less than 1.25 m 2   • Cardiac transplantation, by mouth, ADULT over 18  years, 1.5 g twice daily starting within 5 days of  transplantation   • Hepatic transplantation, by intravenous infusion,  ADULT over 18 years, 1 g twice daily starting within 24  hours of transplantation for 4 days (up to max. 14  days), then by mouth, 1.5 g twice daily as soon as is  tolerated   Capsules, blue/peach, mycophenolate mofetil  250 mg, net price 100-cap pack = £57.57  Tablets, purple, mycophenolate mofetil 500 mg, net  price 50-tab pack = £57.57  Important See Bioavailability, p. 553   Tablets, e/c, mycophenolic acid (as mycophenolate  sodium) 180 mg (green), net price 120-tab pack =  £96.72; 360 mg (orange), 120-tab pack = £193.43.  Label: 25   Dose renal transplantation, 720 mg twice daily starting within 72  hours of transplantation   Equivalence to mycophenolate mofetil Mycophenolic acid  720 mg is approximately equivalent to mycophenolate mofetil  1 g but avoid unnecessary switching because of pharmacokinetic  differences   Prednisolone (section 6.3.2) is widely used in oncology.  It has a marked antitumour effect in acute lympho-  blastic leukaemia, Hodgkin’s disease, and the non-  Hodgkin lymphomas. It has a role in the palliation of  symptomatic end-stage malignant disease when it may  enhance appetite and produce a sense of well-being (see  also Prescribing in Palliative Care, p. 21).   The corticosteroids are also powerful immunosuppres-  sants. They are used to prevent organ transplant rejec-  tion, and in high dose to treat rejection episodes.   Ciclosporin a calcineurin inhibitor, is a potent immu-  nosuppressant which is virtually non-myelotoxic but  markedly nephrotoxic. It has an important role in  organ and tissue transplantation, for prevention of  graft rejection following bone marrow, kidney, liver,  pancreas, heart, lung, and heart-lung transplantation,  and for prophylaxis and treatment of graft-versus-host  disease.   Tacrolimus is also a calcineurin inhibitor. Although not  chemically related to ciclosporin it has a similar mode of  action and side-effects, but the incidence of neurotoxi-  city appears to be greater; cardiomyopathy has also  been reported. Disturbance of glucose metabolism  also appears to be significant.   Sirolimus is a non-calcineurin inhibiting immunosup-  pressant licensed for renal transplantation.   Basiliximab is a monoclonal antibody that prevents T-  lymphocyte proliferation; it is used for prophylaxis of  acute rejection in allogeneic renal transplantation. It is  given with ciclosporin and corticosteroid immunosup-  pression regimens; its use should be confined to specia-  list centres.   Antithymocyte immunoglobulin (rabbit) is licensed  for the prophylaxis of organ rejection in renal and  heart allograft recipients and for the treatment of  corticosteroid-resistant allograft rejection in renal trans-  plantation. Tolerability is increased by pretreatment  with an intravenous corticosteroid and antihistamine;  an antipyretic drug such as paracetamol may also be  beneficial.   Immunosuppressive therapy for renal  transplantation in adults (September 2004)  Immunosuppressive therapy for renal  transplantation in children and adolescents  (April 2006)   For induction therapy in the prophylaxis of organ  rejection, either basiliximab or daclizumab [discon-  tinued] are options for combining with a calcineurin  inhibitor. For each individual, ciclosporin or tacroli-  mus is chosen as the calcineurin inhibitor on the  basis of side-effects.   Mycophenolate mofetil [mycophenolic acid also  available but not licensed for use in children, see  above] is recommended as part of an immunosup-  pressive regimen only if:   • the calcineurin inhibitor is not tolerated, parti-  cularly if nephrotoxicity endangers the trans-  planted kidney; or   • there is very high risk of nephrotoxicity from the  calcineurin inhibitor, requiring a reduction in the  dose of the calcineurin inhibitor or its avoidance.   Sirolimus is recommended as a component of immu-  nosuppressive regimen only if intolerance necessi-  tates the withdrawal of a calcineurin inhibitor.   These recommendations may not be consistent with  the marketing authorisation of some of the products.   Side-effects nausea, vomiting, dysphagia, diarrhoea;  hypotension; infusion-related reactions (including  cytokine release syndrome and anaphylaxis, see notes  above), serum sickness; fever, shivering, increased  susceptibility to infection; increased susceptibility to  malignancy; lymphopenia, neutropenia, thrombocy-  topenia; myalgia; pruritus, rash   • Heart transplantation, by intravenous infusion over at  least 6 hours, 1-2.5 mg/kg daily for 3-5 days    • Renal transplantation, by intravenous infusion over at  least 6 hours, 1-1.5 mg/kg daily for 3-9 days   • Corticosteroid-resistant renal graft rejection, by  intravenous infusion over at least 6 hours, 1.5 mg/kg  daily for 7-14 days   Thymoglobuline® (Genzyme) ▼ (Ml  Intravenous infusion, powder for reconstitution,  rabbit anti-human thymocyte immunoglobulin, net  price 25-mg vial = £158.77   Side-effects severe hypersensitivity reactions and  cytokine release syndrome have been reported   • By intravenous injection or by intravenous infusion,  20 mg within 2 hours before transplant surgery and  20 mg 4 days after surgery; withhold second dose if  severe hypersensitivity or graft loss occurs; CHILD and  ADOLESCENT 1-17 years, body-weight under 35 kg,   10 mg within 2 hours before transplant surgery and  10 mg 4 days after surgery; body-weight over 35 kg,  adult dose   Injection, powder for reconstitution, basiliximab, net  price 10-mg vial = £758.69, 20-mg vial = £842.38  (both with water for injections). For intravenous infu-  sion   Indications see notes above, and under Dose; severe  acute ulcerative colitis [unlicensed indication] (section  1.5.3); rheumatoid arthritis (section 10.1.3); atopic  dermatitis and psoriasis (section 13.5.3)   Cautions monitor kidney function — dose dependent  increase in serum creatinine and urea during first few  weeks may necessitate dose reduction in transplant  patients (exclude rejection if kidney transplant) or  discontinuation in non-transplant patients; monitor  liver function (see Hepatic Impairment below);  monitor blood pressure — discontinue if hypertension  develops that cannot be controlled by anti-  hypertensives; hyperuricaemia; monitor serum  potassium especially in renal dysfunction (risk of  hyperkalaemia); monitor serum magnesium; measure  blood lipids before treatment and thereafter as  appropriate; use with tacrolimus specifically contra-  indicated; for patients other than transplant recipi-  ents, preferably avoid other immunosuppressants  (increased risk of infection and malignancies, includ-  ing lymphoma and skin cancer); avoid excessive  exposure to UV light, including sunlight; interactions:  Appendix 1 (ciclosporin)   Additional cautions in nephrotic syndrome Contra-indi-  cated in uncontrolled hypertension, uncontrolled infections,  and malignancy; in long-term management, perform renal  biopsies at yearly intervals    Hepatic impairment dosage adjustment based on  bilirubin and liver enzymes may be needed   Renal impairment dose as in normal renal function  but see Cautions above; in nephrotic syndrome  reduce dose by 25-50% if serum creatinine more than  30% above baseline on more than one measurement;  in patients with nephrotic syndrome and renal  impairment initially 2.5 mg/kg daily   Side-effects anorexia, nausea, vomiting, abdominal  pain, diarrhoea, gingival hyperplasia, hepatic dys-  function, hypertension, tremor, headache, paraes-  thesia, fatigue, renal dysfunction (renal structural  changes on long-term administration, see also under  Cautions), hyperuricaemia, hyperkalaemia, hypo-  magnesaemia, hyperlipidaemia, hypercholesterol-  aemia, muscle cramps, myalgia, hypertrichosis; less  commonly oedema, weight gain, signs of encephalo-  pathy, anaemia, thrombocytopenia; rarely pancreat-  itis, motor polyneuropathy, menstrual disturbances,  gynaecomastia, microangiopathic haemolytic anae-  mia, haemolytic uraemic syndrome, hyperglycaemia,  muscle weakness, myopathy, visual disturbances  secondary to benign intracranial hypertension (dis-  continue); also reported with infusion anaphylaxis  Dose   • Organ transplantation, used alone, ADULT and CHILD  over 3 months 10-15 mg/kg by mouth 4-12 hours  before transplantation followed by 10-15 mg/kg daily  for 1-2 weeks postoperatively then reduced gradually  to 2-6 mg/kg daily for maintenance (dose should be  adjusted according to blood-ciclosporin concentra-  tion and renal function); dose lower if given conco-  mitantly with other immunosuppressant therapy (e.g.  corticosteroids); if necessary one-third corresponding  oral dose can be given by intravenous infusion over  2-6 hours   • Bone-marrow transplantation, prevention and treat-  ment of graft-versus-host disease, ADULT and CHILD  over 3 months 3-5 mg/kg daily by intravenous infu-  sion over 2-6 hours from day before transplantation  to 2 weeks postoperatively (or 12.5-15 mg/kg daily by  mouth) then 12.5 mg/kg daily by mouth for 3-6  months then tailed off (may take up to a year after  transplantation)   • Nephrotic syndrome, by mouth, 5 mg/kg daily in 2  divided doses; CHILD 6 mg/kg daily in 2 divided doses;  maintenance treatment reduce to lowest effective  dose according to proteinuria and serum creatinine  measurements; discontinue after 3 months if no  improvement in glomerulonephritis or glomerulo-  sclerosis (after 6 months in membranous glomerulo-  nephritis)   Patients should be stabilised on a particular brand of  oral ciclosporin because switching between formula-  tions without close monitoring may lead to clinically  important changes in blood-ciclosporin concentration.  Prescribing and dispensing of ciclosporin should be by  brand name to avoid inadvertent switching. If it is  necessary to switch a patient to a different brand of  ciclosporin, the patient should be monitored closely  for changes in blood-ciclosporin concentration, serum  creatinine, blood pressure, and transplant function.   Capsules, ciclosporin 25 mg (grey), net price 30-cap  pack = £13.80; 50 mg (white), 30-cap pack = £27.00;  100 mg (grey), 30-cap pack = £51.50. Counselling,  administration   Counselling Total daily dose should be taken in 2 divided doses  Deximune® (Dexcel) M]   Capsules, grey, ciclosporin 25 mg, net price 30-cap  pack = £13.94; 50 mg 30-cap pack = £27.31; 100 mg  30-cap pack = £51.83. Counselling, administration  Note Contains ethyl lactate which is metabolised to ethanol  Counselling Total daily dose should be taken in 2 divided doses   Capsules, ciclosporin 10 mg (yellow/white), net price  60-cap pack = £18.48; 25 mg (blue/grey), 30-cap pack  = £18.59; 50 mg (yellow/ white), 30-cap pack =  £36.41; 100 mg (blue/grey), 30-cap pack = £69.11.  Counselling, administration   Oral solution, yellow, sugar-free, ciclosporin 100 mg/  mL, net price 50 mL = £103.55. Counselling, admin-  istration   Counselling Total daily dose should be taken in 2 divided doses  Mix solution with orange juice (or squash) or apple juice (to  improve taste) or with water immediately before taking (and rinse  with more to ensure total dose). Do not mix with grapefruit juice.  Keep medicine measure away from other liquids (including water)   Sandimmun® (Novartis) Ml  Concentrate for intravenous infusion (oily), ciclos-  porin 50 mg/mL. To be diluted before use, net price 1-  mL amp = £1.94; 5-mL amp = £9.17   Excipients include polyoxyl castor oil (risk of anaphylaxis, see Excipi-  ents, p. 2)   Note Observe patients for signs of anaphylaxis for at least 30  minutes after starting infusion and at frequent intervals thereafter   Indications prophylaxis of organ rejection in kidney  allograft recipients (initially in combination with  ciclosporin and corticosteroid, then with cortico-  steroid only); see also under Dose  Cautions monitor kidney function when given with  ciclosporin; monitor whole blood-sirolimus trough  concentration (Afro-Caribbean patients may require  higher doses); hyperlipidaemia (monitor lipids);  monitor urine proteins; increased susceptibility to  infection (especially urinary-tract infection); increased  susceptibility to lymphoma and other malignancies,  particularly of the skin (limit exposure to UV light);  interactions: Appendix 1 (sirolimus)   Hepatic impairment monitor whole blood-sirolimus  level closely and consult local treatment protocol;  clearance reduced in mild to moderate impairment; in  severe impairment decrease dose by 50% and moni-  tor whole blood-sirolimus trough concentration every  5-7 days until 3 consecutive measurements have  shown stable blood-sirolimus concentration    Pregnancy avoid unless essential — (toxicity in animal  studies); effective contraception must be used during  treatment and for 12 weeks after stopping  Breast-feeding discontinue breast-feeding    Side-effects abdominal pain, constipation, nausea,  diarrhoea, ascites, stomatitis; oedema, tachycardia,  hypertension, hypercholesterolaemia, hypertriglycer-  idaemia, venous thromboembolism; pleural effusion,  pneumonitis; headache; pyrexia; proteinuria, haemo-  lytic uraemic syndrome; anaemia, thrombocytopenia,  thrombotic thrombocytopenic purpura, leucopenia,  neutropenia, hypokalaemia, hypophosphataemia,  hyperglycaemia, lymphocele; arthralgia, osteonecro-  sis; epistaxis; acne, rash, impaired healing; less com-  monly pancreatitis, pulmonary embolism, pulmonary  haemorrhage, pericardial effusion, nephrotic  syndrome, pancytopenia; rarely interstitial lung dis-  ease, alveolar proteinosis, hepatic necrosis, lym-  phoedema, and hypersensitivity reactions including  anaphylactic reactions, angioedema, exfoliative  dermatitis, and hypersensitivity vasculitis; focal seg-  mental glomerulosclerosis and reversible impairment  of male fertility also reported   • Initially 6 mg, after surgery (once wound has healed),  then 2 mg once daily (dose adjusted according to  whole blood-sirolimus trough concentration) in com-  bination with ciclosporin and corticosteroid for 2-3  months (sirolimus given 4 hours after ciclosporin);  ciclosporin should then be withdrawn over 4-8 weeks  (if not possible, sirolimus should be discontinued and  an alternate immunosuppressive regimen used)   Note Manufacturer advises pre-dose (‘trough’) whole blood-  sirolimus concentration (using chromatographic assay)  when used with ciclosporin should be 4-12 micrograms/litre  (local treatment protocols may differ); after withdrawal of  ciclosporin pre-dose whole blood-sirolimus concentration  should be 12-20 micrograms/litre (local treatment protocols  may differ); close monitoring of whole blood-sirolimus con-  centration required if concomitant treatment with potent  inducers or inhibitors of metabolism and after discontinuing  them, or if ciclosporin dose reduced significantly or stopped;  see also Hepatic Impairment above  When changing between oral solution and tablets, mea-  surement of whole blood ‘trough’ sirolimus concentration  after 1-2 weeks is recommended  Therapeutic drug monitoring assays Sirolimus whole-  blood concentration is measured using either high perfor-  mance liquid chromatography (HPLC) or immunoassay.  Switching between different immunoassays or between an  immunoassay and HPLC can lead to clinically significant  differences in results and therefore incorrect dose adjust-  ments. Adjustment to the target therapeutic dose range  should be made with knowledge of the assay used and  corresponding reference range   Tablets, coated, sirolimus 0.5 mg (tan), net price 30-  tab pack = £69.00; 1 mg (white), 30-tab pack = £86.49;  2 mg (yellow), 30-tab pack = £172.98. Counselling,  administration   Important The 0.5-mg tablet is not bioequivalent to the 1-  mg, 2 -mg, and 5-mg tablets. Multiples of 0.5-mg tablets  should not be used as a substitute for other tablet strengths   Oral solution, sirolimus 1 mg/mL, net price 60 mL =  £162.41. Counselling, administration  Counselling Food may affect absorption (take at the same time  with respect to food). Mix solution with at least 60 mL water or  orange juice in a glass or plastic container immediately before  taking; refill container with at least 120 mL of water or orange  juice and drink immediately (to ensure total dose). Do not mix  with any other liquids    Indications prophylaxis of organ rejection in liver,  kidney, and heart allograft recipients and allograft  rejection resistant to conventional immunosuppres-  sive regimens, see also notes above; moderate to  severe atopic eczema (section 13.5.3)   Cautions monitor blood pressure, ECG (important:  see Cardiomyopathy below), fasting blood-glucose  concentration, haematological and neurological  (including visual) parameters, electrolytes, hepatic  and renal function; monitor whole blood-tacrolimus  trough concentration (especially during episodes of  diarrhoea) — consult local treatment protocol for  details; QT-interval prolongation; neurotoxicity;  increased risk of infections, malignancies, and lym-  phoproliferative disorders; avoid excessive exposure  to UV light including sunlight; pregnancy (exclude  before starting); interactions: Appendix 1 (tacroli-  mus)   Driving May affect performance of skilled tasks (e.g. driving)  Contra-indications hypersensitivity to macrolides;  avoid concurrent administration with ciclosporin  (care if patient has previously received ciclosporin)  Hepatic impairment dose reduction may be neces-  sary in severe impairment   Pregnancy avoid unless potential benefit outweighs  risk — risk of premature delivery, intra-uterine growth  restriction, and hyperkalaemia; toxicity in animal  studies   Breast-feeding avoid — present in milk  Side-effects nausea, vomiting, diarrhoea, constipa-  tion, dyspepsia, flatulence, bloating, weight changes,  anorexia, gastro-intestinal inflammation, ulceration,  and perforation, hepatic dysfunction, jaundice,  cholestasis, ascites, bile-duct abnormalities, oedema,  tachycardia, hypertension, haemorrhage, throm-  boembolic and ischaemic events, dyspnoea, pleural  effusion, parenchymal lung disorders, sleep distur-  bances, tremor, headache, peripheral neuropathy,  mood changes, depression, confusion, anxiety, psy-  chosis, seizures, paraesthesia, dizziness, renal impair-  ment, renal failure, renal tubular necrosis, urinary  abnormalities, hyperglycaemia, electrolyte distur-  bances (including hyperkalaemia, hypokalaemia, and  hyperuricaemia), blood disorders (including anaemia,  leucopenia, pancytopenia, and thrombocytopenia),  arthralgia, muscle cramp, visual disturbances, photo-  phobia, tinnitus, impaired hearing, alopecia, sweating,  acne; less commonly paralytic ileus, gastro-intestinal  reflux disease, peritonitis, pancreatitis, heart failure,  arrhythmia, cardiac arrest, cerebrovascular accident,  cardiomyopathy (important: see Cardiomyopathy  below), palpitation, respiratory failure, coma, speech  disorder, amnesia, paralysis, influenza-like symptoms,  encephalopathy, coagulation disorders, photosensit-  ivity, cataract, hypoglycaemia, dysmenorrhoea,  hypertonia, dermatitis; rarely pericardial effusion,  respiratory distress syndrome, posterior reversible  encephalopathy syndrome, dehydration, thrombotic  thrombocytopenic purpura, blindness, toxic epider-  mal necrolysis, hirsutism; very rarely myasthenia,  haemorrhagic cystitis, Stevens- Johnson syndrome  Cardiomyopathy Cardiomyopathy has been reported in  children. Patients should be monitored by echocardiogra-  phy for hypertrophic changes — consider dose reduction or  discontinuation if these occur   Adoport®, Prog raj® , ModigraJ® , and Advagraj®  (tacrolimus): serious medication errors  It is important to note the correct use of these med-  icines:   • Adoport ® is an immediate-release formulation that is  taken twice daily, once in the morning and once in the  evening;   • PrograJ ® is an immediate-release formulation that is taken  twice daily, once in the morning and once in the evening;   • ModigraJ ® granules are used to prepare an immediate-  release suspension which is taken twice daily, once in the  morning and once in the evening;   • Advagraj ® is a prolonged-release formulation that is taken  once daily in the morning.   Switching between Adoport ® , PrograJ ® , ModigraJ®,  and Advagraj® requires careful therapeutic monitor-  ing. Substitution should be made only under the close  supervision of a transplant specialist.   Capsules, tacrolimus (as monohydrate) 500 micr-  ograms (white/ivory), net price 50-cap pack = £50.50;  lmg (white /brown), 50-cap pack = £65.52, 100-cap  pack = £131.02; 5 mg (white/orange), 50-cap pack =  £242.05. Label: 23, counselling, driving  Note Tacrolimus is incompatible with PVC  Dose liver transplantation, starting 12 hours after transplanta-  tion, by mouth, 100-200 micrograms/kg daily in 2 divided doses;  CHILD 300 micrograms/kg daily in 2 divided doses  Renal transplantation, starting within 24 hours of transplantation,  by mouth, 200-300 micrograms/kg daily in 2 divided doses;  CHILD 300 micrograms/kg daily in 2 divided doses  Heart transplantation with antibody induction, starting within 5  days of transplantation, by mouth, 75 micrograms/kg daily in 2  divided doses; CHILD, without antibody induction, 300 micr-  ograms/kg daily in 2 divided doses as soon as clinically possible  (8-12 hours after discontinuing intravenous infusion); following  antibody induction, 100-300 micrograms/kg daily in 2 divided  doses    Modigraf® (Astellas) ▼ (Ml  Granules, tacrolimus (as monohydrate), 200 micr-  ograms, net price 50-sachet pack = £71.30; 1 mg, 50-  sachet pack = £356.65. Label: 13, 23, counselling,  driving   Note Tacrolimus is incompatible with PVC  Dose liver transplantation, starting 12 hours after transplanta-  tion, by mouth, 100-200 micrograms/kg daily in 2 divided doses;  CHILD 300 micrograms/kg daily in 2 divided doses  Renal transplantation, starting within 24 hours of transplantation,  by mouth, 200-300 micrograms/kg daily in 2 divided doses;  CHILD 300 micrograms/kg daily in 2 divided doses  Heart transplantation with antibody induction, starting within 5  days of transplantation, by mouth, 75 micrograms/kg daily in 2  divided doses; CHILD, without antibody induction, 300 micr-  ograms/kg daily in 2 divided doses as soon as clinically possible  (8-12 hours after discontinuing intravenous infusion); following  antibody induction, 100-300 micrograms/kg daily in 2 divided  doses   Capsules, tacrolimus (as monohydrate) 500 micr-  ograms (yellow), net price 50-cap pack = £61.88; 1 mg  (white), 50-cap pack = £80.28, 100-cap pack =  £160.54; 5 mg (greyish-red), 50-cap pack = £296.58.  Label: 23, counselling, driving  Note Tacrolimus is incompatible with PVC    Concentrate for intravenous infusion, tacrolimus  5mg/mL. To be diluted before use. Net price 1-mL  amp = £58.46   Excipients include polyoxyl castor oil (risk of anaphylaxis, see Excipi-  ents, p. 2)   Note Tacrolimus is incompatible with PVC  Dose liver transplantation, starting 12 hours after transplanta-  tion, by mouth, 100-200 micrograms/kg daily in 2 divided doses  or by intravenous infusion over 24 hours, 10-50 micrograms /kg  daily for up to 7 days (then transfer to oral therapy); CHILD by  mouth, 300 micrograms/kg daily in 2 divided doses or by intra-  venous infusion over 24 hours, 50 micrograms/kg daily for up to 7  days (then transfer to oral therapy)   Renal transplantation, starting within 24 hours of transplantation,  by mouth, 200-300 micrograms/kg daily in 2 divided doses or by  intravenous infusion over 24 hours, 50-100 micrograms/kg daily  for up to 7 days (then transfer to oral therapy); CHILD by mouth,  300 micrograms/kg daily in 2 divided doses or by intravenous  infusion over 24 hours, 75-100 micrograms/kg daily for up to 7  days (then transfer to oral therapy)   Heart transplantation with antibody induction, starting within 5  days of transplantation, by mouth, 75 micrograms/kg daily in 2  divided doses or by intravenous infusion over 24 hours, 10-  20 micrograms/kg daily for up to 7 days (then transfer to oral  therapy); CHILD, without antibody induction, initially by intra-  venous infusion over 24 hours, 30-50 micrograms/kg daily, then  by mouth, 300 micrograms/kg daily in 2 divided doses as soon as  clinically possible (8-12 hours after discontinuing intravenous  infusion); following antibody induction, by mouth, 100-300 micr-  ograms/kg daily in 2 divided doses  Maintenance treatment, dose adjusted according to response  Rejection therapy, seek specialist advice    M Modified release  Advagraf® (Astellas) (Ml  Capsules, m/r, tacrolimus (as monohydrate)   500 micrograms (yellow/orange), net price 50-cap  pack = £35.79; 1 mg (white/orange), 50-cap pack =  £71.59, 100-cap pack = £143.17; 3 mg (orange), 50-  cap pack = £214.76; 5 mg (red/orange), 50-cap pack  = £266.92. Label: 23, 25, counselling, driving  Dose liver transplantation, starting 12-18 hours after transplan-  tation, by mouth, 100-200 micrograms/kg once daily in the  morning   Renal transplantation, starting within 24 hours of transplantation,  by mouth, 200-300 micrograms/kg once daily in the morning  Rejection therapy, seek specialist advice  CHILD not recommended   Rituximab causes lysis of B lymphocytes. It is licensed  for the treatment of chemotherapy-resistant or relapsed  stage III— IV follicular non-Hodgkin’s lymphoma and, in  combination with other chemotherapy, for previously  untreated stage III— IV follicular lymphoma, and for  previously untreated or relapsed chronic lymphocytic  leukaemia (see NICE guidance below). Rituximab is also  licensed for maintenance therapy in patients with  relapsed or refractory follicular non-Hodgkin’s lymph-  oma that has responded to induction therapy with  chemotherapy (with or without rituximab) (see NICE  guidance below). It is also licensed for use in combina-  tion with other chemotherapy for the treatment of  diffuse large B-cell non-Hodgkin’s lymphoma (see  NICE guidance below). Full resuscitation facilities  should be at hand and as with other cytotoxics, treat-  ment should be undertaken under the close supervision  of a specialist. See section 10.1.3 for the role of ritux-  imab in rheumatoid arthritis.    Rituximab should be used with caution in patients  receiving cardiotoxic chemotherapy or with a history  of cardiovascular disease because exacerbation of  angina, arrhythmia, and heart failure have been  reported. Transient hypotension occurs frequently dur-  ing infusion and antihypertensives may need to be  withheld for 12 hours before infusion. Progressive multi-  focal leucoencephalopathy (which is usually fatal or  causes severe disability) has been reported in associa-  tion with rituximab; patients should be monitored for  cognitive, neurological, or psychiatric signs and symp-  toms. If progressive multifocal leucoencephalopathy is  suspected, suspend treatment until it has been excluded.  Infusion-related side-effects (including cytokine release  syndrome) are reported commonly with anti-lympho-  cyte monoclonal antibodies and occur predominantly  during the first infusion; they include fever and chills,  nausea and vomiting, allergic reactions (such as rash,  pruritus, angioedema, bronchospasm and dyspnoea),  flushing and tumour pain. Patients should be given  paracetamol and an antihistamine before each dose of  anti-lymphocyte monoclonal antibodies to reduce these  effects. Premedication with a corticosteroid should also  be considered. The infusion may have to be stopped  temporarily and the infusion-related effects treated —  consult product literature for appropriate management.  Evidence of pulmonary infiltration and features of  tumour lysis syndrome should be sought if infusion-  related effects occur.    Fatalities following severe cytokine release syndrome  (characterised by severe dyspnoea) and associated with  features of tumour lysis syndrome have occurred after  infusions of anti-lymphocyte monoclonal antibodies.  Patients with a high tumour burden as well as those  with pulmonary insufficiency or infiltration are at  increased risk and should be monitored very closely  (and a slower rate of infusion considered).   Rituximab, in combination with cyclophosphamide,  vincristine, and prednisolone is an option for the  treatment of symptomatic stage III and IV follicular  lymphoma in previously untreated patients.   Rituximab for the treatment of relapsed or  refractory stage III or IV follicular non-  Hodgkin’s lymphoma (February 2008)  Rituximab, in combination with chemotherapy, is an  option for the induction of remission in patients with  relapsed stage III or IV follicular non-Hodgkin’s  lymphoma.   Rituximab monotherapy as maintenance therapy is  an option for the treatment of patients with relapsed  stage III or IV follicular non-Hodgkin’s lymphoma in  remission induced with chemotherapy (with or with-  out rituximab).   Rituximab monotherapy is an option for the treat-  ment of patients with relapsed or refractory stage III  or IV follicular non-Hodgkin’s lymphoma, when all  alternative treatment options have been exhausted  (that is, if there is resistance to or intolerance of  chemotherapy).   Rituximab for the first-line treatment of  chronic lymphocytic leukaemia (July 2009)  Rituximab, in combination with fludarabine and  cyclophosphamide, is recommended as an option  for the first-line treatment of chronic lymphocytic  leukaemia.   Rituximab, in combination with cyclophosphamide,  doxorubicin, vincristine, and prednisolone, is recom-  mended for first-line treatment of CD 2 0-positive  diffuse large-B-cell lymphoma at clinical stage II,  III or IV.   The use of rituximab for localised (stage I) disease  should be limited to clinical trials.    Alemtuzumab causes lysis of B and C lymphocytes and  is licensed for use in patients with chronic lymphocytic  leukaemia for whom fludarabine treatment is not appro-  priate. In common with rituximab, it causes infusion-  related side-effects including cytokine release syndrome  (see above); premedication with an analgesic, an anti-  histamine, and a corticosteroid is recommended.   The Scottish Medicines Consortium (p. 4) has advised  (August 2008) that alemtuzumab is accepted for  restricted use within NHS Scotland for the treatment  of B-cell chronic lymphocytic leukaemia (B-CLL) when  fludarabine combination chemotherapy is not appropri-  ate. Alemtuzumab is restricted to use in patients with  previously untreated B-CLL, with the cytogenetic  abnormality 17p-deletion.   Ofatumumab causes lysis of B lymphocytes. It is  licensed for treatment of chronic lymphocytic leuk-  aemia in patients refractory to fludarabine and alemtu-  zumab. Infusion-related side-effects (including cytokine  release syndrome — see above) have been reported with  ofatumumab; premedication with an analgesic, an anti-  histamine, and a corticosteroid is recommended.   Pregnancy avoid; use effective contraception during  and for 6 months after treatment in men or women   Breast-feeding avoid breast-feeding during treatment  and for at least 4 weeks after administration   MabCampath® (Genzyme) (Ml  Concentrate for intravenous infusion, alemtuzumab  30mg/mL, net price 1-mL vial = £264.11   Contra-indications consult product literature  Renal impairment no information available for  creatinine clearance less than 30 mL/minute  Pregnancy avoid unless potential benefit outweighs  risk; use effective contraception during and for 12  months after treatment   Breast-feeding discontinue breast-feeding during and  for 12 months after treatment — no information avail-  able   Concentrate for intravenous infusion, ofatumumab  100 mg/5 mL, net price = £182.00   Pregnancy avoid unless potential benefit to mother  outweighs risk of B-lymphocyte depletion in fetus —  effective contraception required during and for 12  months after treatment   Concentrate for intravenous infusion, rituximab  10 mg/mL, net price 10-mL vial = £174.63, 50-mL vial  = £873.15   Interferon alfa has shown some antitumour effect in  certain lymphomas and solid tumours. Interferon alfa  preparations are also used in the treatment of chronic  hepatitis B, and chronic hepatitis C ideally in combina-  tion with ribavirin (section 5.3.3). Side-effects are dose-  related, but commonly include anorexia, nausea, diarr-  hoea, influenza-like symptoms, and lethargy. Ocular  side-effects and depression (including suicidal beha-  viour) have also been reported. Myelosuppression may  occur, particularly affecting granulocyte counts. Cardi-  ovascular problems (hypotension, hypertension, palpi-  tation, and arrhythmias), nephrotoxicity and hepatotoxi-  city have been reported. Hypertriglyceridaemia,  sometimes severe, has been observed; monitoring of  lipid concentration is recommended. Other side-effects  include hypersensitivity reactions, thyroid abnormal-  ities, hyperglycaemia, alopecia, psoriasiform rash, con-    fusion, coma and seizures (usually with high doses in the  elderly).   Polyethylene glycol-conjugated (‘pegylated’) derivatives  of interferon alfa (peginterferon alfa-2a and peginter-  feron alfa-2b) are available; pegylation increases the  persistence of the interferon in the blood. The peginter-  ferons are licensed for the treatment of chronic hepatitis  C, ideally in combination with ribavirin (see section  5.3.3). Peginterferon alfa-2a is also licensed for the  treatment of chronic hepatitis B.   NICE guidance (peginterferon alfa, interferon  alfa, and ribavirin for chronic hepatitis C)    IntronA® (Schering-Plough) (Ml  Injection, interferon alfa-2b (rbe) 10 million units/mL,  net price 1-mL vial = £42.35, 2.5-mL vial = £105.95.  For subcutaneous injection or intravenous infusion  Injection pen, interferon alfa-2b (rbe), net price  15 million units/mL, 1.5-mL cartridge = £76.28;   Note Each 1.5-mL multidose cartridge delivers 12 doses of 0.1 mL  i.e. a total of 1.2 mL   For chronic myelogenous leukaemia (as monotherapy or in  combination with cytarabine), hairy cell leukaemia, follicular  lymphoma, lymph or liver metastases of carcinoid tumour,  chronic hepatitis B, chronic hepatitis C, adjunct to surgery in  malignant melanoma and maintenance of remission in multiple  myeloma   Injection, interferon alfa-2a (rbe), net price 6 million  units/mL, 0.5-mL (3 million-unit) prefilled syringe =  £14.20; 9 million units/mL, 0.5-mL (4.5 million-unit)  prefilled syringe = £21.29; 12 million units/mL, 0.5-  mL (6 million-unit) prefilled syringe = £28.37; 18 mil-  lion units/mL, 0.5-mL (9 million-unit) prefilled syringe  = £42.57; 30 million units/mL, 0.6-mL (18 million-  unit) cartridge = £85.15, for use with Roferon pen  device. For subcutaneous injection (cartridges, vials,   For AIDS-related Kaposi's sarcoma, hairy cell leukaemia, chronic  myelogenous leukaemia, advanced renal cell carcinoma, pro-  gressive cutaneous T-cell lymphoma, chronic hepatitis B and  chronic hepatitis C, follicular non-Hodgkin’s lymphoma, adjunct  to surgery in malignant melanoma   Injection, peginterferon alfa-2a, net price 135-micr-  ogram prefilled syringe = £107.76, 180-microgram  prefilled syringe = £124.40. For subcutaneous injec-  tion   Combined with ribavirin for chronic hepatitis C; as monotherapy  for chronic hepatitis C if ribavirin not tolerated or contra-indicated  (see section 5.3.3); as monotherapy for chronic hepatitis B   ViraferonPeg® (Schering-Plough) Ml  Injection, prefilled pen, powder for reconstitution,  peginterferon alfa-2b (rbe), net price 50-microgram  pen = £66.46, 80-microgram pen = £106.34, 100-  microgram pen = £132.92, 120-microgram pen =  £159.51, 150-microgram pen = £199.38 (all with nee-  dles and swabs). For subcutaneous injection  Combined with ribavirin for chronic hepatitis C; as monotherapy  for chronic hepatitis C if ribavirin not tolerated or contra-indicated  (see section 5.3.3)   Interferon beta is licensed for use in patients with  relapsing, remitting multiple sclerosis (characterised  by at least two attacks of neurological dysfunction  over the previous 2 or 3 years, followed by complete  or incomplete recovery) who are able to walk unaided.  Not all patients respond and a deterioration in the bouts  has been observed in some. It is also licensed for use in  patients with a single demyelinating event with an active  inflammatory process, if it is severe enough to require  treatment with an intravenous corticosteroid, and they  are at high risk of developing multiple sclerosis. Inter-  feron beta- lb is also licensed for use in patients with  secondary progressive multiple sclerosis but its role in  this condition has not been confirmed.   Cautions Caution is advised in those with severe  hepatic or renal impairment or a history of cardiac  disorders, depressive disorders (avoid in severe depres-    sion or in those with suicidal ideation), seizures, or  severe myelosupression. Patients should be monitored  for signs of hepatic injury.   Contra-indications Avoid treatment with interferon  beta in patients with severe depressive illness or those  with decompensated liver disease.   Side-effects Side-effects reported most frequently  include irritation at injection site (including inflamma-  tion, hypersensitivity, necrosis) and influenza-like symp-  toms (fever, chills, myalgia, or malaise) but these  decrease over time; nausea and vomiting occur occa-  sionally. Other side-effects include hypersensitivity  reactions (including anaphylaxis and urticaria), blood  disorders, menstrual disorders, mood and personality  changes, suicide attempts, confusion and convulsions;  alopecia, hepatitis, and thyroid dysfunction have been  reported rarely with interferon beta- lb.   Interferon beta and glatiramer acetate are not  recommended for the treatment of multiple sclerosis  in the NHS in England and Wales.   Patients who are currently receiving interferon beta  or glatiramer acetate for multiple sclerosis, whether  as routine therapy or as part of a clinical trial, should  have the option to continue treatment until they and  their consultant consider it appropriate to stop, hav-  ing regard to the established criteria for withdrawal  from treatment.   The Department of Health, the National Assembly  for Wales, the Scottish Executive, the Northern Ire-  land Department of Health, Social Services & Public  Safety, and the manufacturers have reached agree-  ment on a risk-sharing scheme for the NHS supply of  interferon beta and glatiramer acetate for multiple  sclerosis. Health Service Circular (HSC 2002/004)  explains how patients can participate in the scheme.  It is available on the Department of Health website  (www.dh.gov.uk)   Injection, interferon beta-la 60 micrograms (^mil-  lion units)/mL, net price 0.5-mL (30-microgram, 6  million-unit) prefilled syringe = £163.50  Note For intramuscular injection  Injection, powder for reconstitution, interferon beta-   Dose for relapsing, remitting multiple sclerosis or for a single  demyelinating event with an active inflammatory process (if it is  severe enough to require intravenous corticosteroid and patient at  high risk of developing multiple sclerosis), consult product lit-  erature   Injection, interferon beta-la, net price 22-microgram  (6 million-unit) prefilled syringe = £52.06; 44-micr-  ogram (12 million-unit) prefilled syringe = £67.77;  starter pack of 6 x 8.8-microgram (2.4 million-unit)  prefilled syringes with 6 x 22-microgram (6 million-  unit) prefilled syringes = £552.19  Note For subcutaneous injection   Injection, interferon beta-la, 44 micrograms (12 mil-  lion-units/mL), net price 1.5 mL (66-microgram,   18 million-unit) cartridge = £144.48; 88-micrograms  (24 million-units/mL), 1.5 mL (132-microgram, 36  million-unit) cartridge = £171.97; starter pack of 2 x  1.5 mL (132-microgram, 36 million-unit) cartridge =  £343.93   Note Cartridges for use with RebiSmart® auto-injector  device. For subcutaneous injection   Injection ( RebiDose ®), interferon beta- la, net price  22-microgram (6 million-unit) prefilled pen = £52.06;  44-microgram (12 million-unit) prefilled pen = £67.77;  starter pack of 6 x 8.8-microgram (2.4 million-unit)  prefilled pens with 6 x 22-microgram (6 million-unit)  prefilled pens = £552.19  Note For subcutaneous injection   Note An autoinjector device ( Betaject ® Light) is available from  Bayer Schering   Dose for relapsing, remitting multiple sclerosis, for secondary  progressive multiple sclerosis with active disease, or for a single  demyelinating event with an active inflammatory process (if  severe enough to require intravenous corticosteroid and patient at  high risk of developing multiple sclerosis), consult product lit-  erature   Dose for relapsing, remitting multiple sclerosis, for secondary  progressive multiple sclerosis with active disease, or for a single  demyelinating event with an active inflammatory process (if  severe enough to require intravenous corticosteroid and patient at  high risk of developing multiple sclerosis), consult product lit-  erature    Interferon gamma- lb is licensed to reduce the fre-  quency of serious infection in chronic granulomatous  disease and in severe malignant osteopetrosis.   Indications see notes above  Cautions seizure disorders (including seizures asso-  ciated with fever); cardiac disease (including ischae-  mia, congestive heart failure, and arrhythmias);  monitor before and during treatment: haematological  tests (including full blood count, differential white cell  count, and platelet count), blood chemistry tests  (including renal and liver function tests) and urinaly-  sis; avoid simultaneous administration of foreign  proteins including immunological products (risk of  exaggerated immune response); interactions:  Appendix 1 (interferons)   Driving May impair ability to drive or operate machinery;  effects may be enhanced by alcohol  Hepatic impairment manufacturer advises caution in  severe impairment — risk of accumulation  Renal impairment manufacturer advises caution in  severe impairment — risk of accumulation  Pregnancy manufacturers recommend avoid unless  potential benefit outweighs risk (toxicity in animal  studies); effective contraception required during  treatment — consult product literature  Breast-feeding manufacturers advise avoid — no  information available   Side-effects nausea, vomiting; headache, fatigue,  fever; myalgia, arthralgia; rash, injection-site reac-  tions; rarely confusion and systemic lupus erythe-  matosus; also reported, neutropenia, thrombocyto-  penia, and raised liver enzymes  Dose   Immukin® (Boehringer Ingelheim) Ml  Injection, recombinant human interferon gamma-lb  200 micrograms/mL, net price 0.5-mL vial = £66.67  Dose By subcutaneous injection, 50 micrograms/m 2 3 times a  week; patients with body surface area of 0.5 m 2 or less, 1.5 micr-  ograms/kg 3 times a week; not yet recommended for children  under 6 months with chronic granulomatous disease   Aldesleukin (recombinant interleukin-2) is licensed for  metastatic renal cell carcinoma excluding patients in  whom all three of the following prognostic factors are  present: performance status of Eastern Co-operative  Oncology Group of 1 or greater, more than one organ  with metastatic disease sites, and a period of less than  24 months between initial diagnosis of primary tumour  and date of evaluation of treatment. It is usually given by  subcutaneous injection. It is now rarely given by intra-  venous infusion because of an increased risk of capillary  leak syndrome, which can cause pulmonary oedema  and hypotension. Aldesleukin produces tumour shrink-  age in a small proportion of patients, but it has not been  shown to increase survival. Bone-marrow, hepatic,  renal, thyroid, and CNS toxicity is common. It is for  use in specialist units only.   Contra-indications consult product literature  Pregnancy use only if potential benefit outweighs risk  (toxicity in animal studies); ensure effective contra-  ception during treatment in men and women; see also  Reproductive Function, p. 520  Breast-feeding discontinue breast-feeding  Side-effects see section 8.1, notes above, and consult  product literature  Dose   Injection, powder for reconstitution, aldesleukin. Net  price 18-million unit vial = £1 12.00. For subcutaneous  injection or intravenous infusion (but see notes above)   BCG (Bacillus Calmette-Guerin) is a live attenuated  strain derived from Mycobacterium bovis. It is licensed  as a bladder instillation for the treatment of primary or  recurrent bladder carcinoma and for the prevention of  recurrence following transurethral resection.   Cautions screen for active tuberculosis (contra-indi-  cated if tuberculosis confirmed); traumatic catheter-  isation or urethral or bladder injury (delay adminis-  tration until mucosal damage healed)  Contra-indications impaired immune response, HIV  infection, urinary-tract infection, severe haematuria,  tuberculosis, fever of unknown origin  Pregnancy avoid  Breast-feeding avoid   Side-effects cystitis, dysuria, urinary frequency, hae-  maturia, malaise, fever, influenza-like syndrome; also  systemic BCG infection (with fatalities) — consult  product literature; rarely hypersensitivity reactions  (such as arthralgia and rash), orchitis, transient ure-  thral obstruction, bladder contracture, renal abscess;  ocular symptoms reported   Bladder instillation, freeze-dried powder containing  attenuated Mycobacterium bovis prepared from the  Connaught strain of bacillus of Calmette and Guerin,  net price 81-mg vial = £79.23   Bladder instillation, freeze-dried powder containing  attenuated Mycobacterium bovis prepared from the  TICE strain of bacillus of Calmette and Guerin, net  price 12.5-mg vial = £71.61   Canakinumab is a recombinant human monoclonal  antibody that selectively inhibits interleukin- 1 beta  receptor binding. It is licensed for the treatment of  cryopyrin-associated periodic syndrome, including  severe forms of familial cold auto-inflammatory  syndrome (or familial cold urticaria), Muckle-Wells  syndrome, and neonatal-onset multisystem inflamm-  atory disease (also known as chronic infantile neurolo-  gical, cutaneous, articular syndrome), which are rare  inherited auto-inflammatory disorders.   Cautions history of recurrent infection or predisposi-  tion to infection; monitor neutrophil count before  starting treatment, 1-2 months after starting treat-  ment, and periodically thereafter; patients should  receive all recommended vaccinations (including  pneumococcal and inactivated influenza vaccine)  before starting treatment; avoid live vaccines unless  potential benefit outweighs risk — consult product lit-  erature for further information and section 14.1  (P- 746)   Tuberculosis Patients should be evaluated for latent and  active tuberculosis before starting treatment and monitored  for signs and symptoms of tuberculosis during and after  treatment   Contra-indications severe active infection (see also  Cautions); neutropenia; concomitant use with tumour  necrosis factor inhibitors (possible increased risk of  infections)   Hepatic impairment no information available  Renal impairment limited information available but  manufacturer advises no dose adjustment required  Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk; effective contraception  required during treatment and for up to 3 months after  last dose   Breast-feeding consider if benefit outweighs risk —  not known if present in human milk  Side-effects vertigo, increased susceptibility to infec-  tion, injection-site reactions   • By subcutaneous injection, ADULT and CHILD over 4  years, body-weight 15-40 kg, 2 mg/kg every 8 weeks.  If clinical response not achieved 7 days after starting  treatment, a repeat dose of 2 mg/kg can be consid-  ered; if a full response is then achieved, subsequent  dosing should be 4 mg/kg every 8 weeks; body-  weight over 40 kg, 150 mg every 8 weeks. If clinical  response not achieved 7 days after starting treatment,  a repeat dose of 150 mg can be considered; if full  response is then achieved, subsequent dosing should  be 300 mg every 8 weeks   Glatiramer is an immunomodulating drug comprising  synthetic polypeptides. It is licensed for treating initial  symptoms in patients at high risk of developing multiple  sclerosis, and also for reducing the frequency of relapses    in ambulatory patients with relapsing-remitting multiple  sclerosis who have had at least 2 clinical relapses in the  past 2 years. Initiation of treatment with glatiramer  should be supervised by a specialist.   Side-effects hypersensitivity reactions; flushing, chest  pain, palpitation, tachycardia, and dyspnoea may  occur within minutes of injection; nausea, constipa-  tion, dyspepsia; syncope, anxiety, asthenia, depres-  sion, headache, tremor, sweating; oedema, lympha-  denopathy; hypertonia, back pain, arthralgia,  influenza-like symptoms; injection-site reactions,  rash; rarely seizures   Injection, glatiramer acetate 20mg/mL, net price 1-  mL prefilled syringe = £18.73   Histamine is licensed for maintenance therapy, in com-  bination with aldesleukin, in patients with acute myeloid  leukaemia in first remission.   Contra-indications consult product literature  Hepatic impairment increased risk of tachycardia and  hypotension in moderate to severe impairment  Renal impairment increased risk of hypotension in  severe impairment   Lenalidomide is an immunomodulating drug with anti-  neoplastic, anti-angiogenic, and pro-erythropoietic  properties. It is licensed, in combination with dexa-  methasone, for the treatment of multiple myeloma in  patients who have received at least one previous ther-  apy-   The most serious side-effects of lenalidomide are  venous thromboembolism and severe neutropenia.  Lenalidomide is structurally related to thalidomide  and there is a risk of teratogenesis.   The Scottish Medicines Consortium (p. 4) has advised  (April 2010) that lenalidomide, in combination with  dexamethasone, is accepted for restricted use within  NHS Scotland for patients with multiple myeloma who  have received at least two prior therapies.   Lenalidomide in combination with dexamethasone  is an option for the treatment of multiple myeloma in  patients who have received two or more prior thera-  pies. The drug cost of lenalidomide will be met by  the manufacturer for patients who remain on treat-  ment for more than 26 cycles.    Thalidomide is used in combination with melphalan  and prednisolone as first-line treatment for untreated  multiple myeloma, in patients aged 65 years and over, or  for those not eligible for high-dose chemotherapy (for  example, patients with significant co-morbidity such as  cardiac risk factors). It has immunomodulatory and anti-  inflammatory activity. Thalidomide can cause drowsi-  ness, constipation, and on prolonged use peripheral  neuropathy.   Pregnancy For women of child-bearing potential,  pregnancy must be excluded before starting treatment  (perform pregnancy test on initiation or within 3 days  prior to initiation). Women must practise effective  contraception at least 1 month before, during, and for  at least 1 month after treatment (oral combined hormo-  nal contraceptives and copper-releasing intrauterine  devices not recommended) and men should use con-  doms during treatment and for at least 1 week after  stopping if their partner is pregnant or is of child-bearing  potential and not using effective contraception. Women  must comply with a pregnancy prevention programme.   Indications see notes above  Cautions see notes above; monitor full blood count  (including differential white cell count and platelet  count) before treatment and every week for the first 8  weeks then every 4 weeks (reduce dose or interrupt  treatment if neutropenia or thrombocytopenia devel-  op — consult product literature); concomitant drugs  that increase the risk of thromboembolism; high  tumour burden — risk of tumour lysis syndrome, see  p. 520; monitor thyroid function; risk factors for  myocardial infarction; interactions: Appendix 1  (lenalidomide)   Thromboembolism Patients and their carers should be  made aware of the symptoms of thromboembolism and    advised to report sudden breathlessness, chest pain, or  swelling of a limb   Neutropenia and thrombocytopenia Patients and their  carers should be made aware of the symptoms of neutro-  penia and advised to seek medical advice if symptoms  suggestive of neutropenia (such as fever, sore throat) or of  thrombocytopenia (such as bleeding) develop   Renal impairment starting dose 10 mg once daily if  creatinine clearance 30-50 mL/minute; starting dose  15 mg on alternate days if creatinine clearance less  than 30 mL/minute   Side-effects myocardial infarction, hypotension, deep  vein thrombosis; pneumonia, dyspnoea; tremor,  hypoaesthesia, fatigue, asthenia; neutropenia, throm-  bocytopenia, anaemia, lymphopenia, leucopenia;  muscle cramp; pruritus, rash; rarely Stevens-Johnson  syndrome and toxic epidermal necrolysis; interstitial  pneumonitis and pancreatitis also reported  Dose   • ADULT over 18 years, 25 mg once daily for 21 conse-  cutive days of a 28-day cycle; for doses of dexa-  methasone, consult product literature   Capsules, lenalidomide, 5 mg (white), net price 21-  cap pack = £3570.00; 10 mg (blue/yellow), 21-cap  pack = £3780.00; 15 mg (blue/white), 21-cap pack =  £3969.00; 25 mg (white), 21-cap pack = £4368.00.  Label: 25, counselling, symptoms of thromboembo-  lism, neutropenia, or thrombocytopenia, patient  information leaflet    Note Patient, prescriber, and supplying pharmacy must comply  with a pregnancy prevention programme. Every prescription must  be accompanied by a completed Prescription Authorisation Form,  which must be sent to Celgene.   Cautions see notes above; high tumour burden — risk  of tumour lysis syndrome, see p. 520; concomitant  use of drugs which increase risk of peripheral neuro-  pathy or thromboembolism   Thromboembolism Thromboprophylaxis is recommended  for at least the first 5 months of treatment, especially in  patients with additional thrombotic risk factors. Patients and  their carers should be made aware of the symptoms of  thromboembolism and advised to report sudden breath-  lessness, chest pain, or swelling of a limb  Peripheral neuropathy Monitor patients for signs and  symptoms of peripheral neuropathy; patients and their  carers should be advised to seek medical advice if symptoms  such as paraesthesia, abnormal coordination, or weakness  develop. Dose reduction, dose interruption, or treatment  discontinuation may be necessary — consult product litera-  ture. Patients with pre-existing peripheral neuropathy should  not be treated with thalidomide unless the potential clinical  benefits outweigh the risk   Side-effects vomiting, dry mouth, dyspepsia, consti-  pation; bradycardia, cardiac failure, deep vein    thrombosis; dyspnoea, interstitial lung disease,  pulmonary embolism, peripheral oedema; asthenia,  confusion, depression, dizziness, drowsiness, periph-  eral neuropathy, dysaesthesia, paraesthesia, syncope,  tremor; pyrexia; pneumonia; anaemia, leucopenia,  neutropenia, lymphopenia, thrombocytopenia; skin  reactions including Stevens- Johnson syndrome; also  reported toxic epidermal necrolysis, intestinal  obstruction, gastro-intestinal perforation, hypo-  thyroidism, and sexual dysfunction   • ADULT over 18 years, 200 mg once daily at bedtime for  6-week cycle; max. 12 cycles   Thalidomide Celgene® (Celgene) ▼ [Ml  Capsules, thalidomide 50 mg, net price 28-cap pack =  £298.48. Label: 2, counselling, symptoms of peripheral  neuropathy and thromboembolism (see above)   Note Patient, prescribe! - , and supplying pharmacy must comply  with a pregnancy prevention programme. Every prescription must  be accompanied by a complete Prescription Authorisation Form.   Mifamurtide is licensed for high-grade, resectable, non-  metastatic osteosarcoma after complete surgical resec-  tion, in patients 2 to 30 years of age at initial diagnosis. It  is used in combination with chemotherapy.   apy; history of autoimmune, inflammatory, or col-  lagen disease; monitor renal function, hepatic func-  tion and clotting parameters; monitor patients with  history of venous thrombosis, vasculitis, or unstable  cardiovascular disorders for persistent or worsening  symptoms during administration — consult product  literature; interactions: Appendix 1 (mifamurtide)  Hepatic impairment use with caution — no informa-  tion available   Pregnancy avoid; effective contraception required  Breast-feeding avoid — no information available  Side-effects gastro-intestinal disturbances (including  anorexia, nausea, vomiting, diarrhoea, constipation,  abdominal pain, dyspepsia); tachycardia, hyper-  tension, palpitations, hypotension, phlebitis, flushing;  oedema, respiratory disorders (including dyspnoea,  epistaxis, cough, tachypnoea, haemoptysis, pleural  effusion); confusion, depression, insomnia, headache,  dizziness, paraesthesia, hypoaesthesia, tremor, drow-  siness, anxiety; hypokalaemia, anaemia, leucopenia,  thrombocytopenia, granulocytopenia; haematuria,  dysuria, pollakiuria; musculoskeletal pain; blurred  vision; vertigo, tinnitus, hearing loss; sweating, alo-  pecia, rash, dry skin   Intravenous infusion, powder for reconstitution,  mifamurtide encapsulated in liposomes, net price 4-  mg vial = £2375.00   Natalizumab is a monoclonal antibody that inhibits the  migration of leucocytes into the central nervous system,  hence reducing inflammation and demyelination. It is  licensed for use in patients with highly active relapsing-  remitting multiple sclerosis despite treatment with inter-  feron beta or those with rapidly evolving severe relap-  sing-remitting multiple sclerosis. Treatment with natali-  zumab should be initiated and supervised by a  specialist.   Natalizumab is associated with an increased risk of  opportunistic infection and progressive multifocal leu-  coencephalopathy (PML). The risk of developing PML  increases after 2 years of therapy; the risk beyond 3  years treatment is not known. A magnetic resonance  image (MRI) scan is recommended before starting treat-  ment with natalizumab, and annually thereafter. Patients  should be monitored for new or worsening neurological  symptoms, and for cognitive and psychiatric signs of  PML. Treatment should be suspended until PML has  been excluded. If a patient develops an opportunistic  infection or PML, natalizumab should be permanently  discontinued.   Infusion-related side-effects include nausea, vomiting,  flushing, headache, dizziness, fatigue, rigors, pyrexia,  arthralgia, urticaria, and pruritus. Patients should be  observed for hypersensitivity reactions, including  anaphylaxis, during the infusion and for 1 hour after  completion of the infusion. Natalizumab should be dis-  continued permanently if hypersensitivity reaction  occurs.   The Scottish Medicines Consortium (p. 4) has advised  (August 2007) that natalizumab is accepted for  restricted use as single disease-modifying therapy in  highly active relapsing-remitting multiple sclerosis  only in patients with rapidly evolving severe relapsing-  remitting multiple sclerosis defined by 2 or more dis-  abling relapses in 1 year and with 1 or more gadolinium-  enhancing lesions on brain magnetic resonance imaging  (MRI) or a significant increase in T2 lesion load com-  pared with a previous MRI.   Natalizumab for the treatment of adults with  highly active relapsing-remitting multiple  sclerosis (August 2007)   Natalizumab is an option for the treatment only of  rapidly evolving severe relapsing-remitting multiple  sclerosis (RES). RES is defined by 2 or more dis-  abling relapses in 1 year, and 1 or more gadolinium-  enhancing lesions on brain magnetic resonance  imaging (MRI) or a significant increase in T2 lesion  load compared with a previous MRI.   Cautions see notes above and consult product litera-  ture; prior treatment with immunosuppressants;  monitor liver function (see below)   Liver toxicity Liver dysfunction reported; advise patients to  seek immediate medical attention if symptoms such as  jaundice or dark urine develop; discontinue treatment if  significant liver injury occurs   Progressive multifocal leucoencephalopathy (PML)  Patients should be informed about the risks of PML before  starting treatment with natalizumab and again after 2 years;    they should be given an alert card which includes informa-  tion about the symptoms of PML (see also notes above)  Hypersensitivity reactions Patients should be told the  importance of uninterrupted dosing, particularly in the  early months of treatment (intermittent therapy may  increase risk of sensitisation)   Contra-indications progressive multifocal leucoence-  phalopathy; active infection (see notes above); con-  current use of interferon beta or glatiramer acetate;  immunosuppression; active malignancies (except  cutaneous basal cell carcinoma)   Side-effects see notes above; also urinary-tract  infection, nasopharyngitis, autoantibodies, and arthr-  algia; less commonly hypersensitivity reactions (see  above); liver toxicity also reported   • By intravenous infusion, ADULT over 18 years, 300 mg  once every 4 weeks; discontinue if no response after 6  months   Concentrate for intravenous infusion, natalizumab  20mg/mL, net price 15-mL vial = £1130.00. Coun-  selling, liver toxicity, progressive multifocal leucoen-  cephalopathy, and hypersensitivity, patient alert card   Hormonal manipulation has an important role in the  treatment of breast, prostate, and endometrial cancer,  and a more marginal role in the treatment of hyperne-  phroma. These treatments are not curative, but may  provide excellent palliation of symptoms in selected  patients, sometimes for a period of years. Tumour  response, and treatment toxicity should be carefully  monitored and treatment changed if progression occurs  or side-effects exceed benefit.   Pregnancy in first trimester, high doses associated  with vaginal carcinoma, urogenital abnormalities, and  reduced fertility in female offspring; increased risk of  hypospadias in male offspring  Side-effects sodium retention with oedema, throm-  boembolism, jaundice, feminising effects in men; see  also notes above  Dose   Diethylstilbestrol (Non-proprietary) (Mi  Tablets, diethylstilbestrol 1 mg, net price 28 = £53.34;  5 mg, 28 =£180.05   Cautions see section 6.4. 1 . 1 ; interactions: Appendix 1  (oestrogens)   Progestogens have a role in the treatment of endo-  metrial cancer; their use in breast cancer and renal  cell cancer has declined. Progestogens are now rarely  used to treat prostate cancer. Medroxyprogesterone or  megestrol are usually chosen and can be given orally;  high-dose or parenteral treatment cannot be recom-  mended. Side-effects are mild but may include nausea,  fluid retention, and weight gain.   Diethylstilbestrol is sometimes used to treat prostate  cancer, but it is not usually used first-line because of its  side-effects. It is occasionally used in postmenopausal  women with breast cancer. Toxicity is common and  dose-related side-effects include nausea, fluid retention,  and venous and arterial thrombosis. Impotence and  gynaecomastia always occur in men, and withdrawal  bleeding may be a problem in women. Hypercalcaemia  and bone pain may also occur in breast cancer.  Ethinylestradiol is the most potent oestrogen available;  unlike other oestrogens it is only slowly metabolised in  the liver. Ethinylestradiol is licensed for the palliative  treatment of prostate cancer.   Indications see notes above; contraception (section  7.3. 2.2); other indications (section 6.4.1.2)   Cautions see section 6.4. 1.2 and notes above; inter-  actions: Appendix 1 (progestogens)  Contra-indications see section 6.4. 1.2 and notes  above   Breast-feeding present in milk — no adverse effects  reported; see also Parenteral Progestogen-only  Contraceptives (section 7. 3.2.2)    Side-effects see section 6.4. 1.2 and notes above;  glucocorticoid effects at high dose may lead to a  Cushingoid syndrome   Tablets, medroxyprogesterone acetate 100 mg  (scored), net price 60-tab pack = £29.98, 100-tab pack  = £49.94; 200 mg (scored), 30-tab pack = £29.65,   Tablets, medroxyprogesterone acetate 2.5 mg, 5 mg  and 10 mg, see section 6.4.1. 2   Contra-indications see under Medroxyprogesterone  acetate (section 6.4. 1.2) and notes above  Hepatic impairment avoid  Pregnancy avoid; reversible feminisation of male  fetuses reported in animal studies; risk of hypospa-  dias in male fetuses and masculinisation of female  fetuses   Breast-feeding discontinue breast-feeding  Side-effects see under Medroxyprogesterone acetate  (section 6.4. 1.2) and notes above; also reported  vomiting, carpal tunnel syndrome, Cushing’s  syndrome, and tumour flare (with or without hyper-  calcaemia)   Megace® (Bristol-Myers Squibb) (Ml  Tablets, scored, megestrol acetate 160 mg (off-white),  30-tab pack = £19.52   Pregnancy masculinisation of female fetuses and  other defects reported; see also oral Progestogen-only  Contraceptives (section 7.3.2. 1)   Breast-feeding higher doses may suppress lactation  and alter milk composition — use lowest effective  dose; see also oral Progestogen-only Contraceptives  (section 7.3.2. 1)   • Breast cancer, 40 mg daily, increased to 60 mg daily if  required   Testosterone esters (section 6.4.2) have largely been  superseded by other drugs for breast cancer.   The management of patients with breast cancer  involves surgery, radiotherapy, drug therapy, or a com-  bination of these.   For operable breast cancer, treatment before surgery  (neoadjuvant therapy) reduces the size of the tumour  and facilitates breast-conserving surgery; hormone  antagonist therapy (e.g. letrozole) is chosen for steroid  hormone-receptor-positive breast cancer and chemo-  therapy for steroid hormone-receptor-negative tumours  or for younger women.   Early breast cancer All women should be considered  for adjuvant therapy following surgical removal of the  tumour. Adjuvant therapy is used to eradicate the micro-  metastases that cause relapses. Choice of adjuvant  treatment is determined by the risk of recurrence, ster-  oid hormone-receptor status of the primary tumour, and  menopausal status.   Adjuvant therapy comprises cytotoxic chemotherapy  and hormone-antagonist therapy. Women with steroid  hormone-receptor-positive breast cancer are consid-  ered for hormone-antagonist therapy (preceded by cyto-  toxic chemotherapy if necessary) whilst women with  steroid hormone-receptor-negative breast cancer  should be considered for cytotoxic chemotherapy.   Aromatase inhibitors act predominantly by blocking the  conversion of androgens to oestrogens in the peripheral  tissues. They do not inhibit ovarian oestrogen synthesis  and should not be used in premenopausal women.  Anastrozole and letrozole are non-steroidal aromatase  inhibitors; exemestane is a steroidal aromatase inhibi-  tor. Aromatase inhibitors are usually prescribed as initial  adjuvant therapy in postmenopausal women with oes-  trogen-receptor-positive tumours; tamoxifen, an oestro-  gen-receptor antagonist, is used if an aromatase inhibi-  tor is not appropriate. Adjuvant hormone antagonist  therapy should generally be continued for 5 years fol-  lowing removal of the tumour. In postmenopausal  women considered for extended adjuvant therapy, 5  years of tamoxifen is followed by letrozole for a further  2-3 years.   Trastuzumab (section 8.1.5) is licensed for use in early  breast cancer which overexpresses human epidermal  growth factor-2 (HER2) in women who have received  surgery, chemotherapy and radiotherapy (as appropri-  ate).   Premenopausal women with oestrogen-receptor-posi-  tive breast cancer who decline chemotherapy may  benefit from treatment with goserelin (section 8. 3.4.2)  or ovarian ablation.   Advanced breast cancer Treatment of advanced  breast cancer depends on the patient’s drug history  and an assessment of disease severity. Aromatase inhi-  bitors, such as anastrozole or letrozole, are the preferred    treatment in postmenopausal women with oestrogen-  receptor-positive advanced breast cancer, a long dis-  ease-free interval following treatment for early breast  cancer, and disease limited to bone or soft tissues;  tamoxifen can be used if aromatase inhibitors are not  suitable. Progestogens, such as medroxyprogesterone  acetate (section 8.3.2), may be used after aromatase  inhibitors and tamoxifen in postmenopausal women.  Tamoxifen should be considered for pre- and perime-  nopausal women with oestrogen-receptor-positive  breast cancer not previously treated with tamoxifen.  Ovarian suppression is used in pre- and perimenopausal  women who have had disease progression despite treat-  ment with tamoxifen. The gonadorelin analogue gose-  relin (section 8. 3.4.2) is licensed for advanced breast  cancer in pre- and perimenopausal women suitable for  hormone manipulation.   Cytotoxic chemotherapy is indicated for advanced ster-  oid hormone-receptor-negative tumours and for aggres-  sive disease, particularly when metastases involve  visceral sites (e.g. the liver) or if the disease-free interval  following treatment for early breast cancer is short.   Cytotoxic drugs used in breast cancer An anthra-  cycline combined with fluorouracil (section 8.1.3) and  cyclophosphamide (section 8.1.1), and sometimes also  with methotrexate (section 8.1.3) is effective. Cyclo-  phosphamide, methotrexate, and fluorouracil can be  useful if an anthracycline is inappropriate (e.g. in cardiac  disease).   Metastatic disease The choice of chemotherapy  regimen will be influenced by whether the patient has  previously received adjuvant treatment and the pre-  sence of any co-morbidity.   For women who have not previously received chemo-  therapy, an anthracycline (such as doxorubicin or epi-  rubicin) alone or in combination with another cytotoxic  drug is the standard initial therapy for metastatic breast  disease.   Patients with anthracycline-refractory or resistant dis-  ease should be considered for treatment with a taxane  (section 8.1.5) either alone or in combination with  trastuzumab if they have tumours that overexpress  HER2. Other cytotoxic drugs with activity against breast  cancer include capecitabine (section 8.1.3), mitoxan-  trone, mitomycin (both section 8.1.2), and vinorelbine  (section 8.1.4). Trastuzumab alone (section 8.1.5) is an  option for chemotherapy-resistant cancers that over-  express HER2.   (section 6.7.3) is licensed for postmenopausal breast  cancer. It is quite well tolerated but diarrhoea and  abdominal discomfort may be a problem. Trilostane  causes adrenal hypofunction and corticosteroid replace-  ment therapy is needed.   The use of bisphosphonates (section 6.6.2) in patients  with metastatic breast cancer may reduce pain and  prevent skeletal complications of bone metastases.   Indications adjuvant treatment of oestrogen-receptor-  positive early invasive breast cancer in postmeno-  pausal women; adjuvant treatment of oestrogen-  receptor-positive early breast cancer in postmeno-    pausal women following 2-3 years of tamoxifen  therapy; advanced breast cancer in postmenopausal  women which is oestrogen-receptor-positive or  responsive to tamoxifen   Cautions laboratory test for menopause if doubt; sus-  ceptibility to osteoporosis (assess bone mineral den-  sity before treatment and at regular intervals)  Contra-indications not for premenopausal women  Hepatic impairment avoid in moderate to severe  impairment   Side-effects hot flushes, vaginal dryness, vaginal  bleeding, hair thinning, anorexia, nausea, vomiting,  diarrhoea, headache, arthralgia, bone fractures, rash  (including Stevens-Johnson syndrome); asthenia and  drowsiness — may initially affect ability to drive or  operate machinery; slight increases in total choles-  terol levels reported; very rarely allergic reactions  including angioedema and anaphylaxis  Dose   The Scottish Medicines Consortium (p. 4) has advised  (August 2005 and October 2006) that anastrozole  ( Arimidex ®) is accepted for restricted use within NHS  Scotland, within the licensed indications, for early breast  cancer and early invasive breast cancer.   Indications adjuvant treatment of oestrogen-receptor-  positive early breast cancer in postmenopausal  women following 2-3 years of tamoxifen therapy;  advanced breast cancer in postmenopausal women in  whom anti-oestrogen therapy has failed  Cautions interactions: Appendix 1 (exemestane)   Side-effects nausea, vomiting, abdominal pain, dys-  pepsia, constipation, anorexia; dizziness, fatigue,  headache, depression, insomnia; hot flushes, sweat-  ing; alopecia, rash; less commonly drowsiness, asthe-  nia, and peripheral oedema; rarely thrombocytopenia,  leucopenia    Aromasin® (Pharmacia) [Ml  Tablets, s/c, exemestane 25 mg, net price 30-tab pack  = £88.80, 90-tab pack = £266.40. Label: 21  The Scottish Medicines Consortium (p. 4) has advised  (October 2005) that exemestane (Aromasin®) is accepted for  restricted use within NHS Scotland as an adjuvant treatment  in postmenopausal women with oestrogen-receptor-positive  invasive early breast cancer, following 2-3 years of initial  adjuvant tamoxifen therapy.   Indications treatment of oestrogen-receptor-positive  metastatic or locally advanced breast cancer in post-  menopausal women in whom disease progresses or  relapses while on, or after, other anti-oestrogen ther-  apy   Hepatic impairment manufacturer advises caution in  mild to moderate impairment; avoid in severe  impairment   Renal impairment manufacturer advises caution if  creatinine clearance less than 30 mL/minute — no  information available   Side-effects nausea, vomiting, diarrhoea; venous  thromboembolism; anorexia, headache, asthenia;  urinary-tract infections; hot flushes; back pain; rash,  injection-site reactions, hypersensitivity reactions; less  commonly vaginal haemorrhage, vaginal candidiasis,  and leucorrhoea  Dose   • By deep intramuscular injection into buttock, 500 mg  every 2 weeks for the first 3 doses, then 500 mg every  month   Note 500 mg dose should be administered as one 250-mg  injection (slowly over 1-2 minutes) into each buttock   Faslodex® (AstraZeneca) (Ml  Injection (oily), fulvestrant 50mg/mL, net price 1 x  5-mL (250-mg) prefilled syringe = £348.27, 2 x 5-mL  (250-mg) prefilled syringe = £522.41   Indications adjuvant treatment of oestrogen-receptor-  positive early breast cancer in postmenopausal  women; advanced breast cancer in postmenopausal  women (including those in whom other anti-oestrogen  therapy has failed); early invasive breast cancer in  postmenopausal women after standard adjuvant  tamoxifen therapy; pre-operative treatment in post-  menopausal women with localised hormone-recep-  tor-positive breast cancer to allow subsequent breast  conserving surgery   Cautions susceptibility to osteoporosis (assess bone  mineral density before treatment and at regular  intervals)   Hepatic impairment avoid in severe impairment  Renal impairment manufacturer advises caution if  creatinine clearance less than 10 mL/minute  Pregnancy avoid (toxicity in animal studies); manu-  facturer advises effective contraception required until  postmenopausal status fully established  Breast-feeding manufacturer advises avoid  Side-effects hot flushes, nausea, vomiting, fatigue,  dizziness, headache, dyspepsia, constipation, diarr-  hoea, depression, anorexia, appetite increase, hyper-  cholesterolemia, alopecia, increased sweating, rash,  peripheral oedema, musculoskeletal pain, osteo-  porosis, bone fracture; less commonly hypertension,  palpitation, tachycardia, dyspnoea, cough, drowsi-  ness, insomnia, anxiety, memory impairment, dys-    aesthesia, taste disturbance, pruritus, dry skin, urti-  caria, thrombophlebitis, abdominal pain, urinary  frequency, urinary-tract infection, vaginal bleeding,  vaginal discharge, breast pain, pyrexia, mucosal dry-  ness, stomatitis, cataract, eye irritation, blurred vision,  tumour pain, arthritis, leucopenia, general oedema;  rarely pulmonary embolism, arterial thrombosis,  cerebrovascular infarction  Dose   Tablets, f/c, letrozole 2.5 mg. Net price 14-tab pack =  £49.90, 28-tab pack = £84.86   Cautions occasional cystic ovarian swellings in pre-  menopausal women; increased risk of thromboem-  bolic events, especially when used with cytotoxics  (see also below); endometrial changes (important:  see below); porphyria, interactions: Appendix 1  (tamoxifen)   Endometrial changes Increased endometrial changes,  including hyperplasia, polyps, cancer, and uterine sarcoma  reported; prompt investigation required if abnormal vaginal  bleeding including menstrual irregularities, vaginal dis-  charge, and pelvic pain or pressure in those receiving (or  who have received) tamoxifen. Patients should be informed  of the risk of endometrial cancer and told to report relevant  symptoms promptly   Contra-indications treatment of infertility contra-  indicated if personal or family history of idiopathic  venous thromboembolism or genetic predisposition  to thromboembolism   Pregnancy avoid — possible effects on fetal develop-  ment; effective contraception must be used during  treatment and for 2 months after stopping   Side-effects hot flushes, vaginal bleeding and vaginal  discharge (important: see also Endometrial Changes  under Cautions), suppression of menstruation in some  premenopausal women, pruritus vulvae, gastro-  intestinal disturbances, headache, light-headedness,  tumour flare, decreased platelet counts; occasionally  oedema, rarely hypercalcaemia if bony metastases,  alopecia, rashes, uterine fibroids; also visual distur-  bances (including corneal changes, cataracts, retino-  pathy); leucopenia (sometimes with anaemia and  thrombocytopenia), rarely neutropenia; hypertrigly-  ceridaemia reported rarely (sometimes with pan-  creatitis); thromboembolic events reported (see  below); liver enzyme changes (rarely fatty liver,  cholestasis, hepatitis); rarely interstitial pneumonitis,  hypersensitivity reactions including angioedema,  Stevens- Johnson syndrome, bullous pemphigoid; see  also notes above   Risk of thromboembolism Tamoxifen can increase the risk  of thromboembolism particularly during and immediately  after major surgery or periods of immobility (consider  interrupting treatment to initiate anticoagulant measures).  Patients should be made aware of the symptoms of throm-  boembolism and advised to report sudden breathlessness  and any pain in the calf of one leg  Dose   • Anovulatory infertility, 20 mg daily on days 2,3,4 and  5 of cycle; if necessary the daily dose may be    increased to 40 mg then 80 mg for subsequent  courses; if cycles irregular, start initial course on any  day, with subsequent course starting 45 days later or  on day 2 of cycle if menstruation occurs   Tamoxifen (Non-proprietary) (Ml  Tablets, tamoxifen (as citrate) 10 mg, net price 30-tab  pack = £3.08; 20 mg, 30-tab pack = £2.09; 40 mg, 30-  tab pack = £11.27   Indications hormone-dependent metastatic breast  cancer in postmenopausal women  Cautions hypercalcaemia may occur (especially if  bone metastases and usually at beginning of treat-  ment); avoid in acute porphyria (but see section 9.8.2);  history of severe thromboembolic disease; interac-  tions: Appendix 1 (toremifene)   Endometrial changes Increased endometrial changes,  including hyperplasia, polyps and cancer reported. Abnor-  mal vaginal bleeding including menstrual irregularities,  vaginal discharge and symptoms such as pelvic pain or  pressure should be promptly investigated  Contra-indications endometrial hyperplasia, QT pro-  longation (avoid concomitant administration of drugs  that prolong QT interval), electrolyte disturbances  (particularly uncorrected hypokalaemia), bradycardia,  heart failure with reduced left-ventricular ejection  fraction, history of arrhythmias  Hepatic impairment elimination decreased in hepatic  impairment — avoid if severe  Pregnancy avoid  Breast-feeding avoid   Side-effects nausea, vomiting; oedema; depression,  dizziness, fatigue; sweating, hot flushes, vaginal  bleeding or discharge (important: see Cautions); rash;  less commonly anorexia, constipation, increased  weight, thromboembolic events, dyspnoea, insomnia,  headache, endometrial hypertrophy; very rarely  jaundice, transient corneal opacity, and alopecia  Dose   Metastatic cancer of the prostate usually responds to  hormonal treatment aimed at androgen depletion. Stan-  dard treatments include bilateral subcapsular orchidect-  omy or use of a gonadorelin analogue (buserelin, gose-  relin, histrelin, leuprorelin, or triptorelin). The  gonadotrophin-releasing hormone antagonist, degare-  lix, (p. 574) is also available. Response in most patients  lasts for 12 to 18 months. No entirely satisfactory  therapy exists for disease progression despite this treat-  ment (hormone-refractory prostate cancer), but occa-  sional patients respond to other hormone manipulation  e.g. with an anti-androgen. Bone disease can often be  palliated with irradiation or, if widespread, with stron-  tium or prednisolone (section 6.3.2).   Gonadorelin analogues are as effective as orchidectomy  or diethylstilbestrol (section 8.3.1) but are expensive  and require parenteral administration, at least initially.  They cause initial stimulation then depression of lutein-  ising hormone release by the pituitary. During the initial  stage (1-2 weeks) increased production of testosterone  may be associated with progression of prostate cancer.  In susceptible patients this tumour ‘flare’ may cause  spinal cord compression, ureteric obstruction or  increased bone pain. When such problems are anti-  cipated, alternative treatments (e.g. orchidectomy) or  concomitant use of an anti-androgen such as cypro-  terone acetate or flutamide (see below) are recom-  mended; anti-androgen treatment should be started  before the gonadorelin analogue. Gonadorelin analo-  gues are also used in women for breast cancer (section  8.3.4. 1) and other indications (section 6.7.2).   The Scottish Medicines Consortium (p. 4) has advised  (June 2009) that histrelin ( Vantas ®) is accepted for  restricted use within NHS Scotland for the palliative  treatment of advanced prostate cancer in patients with  an anticipated life expectancy of at least one year in  whom annual administration will offer advantages.   Cautions Men at risk of tumour ‘flare’ (see above)  should be monitored closely during the first month of  therapy. Caution is required in patients with metabolic  bone disease because reduced bone mineral density can  occur. The injection site should be rotated.    Side-effects The gonadorelin analogues cause side-  effects similar to the menopause in women and orchi-  dectomy in men and include hot flushes and sweating,  sexual dysfunction, vaginal dryness or bleeding, and  gynaecomastia or changes in breast size. Signs and  symptoms of prostate or breast cancer may worsen  initially (managed in prostate cancer with anti-andro-  gens, see above). Other side-effects include hypersensi-  tivity reactions (rashes, pruritus, asthma, and rarely  anaphylaxis), injection site reactions (see Cautions),  headache (rarely migraine), visual disturbances, dizzi-  ness, arthralgia and possibly myalgia, hair loss, periph-  eral oedema, gastro-intestinal disturbances, weight  changes, sleep disorders, and mood changes.   Side-effects see notes above; worsening hyper-  tension, palpitation, glucose intolerance, altered blood  lipids, thrombocytopenia, leucopenia, nervousness,  fatigue, memory and concentration disturbances,  anxiety, increased thirst, hearing disorders, musculo-  skeletal pain; nasal irritation, nose bleeds and altered  sense of taste and smell (spray formulation only)  Dose   • By subcutaneous injection, 500 micrograms every 8  hours for 7 days, then intranasally, 1 spray into each  nostril 6 times daily (see also notes above)  Counselling Avoid use of nasal decongestants before and  for at least 30 minutes after treatment.   Injection, buserelin (as acetate) 1 mg/mL. Net price 2  x 5.5-mL vial = £23.69    Nasal spray, buserelin (as acetate) 100 micrograms/ Vantas® (Orion) ▼ (Ml   Indications locally advanced prostate cancer as an  alternative to surgical castration; adjuvant treatment  to radiotherapy or radical prostatectomy in patients  with high-risk localised or locally advanced prostate  cancer; neoadjuvant treatment prior to radiotherapy  in patients with high-risk localised or locally advanced  prostate cancer; metastatic prostate cancer; advanced  breast cancer; oestrogen-receptor-positive early  breast cancer (section 8.3.4. 1); endometriosis, endo-  metrial thinning, uterine fibroids, assisted reproduc-  tion (section 6.7.2)   Cautions see notes above; diabetes; risk of ureteric  obstruction and spinal cord compression in men  Contra-indications undiagnosed vaginal bleeding  Pregnancy see Goserelin, section 6.7.2  Breast-feeding see Goserelin, section 6.7.2  Side-effects see notes above; also transient changes  in blood pressure; paraesthesia; rarely hypercal-  caemia (in patients with metastatic breast cancer)  Dose   Implant, goserelin (as acetate) 3.6 mg in prefilled  syringe, net price = £58.50   Dose advanced prostate cancer by subcutaneous injection into  anterior abdominal wall, 3.6 mg every 28 days   Implant, goserelin (as acetate) 3.6 mg in SafeSystem®  syringe applicator, net price each = £65.00  Dose breast cancer and prostate cancer (see indications above)  by subcutaneous injection into anterior abdominal wall, 3.6 mg  every 28 days   Implant, goserelin (as acetate) 10.8 mg in Safe-  System® syringe applicator, net price each = £235.00  Dose prostate cancer (see indications above), by subcutaneous  injection into anterior abdominal wall, 10.8 mg every 12 weeks   Indications advanced prostate cancer  Cautions see notes above; risk of ureteric obstruction  and spinal cord compression  Side-effects see notes above; also hepatic disorder,  dyspnoea, depression, asthenia, elevated blood glu-  cose-concentration, increased urinary frequency,  hypertrichosis; less commonly hypercholesterol-  aemia, palpitation, ventricular extrasystole, haemato-  ma, tremor, anaemia, renal failure, nephrolithiasis,  hypercalcaemia  Dose   1 implant (50 mg) every 12 months; remove after 12  months of treatment   Counselling Avoid wetting arm containing implant for 24  hours and avoid lifting heavy objects or strenuous physical  activity for 7 days after implantation   Indications locally advanced prostate cancer as an  alternative to surgical castration; adjuvant treatment  to radiotherapy or radical prostatectomy in patients  with high-risk localised or locally advanced prostate  cancer; metastatic prostate cancer; endometriosis,  endometrial thinning, uterine fibroids (section 6.7.2)   Cautions see notes above and section 6.7.2; risk of  ureteric obstruction and spinal cord compression in  men   Side-effects see notes above and section 6.7.2; also  fatigue, muscle weakness, paraesthesia, hypertension,  palpitation, alteration of glucose tolerance and of  blood lipids; hypotension, jaundice, thrombocytope-  nia and leucopenia reported  Dose   Injection (microsphere powder for reconstitution),  leuprorelin acetate, net price 3.75-mg vial with 1-mL  vehicle-filled syringe = £75.24   Dose prostate cancer (see indications), by subcutaneous or by  intramuscular injection, 3.75 mg every 4 weeks   Injection (microsphere powder for reconstitution),  leuprorelin acetate, net price 1 1.25-mg vial with 2-mL  vehicle-filled syringe = £225.72  Dose prostate cancer (see indications), by subcutaneous injec-  tion, 11.25 mg every three months   Cautions see notes above; risk of ureteric obstruction  and spinal cord compression in men   Side-effects see notes above; also dry mouth, transi-  ent hypertension, paraesthesia, and increased dysuria   Decapeptyl® SR (Ipsen) (Ml  Injection (powder for suspension), m/r, triptorelin (as  acetate), net price 3-mg vial (with diluent) = £69.00  Dose locally advanced non-metastatic prostate cancer as an  alternative to surgical castration, metastatic prostate cancer, by  intramuscular injection, 3 mg every 4 weeks  Note Each vial includes an overage to allow accurate administra-  tion of a 3-mg dose   Injection (powder for suspension), m/r, triptorelin (as  acetate), net price 1 1.25-mg vial (with diluent) =  £207.00   Dose locally advanced non-metastatic prostate cancer as an  alternative to surgical castration, metastatic prostate cancer, by  intramuscular injection, 11.25 mg every 3 months (see also notes  above)    Gonapeptyl Depot® (Ferring) (Ml  Injection (powder for suspension), triptorelin (as  acetate), net price 3.75-mg prefilled syringe (with  prefilled syringe of vehicle) = £81.69  Dose advanced prostate cancer, by subcutaneous or deep  intramuscular injection, 3.75 mg every 4 weeks (see also notes  above)   are anti-androgens that inhibit the tumour ‘flare’  which may occur after commencing gonadorelin analo-  gue administration. Cyproterone acetate and flutamide  are also licensed for use alone in patients with meta-  static prostate cancer refractory to gonadorelin analo-  gue therapy. Bicalutamide is used for prostate cancer  either alone or as an adjunct to other therapy, according  to the clinical circumstances.   Indications locally advanced prostate cancer at high  risk of disease progression, either alone or as adjuvant  treatment to prostatectomy or radiotherapy; locally  advanced, non-metastatic prostate cancer when sur-  gical castration or other medical intervention inap-  propriate; advanced prostate cancer in combination  with gonadorelin analogue or surgical castration   Cautions consider periodic liver function tests; inter-  actions: Appendix 1 (bicalutamide)   Side-effects nausea, diarrhoea, cholestasis, jaundice;  asthenia, weight gain; gynaecomastia, breast tender-  ness, hot flushes, impotence, decreased libido; anae-  mia; alopecia, dry skin, hirsutism, pruritus; less com-  monly vomiting, abdominal pain, dyspepsia,  interstitial lung disease, pulmonary fibrosis, depres-  sion, haematuria, thrombocytopenia, hypersensitivity  reactions including angioneurotic oedema and urti-  caria; rarely cardiovascular disorders (including  angina, heart failure, and arrhythmias), and hepatic  failure  Dose   • Locally advanced prostate cancer at high risk of dis-  ease progression, 150 mg once daily   • Locally advanced, non-metastatic prostate cancer  when surgical castration or other medical interven-  tion inappropriate, 150 mg once daily   • Advanced prostate cancer, in combination with  gonadorelin analogue or surgical castration, 50 mg  once daily (started at the same time as surgical  castration or at least 3 days before gonadorelin ther-  apy, see also notes above)   Bicalutamide (Non-proprietary) (Ml  Tablets, bicalutamide 50 mg, net price 28-tab pack =  £6.22; 150 mg, 28-tab pack = £12.21   Casodex® (AstraZeneca) (Ml  Tablets, f/c, bicalutamide 50 mg, net price 28-tab  pack = £128.00; 150 mg, 28-tab pack = £240.00    Cautions in prostate cancer, blood counts initially and  throughout treatment; monitor hepatic function (liver  function tests should be performed before treatment,  see also under Side-effects below); monitor adreno-  cortical function regularly; risk of recurrence of  thromboembolic disease; diabetes mellitus, sickle-cell  anaemia, severe depression (in other indications some  of these are contra-indicated, see section 6.4.2)  Driving Fatigue and lassitude may impair performance of  skilled tasks (e.g. driving)   Contra-indications patients with meningioma or his-  tory of meningioma; for contra-indications relating to  other indications see section 6.4.2  Hepatic impairment dose-related toxicity; see also  under cautions (above) and side-effects (below)  Side-effects see section 6.4.2  Hepatotoxicity Direct hepatic toxicity including jaundice,  hepatitis and hepatic failure have been reported (usually after  several months) in patients treated with cyproterone acetate  200-300 mg daily. Liver function tests should be performed  before and regularly during treatment and whenever symp-  toms suggestive of hepatotoxicity occur — if confirmed  cyproterone should normally be withdrawn unless the  hepatotoxicity can be explained by another cause such as  metastatic disease (in which case cyproterone should be  continued only if the perceived benefit exceeds the risk)  Dose    • Prevention of flare with initial gonadorelin analogue  therapy, 200 mg daily in 2-3 divided doses for 5-7  days before initiation of gonadorelin analogue, fol-  lowed by 200 mg daily in 2-3 divided doses for 3-4  weeks after initiation of gonadorelin analogue; max.  300 mg daily   • Long-term palliative therapy where gonadorelin ana-  logues or orchidectomy contra-indicated, not toler-  ated, or where oral therapy preferred, 200-300 mg  daily in 2-3 divided doses    • Hot flushes with gonadorelin analogue therapy or  after orchidectomy, initially 50 mg daily, adjusted  according to response to 50-150 mg daily in 1-3  divided doses   Cyproterone Acetate (Non-proprietary) (Ml  Tablets, cyproterone acetate 50 mg, net price 56-tab  pack = £31.54; 100 mg, 84-tab pack = £85.72.   Cyprostat® (Bayer Schering) (Ml  Tablets, scored, cyproterone acetate 50 mg, net price  168-tab pack = £73.23; 100 mg, 84-tab pack = £73.23.  Label: 21, counselling, driving   Cautions cardiac disease (oedema reported); also liver  function tests, monthly for first 4 months, periodically  thereafter and at the first sign or symptom of liver  disorder (e.g. pruritus, dark urine, persistent anorexia,  jaundice, abdominal pain, unexplained influenza-like  symptoms); avoid excessive alcohol consumption;  avoid in acute porphyria (section 9.8.2); interactions:  Appendix 1 (flutamide)   Side-effects gynaecomastia (sometimes with  galactorrhoea); nausea, vomiting, diarrhoea,  increased appetite, insomnia, tiredness; other side-  effects reported include decreased libido, reduced  sperm count, gastric and chest pain, hypertension,  headache, dizziness, oedema, blurred vision, thirst,    rash, pruritus, haemolytic anaemia, systemic lupus  erythematosus-like syndrome, and lymphoedema;  hepatic injury (with transaminase abnormalities,  cholestatic jaundice, hepatic necrosis, hepatic  encephalopathy and occasional fatality) reported  Dose   Flutamide (Non-proprietary) (Ml  Tablets, flutamide 250 mg. Net price 84-tab pack =  £22.24   Degarelix is a gonadotrophin-releasing hormone  antagonist used to treat advanced hormone-dependent  prostate cancer. It does not induce a testosterone surge  or tumour ‘flare’, therefore anti-androgen therapy is not  required.   Cautions susceptibility to QT-interval prolongation  (avoid concomitant use of drugs that prolong QT  interval); monitor bone density; diabetes  Hepatic impairment manufacturer advises caution in  severe impairment — no information available  Renal impairment manufacturer advises caution in  severe impairment — no information available  Side-effects nausea; dizziness, headache, drowsiness,  insomnia, asthenia; influenza-like symptoms; hot  flushes, sweating (including night sweats), weight  gain; injection-site reactions; less commonly diarr-  hoea, vomiting, abdominal discomfort, dry mouth,  constipation, anorexia, atrio-ventricular block, QT-  interval prolongation, fainting, hypertension, hyper-  sensitivity reactions, depression, anxiety, oedema,  gynaecomastia, micturition urgency, renal impair-  ment, sexual dysfunction, pelvic pain, prostatitis,  testicular pain, anaemia, musculoskeletal pain, tinni-  tus, urticaria, alopecia, and rash    • By subcutaneous injection into the abdominal region,  ADULT over 18 years, initially 240 mg (administered as  2 injections of 120 mg), then 80 mg every 28 days    Firmagon® (Ferring) ▼ (Mi  Injection, powder for reconstitution, degarelix (as  acetate), net price 80-mg vial (with diluent) = £129.37;  2 x 120-mg vials (with diluent) = £260.00   Lanreotide and octreotide are analogues of the hypo-  thalamic release-inhibiting hormone somatostatin. They  are indicated for the relief of symptoms associated with  neuroendocrine (particularly carcinoid) tumours and  acromegaly. Additionally, lanreotide is licensed for the  treatment of thyroid tumours and octreotide is also  licensed for the prevention of complications following  pancreatic surgery; octreotide may also be valuable in  reducing vomiting in palliative care (see p. 23) and in  stopping variceal bleeding [unlicensed indication] — see  also vasopressin and terlipressin (section 6.5.2).    Cautions Growth hormone-secreting pituitary  tumours can expand causing serious complications;  during treatment with somatostatin analogues patients  should be monitored for signs of tumour expansion (e.g.  visual field defects). Ultrasound examination of the  gallbladder is recommended before treatment and at  intervals of 6-12 months during treatment (avoid abrupt  withdrawal of short-acting octreotide — see Side-effects  below). In insulinoma an increase in the depth and  duration of hypoglycaemia may occur (observe patients  when initiating treatment and changing doses); in dia-  betes mellitus, insulin or oral antidiabetic requirements  may be reduced.   Side-effects Gastro-intestinal disturbances including  anorexia, nausea, vomiting, abdominal pain and bloat-  ing, flatulence, diarrhoea, and steatorrhoea may occur  (administering non-depot injections of octreotide  between meals and at bedtime may reduce gastro-intes-  tinal side-effects). Postprandial glucose tolerance may  be impaired and rarely persistent hyperglycaemia  occurs with chronic administration; hypoglycaemia  has also been reported. Gallstones have been reported  after long-term treatment (abrupt withdrawal of subcu-  taneous octreotide is associated with biliary colic and  pancreatitis). Pain and irritation may occur at the injec-  tion site and sites should be rotated. Rarely, pancreatitis  has been reported shortly after administration.   Side-effects see notes above; also reported asthenia,  fatigue, raised bilirubin; less commonly skin nodule,  hot flushes, leg pain, malaise, headache, tenesmus,  decreased libido, drowsiness, pruritus, increased  sweating; rarely hypothyroidism (monitor as neces-  sary)   Somatuline® LA (Ipsen) (Ml  Injection (copolymer microparticles for aqueous  suspension), lanreotide (as acetate) 30-mg vial (with  vehicle) = £323.00   Dose by intramuscular injection, acromegaly and neuroendo-  crine (particularly carcinoid) tumours, initially 30 mg every 14  days, frequency increased to every 7-10 days according to  response   Thyroid tumours, 30 mg every 14 days, frequency increased to  every 10 days according to response   60 mg = £551.00; 90 mg = £736.00; 120 mg = £937.00  Dose by deep subcutaneous injection into the gluteal region,  acromegaly (if somatostatin analogue not given previously),  initially 60 mg every 28 days, adjusted according to response; for  patients treated previously with somatostatin analogue, consult  product literature for initial dose   Neuroendocrine (particularly carcinoid) tumours, initially 60-  120 mg every 28 days, adjusted according to response   Cautions see notes above; monitor thyroid function on  long-term therapy; interactions: Appendix 1  (octreotide)   Hepatic impairment adjustment of maintenance dose  of non-depot preparations may be necessary in  patients with liver cirrhosis   Pregnancy possible effect on fetal growth; manufac-  turer advises use only if potential benefit outweighs  risk and effective contraception required during  treatment   Side-effects see notes above; also bradycardia, dys-  pnoea, headache, dizziness, alopecia, rash; hepatitis  also reported  Dose   • Symptoms associated with carcinoid tumours with  features of carcinoid syndrome, VIPomas, glucago-  nomas, by subcutaneous injection, initially 50 micr-  ograms once or twice daily, gradually increased  according to response to 200 micrograms 3 times  daily (higher doses required exceptionally); mainte-  nance doses variable; in carcinoid tumours discon-  tinue after 1 week if no effect; if rapid response  required, initial dose by intravenous injection (with  ECG monitoring and after dilution to a concentration  of 10-50% with sodium chloride 0.9% injection)   • Acromegaly, short-term treatment before pituitary  surgery or long-term treatment in those inadequately  controlled by other treatment or until radiotherapy  becomes fully effective by subcutaneous injection,  100-200 micrograms 3 times daily; discontinue if no  improvement within 3 months   Octreotide (Non-proprietary) (Ml  Injection, octreotide (as acetate) 50 micrograms/mL,  net price 1-mL amp = £3.72; 100 micrograms/mL, 1-  mL amp = £6.53; 200 micrograms/mL, 5-mL vial =  £69.66; 500 micrograms/mL, 1-mL amp = £33.87   Sandostatin® (Novartis) (Mi  Injection, octreotide (as acetate) 50 micrograms/mL,  net price 1-mL amp = £2.98; 100 micrograms/mL, 1-  mL amp = £5.60; 200 micrograms/mL 5-mL vial =  £69.66; 500 micrograms/mL, 1-mL amp = £27.10   Sandostatin Lar® (Novartis) (Ml  Injection (microsphere powder for aqueous suspen-  sion), octreotide (as acetate) 10-mg vial = £637.50; 20-  mg vial = £850.00; 30-mg vial = £1062.50 (all supplied  with 2. 5-mL diluent-filled syringe)   Dose acromegaly (test dose by subcutaneous injection 50-  100 micrograms if subcutaneous octreotide not previously given),  neuroendocrine (particularly carcinoid) tumour adequately con-  trolled by subcutaneous octreotide, by deep intramuscular injec-  tion into gluteal muscle, initially 20 mg every 4 weeks for 3  months then adjusted according to response; max. 30 mg every 4  weeks   For acromegaly, start depot octreotide 1 day after the last dose of  subcutaneous octreotide (for pituitary surgery give last dose of  depot octreotide at least 3 weeks before surgery); for neuroen-  docrine tumours, continue subcutaneous octreotide for 2 weeks  after first dose of depot octreotide   Iron-deficiency anaemias  Drugs used in megaloblastic anaemias  Drugs used in hypoplastic,  haemolytic, and renal anaemias  Drugs used in platelet disorders  G6PD deficiency  Drugs used in neutropenia  Drugs used to mobilise stem cells   Before initiating treatment for anaemia it is essential to  determine which type is present. Iron salts may be  harmful and result in iron overload if given alone to  patients with anaemias other than those due to iron  deficiency.   Treatment with an iron preparation is justified only in  the presence of a demonstrable iron-deficiency state.  Before starting treatment, it is important to exclude any  serious underlying cause of the anaemia (e.g. gastric  erosion, gastro-intestinal cancer).   Prophylaxis with an iron preparation may be appropri-  ate in malabsorption, menorrhagia, pregnancy, after  subtotal or total gastrectomy, in haemodialysis patients,  and in the management of low birth-weight infants such  as preterm neonates.    Iron salts should be given by mouth unless there are  good reasons for using another route.    Ferrous salts show only marginal differences between  one another in efficiency of absorption of iron. Haemo-  globin regeneration rate is little affected by the type of  salt used provided sufficient iron is given, and in most  patients the speed of response is not critical. Choice of    preparation is thus usually decided by the incidence of  side-effects and cost.   The oral dose of elemental iron for iron-deficiency  anaemia should be 100 to 200 mg daily It is customary  to give this as dried ferrous sulphate, 200 mg ( = 65 mg  elemental iron) three times daily; for prophylaxis of iron-  deficiency anaemia, a dose of ferrous sulphate 200 mg  once or twice daily may be effective. For treatment of  iron-deficiency anaemia in children and for prophylaxis  of iron-deficiency anaemia in babies of low birth weight,  see BNF for Children.    It is important to note that the small doses of folic acid  contained in these preparations are inadequate for the  treatment of megaloblastic anaemias.   Some oral preparations contain ascorbic acid to aid  absorption of the iron but the therapeutic advantage  of such preparations is minimal and cost may be  increased.   There is no justification for the inclusion of other ingre-  dients, such as the B group of vitamins (except folic  acid for pregnant women, see notes above and on  p. 580).   Modified-release preparations Modified-release  preparations of iron are licensed for once-daily dosage,  but have no therapeutic advantage and should not be  used. These preparations are formulated to release iron  gradually; the low incidence of side-effects may reflect  the small amounts of iron available for absorption as the  iron is carried past the first part of the duodenum into an  area of the gut where absorption may be poor.    Therapeutic response The haemoglobin concentra-  tion should rise by about 100-200 mg/ 100 mL (1-2 g/  litre) per day or 2 g/ 100 mL (20 g/litre) over 3-4 weeks.  When the haemoglobin is in the reference range, treat-  ment should be continued for a further 3 months to  replenish the iron stores. Epithelial tissue changes such  as atrophic glossitis and koilonychia are usually  improved, but the response is often slow.    Side-effects Gastro-intestinal irritation can occur with  iron salts. Nausea and epigastric pain are dose-related,  but the relationship between dose and altered bowel  habit (constipation or diarrhoea) is less clear. Oral iron,  particularly modified-release preparations, can exacer-  bate diarrhoea in patients with inflammatory bowel  disease; care is also needed in patients with intestinal  strictures and diverticular disease.   Iron preparations taken orally can be constipating, par-  ticularly in older patients and occasionally lead to faecal  impaction.   If side-effects occur, the dose may be reduced; alterna-  tively, another iron salt may be used, but an improve-  ment in tolerance may simply be a result of a lower  content of elemental iron. The incidence of side-effects  due to ferrous sulphate is no greater than with other iron  salts when compared on the basis of equivalent amounts  of elemental iron.   Tablets, coated, dried ferrous sulphate 200 mg (65 mg  iron), net price 28-tab pack = £1.15  Dose prophylactic, 1 tablet daily; therapeutic, 1 tablet 2-3 times  daily; CHILD, see BNF for Children   Oral drops, ferrous sulphate 125 mg (25 mg iron)/mL,  net price 15-mL = £4.95   Dose ADULT and CHILD over 6 years, prophylactic, 0.6 mL daily;  CHILD under 6 years, see BNF for Children   ^ Modified-release preparations  Feospan® (Intrapharm) Ml  Spansule® (= capsules m/r), clear/red, enclosing  green and brown pellets, dried ferrous sulphate  150 mg (47 mg iron), net price 30-cap pack = £2.11.  Label: 25   Dose 1-2 capsules daily; CHILD over 1 year, 1 capsule daily; can  be opened and sprinkled on food    Iron preparations are a common cause of accidental  overdose in children. For the treatment of iron over-  dose, see Emergency Treatment of Poisoning, p. 38.   Counselling Although iron preparations are best  absorbed on an empty stomach they can be taken  after food to reduce gastro-intestinal side-effects; they  may discolour stools.   Tablets, f/c, m/r, red, dried ferrous sulphate 325 mg  (105 mg iron), net price 30-tab pack = £1.84. Label: 25  Dose ADULT and CHILD over 12 years, prophylactic and thera-  peutic, 1 tablet daily before food    Compound preparations Preparations containing  iron and folic acid are used during pregnancy in  women who are at high risk of developing iron and  folic acid deficiency; they should be distinguished from  those used for the prevention of neural tube defects in  women planning a pregnancy (see p. 580).   Spansule® (= capsules m/r), clear/green, enclosing  brown, yellow, and white pellets, dried ferrous sul-  phate 150 mg (47 mg iron), folic acid 500 micrograms,  net price 30-cap pack = £1.69. Label: 25  Dose 1 capsule daily   Tablets, f/c, red/yellow, dried ferrous sulphate  325 mg (105 mg iron) for sustained release, folic acid  350 micrograms, net price 30-tab pack = £1.89.   Tablets, f/c, red, dried ferrous sulphate 325 mg  (105 mg iron) for sustained release, ascorbic acid  500 mg (as sodium salt), net price 30-tab pack = £1.85.  Label: 25   Indications iron-deficiency anaemia  Cautions interactions: Appendix 1 (iron)  Side-effects see notes above   Tablets, brown, ferrous fumarate 210 mg (68 mg iron),  net price 100 = £1.44   Dose prophylactic, 1 tablet 1-2 times daily; therapeutic, 1 tablet  2-3 times daily   Syrup, brown, ferrous fumarate approx. 140 mg  (45 mg iron)/5 mL, net price 200 mL = £3.11  Dose prophylactic, 5mL twice daily; therapeutic, 10 mL twice  daily; CHILD see BNF for Children   Capsules, red/green, ferrous fumarate 305 mg  (100 mg iron), net price 100 = £2.00  Dose ADULT and CHILD over 12 years, prophylactic, 1 capsule  daily; therapeutic, 1 capsule twice daily   Syrup, brown, sugar-free ferrous fumarate 140 mg  (45 mg iron)/5mL, net price 300 mL = £5.33  Dose ADULT and CHILD over 12 years, prophylactic, 10 mL once  daily; therapeutic, 10 mL 1-2 times daily; PRETERM NEONATE and  NEONATE, see BNF for Children, CHILD 1 month-12 years, pro-  phylactic and therapeutic, 0.5 mL/kg daily in 2-3 divided doses;  max. 20 mL daily   Capsules, red/yellow, ferrous fumarate 305 mg  (100 mg iron), folic acid 350 micrograms, net price  100 = £2.17   Tablets, brown, f/c, ferrous fumarate equivalent to  100 mg iron, folic acid 350 micrograms, net price 28-  tab pack =£1.20  Dose 1 tablet daily   Indications iron-deficiency anaemia  Cautions interactions: Appendix 1 (iron)  Side-effects see notes above   Tablets, red, coated, ferrous gluconate 300 mg (35 mg  iron), net price 28 = £2.95   Dose prophylactic, 2 tablets daily before food; therapeutic, 4-6  tablets daily in divided doses before food; CHILD 6-12 years,  prophylactic and therapeutic, 1-3 tablets daily   Elixir, brown, sugar-free, polysaccharide-iron com-  plex equivalent to 100 mg of iron/5 mL, net price 240-  mL pack = £6.06; GwQ 1 30-mL dropper bottle for  paediatric use = £2.16. Counselling, use of dropper  Dose prophylactic, 2.5 mL daily; therapeutic, 5mL 1-2 times  daily (once daily if required during second and third trimester of  pregnancy); PRETERM NEONATE, NEONATE, and INFANT (from  dropper bottle) 1 drop (approx. 500 micrograms iron) per 450 g  body-weight 3 times daily; CHILD 2-6 years 2.5 mL daily, 6-12  years 5 mL daily   Indications iron-deficiency anaemia  Cautions interactions: Appendix 1 (iron)  Side-effects see notes above   Elixir, sugar-free, sodium feredetate 190 mg equiva-  lent to 27.5 mg of iron/5 mL, net price 100 mL = £1.07  Dose therapeutic, 5mL increasing gradually to lOmL 3 times  daily; CHILD under 1 year, see BNF for Children, CHILD 1-5 years,  therapeutic, 2.5 mL 3 times daily, 6-12 years, therapeutic, 5 mL 3  times daily    Iron can be administered parenterally as iron dextran,  iron sucrose, ferric carboxymaltose or iron isomalto-  side 1000. Parenteral iron is generally reserved for use  when oral therapy is unsuccessful because the patient  cannot tolerate oral iron, or does not take it reliably, or if  there is continuing blood loss, or in malabsorption.  Parenteral iron may also have a role in the management  of chemotherapy-induced anaemia, when given with  erythropoietins, in specific patient groups (see NICE  guidance, p. 583).    Many patients with chronic renal failure who are receiv-  ing haemodialysis (and some who are receiving perito-  neal dialysis) also require iron by the intravenous route  on a regular basis (see also Erythropoietins, section  9.1.3).   With the exception of patients with severe renal failure  receiving haemodialysis, parenteral iron does not pro-  duce a faster haemoglobin response than oral iron  provided that the oral iron preparation is taken reliably  and is absorbed adequately.   Anaphylactic reactions can occur with parenteral  administration of iron complexes. Depending on the  preparation, patients may be required to have a small  test dose initially, see preparations for details; facilities  for cardiopulmonary resuscitation must be available.   Cautions hypersensitivity can occur with parenteral  iron and facilities for cardiopulmonary resuscitation  must be available; oral iron should not be given  concomitantly; allergic disorders including asthma  and eczema; infection (discontinue if ongoing bac-  teraemia); interactions: Appendix 1 (iron)   Hepatic impairment use with caution; avoid in con-  ditions where iron overload increases risk of impair-  ment   Side-effects gastro-intestinal disturbances; headache,  dizziness; rash, injection-site reactions; less commonly  hypotension, flushing, chest pain, peripheral oedema,  hypersensitivity reactions (including anaphylaxis),  fatigue, paraesthesia, malaise, pyrexia, rigors, myalgia,  arthralgia, back pain, pruritus, and urticaria; rarely  dyspnoea   • By slow intravenous injection or by intravenous  infusion, ADULT and CHILD over 14 years, calculated  according to body-weight and iron deficit, consult  product literature   Injection, iron (as ferric carboxymaltose) 50 mg/mL,  net price 2-mL vial = £21.75, 10-mL vial = £108.75   A complex of ferric hydroxide with dextran containing  5% (50 mg/mL) of iron   Indications iron-deficiency anaemia, see notes above  Cautions oral iron not to be given until 5 days after last  injection; interactions: Appendix 1 (iron)  Anaphylaxis Anaphylactic reactions can occur with par-  enteral iron and a test dose is recommended before each  dose; the patient should be carefully observed for 60 minutes  after the first test dose and for 15 minutes after subsequent  test doses (subsequent test doses not necessary for intra-  muscular administration). Facilities for cardiopulmonary re-  suscitation must be available; risk of allergic reactions  increased in immune or inflammatory conditions    Contra-indications history of allergic disorders  including asthma, and eczema; infection; active  rheumatoid arthritis   Hepatic impairment avoid in severe impairment  Renal impairment avoid in acute renal failure  Pregnancy avoid in first trimester  Side-effects less commonly nausea, vomiting, abdo-  minal pain, flushing, dyspnoea, anaphylactic reactions  (see Anaphylaxis above), numbness, cramps, blurred  vision, pruritus, and rash; rarely diarrhoea, chest pain,  hypotension, angioedema, arrhythmias, tachycardia,  dizziness, restlessness, fatigue, seizures, tremor,  impaired consciousness, myalgia, arthralgia, sweat-  ing, and injection-site reactions; very rarely hyper-  tension, palpitation, headache, paraesthesia, haemo-  lysis, and transient deafness  Dose   • By deep intramuscular injection into the gluteal  muscle or by slow intravenous injection or by intra-  venous infusion, calculated according to body-weight  and iron deficit, consult product literature  CHILD under 14 years, not recommended   Injection, iron (as iron dextran) 50 mg/mL, net price  2-mL amp = £7.97, 10-mL amp = £39.85   A complex of ferric iron and isomaltosides containing  10% (100 mg/mL) of iron    Indications iron deficiency anaemia, see notes above  Cautions hypersensitivity can occur with parenteral  iron and facilities for cardiopulmonary resuscitation  must be available — risk of allergic reactions increased  in immune or inflammatory conditions; oral iron  therapy should not be given until 5 days after last  injection; infection (discontinue if ongoing bacterae-  mia)   Contra-indications history of allergic disorders  including asthma, and eczema; active rheumatoid  arthritis   Hepatic impairment avoid in decompensated liver  disease and hepatitis  Pregnancy avoid in first trimester  Side-effects less commonly nausea, vomiting, consti-  pation, abdominal pain, dyspnoea, dysphonia, flush-  ing, numbness, fever, cramps, blurred vision, pruritus,  rash, hypersensitivity reactions (including anaphy-  laxis), injection-site reactions; rarely diarrhoea,  angioedema, tachycardia, arrhythmias, hypotension,  chest pain, malaise, seizures, tremor, dizziness, rest-  lessness, loss of consciousness, altered mental status,  myalgia, arthralgia, sweating; very rarely hyper-  tension, foetal bradycardia, palpitation, headache,  paraesthesia, haemolysis, transient deafness  Dose    • By slow intravenous injection or by intravenous  infusion, ADULT over 18 years, calculated according to  body-weight and iron deficit, consult product litera-  ture   Injection, iron (as iron isomaltoside 1000) 100 mg/  mL, net price 1-mL vial = £16.95, 5-mL vial = £84.75,  10-mL vial = £169.50   A complex of ferric hydroxide with sucrose containing  2% (20 mg/mL) of iron   Indications iron-deficiency anaemia, see notes above  Cautions oral iron therapy should not be given until 5  days after last injection; infection (discontinue if  ongoing bacteraemia); interactions: Appendix 1  (iron)   Anaphylaxis Anaphylactic reactions can occur with par-  enteral iron and a test dose is recommended before the first  dose; the patient should be carefully observed for 15 min-  utes. Facilities for cardiopulmonary resuscitation must be  available   Contra-indications history of allergic disorders  including asthma, eczema, and anaphylaxis  Hepatic impairment use with caution; avoid in con-  ditions where iron overload increases risk of impair-  ment   Pregnancy avoid in first trimester  Side-effects taste disturbances; less commonly  nausea, vomiting, abdominal pain, diarrhoea, hypo-  tension, tachycardia, flushing, palpitation, chest pain,  bronchospasm, dyspnoea, headache, dizziness, fever,  myalgia, pruritus, rash, and injection-site reactions;  rarely peripheral oedema, anaphylactic reactions (see  Anaphylaxis above), fatigue, asthenia, and paraes-  thesia; confusion, arthralgia, and increased sweating  also reported  Dose   • By slow intravenous injection or by intravenous  infusion, calculated according to body-weight and  iron deficit, consult product literature; CHILD not  recommended   Injection, iron (as iron sucrose) 20 mg/mL, net price  5-mL vial = £9.35   Most megaloblastic anaemias result from a lack of either  vitamin B 12 or folate, and it is essential to establish in  every case which deficiency is present and the under-  lying cause. In emergencies, when delay might be  dangerous, it is sometimes necessary to administer  both substances after the bone marrow test while  plasma assay results are awaited. Normally, however,  appropriate treatment should not be instituted until the  results of tests are available.   One cause of megaloblastic anaemia in the UK is perni-  cious anaemia in which lack of gastric intrinsic factor  resulting from an autoimmune gastritis causes mal-  absorption of vitamin B 12 .   Vitamin B 12 is also needed in the treatment of mega-  loblastosis caused by prolonged nitrous oxide anaes-  thesia, which inactivates the vitamin, and in the rare  syndrome of congenital transcobalamin II deficiency.   Vitamin B 12 should be given prophylactically after total  gastrectomy or total ileal resection (or after partial   gastrectomy if a vitamin B 12 absorption test shows vit-  amin B 12 malabsorption).   Apart from dietary deficiency, all other causes of vitamin  B 12 deficiency are attributable to malabsorption. There  is little place for the use of low-dose vitamin B 12 orally  and none for vitamin B 12 intrinsic factor complexes  given by mouth. Vitamin B 12 in larger oral doses of 1-  2 mg daily [unlicensed] may be effective.   Hydroxocobalamin has completely replaced cyano-  cobalamin as the form of vitamin B 12 of choice for  therapy; it is retained in the body longer than cyano-  cobalamin and thus for maintenance therapy can be  given at intervals of up to 3 months. Treatment is  generally initiated with frequent administration of intra-  muscular injections to replenish the depleted body  stores. Thereafter, maintenance treatment, which is  usually for life, can be instituted. There is no evidence  that doses larger than those recommended provide any  additional benefit in vitamin B 12 neuropathy.   Folic acid has few indications for long-term therapy  since most causes of folate deficiency are self-limiting or  will yield to a short course of treatment. It should not be  used in undiagnosed megaloblastic anaemia unless vit-  amin B 12 is administered concurrently otherwise neuro-  pathy may be precipitated (see above).   In folate-deficient megaloblastic anaemia (e.g. because  of poor nutrition, pregnancy, or antiepileptic drugs),  daily folic acid supplementation for 4 months brings  about haematological remission and replenishes body  stores.   For prophylaxis in chronic haemolytic states, mal-  absorption, or in renal dialysis, folic acid is given  daily or sometimes weekly, depending on the diet and  the rate of haemolysis.   For prophylaxis in pregnancy, see Prevention of Neural  Tube Defects below.   Folic acid is also used for the prevention of metho-  trexate-induced side-effects in severe Crohn’s disease  (see section 1.5.3, p. 65), rheumatic disease (see section  10.1.3, p. 645), and severe psoriasis (see section 13.5.3,  p. 721).   Folinic acid is also effective in the treatment of folate-  deficient megaloblastic anaemia but it is generally used  in association with cytotoxic drugs (see section 8.1); it is  given as calcium folinate.   Prevention of neural tube defects Folic acid sup-  plements taken before and during pregnancy can reduce  the occurrence of neural tube defects. The risk of a  neural tube defect occurring in a child should be  assessed and folic acid given as follows:   Women at a low risk of conceiving a child with a  neural tube defect should be advised to take folic  acid as a medicinal or food supplement at a dose of  400 micrograms daily before conception and until  week 12 of pregnancy. Women who have not been  taking folic acid and who suspect they are pregnant  should start at once and continue until week 12 of  pregnancy.   Couples are at a high risk of conceiving a child with  a neural tube defect if either partner has a neural  tube defect (or either partner has a family history of  neural tube defects), if they have had a previous  pregnancy affected by a neural tube defect, or if the    woman has coeliac disease (or other malabsorption  state), diabetes mellitus, sickle-cell anaemia, or is  taking antiepileptic medicines (see also section  4.8.1).   Women in the high-risk group who wish to become  pregnant (or who are at risk of becoming pregnant)  should be advised to take folic acid 5 mg daily and  continue until week 12 of pregnancy (women with  sickle-cell disease should continue taking their nor-  mal dose of folic acid 5 mg daily (or to increase the  dose to 5 mg daily) and continue this throughout  pregnancy).   There is no justification for prescribing multiple-  ingredient vitamin preparations containing vitamin  B 1Z or folic acid.    Cyanocobalamin (Non-proprietary)  tablets Ml cyanocobalamin 50 micrograms. Net  price 50-tab pack = £6.24  Brands include Cytacon ® (M   Note The BP directs that when vitamin B 12 injection is prescribed  or demanded hydroxocobalamin injection shall be dispensed or  supplied   1. (Ml except to treat or prevent vitamin B 12 deficiency in a  patient who is a vegan or who has a proven vitamin B 12  deficiency of dietary origin; endorse prescription ‘SLS’;  currently available brands may not be suitable for vegans —  cyanocobalamin injection may be a suitable alternative   Indications see under dose below; cyanide poisoning  (see Emergency Treatment of Poisoning, p. 39)  Cautions should not be given before diagnosis fully  established but see also notes above; interactions:  Appendix 1 (hydroxocobalamin)   Side-effects nausea, headache, dizziness; fever,  hypersensitivity reactions (including rash and pru-  ritus); injection-site reactions; hypokalaemia and  thrombocytosis during initial treatment; chromaturia   • By intramuscular injection, pernicious anaemia and  other macrocytic anaemias without neurological  involvement, initially 1 mg 3 times a week for 2 weeks  then 1 mg every 3 months   Pernicious anaemia and other macrocytic anaemias  with neurological involvement, initially 1 mg on  alternate days until no further improvement, then  1 mg every 2 months   Prophylaxis of macrocytic anaemias associated with  vitamin B 12 deficiency, 1 mg every 2-3 months  Tobacco amblyopia and Leber’s optic atrophy, initially  1 mg daily for 2 weeks, then 1 mg twice weekly until  no further improvement, thereafter 1 mg every 1-3  months   Hydroxocobalamin (Non-proprietary) (Ml  Injection, hydroxocobalamin 1 mg/mL. Net price 1-  mL amp = 74p   Note The BP directs that when vitamin B 12 injection is prescribed  or demanded hydroxocobalamin injection shall be dispensed or  supplied   • By mouth, vitamin B 12 deficiency of dietary origin, 50-  150 micrograms daily taken between meals; CHILD 50-  105 micrograms daily in 1-3 divided doses   • By intramuscular injection, initially lmg repeated 10  times at intervals of 2-3 days, maintenance 1 mg  every month, but see notes above    Cautions should never be given alone for pernicious  anaemia and other vitamin B 12 deficiency states (may  precipitate subacute combined degeneration of the  spinal cord); interactions: Appendix 1 (folates)  Side-effects rarely gastro-intestinal disturbances   • Folate-deficient megaloblastic anaemia, by mouth,  ADULT and CHILD over 1 year, 5 mg daily for 4 months  (until term in pregnant women); up to 15 mg daily  may be required in malabsorption states; CHILD under  1 year, 500 micrograms/kg daily (max. 5 mg) for up to  4 months; up to 10 mg daily may be required in  malabsorption states   • Prevention of neural tube defects, by mouth, see notes  above   • Prevention of methotrexate-induced side-effects in  severe Crohn’s disease [unlicensed], by mouth, see  section 1.5.3   • Prevention of methotrexate-induced side-effects in  rheumatic disease [unlicensed], by mouth, ADULT over  18 years 5 mg once weekly; CHILD 2-18 years see  BNF for Children   • Prevention of methotrexate-induced side-effects in  severe psoriasis [unlicensed], by mouth, see section  13.5.3   • Prophylaxis in chronic haemolytic states, by mouth,  ADULT 5 mg every 1-7 days depending on underlying  disease   • Prophylaxis of folate deficiency in dialysis, by mouth,  ADULT 5 mg every 1-7 days; CHILD 1-12 years   250 micrograms/kg (max. 10 mg) once daily, CHILD  12-18 years 5-10 mg once daily   Tablets, folic acid 400 micrograms, net price 90-tab  pack = £2.37; 5 mg, 28-tab pack = £1.00  Syrup, folic acid 2.5 mg/5mL, net price 150 mL =  £9.16; 400 micrograms/ 5 mL, 150 mL = £1.40  Brands include Folicare ®, Lexpec ® (sugar-free)   1 . Can be sold to the public provided daily doses do not exceed  500 micrograms   Anabolic steroids (section 6.4.3), pyridoxine, anti-  lymphocyte immunoglobulin, and various corticoster-  oids are used in hypoplastic and haemolytic anaemias.  Antilymphocyte immunoglobulin given intravenously  through a central line over 12-18 hours each day for 5  days produces a response in about 50% of cases of  acquired aplastic anaemia, the response rate may be  increased when ciclosporin is given as well. Severe  reactions are common in the first 2 days and profound  immunosuppression can occur; antilymphocyte  immunoglobulin should be given under specialist super-  vision with appropriate resuscitation facilities. Alterna-  tively, oxymetholone tablets (available from ‘special-  order’ manufacturers or specialist importing companies,  see p. 988) can be used in aplastic anaemia at a dose of  1-5 mg/kg daily for 3 to 6 months.   It is unlikely that dietary deprivation of pyridoxine  (section 9.6.2) produces clinically relevant haematolo-  gical effects. However, certain forms of sideroblastic  anaemia respond to pharmacological doses, possibly  reflecting its role as a co-enzyme during haemoglobin  synthesis. Pyridoxine is indicated in both idiopathic  acquired and hereditary sideroblastic anaemias.  Although complete cures have not been reported,  some increase in haemoglobin can occur; the dose  required is usually high, up to 400 mg daily. Reversible  sideroblastic anaemias respond to treatment of the  underlying cause but in pregnancy, haemolytic anae-  mias, and alcohol dependence, or during isoniazid treat-  ment, pyridoxine is also indicated.   Corticosteroids (see section 6.3) have an important  place in the management of a wide variety of haemato-  logical disorders. They include conditions with an  immune basis such as autoimmune haemolytic anae-  mia, immune thrombocytopenias and neutropenias,  and major transfusion reactions. They are also used in  chemotherapy schedules for many types of lymphoma,  lymphoid leukaemias, and paraproteinaemias, includ-  ing multiple myeloma.   Epoetins (recombinant human erythropoietins) are  used to treat symptomatic anaemia associated with  erythropoietin deficiency in chronic renal failure, to  increase the yield of autologous blood in normal indivi-  duals and to shorten the period of symptomatic anaemia  in patients receiving cytotoxic chemotherapy. Epoetin  beta is also used for the prevention of anaemia in  preterm neonates of low birth-weight; only unpreserved  formulations should be used in neonates because other  preparations may contain benzyl alcohol (see Excipi-  ents, p. 2).   Darbepoetin is a hyperglycosylated derivative of epoe-  tin; it has a longer half-life and can be administered less  frequently than epoetin.   Methoxy polyethylene glycol-epoetin beta is a con-  tinuous erythropoietin receptor activator that is licensed  for the treatment of symptomatic anaemia associated  with chronic kidney disease. It has a longer duration of  action than epoetin.    Other factors, such as iron or folate deficiency, that  contribute to the anaemia of chronic renal failure should  be corrected before treatment and monitored during  therapy. Supplemental iron may improve the response in  resistant patients. Aluminium toxicity, concurrent infec-  tion, or other inflammatory disease can impair the  response to erythropoietin.   MHRA/CHM advice (December 2007) Erythro-  poietins— haemoglobin concentration  Overcorrection of haemoglobin concentration in  patients with chronic kidney disease may increase  the risk of death and serious cardiovascular events,  and in patients with cancer may increase the risk of  thrombosis and related complications:   • patients should not be treated with erythropoie-  tins for the licensed indications in chronic kid-  ney disease or cancer in patients receiving  chemotherapy unless symptoms of anaemia  are present;   • the haemoglobin concentration should be main-  tained within the range 10-12 g/100 mL;   • haemoglobin concentrations higher than 12 g/  100 mL should be avoided;   • the aim of treatment is to relieve symptoms of  anaemia, and in patients with chronic kidney  disease to avoid the need for blood transfusion;  the haemoglobin concentration should not be  increased beyond that which provides adequate  control of symptoms of anaemia (in some  patients, this may be achieved at concentrations  lower than the recommended range).   MHRA/CHM advice (December 2007 and July  2008) Erythropoietins— tumour progression  and survival in patients with cancer  Clinical trial data show an unexplained excess mor-  tality and increased risk of tumour progression in  patients with anaemia associated with cancer who  have been treated with erythropoietins. Many of  these trials used erythropoietins outside of the  licensed indications (i.e. overcorrected haemoglobin  concentration or given to patients who have not  received chemotherapy):   • erythropoietins licensed for the treatment of  symptomatic anaemia associated with cancer,  are licensed only for patients who are receiving  chemotherapy;   • the decision to use erythropoietins should be  based on an assessment of the benefits and risks  for individual patients; blood transfusion may be  the preferred treatment for anaemia associated  with cancer chemotherapy, particularly in those  with a good cancer prognosis.   There have been very rare reports of pure red cell  aplasia in patients treated with erythropoietins. In  patients who develop a lack of efficacy with erythro-  poietin therapy and with a diagnosis of pure red cell  aplasia, treatment with erythropoietins must be dis-  continued and testing for erythropoietin antibodies  considered. Patients who develop pure red cell apla-  sia should not be switched to another form of  erythropoietin.   Epoetin alfa, beta and darbepoetin alfa for  cancer treatment-induced anaemia (May  2008)   Erythropoietin analogues are not recommended for  routine use in the management of cancer treatment-  induced anaemia, but may be considered, in combi-  nation with intravenous iron, for:   • women receiving platinum-based chemotherapy  for ovarian cancer who have symptomatic anae-  mia with a haemoglobin concentration of 8 g/  100 mL or lower (the use of erythropoietin ana-  logues does not preclude the use of existing  approaches to the management of anaemia,  including blood transfusion when necessary);   • patients who cannot be given blood transfusions  and who have profound cancer treatment-  related anaemia that is likely to have an impact  on survival.   Patients currently treated with erythropoietin analo-  gues for the management of cancer treatment-  related anaemia who do not fulfil the criteria out-  lined above can continue therapy until they and their  specialists consider it appropriate to stop.   Side-effects see Epoetin; also, oedema, injection-site  pain; isolated reports of pure red cell aplasia, parti-  cularly following subcutaneous administration in  patients with chronic renal failure (discontinue ther-  apy) — see also notes above  Dose   • Symptomatic anaemia associated with chronic renal  failure in patients on dialysis (see also MHRA/CHM  advice, p. 582), ADULT and CHILD over 11 years, by  subcutaneous or intravenous injection, initially  450 nanograms/kg once weekly, adjusted according  to response by approx. 25% at intervals of at least 4  weeks; maintenance dose, given once weekly or once  every 2 weeks   • Symptomatic anaemia associated with chronic renal  failure in patients not on dialysis (see also MHRA/  CHM advice, p. 582), ADULT and CHILD over 11 years,  by subcutaneous or intravenous injection, initially  450 nanograms/kg once weekly or by subcutaneous  injection, initially 750 nanograms/kg once every 2  weeks; adjusted according to response by approx.  25% at intervals of at least 4 weeks; maintenance  dose, given subcutaneously or intravenously once  weekly or subcutaneously once every 2 weeks or  subcutaneously once every month   Note Subcutaneous route preferred in patients not on haemo-  dialysis. Reduce dose by approximately 25% if rise in haemo-  globin concentration exceeds 2g/100mL over 4 weeks or if  haemoglobin concentration exceeds 12g/100mL; if haemo-    globin concentration continues to rise, despite dose reduction,  suspend treatment until haemoglobin concentration decreases  and then restart at a dose approximately 25% lower than the  previous dose. When changing route give same dose then  adjust according to weekly or fortnightly haemoglobin mea-  surements. Adjust doses not more frequently than every 2  weeks during maintenance treatment  • Symptomatic anaemia in adults with non-myeloid  malignancies receiving chemotherapy (see also  MHRA/CHM advice, p. 582), by subcutaneous  injection, initially 6.75 micrograms/kg once every 3  weeks or 2.25 micrograms/kg once weekly (if  response inadequate after 9 weeks further treatment  may not be effective); if adequate response obtained,  reduce dose by 25-50%   Note Reduce dose by approximately 25-50% if rise in haemo-  globin concentration exceeds 2 g/100 mL over 4 weeks or if  haemoglobin concentration exceeds 12g/100mL; if haemo-  globin concentration continues to rise, despite dose reduction,  suspend treatment until haemoglobin concentration decreases  and restart at a dose approximately 25% lower than the  previous dose. Discontinue approximately 4 weeks after ending  chemotherapy   25 micrograms /mL, net price 0.4 mL (10 micrograms)  = £14.68; 40 micrograms/mL, 0.375 mL (15 micr-  ograms) = £22.03, 0.5 mL (20 micrograms) = £29.37;  100 micrograms/mL, 0.3 mL (30 micrograms) =  £44.05, 0.4 mL (40 micrograms) = £58.73, 0.5 mL  (50 micrograms) = £73.41; 200 micrograms/mL,   0.3 mL (60 micrograms) = £88.09, 0.4 mL (80 micr-  ograms) = £117.45, 0.5 mL (100 micrograms) =  £146.81, 0.65 mL (130 micrograms) = £190.86;   500 micrograms/mL, 0.3 mL (150 micrograms) =  £220.22, 0.6 mL (300 micrograms) = £440.43, lmL  (500 micrograms) = £734.05    Injection (Aranesp® SureClick), prefilled disposable  injection device, darbepoetin alfa, 40 micrograms/  mL, net price 0.5 mL (20 micrograms) = £29.36;   100 micrograms/mL, 0.4 mL (40 micrograms) =  £58.72; 200 micrograms/mL, 0.3 mL (60 micrograms)  = £88.09, 0.4 mL (80 micrograms) = £117.45, 0.5 mL  (100 micrograms) =£146.81; 500 micrograms/mL,  0.3 mL (150 micrograms) = £220.22, 0.6 mL  (300 micrograms) = £440.43, lmL (500 micrograms)  = £734.05   Note The prescriber must specify which epoetin is required,  see also Biosimilar medicines, p. 1   Indications see under preparations, below  Cautions see notes above; also inadequately treated or  poorly controlled blood pressure (monitor closely  blood pressure, reticulocyte counts, haemoglobin, and  electrolytes), interrupt treatment if blood pressure  uncontrolled; sudden stabbing migraine-like pain is  warning of a hypertensive crisis; sickle-cell disease  (lower target haemoglobin concentration may be  appropriate); ischaemic vascular disease; thrombocy-  tosis (monitor platelet count for first 8 weeks); epi-  lepsy; malignant disease; increase in unffactionated or  low molecular weight heparin dose may be needed  during dialysis; risk of thrombosis may be increased  when used for anaemia in adults receiving cancer  chemotherapy; risk of thrombosis may be increased   Contra-indications pure red cell aplasia following  erythropoietin therapy (see also notes above);  uncontrolled hypertension; patients unable to receive  thromboprophylaxis; avoid injections containing  benzyl alcohol in neonates (see under preparations,  below)   Pregnancy no evidence of harm; benefits probably  outweigh risk of anaemia and of transfusion in  pregnancy   Breast-feeding unlikely to be present in milk; minimal  effect on infant   Side-effects diarrhoea, nausea, vomiting; dose-  dependent increase in blood pressure or aggravation  of hypertension; in isolated patients with normal or  low blood pressure, hypertensive crisis with  encephalopathy-like symptoms and generalised tonic-  clonic seizures requiring immediate medical attention;  headache; dose-dependent increase in platelet count  (but thrombocytosis rare) regressing during treat-  ment; influenza-like symptoms (may be reduced if  intravenous injection given over 5 minutes); cardio-  vascular events; shunt thrombosis especially if ten-  dency to hypotension or arteriovenous shunt com-  plications; very rarely sudden loss of efficacy because  of pure red cell aplasia, particularly following subcu-  taneous administration in patients with chronic renal  failure (discontinue erythropoietin therapy) — see also  notes above, hyperkalaemia, hypersensitivity reac-  tions (including anaphylaxis and angioedema), skin  reactions, injection-site reactions, and peripheral  oedema also reported  Dose   Binocrit® (Sandoz) ▼ (Ml  Injection, prefilled syringe, epoetin alfa, net price  1000 units = £5.09; 2000 units = £10.18; 3000 units =  £15.27; 4000 units = £20.36; 5000 units = £25.46;  6000 units = £30.55; 8000 units = £40.73; 10 000 units  = £50.91   Dose symptomatic anaemia associated with chronic renal failure  in patients on haemodialysis (see also MHRA/CHM advice,  p. 582), by intravenous injection over 1-5 minutes, initially  50 units/kg 3 times weekly adjusted according to response in  steps of 25 units/kg 3 times weekly at intervals of at least 4 weeks;  maintenance dose, usually 25-100 units/kg 3 times weekly; CHILD  by intravenous injection initially as for adults; maintenance dose,  body-weight under 10 kg usually 75-150 units/kg 3 times weekly,  body-weight 10-30 kg usually 60-150 units/kg 3 times weekly,  body-weight over 30 kg usually 30-100 units/kg 3 times weekly  Symptomatic anaemia associated with chronic renal failure in  adults on peritoneal dialysis (see also MHRA/ CHM advice,  p. 582), by intravenous injection over 1-5 minutes, initially  50 units/kg twice weekly; maintenance dose 25-50 units/kg twice  weekly   Severe symptomatic anaemia of renal origin in adults with renal  insufficiency not yet on dialysis (see also MHRA/CHM advice,  p. 582), by intravenous injection over 1-5 minutes, initially  50 units/kg 3 times weekly increased according to response in  steps of 25 units/kg 3 times weekly at intervals of at least 4 weeks;  maintenance dose 17-33 units/kg 3 times weekly; max.   Note Reduce dose by approximately 25% if rise in haemoglobin  concentration exceeds 2 g/100 mL over 4 weeks or if haemoglobin  concentration exceeds 12g/100mL; if haemoglobin concentration    continues to rise, despite dose reduction, suspend treatment until  haemoglobin concentration decreases and then restart at a dose  approximately 25% lower than the previous dose.   Symptomatic anaemia in adults receiving cancer chemotherapy  (see also MHRA/CHM advice, p. 582), by subcutaneous injection  (max. 1 mL per injection site), initially 150 units/kg 3 times weekly  (or 450 units/kg once weekly), increased if appropriate rise in  haemoglobin (or reticulocyte count) not achieved after 4 weeks to  300 units/kg 3 times weekly; discontinue if inadequate response  after 4 weeks at higher dose   Note Reduce dose by approximately 25-50% if rise in haemoglo-  bin concentration exceeds 2 g/100 mL over 4 weeks or if hae-  moglobin concentration exceeds 12g/100mL; if haemoglobin  concentration continues to rise, despite dose reduction, suspend  treatment until haemoglobin concentration decreases and then  restart at a dose approximately 25% lower than the previous dose.  Discontinue approximately 4 weeks after ending chemotherapy  To increase yield of autologous blood (to avoid homologous  blood) in predonation programme in moderate anaemia either  when large volume of blood required or when sufficient blood  cannot be saved for elective major surgery, by intravenous  injection over 1-5 minutes, 600 units/kg twice weekly for 3 weeks  before surgery; consult product literature for details and advice on  ensuring high iron stores   Moderate anaemia (haemoglobin concentration 10-13 g/ 100 mL)  before elective orthopaedic surgery in adults with expected  moderate blood loss to reduce exposure to allogeneic blood  transfusion or if autologous transfusion unavailable, by subcuta-  neous injection (max. 1 mL per injection site), 600 units/kg every  week for 3 weeks before surgery and on day of surgery or  300 units/kg daily for 15 days starting 10 days before surgery;  consult product literature for details   Eprex® (janssen-Cilag) (Ml  Injection, prefilled syringe, epoetin alfa, net price  1000 units = £5.53; 2000 units = £11.07; 3000 units =  £16.60; 4000 units = £22.13; 5000 units = £27.66;  6000 units = £33.19; 8000 units = £44.25; 10 000 units  = £55.31; 20 000 units = £110.62; 30 000 units =  £199.11; 40 000 units = £265.48. An auto-injector  device is available for use with prefilled syringes  Dose symptomatic anaemia associated with chronic renal failure  in patients on haemodialysis (see also MHRA/CHM advice,  p. 582), by intravenous injection over 1-5 minutes or by subcu-  taneous injection (max. 1 mL per injection site), initially 50 units/  kg 3 times weekly adjusted according to response in steps of  25 units/kg 3 times weekly at intervals of at least 4 weeks;  maintenance dose, usually a total of 75-300 units/kg weekly (as a  single dose or in divided doses); CHILD by intravenous injection  initially as for adults; maintenance dose, body-weight under 10 kg  usually 75-150 units/kg 3 times weekly, body-weight 10-30 kg  usually 60-150 units/kg 3 times weekly, body-weight over 30 kg  usually 30-100 units/kg 3 times weekly  Symptomatic anaemia associated with chronic renal failure in  adults on peritoneal dialysis (see also MHRA/CHM advice,  p. 582), by intravenous injection over 1-5 minutes or by subcu-  taneous injection (max. 1 mL per injection site), initially 50 units/  kg twice weekly; maintenance dose 25-50 units/kg twice weekly  Severe symptomatic anaemia of renal origin in adults with renal  insufficiency not yet on dialysis (see also MHRA/ CHM advice,  p. 582), by intravenous injection over 1-5 minutes or by subcu-  taneous injection (max. 1 mL per injection site), initially 50 units/  kg 3 times weekly increased according to response in steps of  25 units/kg 3 times weekly at intervals of at least 4 weeks;  maintenance dose 17-33 units/kg 3 times weekly; max.   Note Intravenous route preferred; reduce dose by approximately  25% if rise in haemoglobin concentration exceeds 2 g/ 100 mL over 4  weeks or if haemoglobin concentration exceeds 12 g/100 mL; if  haemoglobin concentration continues to rise, despite dose reduc-  tion, suspend treatment until haemoglobin concentration decreases  and then restart at a dose approximately 25% lower than the  previous dose.   Symptomatic anaemia in adults receiving cancer chemotherapy  (see also MHRA/CHM advice, p. 582), by subcutaneous injection  (max. 1 mL per injection site), initially 150 units/kg 3 times weekly  (or 450 units/kg once weekly), increased if appropriate rise in  haemoglobin (or reticulocyte count) not achieved after 4 weeks to  300 units/kg 3 times weekly; discontinue if inadequate response  after 4 weeks at higher dose   Note Reduce dose by approximately 25-50% if rise in haemoglo-  bin concentration exceeds 2 g/100 mL over 4 weeks or if hae-    moglobin concentration exceeds 12g/100mL; if haemoglobin  concentration continues to rise, despite dose reduction, suspend  treatment until haemoglobin concentration decreases and then  restart at a dose approximately 25% lower than the previous dose.  Discontinue approximately 4 weeks after ending chemotherapy  To increase yield of autologous blood (to avoid homologous  blood) in predonation programme in moderate anaemia either  when large volume of blood required or when sufficient blood  cannot be saved for elective major surgery, by intravenous  injection over 1-5 minutes, 600 units/kg twice weekly for 3 weeks  before surgery; consult product literature for details and advice on  ensuring high iron stores   Moderate anaemia (haemoglobin concentration 10-13 g/100 mL)  before elective orthopaedic surgery in adults with expected  moderate blood loss to reduce exposure to allogeneic blood  transfusion or if autologous transfusion unavailable, by subcuta-  neous injection (max. 1 mL per injection site), 600 units/kg every  week for 3 weeks before surgery and on day of surgery or  300 units/kg daily for 15 days starting 10 days before surgery;  consult product literature for details    M Epoetin beta  NeoRecormon® (Roche) (Ml  Injection, prefilled syringe, epoetin beta, net price  500 units = £3.75; 2000 units = £14.98; 3000 units =  £22.47; 4000 units = £29.96; 5000 units = £37.47;  6000 units = £44.94; 10 000 units = £70.14;   Dose symptomatic anaemia associated with chronic renal failure  (see also MHRA/CHM advice, p. 582), by subcutaneous injec-  tion, ADULT and CHILD, initially 20 units/kg 3 times weekly for 4  weeks, increased according to response at intervals of 4 weeks in  steps of 20 units/kg 3 times weekly; total weekly dose may be  divided into daily doses; maintenance dose, initially reduce dose  by half then adjust according to response at intervals of 1-2  weeks; total weekly maintenance dose may be given as a single  dose or in 3 or 7 divided doses; max. 720 units/kg weekly  By intravenous injection over 2 minutes, ADULT and CHILD, initially  40 units/kg 3 times weekly for 4 weeks, increased according to  response to 80 units/kg 3 times weekly after 4 weeks, with further  increases if needed at intervals of 4 weeks in steps of 20 units/kg 3  times weekly; maintenance dose, initially reduce dose by half then  adjust according to response at intervals of 1-2 weeks; max.   Note Subcutaneous route preferred in patients not on haemodialysis.  Reduce dose by approximately 25% if rise in haemoglobin concen-  tration exceeds 2 g/100 mL over 4 weeks or if haemoglobin con-  centration approaches or exceeds 12g/100mL; if haemoglobin  concentration continues to rise, despite dose reduction, suspend  treatment until haemoglobin concentration decreases and then  restart at a dose approximately 25% lower than the previous dose  Prevention of anaemia of prematurity in neonates with birth-  weight of 0.75-1.5 kg and gestational age of less than 34 weeks, by  subcutaneous injection, 250 units/kg 3 times weekly preferably  starting within 3 days of birth and continued for 6 weeks  Symptomatic anaemia in adults with non-myeloid malignancies  receiving chemotherapy (see also MHRA/CHM advice, p. 582),  by subcutaneous injection, initially 450 units/kg weekly (as a  single dose or in 3-7 divided doses), increased if necessary after 4  weeks (if a rise in haemoglobin of at least 1 g/ 100 mL not  achieved) to 900 units/kg weekly (as a single dose or in 3-7  divided doses); if adequate response obtained reduce dose by 25-  50%; max. 60 000 units weekly   Note Discontinue treatment if haemoglobin concentration does  not increase by at least 1 g/ 100 mL after 8 weeks of therapy  (response unlikely). Reduce dose by approximately 25-50% if  rise in haemoglobin concentration exceeds 2g/100mL over 4  weeks or if haemoglobin concentration exceeds 12 g/100 mL; if  haemoglobin concentration continues to rise, despite dose  reduction, suspend treatment until haemoglobin concentration  decreases and then restart at a dose approximately 25% lower  than the previous dose. Discontinue approximately 4 weeks  after ending chemotherapy   To increase yield of autologous blood (to avoid homologous  blood) in predonation programme in moderate anaemia when  blood-conserving procedures are insufficient or unavailable,  consult product literature    Multidose injection, powder for reconstitution,  epoetin beta, net price 50 000-unit vial = £374.48  (with solvent)   Excipients include phenylalanine up to 5 mg/vial (section 9.4.1), benzyl  alcohol (avoid in neonates, see Excipients p. 2)   Dose symptomatic anaemia associated with chronic renal failure  (see also MHRA/CHM advice, p. 582), by subcutaneous injec-  tion, ADULT and CHILD over 3 years, initially 20 units/kg 3 times  weekly for 4 weeks, increased according to response at intervals  of 4 weeks in steps of 20 units/kg 3 times weekly; total weekly  dose may be divided into daily doses; maintenance dose, initially  reduce dose by half then adjust according to response at intervals  of 1-2 weeks; total weekly maintenance dose may be given as a  single dose or in 3 or 7 divided doses; max. 720 units/kg weekly  By intravenous injection over 2 minutes, ADULT and CHILD over 3  years, initially 40 units/kg 3 times weekly for 4 weeks, increased  according to response to 80 units/kg 3 times weekly after 4 weeks,  with further increases if needed at intervals of 4 weeks in steps of  20 units/kg 3 times weekly; maintenance dose, initially reduce  dose by half then adjust according to response at intervals of 1-2  weeks; max. 720 units/kg weekly    Note Subcutaneous route preferred in patients not on haemodialysis.  Reduce dose by approximately 25% if rise in haemoglobin concen-  tration exceeds 2g/100mL over 4 weeks or if haemoglobin con-  centration approaches or exceeds 12g/100mL; if haemoglobin  concentration continues to rise, despite dose reduction, suspend  treatment until haemoglobin concentration decreases and then  restart at a dose approximately 25% lower than the previous dose  Symptomatic anaemia in adults with non-myeloid malignancies  receiving chemotherapy (see also MHRA/CHM advice, p. 582),  by subcutaneous injection, initially 450 units/kg weekly (as a  single dose or in 3-7 divided doses), increased if necessary after 4  weeks (if a rise in haemoglobin of at least 1 g/100 mL not  achieved) to 900 units/kg weekly (as a single dose or in 3-7  divided doses); if adequate response obtained reduce dose by 25-  50%; max. 60 000 units weekly   Note Discontinue treatment if haemoglobin concentration does  not increase by at least 1 g/ 100 mL after 8 weeks of therapy  (response unlikely). Reduce dose by approximately 25-50% if rise  in haemoglobin concentration exceeds 2 g/100 mL over 4 weeks  or if haemoglobin concentration exceeds 12 g/100 mL; if hae-  moglobin concentration continues to rise, despite dose reduction,  suspend treatment until haemoglobin concentration decreases  and then restart at a dose approximately 25% lower than the  previous dose. Discontinue approximately 4 weeks after ending  chemotherapy   To increase yield of autologous blood (to avoid homologous  blood) in predonation programme in moderate anaemia when  blood-conserving procedures are insufficient or unavailable,  consult product literature   4 Epoetin theta  Eporatio® (Ratiopharm UK) T (^Ml  Injection, prefilled syringe, epoetin theta, net price  1000 units = £5.99; 2000 units = £11.98; 3000 units =  £17.98; 4000 units = £23.97; 5000 units = £29.96; 10  000 units = £59.92; 20 000 units = £119.84; 30  000 units = £179.75   Note If epoetin theta is substituted for another epoetin the same  route of administration should be used   Dose symptomatic anaemia associated with chronic renal failure  (see also MHRA/CHM advice, p. 582), by subcutaneous injec-  tion, ADULT over 18 years, initially 20 units/kg 3 times weekly,  increased after 4 weeks according to response to 40 units/kg 3  times weekly, with further increases if needed at 4-weekly inter-  vals in steps of 25% of the previous dose; maintenance dose,  adjusted if necessary in steps of 25%; weekly maintenance dose  may be given as a single dose or in 3 divided doses; max.   By intravenous injection, ADULT over 18 years, initially 40 units/kg  3 times weekly, increased according to response to 80 units/kg 3  times weekly after 4 weeks, with further increases if needed at  intervals of 4 weeks in steps of 25% of the previous dose;  maintenance dose, adjusted if necessary in steps of 25%; weekly  maintenance dose may be given in 2 divided doses in stable  patients; max. 700 units/kg weekly  Note Subcutaneous route preferred in patients not on haemodialysis.  Reduce dose by 25-50% if rise in haemoglobin concentration    exceeds 2g/100mL over 4 weeks or if haemoglobin concentration  approaches or exceeds 12g/100mL; if haemoglobin concentration  continues to rise, despite dose reduction, suspend treatment until  haemoglobin concentration decreases and then restart at a dose  approximately 25% lower than the previous dose  Symptomatic anaemia in adults with non-myeloid malignancies  receiving cancer chemotherapy (see also MHRA/ CHM advice,  p. 582), by subcutaneous injection, initially 20 000 units once  weekly, increased if necessary after 4 weeks (if a rise in haemo-  globin of at least 1 g/lOOmL not achieved) to 40 000 units once  weekly, with further increase if needed after 4 weeks to max.   Note Discontinue treatment if haemoglobin concentration does  not increase by at least 1 g/lOOmL after 12 weeks of therapy  (response unlikely). Reduce dose by 25-50% if rise in haemoglo-  bin concentration exceeds 2g/100mL over 4 weeks or if hae-  moglobin concentration exceeds 12g/100mL; if haemoglobin  concentration continues to rise, despite dose reduction, suspend  treatment until haemoglobin concentration decreases and then  restart at a dose approximately 25% lower than the previous dose.  Discontinue approximately 4 weeks after ending chemotherapy    4 Epoetin zeta  Retacrit® (Hospira) ▼ (Ml  Injection, prefilled syringe, epoetin zeta, net price  1000 units = £5.66; 2000 units = £11.31; 3000 units =  £16.97; 4000 units = £22.63; 5000 units = £28.28;  6000 units = £33.94; 8000 units = £45.25; 10 000 units  = £56.57; 20 000 units = £203.64; 30 000 units =  £305.46; 40 000 units = £407.27   Dose symptomatic anaemia associated with chronic renal failure  in patients on haemodialysis (see also MHRA/CHM advice,  p. 582), by intravenous injection over 1-5 minutes or by subcu-  taneous injection (max. 1 mL per injection site), initially 50 units/  kg 3 times weekly adjusted according to response in steps of  25 units/kg 3 times weekly at intervals of at least 4 weeks;  maintenance dose, usually 25-100 units/kg 3 times weekly; CHILD  by intravenous injection initially as for adults; maintenance dose,  body-weight under 10 kg usually 75-150 units/kg 3 times weekly,  body-weight 10-30 kg usually 60-150 units/kg 3 times weekly,  body-weight over 30 kg usually 30-100 units/kg 3 times weekly  Symptomatic anaemia associated with chronic renal failure in  adults on peritoneal dialysis (see also MHRA/ CHM advice,  p. 582), by intravenous injection over 1-5 minutes or by subcu-  taneous injection (max. 1 mL per injection site), initially 50 units/  kg twice weekly; maintenance dose 25-50 units/kg twice weekly  Severe symptomatic anaemia of renal origin in adults with renal  insufficiency not yet on dialysis (see also MHRA/CHM advice,  p. 582), by intravenous injection over 1-5 minutes or by subcu-  taneous injection (max. 1 mL per injection site), initially 50 units/  kg 3 times weekly increased according to response in steps of  25 units/kg 3 times weekly at intervals of at least 4 weeks;  maintenance dose 17-33 units/kg 3 times weekly; max.   Note Avoid increasing haemoglobin concentration at a rate exceed-  ing 2 g/100 mL over 4 weeks   Symptomatic anaemia in adults receiving cancer chemotherapy  (see also MHRA/CHM advice, p. 582), by subcutaneous injection  (max. 1 mL per injection site), initially 150 units/kg 3 times weekly  (or 450 units/kg once weekly), increased if appropriate rise in  haemoglobin (or reticulocyte count) not achieved after 4 weeks to  300 units/kg 3 times weekly; discontinue if inadequate response  after 4 weeks at higher dose   Note Reduce dose by approximately 25-50% if rise in haemoglo-  bin concentration exceeds 2g/100mL over 4 weeks or if hae-  moglobin concentration exceeds 12 g/100 mL; if haemoglobin  concentration continues to rise, despite dose reduction, suspend  treatment until haemoglobin concentration decreases and then  restart at a dose approximately 25% lower than the previous dose.  Discontinue approximately 4 weeks after ending chemotherapy  To increase yield of autologous blood (to avoid homologous  blood) in predonation programme in moderate anaemia either  when large volume of blood required or when sufficient blood  cannot be saved for elective major surgery, by intravenous  injection over 1-5 minutes, 600 units/kg twice weekly for 3 weeks  before surgery; consult product literature for details and advice on  ensuring high iron stores   Indications see under Dose below  Cautions see Epoetin  Contra-indications see Epoetin  Pregnancy no evidence of harm in animal studies —  manufacturer advises caution  Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — present in milk in  animal studies   • Symptomatic anaemia associated with chronic kidney  disease in patients on dialysis and not currently  treated with erythropoietins (see also MHRA/CHM  advice, p. 582), ADULT over 18 years, by subcutaneous  or intravenous injection, initially 600 nanograms /kg  once every 2 weeks, adjusted according to response  at intervals of at least 4 weeks; maintenance dose of  double the previous fortnightly dose may be given  every 4 weeks   • Symptomatic anaemia associated with chronic kidney  disease in patients not on dialysis and not currently  treated with erythropoietins (see also MHRA/CHM  advice, p. 582), ADULT over 18 years, by subcutaneous  injection, initially 1.2 micrograms /kg once every 4  weeks, alternatively by subcutaneous or intravenous  injection, initially 600 nanograms/kg once every 2  weeks; dose adjusted according to response at inter-  vals of at least 4 weeks; patients treated once every 2  weeks may be given a maintenance dose of double the  previous fortnightly dose every 4 weeks   • Symptomatic anaemia associated with chronic kidney  disease in patients currently treated with erythro-  poietins (see also MHRA/CHM advice, p. 582), ADULT  over 18 years, by subcutaneous or intravenous  injection, consult product literature   Note Subcutaneous route preferred in patients not on haemo-  dialysis. Reduce dose by approximately 25% if rise in haemo-  globin concentration exceeds 2 g/lOOmL over 4 weeks, or if  haemoglobin concentration approaches or exceeds 12 g/   100 mL; if haemoglobin concentration continues to rise, despite  dose reduction, suspend treatment until haemoglobin concen-  tration decreases and then restart at a dose approximately 25%  lower than the previous dose   Injection, prefilled syringe, methoxy polyethylene  glycol-epoetin beta, net price 30 micrograms/0.3 mL  = £44.05; 50 micrograms/0.3 mL = £73.41; 75 micr-  ograms/0.3 mL = £110.11; 100 micrograms/0.3 mL =  £146.81; 120 micrograms/0.3 mL = £176.18;   150 micrograms/0.3 mL = £220.22; 200 micrograms/  0.3 mL = £293.62; 250 micrograms/0.3 mL = £367.03;  360 micrograms/0.6 mL = £528.56   Sickle-cell disease is caused by a structural abnormality  of haemoglobin resulting in deformed, less flexible red  blood cells. Acute complications in the more severe  forms include sickle-cell crisis, where infarction of the  microvasculature and blood supply to organs results in  severe pain. Sickle-cell crisis requires hospitalisation,    intravenous fluids, analgesia (section 4.7), and treat-  ment of any concurrent infection. Chronic complica-  tions include skin ulceration, renal failure, and increased  susceptibility to infection. Pneumococcal vaccine (sec-  tion 14.4), haemophilus influenzae type b vaccine (sec-  tion 14.4), an annual influenza vaccine (section 14.4)  and prophylactic penicillin (Table 2, section 5.1) reduce  the risk of infection. Hepatitis B vaccine (section 14.4)  should be considered if the patient is not immune.   In most forms of sickle-cell disease, varying degrees of  haemolytic anaemia are present accompanied by  increased erythropoiesis; this may increase folate  requirements and folate supplementation may be neces-  sary (section 9.1.2).   Hydroxycarbamide can reduce the frequency of crises  and the need for blood transfusions in sickle-cell dis-  ease; it should be considered in consultation with a  specialist centre. The beneficial effects of hydroxycar-  bamide may not become evident for several months.  Myelosuppression and skin reactions are the most com-  mon side-effects.   Indications sickle-cell disease (see notes above);  chronic myeloid leukaemia, cancer of the cervix  (section 8.1.5)   Cautions see section 8.1 and notes above; also moni-  tor renal and hepatic function before and during  treatment; monitor full blood count before treatment,  then every 2 weeks for the first 2 months and then  every 2 months thereafter (or every 2 weeks if on  max. dose); leg ulcers (review treatment if cutaneous  vasculitic ulcerations develop); interactions: Appen-  dix 1 (hydroxycarbamide)   Hepatic impairment manufacturer advises caution in  mild to moderate impairment; avoid in severe  impairment   Renal impairment reduce initial dose by 50% if eGFR  less than 60 mL/minute/1.73 m 2 ; avoid if eGFR less  than 30 mL/minute/ 1.73 m 2   Side-effects see section 8.1 and notes above; also  headache; less commonly dizziness and rash; rarely  reduced sperm count and activity; fever, amenor-  rhoea, skin cancers (in elderly patients), bleeding and  hypomagnesaemia also reported   • By mouth, initially 15 mg/kg daily, increased every 12  weeks in steps of 5 mg/kg daily according to  response; usual dose 15-30 mg/kg daily (max.   35 mg/kg daily); CHILD under 18 years, see BNF for  Children   Severe tissue iron overload can occur in aplastic and  other refractory anaemias, mainly as the result of  repeated blood transfusions. It is a particular problem    in refractory anaemias with hyperplastic bone marrow,  especially thalassaemia major, where excessive iron  absorption from the gut and inappropriate iron therapy  can add to the tissue siderosis.    Iron overload associated with haemochromatosis can  be treated with repeated venesection. Venesection may  also be used for patients who have received multiple  transfusions and whose bone marrow has recovered.  Where venesection is contra-indicated, the long-term  administration of the iron chelating compound desferri-  oxamine mesilate is useful. Subcutaneous infusions of  desferrioxamine are given over 8-12 hours, 3-7 times a  week. The dose should reflect the degree of iron over-  load. For children starting therapy (and who have low  iron overload) the dose should not exceed 30 mg/kg.  For established overload the dose is usually between 20  and 50 mg/kg daily. Desferrioxamine (up to 2 g per unit  of blood) may also be given at the time of blood trans-  fusion, provided that the desferrioxamine is not added  to the blood and is not given through the same line as  the blood (but the two may be given through the same  cannula).   Iron excretion induced by desferrioxamine is enhanced  by administration of ascorbic acid (vitamin C, section  9.6.3) 200 mg daily by mouth (100 mg in infants); it  should be given separately from food since it also  enhances iron absorption. Ascorbic acid should not be  given to patients with cardiac dysfunction; in patients  with normal cardiac function ascorbic acid should be  introduced 1 month after starting desferrioxamine.   Desferrioxamine infusion can be used to treat alumin-  ium overload in dialysis patients; theoretically 100 mg  of desferrioxamine binds with 4. 1 mg of aluminium.    Deferasirox, an oral iron chelator, is licensed for the  treatment of chronic iron overload in adults and chil-  dren over 6 years with thalassaemia major who receive  frequent blood transfusions (more than 7 mL/kg/month  of packed red blood cells). It is also licensed for chronic  iron overload when desferrioxamine is contra-indicated  or inadequate in patients with thalassaemia major who  receive infrequent blood transfusions (less than 7 mL/  kg/month of packed red blood cells), in patients with  other anaemias, and in children aged 2 to 5 years.   The Scottish Medicines Consortium (p. 4) has advised  (January 2007) that deferasirox is accepted for  restricted use within NHS Scotland for the treatment  of chronic iron overload associated with the treatment  of rare acquired or inherited anaemias requiring recur-  rent blood transfusions. It is not recommended for  patients with myelodysplastic syndromes.    Deferiprone, an oral iron chelator, is licensed for the  treatment of iron overload in patients with thalassaemia  major in whom desferrioxamine is contra-indicated or is  inadequate. Blood dyscrasias, particularly agranulocyto-  sis, have been reported with deferiprone.   Indications see notes above  Cautions eye and ear examinations required before  treatment and annually during treatment; monitor  body-weight, height, and sexual development in chil-  dren annually; monitor serum-ferritin concentration  monthly; elderly (increased risk of side-effects); risk of  gastro-intestinal ulceration and haemorrhage; platelet  count less than 50 x 10 9 /litre; consider treatment    interruption if unexplained cytopenia occurs; not  recommended in conditions which may reduce life  expectancy (e.g. high-risk myelodysplastic syn-  dromes); history of liver cirrhosis; test liver function  before treatment, then every 2 weeks during the first  month, and then monthly; measure baseline serum  creatinine and monitor renal function weekly during  the first month of treatment and monthly thereafter;  test for proteinuria monthly; interactions: Appendix 1  (deferasirox)   Hepatic impairment manufacturer advises caution —  no information available; avoid in severe impairment  Renal impairment reduce dose by 10 mg/kg if eGFR  60-90 mL/minute/ 1.73 m 2 and if serum creatinine  increased by more than 33% of baseline measurement  on 2 consecutive occasions — interrupt treatment if  deterioration in renal function persists after dose  reduction; avoid if eGFR less than 60 mL/minute/  1.73 m 2   Side-effects gastro-intestinal disturbances (including  ulceration and fatal haemorrhage); headache; protei-  nuria; pruritus, rash; less commonly hepatitis, chole-  lithiasis, oedema, fatigue, anxiety, sleep disorder, diz-  ziness, pyrexia, pharyngitis, glucosuria, renal  tubulopathy, disturbances of hearing and vision  (including lens opacity and maculopathy), and skin  pigmentation; hepatic failure, acute renal failure,  blood disorders (including agranulocytosis, neutro-  penia, pancytopenia, and thrombocytopenia), hyper-  sensitivity reactions (including anaphylaxis and  angioedema), alopecia also reported  Dose   • ADULT and CHILD over 2 years initially 10-30 mg/kg  once daily according to serum-ferritin concentration  and amount of transfused blood (consult product  literature); maintenance, adjust dose every 3-6  months in steps of 5-10 mg/kg according to serum-  ferritin concentration; usual max. 30 mg/kg daily, but  may be increased to max. 40 mg/kg daily and reduced  in steps of 5-10 mg/kg once control achieved   Dispersible tablets, deferasirox 125 mg, net price 28-  tab pack = £117.60; 250 mg, 28-tab pack = £235.20;  500 mg, 28-tab pack = £470.40. Label: 13, 22, coun-  selling, administration   Counselling Tablets should be dispersed in water, orange juice, or  apple juice; if necessary resuspend residue   Cautions monitor neutrophil count weekly and dis-  continue treatment if neutropenia develops; monitor  plasma-zinc concentration   Blood disorders Patients or their carers should be told how  to recognise signs of neutropenia and advised to seek  immediate medical attention if symptoms such as fever or  sore throat develop   Pregnancy manufacturer advises avoid before  intended conception and during pregnancy — terato-  genic and embryotoxic in animal studies; contra-  ception advised in women of child-bearing potential   Side-effects gastro-intestinal disturbances (reducing  dose and increasing gradually may improve toler-  ance), increased appetite; headache; red-brown urine  discoloration; neutropenia, agranulocytosis; zinc  deficiency; arthropathy  Dose   • ADULT and CHILD over 6 years 25 mg/kg 3 times daily  (max. 100 mg/kg daily)   Ferriprox® (Swedish Orphan) (Ml  Tablets, f/c, scored, deferiprone 500 mg, net price  100-tab pack = £152.39. Label: 14, counselling, blood  disorders   Cautions eye and ear examinations before treatment  and at 3-month intervals during treatment; monitor  body-weight and height in children at 3-month inter-  vals — risk of growth retardation with excessive doses;  aluminium-related encephalopathy (may exacerbate  neurological dysfunction); interactions: Appendix 1  (desferrioxamine)   Pregnancy teratogenic in animal studies; manufac-  turer advises use only if potential benefit outweighs  risk   Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — no information  available   Side-effects nausea, vomiting, abdominal pain;  headache; pyrexia; growth retardation and bone dis-  orders (see Cautions); arthralgia, myalgia; hearing  disturbances; injection-site reactions; rarely diarr-  hoea, hepatic impairment, hypotension (especially  when given too rapidly by intravenous injection),  anaphylaxis, Yersinia and mucormycosis infections,  blood dyscrasias (including thrombocytopenia and  leucopenia), leg cramps, bone pain, visual distur-  bances (including lens opacity and retinopathy), rash;  very rarely acute respiratory distress, neurological  disturbances (including dizziness, neuropathy, con-  vulsions, and paraesthesia), renal impairment; muscle  spasms also reported  Dose   Desferrioxamine mesilate (Non-proprietary) (Ml  Injection, powder for reconstitution, desferrioxamine  mesilate, net price 500-mg vial = £4.26; 2-g vial =  £17.05   Injection, powder for reconstitution, desferrioxamine  mesilate, net price 500-mg vial = £4.67, 2-g vial =  £18.66   Eculizumab, a recombinant monoclonal antibody, inhi-  bits terminal complement activation at the C5 protein  and thereby reduces haemolysis. It is used to reduce  haemolysis in paroxysmal nocturnal haemoglobinuria, a  severe and disabling form of haemolytic anaemia.   Indications paroxysmal nocturnal haemoglobinuria,  in those with a history of blood transfusions (specialist  use only)   Cautions active systemic infection; monitor for intra-  vascular haemolysis (including serum-lactate  dehydrogenase concentration) for at least 8 weeks  after discontinuation   Meningococcal infection Vaccinate against Neisseria  meningitidis at least 2 weeks before treatment (tetravalent  vaccine against serotypes A, C, W135 and Y recommended);  revaccinate according to current medical guidelines. Advise  patient to report promptly any signs of meningococcal  infection. Other immunisations should also be up to date  (section 14.1)   Contra-indications unresolved Neisseria meningitidis  infection; patients unvaccinated against Neisseria  meningitidis (see Cautions above); known or sus-  pected hereditary complement deficiencies   Pregnancy no information available — use only if  potential benefit outweighs risk; human IgG anti-  bodies known to cross placenta; manufacturer advises  effective contraception during and for 5 months after  treatment   Breast-feeding no information available — manufac-  turer advises avoid breast-feeding during and for 5  months after treatment   Side-effects gastro-intestinal disturbances; oedema;  cough, nasopharyngitis; headache, dizziness, fatigue,  dysgeusia, paraesthesia; infection (including  meningococcal infection); spontaneous erection,  dysuria; arthralgia, myalgia; blood disorders (includ-  ing thrombocytopenia); alopecia, pruritus, rash;  influenza-like symptoms; infusion-related reactions;  less commonly anorexia, gingival pain, jaundice, pal-  pitation, haematoma, hypotension, chest pain, syn-  cope, hot flushing, epistaxis, anxiety, depression,  mood changes, sleep disturbances, Graves’ disease,  menstrual disorders, renal impairment, malignant  melanoma, muscle spasms, myelodysplastic  syndrome, visual disturbances, tinnitus, hyperhidrosis,  petechiae, and skin depigmentation   • By intravenous infusion, ADULT over 18 years, initially  600 mg once a week for 4 weeks, then 900 mg on  week 5; maintenance, 900 mg once every 12-16 days   Concentrate for intravenous infusion, eculizumab  lOmg/mL, net price 30-mL vial = £3150.00. Coun-  selling, meningococcal infection, patient information  card    Acute idiopathic thrombocytopenic purpura is usually  self-limiting in children. In adults, idiopathic thrombo-  cytopenic purpura can be treated with a corticosteroid,  e.g. prednisolone 1 mg/kg daily, gradually reducing the  dose over several weeks. Splenectomy is considered if a  satisfactory platelet count is not achieved or if there is a  relapse on reducing the dose of corticosteroid or with-  drawing it.   Immunoglobulin preparations (section 14.5.1), are also  used in idiopathic thrombocytopenic purpura or where  a temporary rapid rise in platelets is needed, as in  pregnancy or pre-operatively; they are also used for  children often in preference to a corticosteroid. Anti-  D (Rh 0 ) immunoglobulin (section 14.5.3) is effective in  raising the platelet count in about 80% of unsplenecto-  mised rhesus-positive individuals; its effects may last  longer than normal immunoglobulin for intravenous  use, but further doses are usually required.   Other therapy that has been tried in refractory idio-  pathic thrombocytopenic purpura includes azathioprine  (section 8.2.1), cyclophosphamide (section 8.1.1), vin-  cristine (section 8.1.4), ciclosporin (section 8.2.2), and  danazol (section 6.7.2). Rituximab (section 8.2.3) may  also be effective and in some cases induces prolonged  remission. For patients with chronic severe thrombocy-  topenia refractory to other therapy, tranexamic acid  (section 2.11) may be given to reduce the severity of  haemorrhage.    The Scottish Medicines Consortium (p. 4) has advised  (September 2009) that romiplostim ( Nplate ®) is    Eltrombopag and romiplostim are thrombopoietin  receptor agonists licensed for the treatment of chronic  idiopathic thrombocytopenic purpura in splenecto-  mised patients refractory to other treatments, such as  corticosteroids or immunoglobulins, or as a second-line  treatment in non-splenectomised patients when surgery  is contra-indicated (see also NICE guidance below).  Eltrombopag is an oral preparation and romiplostim is  an injection which is made biosynthetically by recom-  binant DNA technology; they should both be used under  the supervision of a specialist.   The Scottish Medicines Consortium (p. 4) has advised  (July 2010) that eltrombopag ( Revolade ®) is accepted  for restricted use within NHS Scotland for the treatment  of both splenectomised and non-splenectomised  patients with severe symptomatic immune (idiopathic)  thrombocytopenic purpura or a high risk of bleeding.   Eltrombopag for the treatment of chronic  immune (idiopathic) thrombocytopenic  purpura (October 2010)   Eltrombopag is not recommended for the treatment  of chronic immune (idiopathic) thrombocytopenic  purpura in splenectomised adults refractory to  other treatments, such as corticosteroids or immu-  noglobulins, or as a second-line treatment in non-  splenectomised adults when surgery is contra-indi-  cated.    accepted for restricted use within NHS Scotland for  patients with severe symptomatic idiopathic thrombo-  cytopenic purpura or those at high risk of bleeding.   Cautions patients of East Asian origin (see under  Dose); risk factors for thromboembolism; monitor full  blood count including platelet count and peripheral  blood smears every week during treatment until a  stable platelet count is reached (50 x 1 0 9 /litre or  more for at least 4 weeks), then monthly thereafter;  monitor liver function before treatment, every two  weeks when adjusting the dose, and monthly there-  after; regular ophthalmological examinations for cat-  aract formation recommended; interactions: Appen-  dix 1 (eltrombopag)   Renal impairment use with caution  Pregnancy avoid — toxicity in animal studies; ensure  effective contraception during treatment  Breast-feeding manufacturer advises avoid  Side-effects gastro-intestinal disturbances including  nausea, diarrhoea, abdominal pain, and constipation;  peripheral oedema; headache, insomnia, paraesthesia,  fatigue; arthralgia, bone pain, myalgia; cataract, dry  eye; pruritus, rash, alopecia; less commonly dry  mouth, gingival bleeding, haemorrhoids, taste distur-  bances, cholestasis, hepatitis, anorexia, changes in  appetite, weight gain, flushing, palpitation, QT-inter-  val prolongation, hypertension, tachycardia, throm-  boembolic events (including deep vein thrombosis,  pulmonary embolism, and acute myocardial infarc-  tion), cough, sleep disorders, mood changes, depres-  sion, anxiety, dizziness, migraine, hemiparesis, tremor,  peripheral neuropathy, respiratory and urinary tract  infections, renal failure, nocturia, rectosigmoid cancer,  blood disorders (including anaemia, and thrombocy-  topenia), gout, eye disorders, vertigo, epistaxis, skin  reactions including ecchymosis, and sweating    • ADULT over 18 years, initially 50 mg once daily  (patients of EAST ASIAN origin such as Chinese, Japa-  nese, Taiwanese, or Korean, initially 25 mg once  daily), adjusted to achieve a platelet count of 50 x  1 0 9 /litre or more (consult product literature for dose  adjustments); max. 75 mg once daily; discontinue if  inadequate response after 4 weeks at maximum dose  Counselling Each dose should be taken at least 4 hours  before or after any dairy products (or foods containing cal-  cium), indigestion remedies, or medicines containing alu-  minium, calcium, iron, magnesium, zinc, or selenium to  reduce possible interference with absorption   Tablets, f/c, eltrombopag (as olamine) 25 mg (white),  net price 28-tab pack = £770.00; 50 mg (brown), 28-  tab pack = £1540.00. Counselling, see above   Indications see notes above  Cautions monitor full blood count and peripheral  blood smears for morphological abnormalities before    and during treatment; monitor platelet count weekly  until 50 x 10 9 /litre or more for at least 4 weeks  without dose adjustment, then monthly thereafter  Driving Dizziness may affect performance of skilled tasks  (e g. driving)   Side-effects gastro-intestinal disturbances; flushing,  oedema; dizziness, migraine, insomnia, fatigue, asth-  enia, paraesthesia; influenza-like symptoms; arthr-  algia, myalgia, bone pain, muscle spasm; increased  bone marrow reticulin; ecchymosis, rash; injection-  site reactions  Dose   • By subcutaneous injection, ADULT over 18 years,  initially 1 microgram/kg once weekly, adjusted in  steps of 1 microgram/kg at weekly intervals until a  stable platelet count of 50 x 10 9 /litre or more is  reached (consult product literature for dose adjust-  ments); max. 10 micrograms /kg once weekly; dis-  continue if inadequate response after 4 weeks at  maximum dose   Injection, powder for reconstitution, romiplostim, net  price 250-microgram vial (available with or without  solvent) = £482.00   Anagrelide inhibits platelet formation. It is licensed for  essential thrombocythaemia in patients at risk of  thrombo-haemorrhagic events who have not responded  adequately to other drugs or who cannot tolerate other  drugs. Anagrelide should be initiated under specialist  supervision.   Cautions cardiovascular disease — assess cardiac  function before and during treatment; concomitant  aspirin in patients at risk of haemorrhage; monitor full  blood count (monitor platelet count every 2 days for 1  week, then weekly until maintenance dose estab-  lished), liver function, serum creatinine and urea;  interactions: Appendix 1 (anagrelide)   Driving Dizziness may affect performance of skilled tasks  (e g. driving)   Hepatic impairment manufacturer advises caution in  mild impairment; avoid in moderate to severe  impairment   Renal impairment manufacturer advises avoid if  eGFR less than 50 mL/minute/ 1.73 m 2    Side-effects gastro-intestinal disturbances; palpita-  tion, tachycardia, fluid retention; headache, dizziness,  fatigue; anaemia; rash; less commonly pancreatitis,  gastro-intestinal haemorrhage, congestive heart fail-  ure, hypertension, arrhythmias, syncope, chest pain,  dyspnoea, sleep disturbances, paraesthesia,  hypoaesthesia, depression, nervousness, confusion,  amnesia, fever, weight changes, impotence, blood  disorders, myalgia, arthralgia, epistaxis, dry mouth,  alopecia, skin discoloration, and pruritus; rarely gas-  tritis, colitis, postural hypotension, angina, myocardial  infarction, vasodilatation, pulmonary hypotension,  pulmonary infiltrates, migraine, drowsiness, impaired  coordination, dysarthria, asthenia, tinnitus, renal fail-  ure, nocturia, visual disturbances, and gingival  bleeding; allergic alveolitis and hepatitis also reported  Dose   • Initially 500 micrograms twice daily adjusted accord-  ing to response in steps of 500 micrograms daily at  weekly intervals to max. 10 mg daily (max. single dose  2.5 mg); usual dose range 1-3 mg daily in divided  doses    Glucose 6-phosphate dehydrogenase (G6PD) deficiency  is highly prevalent in individuals originating from most  parts of Africa, from most parts of Asia, from Oceania,  and from Southern Europe; it can also occur, rarely, in  any other individuals. G6PD deficiency is more common  in males than it is in females.    Individuals with G6PD deficiency are susceptible to  developing acute haemolytic anaemia when they take  a number of common drugs. They are also susceptible  to developing acute haemolytic anaemia when they eat  fava beans (broad beans, Vida faba)\ this is termed  favism and can be more severe in children or when the  fresh fava beans are eaten raw.   When prescribing drugs for patients with G6PD defi-  ciency, the following three points should be kept in  mind:   • G6PD deficiency is genetically heterogeneous; sus-  ceptibility to the haemolytic risk from drugs varies;  thus, a drug found to be safe in some G6PD-defi-  cient individuals may not be equally safe in others;   • manufacturers do not routinely test drugs for their  effects in G6PD-deficient individuals;   • the risk and severity of haemolysis is almost always  dose-related.   The lists below should be read with these points in mind.  Ideally, information about G6PD deficiency should be  available before prescribing a drug listed below. How-  ever, in the absence of this information, the possibility of  haemolysis should be considered, especially if the  patient belongs to a group in which G6PD deficiency  is common.    in the absence of an exogenous trigger. These patients  must be regarded as being at high risk of severe exacer-  bation of haemolysis following administration of any of  the drugs listed below.    Drugs with definite risk of haemolysis in most  G6PD-deficient individuals  Dapsone and other sulfones (higher doses for  dermatitis herpetiformis more likely to cause pro-  blems)   Primaquine (30 mg weekly for 8 weeks has been  found to be without undue harmful effects in African  and Asian people, see section 5.4.1)   Sulfonamides (including co-trimoxazole; some sulfo-  namides, e.g. sulfadiazine, have been tested and  found not to be haemolytic in many G6PD-deficient  individuals)    Drugs with possible risk of haemolysis in  some G6PD-deficient individuals  Aspirin (acceptable up to a dose of at least 1 g daily  in most G6PD-deficient individuals)   Note Naphthalene in mothballs also causes haemolysis in  individuals with G6PD deficiency   human granulocyte-colony stimulating  factor (rhG-CSF) stimulates the production of neutro-  phils and may reduce the duration of chemotherapy-  induced neutropenia and thereby reduce the incidence  of associated sepsis; there is as yet no evidence that it  improves overall survival. Filgrastim (unglycosylated  rhG-CSF) and lenograstim (glycosylated rhG-CSF)  have similar effects; both have been used in a variety  of clinical settings, but they do not have any clear-cut  routine indications. In congenital neutropenia filgrastim  usually increases the neutrophil count with an appro-  priate clinical response. Prolonged use may be asso-  ciated with an increased risk of myeloid malignancy.  Pegfilgrastim is a polyethylene glycol-conjugated  (‘pegylated’) derivative of filgrastim; pegylation  increases the duration of filgrastim activity.    Avery few G6PD-deficient individuals with chronic non- Granulocyte-colony stimulating factors should only be  spherocytic haemolytic anaemia have haemolysis even prescribed by those experienced in their use.    Cautions Granulocyte-colony stimulating factors  should be used with caution in patients with pre-malig-  nant or malignant myeloid conditions. Full blood counts  including differential white cell and platelet counts  should be monitored. Treatment should be withdrawn  in patients who develop signs of pulmonary infiltration.  There have been reports of pulmonary infiltrates leading  to acute respiratory distress syndrome — patients with a  history of pulmonary infiltrates or pneumonia may be at  higher risk. Granulocyte-colony stimulating factors  should be used with caution in patients with sickle-cell  disease. Spleen size should be monitored during treat-  ment because there is a risk of splenomegaly and  rupture.   Pregnancy There have been reports of toxicity in  animal studies and manufacturers advise not to use  granulocyte-colony stimulating factors during  pregnancy unless the potential benefit outweighs the  risk.    Breast-feeding There is no evidence for the use of  granulocyte-colony stimulating factors during breast-  feeding and manufacturers advise avoiding their use.    Side-effects Side-effects of granulocyte-colony stimu-  lating factors include gastro-intestinal disturbances,  anorexia, headache, asthenia, fever, musculoskeletal  pain, bone pain, rash, alopecia, injection-site reactions,  thrombocytopenia, and leucocytosis. Less commonly  chest pain can occur. Pulmonary side-effects, particu-  larly interstitial pneumonia (see Cautions above), cuta-  neous vasculitis and acute febrile neutrophilic derma-  tosis have rarely been reported.   Indications (specialist use only) reduction in duration  of neutropenia and incidence of febrile neutropenia in  cytotoxic chemotherapy for malignancy (except  chronic myeloid leukaemia and myelodysplastic syn-  dromes); reduction in duration of neutropenia (and  associated sequelae) in myeloablative therapy fol-  lowed by bone-marrow transplantation; mobilisation  of peripheral blood progenitor cells for harvesting and  subsequent autologous or allogeneic infusion; severe  congenital neutropenia, cyclic neutropenia, or idio-  pathic neutropenia and history of severe or recurrent  infections (distinguish carefully from other haemato-  logical disorders, consult product literature); persis-  tent neutropenia in advanced HIV infection  Cautions see notes above; also regular morphological  and cytogenetic bone-marrow examinations recom-  mended in severe congenital neutropenia (possible  risk of myelodysplastic syndromes or leukaemia);  secondary acute myeloid leukaemia; osteoporotic  bone disease (monitor bone density if given for more  than 6 months); interactions: Appendix 1 (filgrastim)  Contra-indications severe congenital neutropenia  (Kostmann’s syndrome) with abnormal cytogenetics  Pregnancy see notes above  Breast-feeding see notes above   Side-effects see notes above; also mucositis, splenic  enlargement, hepatomegaly, transient hypotension,  epistaxis, urinary abnormalities (including dysuria,  proteinuria, and haematuria), osteoporosis, exacer-  bation of rheumatoid arthritis, anaemia, transient  decrease in blood glucose, pseudogout, and raised  uric acid; very rarely splenic rupture   • Cytotoxic-induced neutropenia, preferably by subcu-  taneous injection or by intravenous infusion (over 30  minutes), ADULT and CHILD, 500 000 units/kg daily  started at least 24 hours after cytotoxic chemother-  apy, continued until neutrophil count in normal range,  usually for up to 14 days (up to 38 days in acute  myeloid leukaemia)   • Myeloablative therapy followed by bone-marrow  transplantation, by intravenous infusion over 30  minutes or over 24 hours or by subcutaneous infu-  sion over 24 hours, 1 million units /kg daily, started at  least 24 hours following cytotoxic chemotherapy (and  within 24 hours of bone-marrow infusion), then  adjusted according to neutrophil count (consult pro-  duct literature)   • Mobilisation of peripheral blood progenitor cells for  autologous infusion, used alone, by subcutaneous  injection or by subcutaneous infusion over 24 hours,  1 million units /kg daily for 5-7 days; used following  adjunctive myelosuppressive chemotherapy (to  improve yield), by subcutaneous injection,   500 000 units/kg daily, started the day after complet-  ing chemotherapy and continued until neutrophil  count in normal range; for timing of leucopheresis  consult product literature   • Mobilisation of peripheral blood progenitor cells in  normal donors for allogeneic infusion, by subcuta-  neous injection, ADULT under 60 years and CHILD over  16 years, 1 million units/kg daily for 4-5 days; for  timing of leucopheresis consult product literature   • Severe chronic neutropenia, by subcutaneous injec-  tion, ADULT and CHILD, in severe congenital neutrope-  nia, initially 1.2 million units/kg daily in single or  divided doses (initially 500 000 units/kg daily in idio-  pathic or cyclic neutropenia), adjusted according to  response (consult product literature)   • Persistent neutropenia in HIV infection, by subcuta-  neous injection, initially 100 000 units/kg daily,  increased as necessary until neutrophil count in nor-  mal range (usual max. 400 000 units/kg daily), then  adjusted to maintain neutrophil count in normal range  (consult product literature)    Neupogen® (Amgen) (Ml  Injection, filgrastim 30 million-units (300micr-  ograms)/mL, net price 1-mL vial = £58.56   Injection (Singleject®), filgrastim 60 million-units  (600 micrograms) /mL, net price 0.5-mL prefilled  syringe = £58.56; 96 million-units (960 micrograms)/  mL, 0.5-mL prefilled syringe = £93.40    Nivestim® (Hospira) ▼ (Ml  Injection, prefilled syringe, filgrastim, net price  12 million-units (120micrograms)/0.2mL = £36.00;  30 million-units (300micrograms)/0.5mL = £58.00;  48 million-units (480 micrograms)/0.5mL = £93.00  Note Biosimilar medicine, p. 1   Injection, prefilled syringe, filgrastim, net price  30 million-units (300micrograms)/0.5mL = £62.26;  48 million-units (480micrograms)/0.8mL = £99.29  Note Biosimilar medicine, p. 1   Injection, prefilled syringe, filgrastim, net price  30 million-units (300micrograms)/0.5mL = £62.25;  48 million-units (480micrograms)/0.8mL = £99.29  Note Biosimilar medicine, p. 1   Zarzio® (Sandoz) T (Ml  Injection, prefilled syringe, filgrastim, net price  30 million-units (300micrograms)/0.5mL = £59.00;  48 million-units (480micrograms)/0.5mL = £94.00  Note Biosimilar medicine, p. 1   Indications (specialist use only) reduction in the  duration of neutropenia and associated complications  following peripheral stem cells or bone-marrow  transplantation for non-myeloid malignancy, or fol-  lowing treatment with cytotoxic chemotherapy asso-  ciated with a significant incidence of febrile neutro-  penia; mobilisation of peripheral blood progenitor  cells for harvesting and subsequent infusion   Side-effects see notes above; also mucositis, splenic  rupture, and toxic epidermal necrolysis   • Following bone-marrow transplantation, by intra-  venous infusion or subcutaneous injection, ADULT and  CHILD over 2 years 19.2 million units/m 2 daily started  the day after transplantation, continued until neutro-  phil count stable in acceptable range (max. 28 days)   • Following peripheral stem cells transplantation, by  intravenous infusion or subcutaneous injection,  ADULT 19.2 million units/m 2 daily started the day after  transplantation, continued until neutrophil count  stable in acceptable range (max. 28 days); CHILD see  BNF for Children   • Cytotoxic-induced neutropenia, by subcutaneous  injection, ADULT 19.2 million units/m 2 daily started the  day after completion of chemotherapy, continued  until neutrophil count stable in acceptable range  (max. 28 days); CHILD see BNF for Children   • Mobilisation of peripheral blood progenitor cells, used  alone, by subcutaneous injection, ADULT 1.28 mil-  lion units/kg daily for 4-6 days (5-6 days in healthy  donors); used following adjunctive myelosuppressive  chemotherapy (to improve yield), by subcutaneous  injection, 19.2 million units/m 2 daily, started 1-5 days  after completion of chemotherapy and continued until  neutrophil count in acceptable range; for timing of  leucopheresis consult product literature; CHILD see  BNF for Children   Injection, powder for reconstitution, lenograstim, net  price 13.4 million-unit (105-microgram) vial = £40.11;  33.6 million-unit (263-microgram) vial = £62.54 (both  with 1-mL prefilled syringe water for injections)   Indications (specialist use only) reduction in duration  of neutropenia and incidence of febrile neutropenia in  cytotoxic chemotherapy for malignancy (except  chronic myeloid leukaemia and myelodysplastic syn-  dromes)   Cautions see notes above; also acute leukaemia and  myelosuppressive chemotherapy; interactions:  Appendix 1 (filgrastim)   Note Dose expressed as filgrastim  • By subcutaneous injection, ADULT over 18 years, 6 mg  (0.6 mL) for each chemotherapy cycle, starting 24  hours after chemotherapy   Injection, pegfilgrastim (expressed as filgrastim)  lOmg/mL, net price 0.6-mL (6-mg) prefilled syringe  = £686.38    Plerixafor is a chemokine receptor antagonist licensed  to mobilise haematopoietic stem cells to peripheral  blood for collection and subsequent autologous trans-  plantation in patients with lymphoma or multiple myel-  oma. Plerixafor should be given under specialist super-  vision following 4 days treatment with a granulocyte-  colony stimulating factor (section 9.1.6)   Renal impairment reduce dose to 160 micrograms/  kg daily if creatinine clearance 20-50 mL/minute; no  information available if creatinine clearance less than  20 mL/minute   Side-effects gastro-intestinal disturbances, dry  mouth, oral hypoaesthesia; dizziness, headache,  insomnia, fatigue; arthralgia, musculoskeletal pain;  erythema, sweating; injection-site reactions; less  commonly hypersensitivity reactions including dys-  pnoea and periorbital swelling  Dose   240 micrograms/kg daily 6-1 1 hours before initiation  of apheresis; usual duration 2-4 days (max. 7 days)    Mozobil® (Genzyme) ▼ (Ml  Injection, plerixafor 20mg/mL, net price 1.2mL-vial  = £4882.77   Oral preparations for fluid and  electrolyte imbalance  Parenteral preparations for fluid and  electrolyte imbalance    Faeces, vomit, or aspiration should be saved and analysed  where possible if abnormal losses are suspected; where this is  impracticable the approximations above may be helpful in  planning replacement therapy   Sodium and potassium salts, which may be given by  mouth to prevent deficiencies or to treat established  deficiencies of mild or moderate degree, are discussed    in this section. Oral preparations for removing excess  potassium and preparations for oral rehydration therapy  are also included here. Oral bicarbonate, for metabolic  acidosis, is also described in this section.    • in those taking digoxin or anti-arrhythmic drugs,  where potassium depletion may induce arrhyth-  mias;    • in patients in whom secondary hyperaldosteronism  occurs, e.g. renal artery stenosis, cirrhosis of the  liver, the nephrotic syndrome, and severe heart  failure;    • in patients with excessive losses of potassium in the  faeces, e.g. chronic diarrhoea associated with intes-  tinal malabsorption or laxative abuse.    Measures to compensate for potassium loss may also be  required in the elderly since they frequently take inade-  quate amounts of potassium in the diet (but see below  for warning on renal insufficiency). Measures may  also be required during long-term administration of  drugs known to induce potassium loss (e.g. corticoster-  oids). Potassium supplements are seldom required with  the small doses of diuretics given to treat hypertension;  potassium-sparing diuretics (rather than potassium  supplements) are recommended for prevention of hypo-  kalaemia due to diuretics such as furosemide or the  thiazides when these are given to eliminate oedema.    Dosage If potassium salts are used for the prevention  of hypokalaemia, then doses of potassium chloride 2 to  4 g (approx. 25 to 50 mmol) daily (in divided doses) by  mouth are suitable in patients taking a normal diet.  Smaller doses must be used if there is renal insufficiency  (common in the elderly) to reduce the risk of hyper-  kalaemia. Potassium salts cause nausea and vomiting  and poor compliance is a major limitation to their  effectiveness; when appropriate, potassium-sparing  diuretics are preferable (see also above). Regular mon-  itoring of plasma-potassium concentration is essential in  those taking potassium supplements. When there is  established potassium depletion larger doses may be  necessary, the quantity depending on the severity of any  continuing potassium loss (monitoring of plasma-potas-  sium concentration and specialist advice would be  required). Potassium depletion is frequently associated  with chloride depletion and with metabolic alkalosis,  and these disorders require correction.   Administration Potassium salts are preferably given  as a liquid (or effervescent) preparation, rather than  modified-release tablets; they should be given as the  chloride (the use of effervescent potassium tablets BPC  1968 should be restricted to hyperchloraemic states,  section 9.2. 1.3).   Salt substitutes A number of salt substitutes which contain  significant amounts of potassium chloride are readily available  as health food products (e.g. LoSalt ® and Ruthmol®). These  should not be used by patients with renal failure as potassium  intoxication may result.   Indications potassium depletion (see notes above)  Cautions see notes above; cardiac disease; elderly;  with modified-release preparations, intestinal stric-  ture, history of peptic ulcer, hiatus hernia; interac-  tions: Appendix 1 (potassium salts)  Contra-indications plasma-potassium concentration  above 5 mmol/litre   Renal impairment close monitoring required — risk of  hyperkalaemia; avoid in severe impairment  Side-effects nausea, vomiting, abdominal pain, diarr-  hoea, flatulence; with modified-release preparations,  gastro-intestinal obstruction, ulceration and bleeding  also reported  Dose   Note Do not confuse Effervescent Potassium Tablets BPC  1968 (section 9.2. 1.3) with effervescent potassium chloride  tablets. Effervescent Potassium Tablets BPC 1968 do not  contain chloride ions and their use should be restricted to  hyperchloraemic states (section 9.2. 1.3).   Tablets, effervescent, potassium bicarbonate and  chloride equivalent to potassium 470 mg (12 mmol of  K + ) and chloride 285 mg (8 mmol of Cl"). Net price 20  = £1.53. Label: 13, 21   Tablets, m/r, orange, s/c, potassium chloride 600 mg  (8 mmol each of K + and Cl"), net price 100 = £2.14.  Label: 25, 27, counselling, swallow whole with fluid  during meals while sitting or standing   Acute severe hyperkalaemia (plasma-potassium con-  centration above 6.5mmol/L or in the presence of  ECG changes) calls for urgent treatment with 10-  20 mL of calcium gluconate 10% by slow intravenous  injection, titrated and adjusted to ECG improvement, to  temporarily protect against myocardial excitability. An  intravenous injection of soluble insulin (5-10 units) with  50 mL glucose 50% given over 5-15 minutes, reduces  serum-potassium concentration; this is repeated if  necessary or a continuous infusion instituted. Salbut-  amol [unlicensed indication], by nebulisation or slow  intravenous injection may also reduce plasma-potas-  sium concentration; it should be used with caution in  patients with cardiovascular disease. The correction of  causal or compounding acidosis with sodium bicarb-  onate infusion (section 9.2.2) should be considered  (important: preparations of sodium bicarbonate and  calcium salts should not be administered in the same  line — risk of precipitation). Drugs exacerbating hyper-  kalaemia should be reviewed and stopped as appropri-  ate; occasionally haemodialysis is needed.    Ion-exchange resins may be used to remove excess  potassium in mild hyperkalaemia or in moderate hyper-  kalaemia when there are no ECG changes.    Indications hyperkalaemia associated with anuria or  severe oliguria, and in dialysis patients  Cautions children (impaction of resin with excessive  dosage or inadequate dilution); monitor for electrolyte  disturbances (stop if plasma-potassium concentration  below 5 mmol/litre); sodium-containing resin in  congestive heart failure, hypertension, and oedema;  interactions: Appendix 1 (polystyrene sulphonate  resins)   Contra-indications obstructive bowel disease; neo-  nates with reduced gut motility; calcium-containing  resin in hyperparathyroidism, multiple myeloma, sar-  coidosis, or metastatic carcinoma  Renal impairment use sodium-containing resin with  caution    Pregnancy manufacturers advise use only if potential  benefit outweighs risk — no information available  Breast-feeding manufacturers advise use only if  potential benefit outweighs risk — no information  available    Side-effects faecal impaction following rectal admin-  istration, gastro-intestinal concretions following oral  administration, intestinal necrosis reported with con-  comitant use of sorbitol, gastric irritation, anorexia,  nausea, vomiting, constipation (discontinue treat-  ment — avoid magnesium-containing laxatives), diarr-  hoea, hypomagnesaemia; gastro-intestinal obstruc-  tion, ulceration, necrosis, and ischaemic colitis also  reported; with calcium-containing resin, hypercal-  caemia (including in dialysed patients and occasion-  ally in those with renal impairment); with sodium-  containing resin, sodium retention, hypocalcaemia   • By mouth, 15 g 3-4 times daily in water (not fruit  squash which has a high potassium content) or as a  paste; CHILD 0.5-1 g/kg daily in divided doses   • By rectum, as an enema, 30 g in methylcellulose  solution, retained for 9 hours followed by irrigation to  remove resin from colon; NEONATE and CHILD, 0.5-1 g/  kg daily    Sodium chloride is indicated in states of sodium deple-  tion and usually needs to be given intravenously (sec-  tion 9.2.2). In chronic conditions associated with mild or  moderate degrees of sodium depletion, e.g. in salt-losing  bowel or renal disease, oral supplements of sodium  chloride or sodium bicarbonate (section 9.2. 1.3),  according to the acid-base status of the patient, may  be sufficient.   Indications sodium depletion — see also 9.2.2. 1;  nebuliser diluent (section 3.1.5); eye (section 11.8.1);  oral hygiene (section 12.3.4); wound irrigation (sec-  tion 13.11.1)   Dose prophylaxis of sodium chloride deficiency 4-8 tablets daily  with water (in severe depletion up to max. 20 tablets daily)  Chronic renal salt wasting, up to 20 tablets daily with appropriate  fluid intake   As a worldwide problem diarrhoea is by far the most  important indication for fluid and electrolyte replace-  ment. Intestinal absorption of sodium and water is  enhanced by glucose (and other carbohydrates). Repla-  cement of fluid and electrolytes lost through diarrhoea  can therefore be achieved by giving solutions containing  sodium, potassium, and glucose or another carbohy-  drate such as rice starch.   • be slightly hypo-osmolar (about 250 mmol/litre) to  prevent the possible induction of osmotic diarrhoea;   It is the policy of the World Health Organization (WHO)  to promote a single oral rehydration solution but to use  it flexibly (e.g. by giving extra water between drinks of  oral rehydration solution to moderately dehydrated  infants).    Oral rehydration solutions used in the UK are lower in  sodium (50-60 mmol/litre) than the WHO formulation  since, in general, patients suffer less severe sodium loss.    Rehydration should be rapid over 3 to 4 hours (except in  hypematraemic dehydration in which case rehydration  should occur more slowly over 12 hours). The patient  should be reassessed after initial rehydration and if still  dehydrated rapid fluid replacement should continue.    Once rehydration is complete further dehydration is  prevented by encouraging the patient to drink normal  volumes of an appropriate fluid and by replacing con-  tinuing losses with an oral rehydration solution; in  infants, breast-feeding or formula feeds should be  offered between oral rehydration drinks.   • According to fluid loss, usually 200-400 mL solution  after every loose motion; INFANT 1-1 Vi times usual  feed volume; CHILD 200 mL after every loose motion   Note After reconstitution any unused solution should be dis-  carded no later than 1 hour after preparation unless stored in a  refrigerator when it may be kept for up to 24 hours   Oral powder, sodium chloride 470 mg, potassium  chloride 300 mg, disodium hydrogen citrate 530 mg,  glucose 3.56 g/ sachet, net price 6-sachet pack =  £2.25, 20-sachet pack (black currant- or citrus-fla-  voured or natural) = £6.72   Note Reconstitute 1 sachet with 200 mL of water (freshly boiled  and cooled for infants); 5 sachets reconstituted with 1 litre of water  provide Na + 60 mmol, K + 20 mmol, Cl" 60 mmol, citrate 10 mmol,  and glucose 90 mmol   Oral powder, sodium chloride 350 mg, potassium  chloride 300 mg, sodium citrate 580 mg, cooked rice  powder 6 g/sachet, net price 6-sachet pack (apricot-,  black currant- or raspberry-flavoured) = £2.50, 20-  sachet pack (apricot-flavoured) = £7.13  Note Reconstitute 1 sachet with 200 mL of water (freshly boiled  and cooled for infants); 5 sachets when reconstituted with 1 litre of  water provide Na + 60 mmol, K + 20 mmol, Cl" 50 mmol and citrate  10 mmol; contains aspartame (section 9.4.1)   Oral powder, sodium chloride 236 mg, potassium  chloride 300 mg, sodium bicarbonate 500 mg, anhy-  drous glucose 4 g/sachet (banana-, black currant-,  lemon and lime-, or orange-flavoured). Net price 6-  sachet (plain or multiflavoured) pack = £1.33, 20-  sachet (single- or multiflavoured) pack = £4.99  Note Reconstitute 1 sachet with 200 mL of water (freshly boiled  and cooled for infants); 5 sachets when reconstituted with 1 litre of  water provide Na + 50 mmol, K + 20 mmol, Cl" 40 mmol, HC0 3 "  30 mmol, and glucose 111 mmol   Oral powder, sodium chloride 2.6 g, potassium  chloride 1.5 g, sodium citrate 2.9 g, anhydrous glucose  13.5 g. To be dissolved in sufficient water to produce  1 litre (providing Na + 75 mmol, K + 20 mmol, Cl"   65 mmol, citrate 10 mmol, glucose 75 mmol/litre)  Note Recommended by the WHO and the United Nations Chil-  dren’s Fund but not commonly used in the UK.    Sodium bicarbonate is given by mouth for chronic  acidotic states such as uraemic acidosis or renal tubular  acidosis. The dose for correction of metabolic acidosis is  not predictable and the response must be assessed;  sodium bicarbonate 4.8 g daily (57 mmol each of Na +  and HC0 3 “) or more may be required. For severe  metabolic acidosis, sodium bicarbonate can be given  intravenously (section 9.2.2).    Sodium bicarbonate may also be used to increase the  pH of the urine (see section 7.4.3); for use in dyspepsia  see section 1.1.1.    Sodium supplements may increase blood pressure or  cause fluid retention and pulmonary oedema in those at  risk; hypokalaemia may be exacerbated.   Where hyperchloraemic acidosis is associated with  potassium deficiency, as in some renal tubular and  gastro-intestinal disorders it may be appropriate to  give oral potassium bicarbonate, although acute or  severe deficiency should be managed by intravenous  therapy.   Contra-indications hypochloraemia; plasma-potas-  sium concentration above 5 mmol/litre  Renal impairment close monitoring required — high  risk of hyperkalaemia; avoid in severe impairment  Side-effects nausea, vomiting, abdominal pain, diarr-  hoea, and flatulence  Dose   Potassium Tablets, Effervescent (Non-proprietary)  Effervescent tablets, potassium bicarbonate 500 mg,  potassium acid tartrate 300 mg, each tablet providing  6.5 mmol of K + . To be dissolved in water before  administration. Net price 56 = £33.38. Label: 13, 21  Note These tablets do not contain chloride; for effervescent  tablets containing potassium and chloride, see under Potassium  Chloride, section 9.2. 1.1   Solutions of electrolytes are given intravenously, to meet  normal fluid and electrolyte requirements or to replen-  ish substantial deficits or continuing losses, when the  patient is nauseated or vomiting and is unable to take  adequate amounts by mouth. When intravenous admin-  istration is not possible, fluid (as sodium chloride 0.9%  or glucose 5%) can also be given by subcutaneous  infusion (hypodermoclysis).   The nature and severity of the electrolyte imbalance  must be assessed from the history and clinical and  biochemical investigations. Sodium, potassium, chlor-  ide, magnesium, phosphate, and water depletion can  occur singly and in combination with or without dis-   turbances of acid-base balance; for reference to the use  of magnesium and phosphates, see section 9.5.   Isotonic solutions may be infused safely into a periph-  eral vein. Solutions more concentrated than plasma, e.g.  20% glucose, are best given through an indwelling  catheter positioned in a large vein.    Sodium chloride in isotonic solution provides the most  important extracellular ions in near physiological con-  centrations and is indicated in sodium depletion, which  can arise from such conditions as gastro-enteritis, dia-  betic ketoacidosis, ileus, and ascites. In a severe deficit  of 4 to 8 litres, 2 to 3 litres of isotonic sodium chloride  may be given over 2 to 3 hours; thereafter the infusion  can usually be at a slower rate. Excessive administration  should be avoided; the jugular venous pressure should  be assessed, the bases of the lungs should be examined  for crepitations, and in elderly or seriously ill patients it  is often helpful to monitor the right atrial (central)  venous pressure.   Chronic hyponatraemia arising from inappropriate  secretion of antidiuretic hormone should ideally be  corrected by fluid restriction. However, if sodium chlor-  ide is required for acute or chronic hyponatraemia,  regardless of the cause, the deficit should be corrected  slowly to avoid the risk of osmotic demyelination  syndrome and the rise in plasma-sodium concentration  should not exceed 10 mmol/litre in 24 hours. In severe  hyponatraemia, sodium chloride 1.8% may be used  cautiously.    Compound sodium lactate (Hartmann’s solution) can  be used instead of isotonic sodium chloride solution  during or after surgery, or in the initial management of  the injured or wounded; it may reduce the risk of  hyperchloraemic acidosis.   Sodium chloride and glucose solutions are indicated  when there is combined water and sodium depletion. A  1 : 1 mixture of isotonic sodium chloride and 5% glucose  allows some of the water (free of sodium) to enter body  cells which suffer most from dehydration while the  sodium salt with a volume of water determined by the  normal plasma Na + remains extracellular. Maintenance  fluid should accurately reflect daily requirements and  close monitoring is required to avoid fluid and electro-  lyte imbalance. Illness or injury increase the secretion of  anti-diuretic hormone and therefore the ability to  excrete excess water may be impaired. Injudicious use  of hypotonic solutions such as sodium chloride 0.18%  and glucose 4% may also cause dilutional hyponatr-  aemia especially in children and the elderly; if neces-  sary, guidance should be sought from a clinician experi-  enced in the management of fluid and electrolytes.   Combined sodium, potassium, chloride, and water  depletion may occur, for example, with severe diarrhoea  or persistent vomiting; replacement is carried out with  sodium chloride intravenous infusion 0.9% and glucose  intravenous infusion 5% with potassium as appropriate.   Indications electrolyte imbalance — see also section  9.2. 1.2; nebuliser diluent (section 3.1.5); eye (section  11.8.1); oral hygiene (section 12.3.4); wound irrigation  (section 13.11.1)    Cautions restrict intake in impaired renal function,  cardiac failure, hypertension, peripheral and pulm-  onary oedema, toxaemia of pregnancy  Side-effects administration of large doses may give  rise to sodium accumulation, oedema, and hyper-  chloraemic acidosis  Dose   Intravenous infusion, usual strength sodium chloride  0.9% (9g, 150 mmol each of Na + and Cl” /litre), this  strength being supplied when normal saline for  injection is requested. Net price 2-mL amp = 32p; 5-  mL amp = 38p; 10-mL amp = 52p; 20-mL amp =  £1.04; 50-mL amp = £3.63   In hospitals, 500- and 1000-mL packs, and sometimes other sizes,  are available   Note The term ‘normal saline’ should not be used to describe  sodium chloride intravenous infusion 0.9%; the term ‘physio-  logical saline’ is acceptable but it is preferable to give the com-  position (i.e. sodium chloride intravenous infusion 0.9%).   Intravenous infusion, sodium chloride 0.18% (Na +  and Cl" each 30 mmol/litre), glucose 4%   In hospitals, usually 500-mL packs and sometimes other sizes are  available   Intravenous infusion, sodium chloride 0.45% (Na +  and Cl" each 75 mmol/litre), glucose 2.5%   In hospitals, usually 500-mL packs and sometimes other sizes are  available   Intravenous infusion, sodium chloride 0.45% (Na +  and Cl” each 75 mmol/litre), glucose 5%   In hospitals, usually 500-mL packs and sometimes other sizes are  available   Intravenous infusion, sodium chloride 0.9% (Na +  and Cl" each 150 mmol/litre), glucose 5%   In hospitals, usually 500-mL packs and sometimes other sizes are  available    Note See above for warning on hyponatraemia especially in children  and elderly   Calcium chloride (dihydrate) 322 micrograms, potas-  sium chloride 300 micrograms, sodium chloride  8.6 mg/mL, providing the following ions (in mmol/  litre), Ca 2+ 2.2, K + 4, Na + 147, Cl" 156  In hospitals, 500- and 1000-mL packs, and sometimes other sizes,  are available   Intravenous infusion, sodium chloride 0.6%, sodium  lactate 0.32%, potassium chloride 0.04%, calcium  chloride 0.027% (containing Na + 131 mmol, K +   5 mmol, Ca 2+ 2 mmol, HC0 3 " (as lactate) 29 mmol,  Cl” 111 mmol/litre)   In hospitals, 500- and 1000-mL packs, and sometimes other sizes,  are available   Glucose solutions (5%) are used mainly to replace water  deficit and should not be given alone except when there  is no significant loss of electrolytes; prolonged admin-    istration of glucose solutions without electrolytes can  lead to hyponatraemia and other electrolyte distur-  bances. Average water requirements in a healthy adult  are 1.5 to 2.5 litres daily and this is needed to balance  unavoidable losses of water through the skin and lungs  and to provide sufficient for urinary excretion. Water  depletion (dehydration) tends to occur when these  losses are not matched by a comparable intake, as  may occur in coma or dysphagia or in the elderly or  apathetic who may not drink enough water on their own  initiative.   Excessive loss of water without loss of electrolytes is  uncommon, occurring in fevers, hyperthyroidism, and in  uncommon water-losing renal states such as diabetes  insipidus or hypercalcaemia. The volume of glucose  solution needed to replace deficits varies with the sever-  ity of the disorder, but usually lies within the range of 2  to 6 litres.   Glucose solutions are also used to correct and prevent  hypoglycaemia and to provide a source of energy in  those too ill to be fed adequately by mouth; glucose  solutions are a key component of parenteral nutrition  (section 9.3).   Glucose solutions are given in regimens with calcium  and insulin for the emergency management of hyper-  kalaemia (see p. 595). They are also given, after correc-  tion of hyperglycaemia, during treatment of diabetic  ketoacidosis, when they must be accompanied by con-  tinuing insulin infusion.   Note Glucose BP is the monohydrate but Glucose Intra-  venous Infusion BP is a sterile solution of anhydrous glucose  or glucose monohydrate, potency being expressed in terms  of anhydrous glucose   Indications fluid replacement (see notes above), pro-  vision of energy (section 9.3); hypoglycaemia (section  6.1.4)   Side-effects glucose injections especially if hyper-  tonic may have a low pH and may cause venous  irritation and thrombophlebitis   • Water replacement, see notes above; energy source,  1-3 litres daily of 20-50% solution   Glucose Intravenous Infusion (Non-proprietary) (Ml  Intravenous infusion, glucose or anhydrous glucose  (potency expressed in terms of anhydrous glucose),  usual strength 5% (50 mg/mL), 10% (100 mg/mL),  and 20% (200 mg/mL); 20% solution, net price 20-mL  amp = £2.04; 50% solution, 1 20-mL amp = 95p, 50-mL  vial = £2.13   In hospitals, 500- and 1000-mL packs, and sometimes other sizes  and strengths, are available; also available as Minijet® Glucose,  50% in 50-mL disposable syringe 1   Potassium chloride and sodium chloride intravenous  infusion is the initial treatment for the correction of  severe hypokalaemia and when sufficient potassium  cannot be taken by mouth. Ready-mixed infusion solu-  tions should be used when possible; alternatively, potas-  sium chloride concentrate, as ampoules containing 1.5 g    (K + 20 mmol) in 10 mL, is thoroughly mixed with  500 mL of sodium chloride 0.9% intravenous infusion  and given slowly over 2 to 3 hours, with specialist advice  and ECG monitoring in difficult cases. Higher concen-  trations of potassium chloride may be given in very  severe depletion, but require specialist advice.   Repeated measurement of plasma-potassium concen-  tration is necessary to determine whether further infu-  sions are required and to avoid the development of  hyperkalaemia, which is especially likely in renal impair-  ment.   Initial potassium replacement therapy should not  involve glucose infusions, because glucose may cause  a further decrease in the plasma-potassium concentra-  tion.   Indications electrolyte imbalance; see also oral  potassium supplements, section 9.2. 1.1  Cautions for intravenous infusion the concentration of  solution should not usually exceed 3 g (40 mmol)/  litre; specialist advice and ECG monitoring (see notes  above); interactions: Appendix 1 (potassium salts)  Contra-indications plasma-potassium concentration  above 5 mmol/litre   Potassium Chloride and Glucose Intravenous  Infusion (Non-proprietary) (Ml  Intravenous infusion, usual strength potassium  chloride 0.3% (3 g, 40 mmol each of K + and Cl" /litre)  or 0.15% (1.5 g, 20 mmol each of K + and Cl" /litre)  with 5% of anhydrous glucose   In hospitals, 500- and 1000-mL packs, and sometimes other sizes,  are available   Potassium Chloride and Sodium Chloride Intra-  venous Infusion (Non-proprietary) (Ml  Intravenous infusion, usual strength potassium  chloride 0.15% (1.5 g/litre) with sodium chloride 0.9%  (9g/litre), containing K + 20 mmol, Na + 150 mmol,  and Cl" 170 mmol/litre or potassium chloride 0.3%  (3 g/litre) with sodium chloride 0.9% (9 g/litre), con-  taining K + 40 mmol, Na + 150 mmol, and Cl"   In hospitals, 500- and 1000-mL packs, and sometimes other sizes,  are available   Potassium Chloride, Sodium Chloride, and Glu-  cose Intravenous Infusion (Non-proprietary) (M\  Intravenous infusion, sodium chloride 0.45% (4.5 g,  Na + 75 mmol/litre) with 5% of anhydrous glucose and  usually sufficient potassium chloride to provide K +  10-40 mmol/litre (to be specified by the prescriber)  In hospitals, 500- and 1000-mL packs, and sometimes other sizes,  are available   (150 mg, approximately 2 mmol each of K + and Cl"/  mL). Net price 10-mL amp = 48p  Important Must be diluted with not less than 50 times its volume  of sodium chloride intravenous infusion 0.9% or other suitable  diluent and mixed well   Solutions containing 10 and 20% of potassium chloride are also  available in both 5- and 10-mL ampoules   Sodium bicarbonate is used to control severe metab-  olic acidosis (pH < 7.1) particularly that caused by loss  of bicarbonate (as in renal tubular acidosis or from  excessive gastro-intestinal losses). Mild metabolic aci-  dosis associated with volume depletion should first be  managed by appropriate fluid replacement because aci-  dosis usually resolves as tissue and renal perfusion are  restored. In more severe metabolic acidosis or when the  acidosis remains unresponsive to correction of anoxia  or hypovolaemia, sodium bicarbonate (1.26%) can be  infused over 3-4 hours with plasma-pH and electrolyte  monitoring. In severe shock (section 2.7.1), for example  in cardiac arrest, metabolic acidosis can develop with-  out sodium or volume depletion; in these circumstances  sodium bicarbonate is best given as a small volume of  hypertonic solution, such as 50 mL of 8.4% solution  intravenously; plasma-pH and electrolytes should be  monitored.   Sodium lactate intravenous infusion is no longer used  in metabolic acidosis because of the risk of producing  lactic acidosis, particularly in seriously ill patients with  poor tissue perfusion or impaired hepatic function.   For chronic acidotic states, sodium bicarbonate can be  given by mouth (section 9.2. 1.3).   • By slow intravenous injection, a strong solution (up to  8.4%), or by continuous intravenous infusion, a  weaker solution (usually 1.26%), an amount appro-  priate to the body base deficit (see notes above)   In hospitals, 500- and 1000-mL packs, and sometimes other sizes,  are available   Minijet® Sodium Bicarbonate (UCB Pharma) (Ml  Intravenous injection, sodium bicarbonate in dispo-  sable syringe, net price 4.2%, 10 mL = £11.03; 8.4%,  10 mL = £11.10, 50 mL = £12.15    Intravenous infusion, sodium chloride 0.18% (1.8 g,  Na + 30 mmol/litre) with 4% of anhydrous glucose and  usually sufficient potassium chloride to provide K +  10-40 mmol/litre (to be specified by the prescriber)  In hospitals, 500- and 1000-mL packs, and sometimes other sizes,  are available   Sodium Lactate (Non-proprietary) (MIL^  Intravenous infusion, sodium lactate m/6, contains  the following ions (in mmol/litre), Na + 167, HC0 3 "  (as lactate) 167   Net price 1-mL amp = 18p; 2-mL amp = 20p; 5-mL  amp = 36p; 10-mL amp = 37p, 10-mL vial = £1.40; 20-  mL amp = 92p; 50-mL amp = £1.91; 100-mL vial =  £ 2.01   Plasma and plasma substitutes (‘colloids’) contain large  molecules that do not readily leave the intravascular  space where they exert osmotic pressure to maintain  circulatory volume. Compared to fluids containing elec-  trolytes such as sodium chloride and glucose (‘crystal-  loids’), a smaller volume of colloid is required to pro-  duce the same expansion of blood volume, thereby  shifting salt and water from the extravascular space. If  resuscitation requires a volume of fluid that exceeds the  maximum dose of the colloid then crystalloids can be  given; packed red cells may also be required.   Albumin solutions, prepared from whole blood, con-  tain soluble proteins and electrolytes but no clotting  factors, blood group antibodies, or plasma cholines-  terases; they may be given without regard to the reci-  pient’s blood group.   Albumin is usually used after the acute phase of illness,  to correct a plasma-volume deficit; hypoalbuminaemia  itself is not an appropriate indication. The use of  albumin solutions in acute plasma or blood loss may  be wasteful; plasma substitutes are more appropriate.  Concentrated albumin solutions (20%) can be used  under specialist supervision in patients with an intra-  vascular fluid deficit and oedema because of interstitial  fluid overload, to restore intravascular plasma volume  with less exacerbation of the salt and water overload  than isotonic solutions. Concentrated albumin solutions  may also be used to obtain a diuresis in hypoalbumi-  naemic patients (e.g. in hepatic cirrhosis).   Recent evidence does not support the previous view  that the use of albumin increases mortality.   Plasma and plasma substitutes are often used in very  ill patients whose condition is unstable. Therefore,  close monitoring is required and fluid and electrolyte  therapy should be adjusted according to the patient’s  condition at all times.   A solution containing protein derived from plasma,  serum, or normal placentas; at least 95% of the  protein is albumin. The solution may be isotonic  (containing 3.5-5% protein) or concentrated (con-  taining 15-25% protein).   Cautions history of cardiac or circulatory disease  (administer slowly to avoid rapid rise in blood pres-  sure and cardiac failure, and monitor cardiovascular  and respiratory function); increased capillary perme-  ability; correct dehydration when administering con-  centrated solution   Indications: acute or sub-acute loss of plasma volume  e.g. in burns, pancreatitis, trauma, and complications  of surgery; plasma exchange  Available as: Human Albumin Solution 4.5 % (50-,  100-, 250- and 400-mL bottles — Baxter); Human  Albumin Solution 5% (250- and 500-mL bottles —  Baxter); Albunorm® 5% (100-, 250-, and 500-mL  bottles — Octapharm); Octalbin ® 5% (100- and 250-  mL bottles — Octapharm); Zenalb® 4.5% (50-, 100-,  250-, and 500-mL bottles — BPL)   Indications: severe hypoalbuminaemia associated  with low plasma volume and generalised oedema  where salt and water restriction with plasma volume  expansion are required; adjunct in the treatment of  hyperbilirubinaemia by exchange transfusion in the  newborn; paracentesis of large volume ascites asso-  ciated with portal hypertension  Available as: Human Albumin Solution 20% (50- and  100-mL vials — Baxter); Albunorm® 20% (50- and  100-mL bottles — Octapharm); Flexbumin® 20% (50-  and 100-mL bags — Baxter);Octa/6//7® 20% (50- and  100-mL bottles — Octapharm); Zenalb® 20% (50- and  100-mL bottles — BPL)   Dextran, gelatin, and the etherified starches (heta-  starch, pentastarch, and tetrastarch) are macromolecu-  lar substances which are metabolised slowly; they may  be used at the outset to expand and maintain blood  volume in shock arising from conditions such as bums  or septicaemia. Plasma substitutes may be used as an  immediate short-term measure to treat haemorrhage  until blood is available. They are rarely needed when  shock is due to sodium and water depletion because, in  these circumstances, the shock responds to water and  electrolyte repletion; see also section 2.7.1 for the  management of shock.   Plasma substitutes should not be used to maintain  plasma volume in conditions such as burns or peritonitis  where there is loss of plasma protein, water, and elec-  trolytes over periods of several days or weeks. In these  situations, plasma or plasma protein fractions contain-  ing large amounts of albumin should be given.   Large volumes of some plasma substitutes can increase  the risk of bleeding through depletion of coagulation  factors.   Dextran 70 by intravenous infusion is used for volume  expansion. Dextran may interfere with blood group  cross-matching or biochemical measurements, and  these should be carried out before infusion is begun.   Plasma and plasma substitutes are often used in very  ill patients whose condition is unstable. Therefore,  close monitoring is required and fluid and electrolyte  therapy should be adjusted according to the patient’s  condition at all times.    Cautions Plasma substitutes should be used with  caution in patients with cardiac disease, liver disease,  or renal impairment; urine output should be monitored.  Care should be taken to avoid haematocrit concentra-    tion from falling below 25-30% and the patient should  be monitored for hypersensitivity reactions.   Side-effects Hypersensitivity reactions may occur  including, rarely, severe anaphylactic reactions. Transi-  ent increase in bleeding time may occur.   Indications short-term blood volume expansion  Cautions see notes above; can interfere with some  laboratory tests (see also above); where possible,  monitor central venous pressure  Pregnancy avoid — reports of anaphylaxis in mother  causing fetal anoxia, neurological damage and death  Side-effects see notes above  Dose   RescueFlow® (Vitaline) [Ml  Intravenous infusion, dextran 70 intravenous infu-  sion 6% in sodium chloride intravenous infusion 7.5%.  Net price 250-mL bag = £28.50   Dose initial treatment of hypovolaemia with hypotension  induced by traumatic injury, by intravenous infusion over 2-5  minutes, 250 mL, followed immediately by administration of iso-  tonic fluids   • By intravenous infusion, initially 500-1000 mL of a  3.5-4% solution (see notes above)   Intravenous infusion, succinylated gelatin (modified  fluid gelatin, average molecular weight 30 000) 40 g  (4%), Na + 154 mmol, Cl" 120 mmol/litre, net price  500-mL Ecobag® = £5.15, 1-litre Ecobag® = £9.67   Geloplasma® (Fresenius Kabi) [Ml  Intravenous infusion, partially hydrolysed and suc-  cinylated gelatin (modified liquid gelatin) (as anhy-  drous gelatin) 30 g (3%), Na + 150 mmol, K + 5 mmol,  Mg 2+ 1.5 mmol, CT 100 mmol, lactate 30 mmol/litre,  net price 500-mL bag = £5.05   Intravenous infusion, succinylated gelatin (modified  fluid gelatin, average molecular weight 30 000) 40 g  (4%), Na + 145 mmol, K + 4 mmol, Mg 2+ 0.9 mmol, Cl"  105 mmol, lactate 25 mmol/litre, net price 500-mL  bag = £7.53, 1-litre bag = £14.54   Intravenous infusion, succinylated gelatin (modified  fluid gelatin, average molecular weight 30 000) 40 g  (4%), Na + 154 mmol, Cl" 125 mmol/litre, net price  500-mL bag = £4.70, 1-litre bag = £9.09   A starch composed of more than 90% of amylopectin  that has been etherified with hydroxyethyl groups; the  terms tetrastarch, pentastarch, and hetastarch reflect  the degree of etherification   Intravenous infusion, hetastarch (weight average  molecular weight 450 000) 6% in sodium chloride  intravenous infusion 0.9%, net price 500-mL bag =  £ 8.00   Dose by intravenous infusion, 500-1000 mL; usual daily max.  1500mL (see notes above)   Pentastarch (Non-proprietary) (Ml  Intravenous infusion, pentastarch (weight average  molecular weight 200 000), net price (in sodium  chloride intravenous infusion 0.9%) 10%, 500-mL bag  = £9.24   Dose by intravenous infusion, pentastarch 10%, 500-1000 mL;  max. 1500 mL daily (see notes above)    HAES-steril® (Fresenius Kabi) (MO  Intravenous infusion, pentastarch (weight average  molecular weight 200 000) 10% in sodium chloride  intravenous infusion 0.9%, net price 500 mL = £16.50  Dose by intravenous infusion, up to 1500 mL daily (see notes  above)   Intravenous infusion, pentastarch (weight average  molecular weight 200 000), net price (both in sodium  chloride intravenous infusion 0.9%) 6%, 500 mL =  £12.50; 10%, 500 mL =£16.50    Dose by intravenous infusion, pentastarch 6%, up to 2500 mL  daily; pentastarch 10%, up to 1500 mL daily (see notes above)   Intravenous infusion, hydroxyethyl starch (weight  average molecular weight 130 000) 6% in sodium  chloride 0.625%, containing Na + 140 mmol, K +   4 mmol, Mg 2+ 1 mmol, Cl 118 mmol, Ca 2+ 2.5 mmol,  acetate 24 mmol, malate 5 mmol/litre, net price 500-  mL bag = £13.50   Dose by intravenous infusion, up to 50mL/kg daily (see notes  above)   Intravenous infusion, hydroxyethyl starch (weight  average molecular weight 130 000) 10% in sodium  chloride 0.625%, containing Na + 140 mmol,  K + 4mmol, Mg 2+ lmmol, Cl" 118 mmol, Ca 2+   2.5 mmol, acetate 24 mmol, malate 5 mmol/litre, net  price 500-mL bag = £17.50   Dose by intravenous infusion, up to 30mL/kg daily (see notes  above)   Intravenous infusion, hydroxyethyl starch (weight  average molecular weight 130 000) 6% in sodium   Dose by intravenous infusion, up to 50mL/kg daily (see notes  above)   Volulyte® (Fresenius Kabi) (Ml  Intravenous infusion, hydroxyethyl starch (weight  average molecular weight 130 000) 6% in sodium  chloride intravenous infusion 0.6%, containing Na +  137 mmol, K + 4 mmol, Mg 2+ 1.5 mmol, CL 110 mmol,  acetate 34 mmol/litre, net price 500-mL bag = £13.50  Dose by intravenous infusion, up to 50mL/kg daily (see notes  above)   Voluven® (Fresenius Kabi) (Ml  Intravenous infusion, hydroxyethyl starch (weight  average molecular weight 130 000) 6% in sodium  chloride intravenous infusion 0.9%, net price 500-mL  bag =£12.50   Dose by intravenous infusion, up to 50mL/kg daily (see notes  above)   Intravenous infusion, hydroxyethyl starch (weight  average molecular weight 200 000) 6% in sodium  chloride intravenous infusion 7.2%, net price 250-mL  bag = £28.00   Cautions see notes above; also diabetes  Dose by intravenous injection over 2-5 minutes, 4mL/kg as a  single dose, followed immediately by administration of appropri-  ate replacement fluids   When adequate feeding through the alimentary tract is  not possible, nutrients may be given by intravenous  infusion. This may be in addition to ordinary oral or  tube feeding — supplemental parenteral nutrition, or  may be the sole source of nutrition — total parenteral  nutrition (TPN). Indications for this method include  preparation of undernourished patients for surgery,  chemotherapy, or radiation therapy; severe or pro-  longed disorders of the gastro-intestinal tract; major  surgery, trauma, or bums; prolonged coma or refusal  to eat; and some patients with renal or hepatic failure.  The composition of proprietary preparations available is  given in the table Proprietary Infusion Fluids for Par-  enteral Feeding, p. 603.    Parenteral nutrition requires the use of a solution con-  taining amino acids, glucose, fat, electrolytes, trace  elements, and vitamins. This is now commonly provided  by the pharmacy in the form of a 3-litre bag. A single  dose of vitamin B 12 , as hydroxocobalamin, is given by  intramuscular injection; regular vitamin B 12 injections  are not usually required unless total parenteral nutrition  continues for many months. Folic acid is given in a dose  of 15 mg once or twice each week, usually in the  nutrition solution. Other vitamins are usually given  daily; they are generally introduced in the parenteral  nutrition solution. Alternatively, if the patient is able to  take small amounts by mouth, vitamins may be given  orally.    The nutrition solution is infused through a central  venous catheter inserted under hill surgical precautions.  Alternatively, infusion through a peripheral vein may be  used for supplementary as well as total parenteral  nutrition for periods of up to a month, depending on  the availability of peripheral veins; factors prolonging  cannula life and preventing thrombophlebitis include    the use of soft polyurethane paediatric cannulas and  use of feeds of low osmolality and neutral pH. Only  nutritional fluids should be given by the dedicated intra-  venous line.   Before starting, the patient should be well oxygenated  with a near normal circulating blood volume and atten-  tion should be given to renal function and acid-base  status. Appropriate biochemical tests should have been  carried out beforehand and serious deficits corrected.  Nutritional and electrolyte status must be monitored  throughout treatment.   Complications of long-term parenteral nutrition include  gall bladder sludging, gall stones, cholestasis and abnor-  mal liver function tests. For details of the prevention and  management of parenteral nutrition complications, spe-  cialist literature should be consulted.   Protein is given as mixtures of essential and non-essen-  tial synthetic L-amino acids. Ideally, all essential amino  acids should be included with a wide variety of non-  essential ones to provide sufficient nitrogen together  with electrolytes (see also section 9.2.2). Solutions vary  in their composition of amino acids; they often contain  an energy source (usually glucose) and electrolytes.  Energy is provided in a ratio of 0.6 to 1.1 megajoules  (1 50-250 kcals) per gram of protein nitrogen. Energy  requirements must be met if amino acids are to be  utilised for tissue maintenance. A mixture of carbohy-  drate and fat energy sources (usually 30-50% as fat)  gives better utilisation of amino acids than glucose  alone.   Glucose is the preferred source of carbohydrate, but if  more than 180 g is given per day frequent monitoring of  blood glucose is required, and insulin may be necessary.  Glucose in various strengths from 10 to 50% must be  infused through a central venous catheter to avoid  thrombosis.   In parenteral nutrition regimens, it is necessary to  provide adequate phosphate in order to allow phos-  phorylation of glucose and to prevent hypophosphatae-  mia; between 20 and 30 mmol of phosphate is required  daily.   Fructose and sorbitol have been used in an attempt to  avoid the problem of hyperosmolar hyperglycaemic  non-ketotic acidosis but other metabolic problems  may occur, as with xylitol and ethanol which are now  rarely used.   Fat emulsions have the advantages of a high energy to  fluid volume ratio, neutral pH, and iso-osmolarity with  plasma, and provide essential fatty acids. Several days of  adaptation maybe required to attain maximal utilisation.  Reactions include occasional febrile episodes (usually  only with 20% emulsions) and rare anaphylactic  responses. Interference with biochemical measurements  such as those for blood gases and calcium may occur if  samples are taken before fat has been cleared. Daily  checks are necessary to ensure complete clearance from  the plasma in conditions where fat metabolism may be  disturbed. Additives should not be mixed with fat  emulsions unless compatibility is known.   Because of the complex requirements relating to  parenteral nutrition full details relating to adminis-  tration have been omitted. In all cases product  literature and other specialist literature should be  consulted.   Net price (dual compartment bag  of amino acids with electrolytes  lOOOmL and glucose 20% with  calcium lOOOmL) = £29.00   Ca 2+ 2.3 mmol, phosphate  15 mmol, anhydrous glu-  cose 100 g   Net price (dual compartment bag  of amino acids with electrolytes  lOOOmL and glucose 30% with  calcium lOOOmL) = £33.00   Ca 2+ 2.3 mmol, phosphate  15 mmol, anhydrous glu-  cose 150g   Net price 100 mL = £6.28; 250 mL  = £10.08; 500 mL = £13.88    purified olive and soya oil  200 g, glycerol 22.5 g, egg  phosphatides 12 g    Intralipid 10% (Fresenius Kabi)  Net price 100 mL = £4.70; 500 mL  = £10.30   Intralipid 20% (Fresenius Kabi)  Net price 100 mL = £7.05; 250 mL  = £11.60; 500 mL = £15.45    Net price (triple compartment bag  of amino acids and electrolytes  300 mL, 450 mL, 600 mL, or  750 mL; glucose 526 mL, 790 mL,  1053 mL, or 1316mL; lipid emul-  sion 200 mL, 300 mL, 400 mL, or  500 mL) 1026 mL = £35.00,   1540 mL = £50.00, 2053 mL =  £67.00, 2566 mL = £70.00   Net price (triple compartment bag  of amino acids and electrolytes  300 mL, 400 mL, or 500 mL; glu-  cose 885 mL, 1180mL, or  1475 mL; lipid emulsion 255 mL,  340 mL, or 425 mL) 1440mL =  £35.00, 1920 mL = £50.00,    9.7 mmol, anhydrous glu-  cose 97 g, soya oil 39 g    Ca 2+ 1.4 mmol, phosphate  7.5 mmol, anhydrous glu-  cose 67.5 g, soya oil 35.4 g   Net price 100 mL = £18.00; 250 mL  = £30.00; 500 mL = £38.00   omega-3-acid triglycerides  20 g, soya oil 80 g, med-  ium-chain triglycerides    1. Note. 1000 kcal = 4200 kJ; 1000 kJ = 238.8 kcal. All entries are iMl   Net price 100 mL = £12.51; 250 mL  = £11.30; 500 mL = £19.18   Net price (dual compartment bag  of amino acids 400 mL or 800 mL;  glucose 600 mL or 1200 mL)   Net price (dual compartment bag  of amino acids 400 mL or 800 mL;  glucose 600 mL or 1200mL)   Net price (dual compartment bag  of amino acids 400 mL or 800 mL;  glucose 600 mL or 1200 mL)   Net price (dual compartment bag  of amino acids 500 mL or 750 mL;  glucose 500 mL or 750 mL)   Net price (triple compartment bag  of amino acids 500 mL, 750 mL or  1000 mL; glucose 500 mL, 750 mL  or 1000 mL; lipid emulsion 20%   Net price (triple compartment bag  of amino acids 500 mL, 750 mL or  1000 mL; glucose 500 mL, 750 mL  or 1000 mL; lipid emulsion 20%    Ca 2+ 3.6 mmol, acid phos-  phate 12.8 mmol, anhy-  drous glucose 125 g    Ca 2+ 2.5 mmol, acid phos-  phate 5.7 mmol, anhy-  drous glucose 80 g    Ca 2+ 3.6 mmol, acid phos-  phate 20 mmol, anhydrous  glucose 150g   24micromol, phosphate  6 mmol, anhydrous glucose  64 g, soya oil 20 g, med-  ium-chain triglycerides 20 g    Ca 2+ 3.2 mmol, Zn 2+  24micromol, phosphate  12 mmol, anhydrous glu-  cose 120 g, soya oil 20 g,  medium-chain triglycerides   Net price (triple compartment bag  of amino acids 500 mL, 750 mL or   1000 mL; glucose 500 mL, 750 mL  or 1000 mL; lipid emulsion 20%   anhydrous glucose 120 g,  soya oil 20 g, medium-  chain triglycerides 20 g   Net price (triple compartment bag  of amino acids 500 mL, 750 mL or   1000 mL; glucose 500 mL, 750 mL  or 1000 mL; lipid emulsion 20%   16 mmol, anhydrous glu-  cose 144 g, soya oil 20 g,  medium-chain triglycerides   Net price (triple compartment bag  of amino acids 500 mL, 750 mL or   1000 mL; glucose 500 mL, 750 mL  or 1000 mL; lipid emulsion 20%   anhydrous glucose 144 g,  soya oil 20 g, medium-  chain triglycerides 20 g    1. Note. 1000 kcal = 4200 kJ; 1000 kJ = 238.8 kcal. All entries are iMl   1000 mL; glucose 500 mL, 750 mL  or 1000 mL; lipid emulsion 250 mL,   cose 120 g, refined soya oil  16 g, medium-chain tri-  glycerides 20 g, omega-3-  acid triglycerides 4g   800 mL; glucose 40% 800 mL; lipid  emulsion 20% 400 mL) 2000 mL =    1. Note. 1000 kcal = 4200 kJ; 1000 kJ = 238.8 kcal. All entries are (Ml    fish oil 30 g, olive oil 50 g,  soya oil 60 g, medium-  chain triglycerides 60 g   Net price (triple compartment bag  of amino acids 500 mL, 750 mL or  1000 mL; glucose 42% 298 mL,   446 mL or 595 mL; lipid emulsion  188 mL, 281 mL or 375 mL)   986 mL = £66.50, 1477 mL =  £69.00, 1 970 mL = £74.00    phosphate 2.8 mmol,  anhydrous glucose 127 g,  glycerol 4.23 g, egg phos-  pholipids 4.56 g, purified  structured triglyceride   38.5 g (contains coconut  oil, palm kernel oil and  soya oil trigylcerides)    purified structured trigly-  ceride 200 g (contains  coconut oil, palm kernel  oil, and soya oil tri-  glycerides)   Net price 500 mL = £9.64; 1000 mL  = £17.13; 3000 mL = £48.98   Net price 100 mL = £3.80; 500 mL  = £7.70; 1000 mL = £13.40   Compatibility with the infusion solution must be  ascertained before adding supplementary prepara-  tions.    Addiphos® (Fresenius Kabi) (Ml  Solution, sterile, phosphate 40 mmol, K + 30 mmol,  Na + 30 mmol/20 mL. For addition to Vamin® solu-  tions and glucose intravenous infusions. Net price 20-  mL vial = £1.53   Additrace® (Fresenius Kabi) [Ml  Solution, trace elements for addition to Vamin ®  solutions and glucose intravenous infusions, traces of  Fe 3+ , Zn 2+ , Mn 2+ , Cu 2+ , Cr 3+ , Se 4+ , Mo 6+ , F", I~. For  adults and children over 40 kg. Net price 10-mL amp  = £2.31   Solution, r/Z-alpha tocopherol 11.2 units, ascorbic  acid 125 mg, biotin 69 micrograms, colecalciferol  220 units, cyanocobalamin 6 micrograms, folic acid  414 micrograms, glycine 250 mg, nicotinamide 46 mg,  pantothenic acid (as dexpanthenol) 17.25 mg, pyrid-  oxine hydrochloride 5.5 mg, retinol (as palmitate)  3500 units, riboflavin (as dihydrated sodium phos-  phate) 4. 14 mg, thiamine (as cocarboxylase tetrahy-  drate) 3.51 mg. Dissolve in 5 mL water for injections.  Net price per vial = £4.64   Solution, trace elements for addition to infusion  solutions, Fe 2+ , Zn 2+ , Cu 2+ , Mn 2+ , F", Co 2+ , I - , Se 4+ ,  Mo 6+ , Cr 3+ . For adults over 40 kg. Net price 40-mL vial  = £ 2.00   Dipeptiven® (Fresenius Kabi) Ml  Solution, 7V(2)-L-alanyl-L-glutamine 200mg/mL  (providing L-alanine 82 mg, L-glutamine 134.6 mg).  For addition to infusion solutions containing amino  acids. Net price 50 mL = £16.40, 100 mL = £30.50  Dose amino acid supplement for hypercatabolic or hypermeta-  bolic states, 300-400 mg/kg daily; max. 400 mg/kg daily, dose not  to exceed 20% of total amino acid intake   Glycophos® Sterile Concentrate (Fresenius Kabi) [Ml  Solution, sterile, phosphate 20 mmol, Na + 40 mmol/  20 mL. For addition to Vamin® and Vaminolact®  solutions, and glucose intravenous infusions. Net  price 20-mL vial = £4.60   Peditrace® (Fresenius Kabi) (Ml  Solution, trace elements for addition to  Vaminolact®, Vamin® 14 Electrolyte-Free solutions  and glucose intravenous infusions, traces of Zn 2+ ,  Cu 2+ , Mn 2+ , Se 4+ , F~, I - . For use in neonates (when  kidney function established, usually second day of  life), infants, and children. Net price 10-mL vial =  £4.18   Cautions reduced biliary excretion especially in cholestatic liver  disease or in markedly reduced urinary excretion (careful bio-  chemical monitoring required); total parenteral nutrition exceed-  ing 1 month (measure serum manganese concentration and check  liver function before commencing treatment and regularly during  treatment) — discontinue if manganese concentration raised or if  cholestasis develops    pantothenate 16.5 mg, thiamine mononitrate 3.1 mg.  Dissolve in water for injections or glucose intravenous  infusion for adding to glucose intravenous infusion or  Intralipid ® ; dissolve in Vitlipid N® or Intralipid® for  adding to Intralipid® only. Net price per vial = £2.32   Solution, trace elements for addition to infusion  solutions, Fe 2+ , Zn 2+ , Mn 2+ , Cu 2+ , Cr 3+ , Se 4+ , Mo 6+ , I“,  F~. For adults. Net price 10-mL amp = £1.90   Vitlipid N® (Fresenius Kabi) (Ml  Emulsion, adult, vitamin A 330 units, ergocalciferol  20 units, (//-alpha tocopherol 1 unit, phytomenadione  15micrograms/mL. For addition to Intralipid®. For  adults and children over 11 years. Net price 10-mL  amp = £2.32   Emulsion, infant, vitamin A 230 units, ergocalciferol  40 units, (//-alpha tocopherol 0.7 unit, phytomena-  dione 20 micrograms/mL. For addition to Intralipid®.  Net price 10-mL amp = £2.32   These are preparations that have been modified to  eliminate a particular constituent from a food or that  are nutrient mixtures formulated as food substitutes for  patients who either cannot tolerate or cannot metabo-  lise certain common constituents of food. In certain  clinical conditions, some food preparations are regarded  as drugs and can be prescribed within the NHS if they  have been approved by the Advisory Committee on  Borderline Substances (ACBS) — see Appendix 7.   Phenylketonuria Phenylketonuria (hyperphenylalani-  naemia, PKU), which results from the inability to meta-  bolise phenylalanine, is managed by restricting dietary  intake of phenylalanine to a small amount sufficient for  tissue building and repair.   Sapropterin, a synthetic form of tetrahydrobiopterin, is  licensed as an adjunct to dietary restriction of phenyla-  lanine in the management of patients with phenylketon-  uria and tetrahydrobiopterin deficiency.   Aspartame (used as a sweetener in some foods and  medicines) contributes to the phenylalanine intake and  may affect control of phenylketonuria. Where the pre-  sence of aspartame is specified in the product literature  this is indicated in the BNF against the preparation; the  patient should be informed of this.   Coeliac disease Intolerance to gluten in coeliac  disease is managed by completely eliminating gluten  from the diet. A range of gluten-free products is avail-  able for prescription — see Appendix 7, p. 925.   Solivito N® (Fresenius Kabi) Ml  Solution, powder for reconstitution, biotin 60 micr-  ograms, cyanocobalamin 5 micrograms, folic acid  400 micrograms, glycine 300 mg, nicotinamide 40 mg,  pyridoxine hydrochloride 4.9 mg, riboflavin sodium  phosphate 4.9 mg, sodium ascorbate 113 mg, sodium   Note Sapropterin is a synthetic form of tetrahydrobiopterin  Indications see under Dose below  Cautions monitor blood-phenylalanine concentration  before and after first week of treatment — if    unsatisfactory response increase dose at weekly  intervals to max. dose and monitor blood-phenyla-  lanine concentration weekly; discontinue treatment  if unsatisfactory response after 1 month; monitor  blood-phenylalanine and tyrosine concentrations 1-2  weeks after dose adjustment and during treatment;  history of convulsions   Side-effects diarrhoea, vomiting, abdominal pain;  nasal congestion, cough, pharyngolaryngeal pain;  headache   • Phenylketonuria (specialist use only), by mouth, ADULT  and CHILD over 4 years, initially 10 mg/kg once daily,  preferably in the morning, adjusted according to  response; usual dose 5-20 mg/kg daily   • Tetrahydrobiopterin deficiency (specialist use only),  by mouth, ADULT and CHILD initially 2-5 mg/kg once  daily, preferably in the morning, adjusted according to  response; max. 20 mg/kg daily; total daily dose may  alternatively be given in 2-3 divided doses   Dispersible tablets, sapropterin dihydrochloride  100 mg, net price 30-tab pack = £597.22, 120-tab pack  = £2388.88. Label: 13, 21   Counselling Tablets should be dissolved in water and taken  within 20 minutes    The body’s reserves of protein rapidly become  exhausted in severely ill patients, especially during  chronic illness or in those with severe bums, extensive  trauma, pancreatitis, or intestinal fistula. Much can be  achieved by frequent meals and by persuading the  patient to take supplementary snacks of ordinary food  between the meals.    However, extra calories, protein, other nutrients, and  vitamins are often best given by supplementing ordinary  meals with enteral sip or tube feeds (preparations, see  Appendix 7).   When patients cannot feed normally, for example,  patients with severe facial injury, oesophageal obstruc-  tion, or coma, a nutritionally complete diet of enteral  feeds must be given. The advice of a dietitian should be  sought to determine the protein and total energy  requirement of the patient and the form and relative  contribution of carbohydrate and fat to the energy  requirements.   Most enteral feeds contain protein derived from cows’  milk or soya. Elemental feeds containing protein hydro-  lysates or free amino acids can be used for patients who  have diminished ability to break down protein, for  example in inflammatory bowel disease or pancreatic  insufficiency.   Even when nutritionally complete feeds are given, water  and electrolyte balance should be monitored. Haema-  tological and biochemical parameters should also be    monitored, particularly in clinically unstable patients.  Extra minerals (e.g. magnesium and zinc) may be  needed in patients where gastro-intestinal secretions  are being lost. Additional vitamins may also be needed.  Feeds containing vitamin K may affect the INR in  patients receiving warfarin — see interactions: Appen-  dix 1 (vitamins).   Children Children have special requirements and in  most situations liquid feeds prepared for adults are  totally unsuitable — the advice of a paediatric dietitian  should be sought; see also BNF for Children, section  9.4.2    Calcium supplements are usually only required where  dietary calcium intake is deficient. This dietary require-  ment varies with age and is relatively greater in child-  hood, pregnancy, and lactation, due to an increased  demand, and in old age, due to impaired absorption.  In osteoporosis, a calcium intake which is double the  recommended amount reduces the rate of bone loss. If  the actual dietary intake is less than the recommended  amount, a supplement of as much as 40 mmol is appro-  priate, see also Osteoporosis, p. 469 and Vitamin D,  p. 617.    In severe acute hypocalcaemia or hypocalcaemic  tetany, an initial slow intravenous injection of 10-  20 mL of calcium gluconate injection 10% (providing  approximately 2.25-4.5 mmol of calcium) should be  given, with plasma-calcium and ECG monitoring (risk  of arrhythmias if given too rapidly), and either repeated  as required or, if only temporary improvement, followed  by a continuous intravenous infusion to prevent recur-  rence. For infusion, dilute 100 mL of calcium gluconate  10% in 1 litre of glucose 5% or sodium chloride 0.9%  and give at an initial rate of 50mL/hour adjusted  according to response. Calcium chloride injection is  also available, but is more irritant; care should be  taken to prevent extravasation. Oral supplements of  calcium and vitamin D may also be required in persis-  tent hypocalcaemia (see also section 9.6.4). Concurrent    hypomagnesaemia should be corrected with magnes-  ium sulphate (section 9.5. 1.3).   For the role of calcium gluconate in temporarily redu-  cing the toxic effects of hyperkalaemia, see p. 595.   Indications see notes above; calcium deficiency  Cautions sarcoidosis; history of nephrolithiasis; avoid  calcium chloride in respiratory acidosis or respiratory  failure; interactions: Appendix 1 (antacids, calcium  salts)   Contra-indications conditions associated with hyper-  calcaemia and hypercalciuria (e.g. some forms of  malignant disease)   Side-effects gastro-intestinal disturbances; brady-  cardia, arrhythmias; with injection, peripheral vaso-  dilatation, fall in blood pressure, injection-site reac-  tions, severe tissue damage with extravasation  Dose   • By slow intravenous injection, acute hypocalcaemia,  calcium gluconate 1-2 g (Ca 2+ 2.25-4.5 mmol); CHILD  see BNF for Children   Sandocal 400 tablets, effervescent, orange flavour,  calcium lactate gluconate 930 mg, calcium carbonate  700 mg, providing calcium 400 mg (Ca 2+ 10 mmol),  net price 5 x 20-tab pack = £6.87. Label: 13   Sandocal 1000 tablets, effervescent, orange flavour,  calcium lactate gluconate 2.263 g, calcium carbonate  1.75 g, providing 1 g calcium (Ca 2+ 25 mmol), net price  3 x 10-tab pack = £6.17. Label: 13   ^ Parenteral preparations  Calcium Gluconate (Non-proprietary) (Ml  Injection, calcium gluconate 10% (calcium 8.4 mg or  Ca 2+ 226 micromol/mL), net price 10-mL amp = 60p  Note The MHRA has advised that repeated or prolonged  administration of calcium gluconate injection packaged in  10 mL glass containers is contra-indicated in children under  18 years and in patients with renal impairment owing to the  risk of aluminium accumulation; in these patients the use of  calcium gluconate injection packaged in plastic containers is  recommended   Calcium Chloride (Non-proprietary) Ml  Injection, calcium chloride dihydrate 10% (calcium  27.3 mg or Ca 2+ 680 micromol/mL), net price 10-mL  disposable syringe = £5.10  Brands include Minijet ® Calcium Chloride 10%   Injection, calcium chloride dihydrate 13.4% (calcium  36 mg or Ca 2+ 910 micromol/mL), net price 10-mL  amp = £14.94   Effervescent tablets, calcium gluconate 1 g (calcium  89 mg or Ca 2+ 2.23 mmol), net price 28-tab pack =  £14.83. Label: 13   Tablets, calcium lactate 300 mg (calcium 39 mg or  Ca 2+ 1 mmol), net price 84 = £2.92   Chewable tablets, fruit flavour, calcium carbonate  1.5 g (calcium 600 mg or Ca 2+ 15 mmol), net price  100-tab pack = £7.25. Label: 24   Tablets, effervescent, pink, calcium carbonate 1.25 g,  providing calcium citrate when dispersed in water  (calcium 500 mg or Ca 2+ 12.5 mmol), net price 76-tab  pack = £11.81. Label: 13   Tablets (chewable), orange flavour, calcium carb-  onate 1.25 g (calcium 500 mg or Ca 2+ 12.5 mmol), net  price 100-tab pack = £9.33. Label: 24  Forte tablets (chewable), orange flavour, scored,  calcium carbonate 2.5 g (calcium 1 g or Ca 2+   Tablets, pink, f/c, calcium carbonate 1.25 g (calcium  500 mg or Ca 2+ 12.5 mmol), net price 100-tab pack =  £9.46. Label: 25   Syrup, orange flavour, calcium glubionate 1.09 g,  calcium lactobionate 727 mg (calcium 108.3 mg or  Ca 2+ 2.7 mmol)/5 mL, net price 300 mL = £4.07   Severe hypercalcaemia Severe hypercalcaemia calls  for urgent treatment before detailed investigation of the  cause. Dehydration should be corrected first with intra-  venous infusion of sodium chloride 0.9%. Drugs (such  as thiazides and vitamin D compounds) which promote  hypercalcaemia, should be discontinued and dietary  calcium should be restricted.   If severe hypercalcaemia persists drugs which inhibit  mobilisation of calcium from the skeleton may be  required. The bisphosphonates are useful and  disodium pamidronate (section 6.6.2) is probably the  most effective.   Corticosteroids (section 6.3) are widely given, but may  only be useful where hypercalcaemia is due to sarcoi-  dosis or vitamin D intoxication; they often take several  days to achieve the desired effect.   Calcitonin (section 6.6.1) is relatively non-toxic but its  effect can wear off after a few days despite continued  use; it is rarely effective where bisphosphonates have  failed to reduce serum calcium adequately.   After treatment of severe hypercalcaemia the under-  lying cause must be established. Further treatment is    governed by the same principles as for initial therapy.  Salt and water depletion and drugs promoting hyper-  calcaemia should be avoided; oral administration of a  bisphosphonate may be useful.   Hyperparathyroidism Cinacalcet is licensed for the  treatment of secondary hyperparathyroidism in dialysis  patients with end-stage renal disease (but see NICE  guidance below), for primary hyperparathyroidism in  patients where parathyroidectomy is inappropriate, and  for the treatment of hypercalcaemia in parathyroid  carcinoma. Cinacalcet reduces parathyroid hormone  which leads to a decrease in serum calcium concentra-  tions.   Paricalcitol (section 9.6.4) is also licensed for the pre-  vention and treatment of secondary hyperparathyroid-  ism associated with chronic renal failure.   Cinacalcet for the treatment of secondary  hyperparathyroidism in patients with end-  stage renal disease on maintenance dialysis  therapy (January 2007)   Cinacalcet is not recommended for the routine treat-  ment of secondary hyperparathyroidism in patients  with end-stage renal disease on maintenance  dialysis therapy.   Cinacalcet is recommended for the treatment of  refractory secondary hyperparathyroidism in  patients with end-stage renal disease (including  those with calciphylaxis) only in those:   • who have ‘very uncontrolled’ plasma concentra-  tion of intact parathyroid hormone (defined as  greater than 85 picomol/litre) refractory to stan-  dard therapy, and a normal or high adjusted  serum calcium concentration,   • in whom surgical parathyroidectomy is contra-  indicated, in that the risks of surgery outweigh  the benefits.   Response to treatment should be monitored regu-  larly and treatment should be continued only if a  reduction in the plasma concentration of intact  parathyroid hormone of 30% or greater is seen  within 4 months of treatment.   Hypercalciuria Hypercalciuria should be investigated  for an underlying cause, which should be treated. Where  a cause is not identified (idiopathic hypercalciuria), the  condition is managed by increasing fluid intake and  giving bendroflumethiazide in a dose of 2.5 mg daily  (a higher dose is not usually necessary). Reducing diet-  ary calcium intake may be beneficial but severe restric-  tion of calcium intake has not proved beneficial and may  even be harmful.   Indications see under Dose and notes above  Cautions measure serum-calcium concentration  before initiation of treatment and within 1 week after  starting treatment or adjusting dose, then monthly for  secondary hyperparathyroidism and every 2-3  months for primary hyperparathyroidism and para-    thyroid carcinoma; treatment should not be initiated  in patients with hypocalcaemia; in secondary hyper-  parathyroidism measure parathyroid hormone con-  centration 1-4 weeks after starting treatment or  adjusting dose, then every 1-3 months; dose adjust-  ment may be necessary if smoking started or stopped  during treatment; interactions: Appendix 1 (cinacal-  cet)   Side-effects nausea, vomiting, anorexia; dizziness,  paraesthesia, asthenia; reduced testosterone concen-  trations; myalgia; rash; less commonly dyspepsia,  diarrhoea, and seizures; hypotension, heart failure,  and allergic reactions (including angioedema) also  reported  Dose   • Secondary hyperparathyroidism in patients with end-  stage renal disease on dialysis (but see notes above),  ADULT over 18 years, initially 30 mg once daily,  adjusted every 2-4 weeks to max. 180 mg daily   • Hypercalcaemia of primary hyperparathyroidism or  parathyroid carcinoma, ADULT over 18 years, initially  30 mg twice daily, adjusted every 2-4 weeks accord-  ing to response up to max. 90 mg 4 times daily   30 mg, net price 28-tab pack = £121.36; 60 mg, 28-tab  pack = £223.87; 90 mg, 28-tab pack = £335.81.    Magnesium is an essential constituent of many enzyme  systems, particularly those involved in energy genera-  tion; the largest stores are in the skeleton.    Magnesium salts are not well absorbed from the gastro-  intestinal tract, which explains the use of magnesium  sulphate (section 1.6.4) as an osmotic laxative.    Magnesium is excreted mainly by the kidneys and is  therefore retained in renal failure, but significant hyper-  magnesaemia (causing muscle weakness and arrhyth-  mias) is rare.    Hypomagnesaemia Since magnesium is secreted in  large amounts in the gastro-intestinal fluid, excessive  losses in diarrhoea, stoma or fistula are the most com-  mon causes of hypomagnesaemia', deficiency may also  occur in alcoholism or as a result of treatment with  certain drugs. Hypomagnesaemia often causes second-  ary hypocalcaemia, and also hypokalaemia and hypo-  natraemia.   Symptomatic hypomagnesaemia is associated with a  deficit of 0.5-1 mmol/kg; up to 160 mmol Mg 2+ over up  to 5 days may be required to replace the deficit (allow-  ing for urinary losses). Magnesium is given initially by  intravenous infusion or by intramuscular injection of  magnesium sulphate; the intramuscular injection is  painful. Plasma magnesium concentration should be  measured to determine the rate and duration of infusion    and the dose should be reduced in renal impairment. To  prevent recurrence of the deficit, magnesium may be  given by mouth in a dose of 24 mmol Mg 2+ daily in  divided doses; suitable preparations are magnesium  glycerophosphate tablets or liquid [unlicensed], avail-  able from ‘special-order’ manufacturers or specialist  importing companies, see p. 988. For maintenance  (e.g. in intravenous nutrition), parenteral doses of  magnesium are of the order of 10-20 mmol Mg 2+ daily  (often about 12 mmol Mg 2+ daily).   Arrhythmias Magnesium sulphate has also been  recommended for the emergency treatment of serious  arrhythmias, especially in the presence of hypokalaemia  (when hypomagnesaemia may also be present) and  when salvos of rapid ventricular tachycardia show the  characteristic twisting wave front known as torsade de  pointes (see also section 2.3.1). The usual dose of  magnesium sulphate by intravenous injection is 2g  (8 mmol Mg 2+ ) over 10-15 minutes (repeated once if  necessary).   Myocardial infarction Limited evidence that  magnesium sulphate prevents arrhythmias and reperfu-  sion injury in patients with suspected myocardial infarc-  tion has not been confirmed by large studies. Routine  use of magnesium sulphate for this purpose is not  recommended. For the management of myocardial  infarction, see section 2.10.1.   Eclampsia and pre-eclampsia Magnesium sulphate  is the drug of choice for the treatment of seizures and  the prevention of recurrent seizures in women with  eclampsia. Regimens may vary between hospitals. Cal-  cium gluconate injection is used for the management of  magnesium toxicity.   Magnesium sulphate is also of benefit in women with  pre-eclampsia in whom there is concern about devel-  oping eclampsia. The patient should be monitored care-  fully (see under Magnesium Sulphate).   Indications see notes above; constipation (section  1.6.4); severe acute asthma (section 3.1); paste for  boils (section 13.10.5)   Cautions see notes above; in severe hypomagnes-  aemia administer initially via controlled infusion  device (preferably syringe pump); monitor blood  pressure, respiratory rate, urinary output and for signs  of overdosage (loss of patellar reflexes, weakness,  nausea, sensation of warmth, flushing, drowsiness,  double vision, and slurred speech); interactions:  Appendix 1 (magnesium, parenteral)   Pregnancy not known to be harmful for short-term  intravenous administration in eclampsia, but exces-  sive doses in third trimester cause neonatal respir-  atory depression   Side-effects generally associated with hypermagne-  saemia, nausea, vomiting, thirst, flushing of skin,  hypotension, arrhythmias, coma, respiratory depres-  sion, drowsiness, confusion, loss of tendon reflexes,  muscle weakness; colic and diarrhoea following oral  administration   • Prevention of seizures in pre-eclampsia [unlicensed  indication], initially by intravenous injection over 5-  15 minutes, 4 g followed by intravenous infusion, 1 g/  hour for 24 hours; if seizure occurs, additional dose by  intravenous injection, 2g   • Treatment of seizures and prevention of seizure  recurrence in eclampsia, initially by intravenous  injection over 5-15 minutes, 4g, followed by intra-  venous infusion, 1 g/hour for 24 hours after seizure or  delivery, whichever is later; if seizure recurs, increase  the infusion rate to 1.5-2 g/hour or give an additional  dose by intravenous injection, 2g   Intravenous administration For intravenous injection con-  centration of magnesium sulphate should not exceed 20%   (dilute 1 part of magnesium sulphate injection 50% with at least   Magnesium Sulphate (Non-proprietary) (Ml  Injection, magnesium sulphate (as heptahydrate) 20%  (Mg 2+ approx. 0.8mmol/mL), net price 20-mL (4-g)  amp = £2.75; 50% (Mg 2+ approx. 2mmol/mL), 2-mL  (1-g) amp = £2.39, 4-mL (2-g) prefilled syringe =  £7.39, 5-mL (2.5-g) amp = £3.00, 10-mL (5-g) amp =  69p; 10-mL (5-g) prefilled syringe = £4.95  Brands include Minijet® Magnesium Sulphate 50%   Oral phosphate supplements may be required in addi-  tion to vitamin D in a small minority of patients with  hypophosphataemic vitamin D-resistant rickets. Diarr-  hoea is a common side-effect and should prompt a  reduction in dosage.   Phosphate infusion is occasionally needed in alcohol  dependence or in phosphate deficiency arising from use  of parenteral nutrition deficient in phosphate supple-  ments; phosphate depletion also occurs in severe dia-  betic ketoacidosis. For established hypophosphatae-  mia, monobasic potassium phosphate may be infused  at a rate of 9 mmol every 12 hours. In critically ill  patients, the dose of phosphate can be increased up to  500 micromol/kg (approx. 30 mmol in adults, max.  50 mmol), infused over 6-12 hours, according to sever-  ity. Excessive doses of phosphates may cause hypocalc-  aemia and metastatic calcification; it is essential to  monitor closely plasma concentrations of calcium,  phosphate, potassium, and other electrolytes.   For phosphate requirements in total parenteral nutri-  tion regimens, see section 9.3.   Phosphates (Fresenius Kabi) (Ml  Intravenous infusion, phosphates (providing P0 4 3-  100 mmol, K + 19 mmol, and Na + 162 mmol/litre), net  price 500 mL ( Polyfusor ®) = £3.75.   Tablets, effervescent, anhydrous sodium acid phos-  phate 1.936 g, sodium bicarbonate 350 mg, potassium  bicarbonate 315 mg, equivalent to phosphorus 500 mg  (phosphate 16.1 mmol), sodium 468.8 mg (Na +   Dose vitamin D-resistant hypophosphataemic osteomalacia, 4-6  tablets daily; CHILD under 5 years 2-3 tablets daily   Calcium-containing preparations are used as phos-  phate-binding agents in the management of hyper-  phosphataemia complicating renal failure. Aluminium-  containing preparations are rarely used as phosphate-  binding agents and can cause aluminium accumulation.   Sevelamer hydrochloride and sevelamer carbonate  are both licensed for the treatment of hyperphospha-  taemia in patients on haemodialysis or peritoneal  dialysis. Sevelamer carbonate is also licensed for the  treatment of patients with chronic kidney disease not on  dialysis who have a serum-phosphate concentration of  1.78mmol/L or more.   Lanthanum is licensed for the control of hyperphospha-  taemia in patients with chronic renal failure on haemo-  dialysis or continuous ambulatory peritoneal dialysis  (CAPD), and in patients with chronic kidney disease  not on dialysis who have a serum-phosphate concentra-  tion of 1.78mmol/L or more that cannot be controlled  by a low-phosphate diet.   The Scottish Medicines Consortium (p. 4) has advised  (March 2007) that lanthanum ( Fosrenol ®) is accepted  for restricted use within NHS Scotland for the control of  hyperphosphataemia in patients with chronic renal  failure on haemodialysis or continuous ambulatory  peritoneal dialysis, as a second-line agent, where a  non-aluminium, non-calcium phosphate binder is  required.   Capsules, green/red, dried aluminium hydroxide  475 mg (low Na + ), net price 120-cap pack = £3.75  Dose phosphate-binding agent in renal failure, 4-20 capsules  daily in divided doses with meals   Tablets, yellow, scored, calcium acetate 1 g (calcium  250 mg or Ca 2+ 6.2 mmol), net price 180-tab pack =  £19.79. Counselling, do not chew, with meals  Dose initially 1 tablet 3 times daily with meals, adjusted  according to serum-phosphate concentration (usual dose 4-6  tablets daily (1 or 2 tablets with each meal)); max. 12 tablets daily   PhosLo® (Fresenius Medical Care) (Ml  Capsules, calcium acetate (anhydrous) 667 mg (cal-  cium 169 mg or Ca 2+ 4.2 mmol), net price 200-cap  pack = £14.40. Counselling, with meals   Dose initially 2 capsules with each meal, adjusted according to  serum-phosphate concentration (usual dose 3 or 4 capsules with  each meal)   ^With magnesium carbonate  Osvaren® (Fresenius Medical Care) (Ml  Tablets, f/c, scored, calcium acetate 435 mg (calcium  110 mg or Ca 2+ 2.7 mmol), heavy magnesium carb-  onate 235 mg (magnesium 60 mg), net price 180-tab  pack = £24.00. Counselling, do not crush or chew,  with meals, avoid other drugs at same time (see  below)   Dose ADULT over 18 years, initially 1 tablet 3 times daily with  meals, adjusted according to serum-phosphate concentration  (usual dose 3-10 tablets daily); max. 12 tablets daily  Counselling Manufacturers advise that other drugs should be  taken at least 2 hours before or 3 hours after Osvaren ® to reduce  possible interference with absorption of other drugs   Cautions acute peptic ulcer; ulcerative colitis; Crohn’s  disease; bowel obstruction; monitor liver function;  interactions: Appendix 1 (lanthanum)   Side-effects gastro-intestinal disturbances; hypocalc-  aemia; less commonly anorexia, increased appetite,  taste disturbances, dry mouth, thirst, stomatitis, chest  pain, peripheral oedema, headache, dizziness, vertigo,  asthenia, fatigue, malaise, hyperglycaemia, hyperpar-  athyroidism, hypercalcaemia, hypophosphataemia,  eosinophilia, arthralgia, myalgia, osteoporosis,  sweating, alopecia, pruritus, and erythematous rash;  accumulation of lanthanum in bone, and transient  changes in QT interval also reported  Dose   • ADULT over 18 years, initially 750 mg daily in divided  doses chewed with or immediately after meals,  adjusted according to serum-phosphate concentra-  tion every 2-3 weeks (usual dose range 1.5-3 g daily  in divided doses)   Tablets (chewable), lanthanum (as carbonate hydrate)  500 mg, net price 90-tab pack = £114.13; 750mg, 90-  tab pack = £152.17; 1 g, 90-tab pack = £161.33.  Label: 21, counselling, to be chewed   Indications hyperphosphataemia in patients on  haemodialysis or peritoneal dialysis  Cautions gastro-intestinal disorders; interactions:   Contra-indications bowel obstruction  Pregnancy manufacturer advises use only if potential  benefit outweighs risk   Breast-feeding manufacturer advises use only if  potential benefit outweighs risk  Side-effects nausea, vomiting, abdominal pain, con-  stipation, diarrhoea, dyspepsia, flatulence; very rarely  intestinal obstruction; also reported intestinal per-  foration, ileus, diverticulitis, pruritus, rash  Dose   • ADULT over 18 years, initially 2. 4-4.8 g daily in 3  divided doses with meals, adjusted according to  serum-phosphate concentration (usual dose range  2.4-12 g daily in 3 divided doses)   Renagel® (Genzyme) (Ml  Tablets, f/c, sevelamer hydrochloride 800 mg, net  price 180-tab pack = £117.97. Label: 25, counselling,  with meals   Indications hyperphosphataemia in patients on  haemodialysis or peritoneal dialysis, and patients with  chronic kidney disease not on dialysis who have a  serum-phosphate concentration of 1.78 mmol /L or  more   Contra-indications bowel obstruction  Pregnancy manufacturer advises use only if potential  benefit outweighs risk   Breast-feeding unlikely to be present in milk (how-  ever, manufacturer advises avoid)   Side-effects nausea, vomiting, abdominal pain, con-  stipation, diarrhoea, dyspepsia, flatulence; also  reported intestinal obstruction and perforation, ileus,  pruritus, rash  Dose   • ADULT over 18 years, initially 2.4-4.8g daily in 3  divided doses with meals, adjusted according to  serum-phosphate concentration every 2-4 weeks  (usual dose approx. 6 g daily in 3 divided doses)   Powder for oral suspension, pale yellow, sevelamer  carbonate 2.4 g, net price 60-sachet pack (citrus-fla-  voured) = £117.97. Label: 13, counselling, with meals  Note Each sachet to be dispersed in 60 mL water   Availability of adequate fluoride confers significant  resistance to dental caries. It is now considered that  the topical action of fluoride on enamel and plaque is  more important than the systemic effect.   When the fluoride content of drinking water is less than  700 micrograms per litre (0.7 parts per million), daily  administration of fluoride tablets or drops provides  suitable supplementation. Systemic fluoride supple-  ments should not be prescribed without reference to  the fluoride content of the local water supply. Infants  need not receive fluoride supplements until the age of 6  months.   Dentifrices which incorporate sodium fluoride or mono-  fluorophosphate are also a convenient source of fluo-  ride.   Individuals who are either particularly caries prone or  medically compromised may be given additional pro-  tection by use of fluoride rinses or by application of  fluoride gels. Rinses may be used daily or weekly; daily  use of a less concentrated rinse is more effective than  weekly use of a more concentrated one. High-strength  gels must be applied regularly under professional super-  vision; extreme caution is necessary to prevent children  from swallowing any excess. Less concentrated gels are  available for home use. Varnishes are also available and  are particularly valuable for young or disabled children  since they adhere to the teeth and set in the presence of  moisture.   Fluoride mouthwash, oral drops, tablets and tooth-  paste are prescribable on form FP10D (GP14 in  Scotland, WP10D in Wales; for details see prepara-  tions, p. 614).   There are also arrangements for health authorities to  supply fluoride tablets in the course of pre-school  dental schemes, and they may also be supplied in  school dental schemes.   Fluoride gels are not prescribable on form FP10D  (GP14 in Scotland, WP10D in Wales).   Side-effects occasional white flecks on teeth with  recommended doses; rarely yellowish-brown disco-  loration if recommended doses are exceeded   • Water content less than F" 300 micrograms/litre (0.3  parts per million), CHILD up to 6 months none; 6  months-3 years F~ 250 micrograms daily, 3-6 years  F" 500 micrograms daily, over 6 years F" 1 mg daily   • Water content between F“ 300 and 700 micrograms/  litre (0.3-0. 7 parts per million), CHILD up to 3 years  none, 3-6 years F - 250 micrograms daily, over 6 years  F“ 500 micrograms daily   • Water content above F~ 700 micrograms /litre (0.7  parts per million), supplements not advised   and the British Association for the Study of Community Den-  tistry (Br Dent J 1997; 182: 6-7)   Counselling Tablets should be sucked or dissolved in the  mouth and taken preferably in the evening   Fluotabs 6+ years, orange-flavoured, scored, sodium  fluoride 2.2 mg (F~ 1 mg), net price 200-tab pack =  £2.38   Tablets, buff, sodium fluoride 1.1 mg (F~ 500 micr-  ograms), net price 200-tab pack = £2.54; 2.2 mg (F~   Tablets 0.5, purple, grape-flavoured, scored, sodium  fluoride 1.1 mg (F~ 500 micrograms), net price 200-  tab pack = £1.91   Tablets 1.0, orange, orange-flavoured, scored, sod-  ium fluoride 2.2 mg (F~ 1 mg), net price 200-tab pack  = £1.91   Note Fluoride supplements not considered necessary below 6  months of age (see notes above)   Fluodrops® (= paediatric drops), sugar-free, sodium  fluoride 550 micrograms (F~ 250 micrograms)/   Rinse mouth for 1 minute and spit out  Counselling Avoid eating, drinking, or rinsing mouth for 15  minutes after use   Daily fluoride mouthrinse (= mouthwash), blue,  sodium fluoride 0.05%. Net price 250 mL = £1.51  Dose CHILD 6 years and over, for daily use, rinse with 10 mL  Dental prescribing on NHS May be prescribed as Sodium  Fluoride Mouthwash 0.05%   Fluorinse (= mouthwash), red, sodium fluoride 2%.  Net price 100 mL = £4.97. Counselling, see above  Dose CHILD 8 years and over, for daily use, dilute 5 drops to  10 mL of water; for weekly use, dilute 20 drops to 10 mL  Dental prescribing on NHS May be prescribed as Sodium  Fluoride Mouthwash 2%   Dose ADULT and CHILD 3 years and over, for daily use, using a  toothbrush, apply onto all tooth surfaces  Counselling Swish between teeth for 1 minute before spitting out.  Avoid eating, drinking, or rinsing mouth for at least 30 minutes  after use   Duraphat® (Colgate-Palmolive) [Ml  Duraphat® ‘2800 ppm’ toothpaste, sodium fluoride  0.619%. Net price 75 mL = £3.26, dual pack  (2x75mL) = £5.54. Counselling, see below  Dose ADULT and CHILD over 10 years, apply 1 cm twice daily  using a toothbrush   Counselling Brush teeth for 1 minute before spitting out. Avoid  drinking or rinsing mouth for 30 minutes after use  Dental prescribing on NHS May be prescribed as Sodium  Fluoride Toothpaste 0.619%   Zinc supplements should not be given unless there is  good evidence of deficiency (hypoproteinaemia spur-  iously lowers plasma-zinc concentration) or in zinc-  losing conditions. Zinc deficiency can occur as a result  of inadequate diet or malabsorption; excessive loss of  zinc can occur in trauma, bums, and protein-losing  conditions. A zinc supplement is given until clinical  improvement occurs, but it may need to be continued  in severe malabsorption, metabolic disease (section  9.8.1), or in zinc-losing states.   Parenteral nutrition regimens usually include trace  amounts of zinc (section 9.3). If necessary, further zinc  can be added to intravenous feeding regimens. A sug-  gested dose for intravenous nutrition is elemental zinc  6.5 mg (Zn 2+ lOOmicromol) daily.   Indications zinc deficiency or supplementation in  zinc-losing conditions  Cautions interactions: Appendix 1 (zinc)   Pregnancy crosses placenta; risk theoretically mini-  mal, but no information available  Breast-feeding present in milk; risk theoretically  minimal, but no information available    Side-effects abdominal pain, dyspepsia, nausea,  vomiting, diarrhoea, gastric irritation; irritability,  headache, lethargy   Zinc Sulphate (Non-proprietary) tMl  Injection, zinc sulphate 14.6mg/mL (zinc 50micr-  omol/mL), net price 10 mL vial = £2.50   Effervescent tablets, zinc sulphate monohydrate  125 mg (45 mg zinc), net price 30 = £4.32. Label: 13,  21   Dose ADULT and CHILD over 30 kg, 1 tablet in water 1-3 times  daily after food; CHILD under 10 kg, ‘/z tablet daily; 10-30 kg, 'A  tablet 1-3 times daily    Selenium deficiency can occur as a result of inadequate  diet or prolonged parenteral nutrition. A selenium sup-  plement should not be given unless there is good  evidence of deficiency.   • By mouth or by intramuscular injection or by intra-  venous injection, 100-500 micrograms daily   Selenase® (Oxford Nutrition) (Ml  Oral solution, selenium (as sodium selenite penta-  hydrate) 50 micrograms /mL, net price 2-mL amp =  £1.03, 10-mL bottle = £4.05   Injection, selenium (as sodium selenite pentahydrate)  50 micrograms /mL, net price 2-mL amp = £1.50, 10-  mL vial = £4.25   Vitamin A  Vitamin B group  Vitamin C  Vitamin D  Vitamin E  Vitamin K   Vitamins are used for the prevention and treatment of  specific deficiency states or where the diet is known to  be inadequate; they may be prescribed in the NHS to  prevent or treat deficiency but not as dietary supple-  ments.   Their use as general ‘pick-me-ups’ is of unproven value  and, in the case of preparations containing vitamin A or  D, may actually be harmful if patients take more than the  prescribed dose. The ‘fad’ for mega-vitamin therapy  with water-soluble vitamins, such as ascorbic acid and  pyridoxine, is unscientific and can be harmful.    Dietary reference values for vitamins are available in the  Department of Health publication:   Dietary Reference Values for Food Energy and Nutrients for  the United Kingdom: Report of the Panel on Dietary Refer-  ence Values of the Committee on Medical Aspects of Food  Policy. Report on Health and Social Subjects 41. London:  HMSO, 1991   Dental patients It is unjustifiable to treat stomatitis or  glossitis with mixtures of vitamin preparations; this  delays diagnosis and correct treatment.   Most patients who develop a nutritional deficiency  despite an adequate intake of vitamins have malabsorp-  tion and if this is suspected the patient should be  referred to a medical practitioner.   Deficiency of vitamin A (retinol) is associated with  ocular defects (particularly xerophthalmia) and an  increased susceptibility to infections, but deficiency is  rare in the UK (even in disorders of fat absorption).   Massive overdose can cause rough skin, dry hair, an  enlarged liver, and a raised erythrocyte sedimentation  rate and raised serum calcium and serum alkaline  phosphatase concentrations.   Pregnancy In view of evidence suggesting that high  levels of vitamin A may cause birth defects, women who  are (or may become) pregnant are advised not to take  vitamin A supplements (including tablets and fish-liver  oil drops), except on the advice of a doctor or an  antenatal clinic; nor should they eat liver or products  such as liver pate or liver sausage.   Breast-feeding theoretical risk of toxicity in infants of  mothers taking large doses   Capsules, vitamin A 4000 units, vitamin D 400 units,  net price 84-cap pack = £3.44  Note May be difficult to obtain   Oral drops, vitamin A 5000 units, vitamin D  2000 units, ascorbic acid 150mg/mL  Available free of charge to children under 4 years in families on the  Healthy Start Scheme, or alternatively may be available direct to    the public — further information for healthcare professionals can  be accessed at http://tinjmrl.com/3yckebe. Beneficiaries can  contact their midwife or health visitor for further information on  where to obtain supplies.   Dose prevention of vitamin deficiency, CHILD 1 month-5 years, 5  drops daily (5 drops contain vitamin A approx. 700 units, vitamin  D approx. 300 units, ascorbic acid approx. 20 mg)   Note Healthy Start Vitamins for women (containing ascorbic  acid, vitamin D, and folic acid) are also available free of charge  to women on the Healthy Start Scheme during pregnancy and  until their baby is one year old, or alternatively may be available  direct to the public — further information for healthcare profes-  sionals can be accessed at http://tinjmrl.com/3yckebe. Benefi-  ciaries can contact their midwife or health visitor for further  information on where to obtain supplies.   Deficiency of the B vitamins, other than vitamin B 12  (section 9.1.2), is rare in the UK and is usually treated by  preparations containing thiamine (BJ, riboflavin (B 2 ),  and nicotinamide, which is used in preference to nico-  tinic acid, as it does not cause vasodilatation. Other  members (or substances traditionally classified as mem-  bers) of the vitamin B complex such as aminobenzoic  acid, biotin, choline, inositol, and pantothenic acid or  panthenol may be included in vitamin B preparations  but there is no evidence of their value.   The severe deficiency states Wernicke’s encephalopathy  and Korsakoff’s psychosis, especially as seen in chronic  alcoholism (section 4.10.1), are best treated initially by  the parenteral administration of B vitamins ( Pabrinex ®),  followed by oral administration of thiamine in the  longer term. Anaphylaxis has been reported with  parenteral B vitamins (see MHRA/CHM advice, below).   As with other vitamins of the B group, pyridoxine (B 6 )  deficiency is rare, but it may occur during isoniazid  therapy (section 5.1.9) or penicillamine treatment in  Wilson’s disease (section 9.8.1) and is characterised by  peripheral neuritis. High doses of pyridoxine are given in  some metabolic disorders, such as hyperoxaluria, and it  is also used in sideroblastic anaemia (section 9.1.3).  There is evidence to suggest that pyridoxine in a dose  not exceeding 100 mg daily may provide some benefit in  premenstrual syndrome. It has been tried for a wide  variety of other disorders, but there is little sound  evidence to support the claims of efficacy, and over-  dosage induces toxic effects.    Nicotinic acid inhibits the synthesis of cholesterol and  triglyceride (see section 2.12). Folic acid and vitamin B 12  are used in the treatment of megaloblastic anaemia  (section 9.1.2). Folinic acid (available as calcium folin-  ate) is used in association with cytotoxic therapy (sec-  tion 8.1).   Although potentially serious allergic adverse reactions  may rarely occur during, or shortly after, parenteral  administration, the CHM has recommended that:   1. This should not preclude the use of parenteral  thiamine in patients where this route of admin-  istration is required, particularly in patients at  risk of Wemicke-Korsakoff syndrome where  treatment with thiamine is essential;   2. Intravenous administration should be by infu-  sion over 30 minutes;   3. Facilities for treating anaphylaxis (including re-  suscitation facilities) should be available when  parenteral thiamine is administered.    Breast-feeding severely thiamine-deficient mothers  should avoid breast-feeding as toxic methyl-glyoxal  present in milk   • Mild deficiency, by mouth, 25-100 mg daily; severe  deficiency, 200-300 mg daily in divided doses   Tablets, thiamine hydrochloride 50 mg, net price 100  = £5.19; 100 mg, 100 = £8.04  Brands include Benerva ®   Pabrinex® (Archimedes) (Ml  I/M High Potency injection, for intramuscular use  only, ascorbic acid 500 mg, nicotinamide 160 mg,  pyridoxine hydrochloride 50 mg, riboflavin 4 mg,  thiamine hydrochloride 250 mg/7 mL. Net price 7 mL  (in 2 amps) = £1.96   I /V High Potency injection, for intravenous use only,  ascorbic acid 500 mg, anhydrous glucose 1 g, nico-  tinamide 160 mg, pyridoxine hydrochloride 50 mg,  riboflavin 4 mg, thiamine hydrochloride 250 mg/   10 mL. Net price 10 mL (in 2 x 5mL amps) = £1.96  Parenteral vitamins B and C for rapid correction of severe  depletion or malabsorption (e.g. in alcoholism, after acute  infections, postoperatively, or in psychiatric states), mainte-  nance of vitamins B and C in chronic intermittent haemo-  dialysis   Treatment of Wernicke’s encephalopathy, by intravenous infusion  of I/V High Potency or by deep intramuscular injection into the  gluteal muscle of I/M High Potency, 2 pairs 3 times daily for 2  days; if no response, discontinue; if symptoms resolve after 2 days,  give 1 pair once daily for 5 days or for as long as improvement  continues   Prophylaxis of Wernicke’s encephalopathy in alcohol dependence,  by intravenous infusion of I/V High Potency or by deep intra-  muscular injection into the gluteal muscle of I /M High Potency, 1  pair once daily for 3-5 days   Psychosis following narcosis or electroconvulsive therapy, toxicity  from acute infections, by intravenous infusion of I/V High  Potency or by deep intramuscular injection into the gluteal  muscle of I/M High Potency, 1 pair twice daily for up to 7 days  Haemodialysis, by intravenous infusion of I/V High Potency (in  sodium chloride intravenous infusion 0.9%), 1 pair every 2 weeks   Side-effects sensory neuropathy reported with high  doses given for extended periods   • Isoniazid-induced neuropathy, prophylaxis 10 mg  daily [or 20 mg daily if suitable product not available];  treatment, 50 mg three times daily; CHILD under 18  years see BNF for Children   • Penicillamine-induced neuropathy, prophylaxis in  Wilson’s disease [unlicensed use] (see also notes  above), 20 mg daily; CHILD under 18 years see BNF for  Children   • Premenstrual syndrome [unlicensed use], 50-100 mg  daily (see notes above)   Prolonged use of pyridoxine in a dose of 10 mg daily is  considered safe but the long-term use of pyridoxine in  a dose of 200 mg or more daily has been associated  with neuropathy. The safety of long-term pyridoxine  supplementation with doses above 10 mg daily has not  been established.   Tablets, pyridoxine hydrochloride 10 mg, net price  500 = £8.53; 20 mg, 500 = £8.53; 50 mg, 28 = £1.52   Tablets, brown, f/c or s/c, nicotinamide 20 mg,  pyridoxine hydrochloride 2 mg, riboflavin 2 mg, thia-  mine hydrochloride 5 mg. Net price 28-tab pack =  £2.30   Syrup, thiamine hydrochloride 5 mg, riboflavin 2 mg,  nicotinamide 20 mg, pyridoxine hydrochloride 2 mg,  panthenol 3mg/5mL. Net price 150 mL = £2.41   Potassium aminobenzoate has been used in the treat-  ment of various disorders associated with excessive  fibrosis such as scleroderma but its therapeutic value   Capsules, potassium aminobenzoate 500 mg, net  price 240 =£35.80. Label: 21  Envules® (= powder in sachets), potassium amino-  benzoate 3 g, net price 40 sachets = £27.45. Label: 13,  21   Dose Peyronie's disease, scleroderma, 12 g daily in divided doses  after food    Vitamin C therapy is essential in scurvy, but less florid  manifestations of vitamin C deficiency are commonly  found, especially in the elderly. It is rarely necessary to  prescribe more than 100 mg daily except early in the  treatment of scurvy.   Severe scurvy causes gingival swelling and bleeding  margins as well as petechiae on the skin. This is, how-  ever, exceedingly rare and a patient with these signs is  more likely to have leukaemia. Investigation should not  be delayed by a trial period of vitamin treatment.   Claims that vitamin C ameliorates colds or promotes  wound healing have not been proved.   Indications prevention and treatment of scurvy  Cautions interactions: Appendix 1 (vitamins)   • Prophylactic, 25-75 mg daily; therapeutic, not less  than 250 mg daily in divided doses   Tablets, ascorbic acid 50 mg, net price 28 = £1.79;  100 mg, 28 = £1.42; 200 mg, 28 = £1.42; 500 mg (label:  24), 28 = £2.34  Brands include Redoxon ® (S?)   Vitamin D is used for a range of compounds  which possess the property of preventing or curing rickets.  They include ergocalciferol (calciferol, vitamin D 2 ), colecalci-  ferol (vitamin D 3 ), dihydrotachysterol, alfacalcidol (la-  hydroxycholecalciferol), and calcitriol (1,25-dihydroxychole-  calciferol).   Simple vitamin D deficiency can be prevented by taking  an oral supplement of only 10 micrograms (400 units) of  ergocalciferol (calciferol, vitamin D 2 ) or colecalciferol  (vitamin D 3 ) daily. Vitamin D deficiency can occur in  people whose exposure to sunlight is limited and in  those whose diet is deficient in vitamin D. In these    individuals, ergocalciferol or colecalciferol in a dose of  20 micrograms (800 units) daily by mouth may be given  to treat vitamin D deficiency; higher doses may be  necessary for severe deficiency. Patients who do not  respond should be referred to a specialist.   Preparations containing calcium with colecalciferol  are available for the management of combined calcium  and vitamin D deficiency, or for those at high risk of  deficiency (see also Osteoporosis, p. 469 and Calcium  Supplements, p. 608).   Vitamin D deficiency caused by intestinal malabsorp-  tion or chronic liver disease usually requires vitamin D  in pharmacological doses, such as ergocalciferol tablets  up to 1 mg (40 000 units) daily; the hypocalcaemia of  hypoparathyroidism often requires doses of up to  2.5 mg (100 000 units) daily in order to achieve normo-  calcaemia.   Vitamin D requires hydroxylation by the kidney to its  active form, therefore the hydroxylated derivatives alfa-  calcidol or calcitriol should be prescribed if patients  with severe renal impairment require vitamin D therapy.  Calcitriol is also licensed for the management of post-  menopausal osteoporosis.   Paricalcitol, a synthetic vitamin D analogue, is licensed  for the prevention and treatment of secondary hyper-  parathyroidism associated with chronic renal failure  (section 9.5. 1.2).   Important. All patients receiving pharmacological  doses of vitamin D should have their plasma-calcium  concentration checked at intervals (initially once or  twice weekly) and whenever nausea or vomiting occur.   Cautions take care to ensure correct dose in infants;  monitor plasma-calcium concentration in patients  receiving high doses and in renal impairment (see  notes above); interactions: Appendix 1 (vitamins)  Contra-indications hypercalcaemia; metastatic calci-  fication   Side-effects symptoms of overdosage include ano-  rexia, lassitude, nausea and vomiting, diarrhoea,  constipation, weight loss, polyuria, sweating, head-  ache, thirst, vertigo, and raised concentrations of  calcium and phosphate in plasma and urine  Dose   Note There is no plain vitamin D tablet available for treating  simple deficiency (see notes above). Alternatives include vita-  mins capsules (section 9.6.7), preparations of vitamins A and D  (section 9.6.1), and calcium and ergocalciferol tablets (see  below).   Tablets, calcium lactate 300 mg, calcium phosphate  150 mg (calcium 97 mg or Ca 2+ 2.4 mmol), ergocalci-  ferol 10 micrograms (400 units). Net price 28-tab pack   Note The BP directs that when calciferol is prescribed or  demanded, colecalciferol or ergocalciferol should be dis-  pensed or supplied   Tablets, ergocalciferol 250 micrograms (10 000 units),  net price 100 = £21.99; 1.25 mg (50 000 units), 100 =  £30.34   Important When the strength of the tablets ordered or prescribed  is not clear, the intention of the prescriber with respect to the  strength (expressed in micrograms or milligrams per tablet)  should be ascertained.   Injection, for intramuscular use only, ergocalciferol,  7.5 mg (300 000units)/mL in oil, net price 1-mL amp  = £8.50, 2-mL amp = £9.85   Cautions see under Ergocalciferol; also nephrolithiasis  Contra-indications see under Ergocalciferol  Pregnancy see under Ergocalciferol  Breast-feeding see under Ergocalciferol  Side-effects see under Ergocalciferol; also rarely  nephrocalcinosis, pruritus, rash, and urticaria  Dose   • By mouth or by intravenous injection over 30 sec-  onds, ADULT and CHILD over 20 kg, initially 1 microgram  daily (elderly 500 nanograms), adjusted to avoid  hypercalcaemia; maintenance, usually 0.25-1 micr-  ogram daily; NEONATE and PRETERM NEONATE initially  50-100 nanograms/kg daily, CHILD under 20 kg initi-  ally 50 nanograms/kg daily   Alfacalcidol (Non-proprietary) (Ml  Capsules, alfacalcidol 250 nanograms, net price 30-  cap pack = £5.94; 500 nanograms 30-cap pack =  £11.64; 1 microgram 30-cap pack = £15.91   Capsules, alfacalcidol 250 nanograms (white), net  price 30-cap pack = £3.37; 500 nanograms (red), 30-  cap pack = £6.27; 1 microgram (brown), 30-cap pack  = £8.75   Oral drops, sugar-free, alfacalcidol 2 micrograms /mL  (1 drop contains approx. 100 nanograms), net price  10 mL = £22.49   Note The concentration of alfacalcidol in One- Alpha ® drops is 10  times greater than that of the former preparation One-Alpha ®  solution.   Injection, alfacalcidol 2 micrograms/mL, net price  0.5-mL amp = £2.16, 1-mL amp = £4.11   Excipients include alcohol, propylene glycol (caution in neonates, see  Excipients, p. 2)   Indications see notes above  Cautions see under Ergocalciferol; monitor plasma  calcium, phosphate, and creatinine during dosage  titration   Granules, effervescent, lemon flavour, calcium carb-  onate 1.25 g (calcium 500 mg or Ca 2+ 12.5 mmol),  colecalciferol 11 micrograms (440units)/sachet, net  price 30-sachet pack = £4.06. Label: 13    Contra-indications see under Ergocalciferol  Pregnancy see under Ergocalciferol  Breast-feeding see under Ergocalciferol  Side-effects see under Ergocalciferol   • By mouth, renal osteodystrophy, initially 250 nan-  ograms daily, or on alternate days (in patients with  normal or only slightly reduced plasma-calcium con-  centration), increased if necessary in steps of   250 nanograms at intervals of 2-4 weeks; usual dose  0.5-1 microgram daily; CHILD not established  Established postmenopausal osteoporosis, 250 nan-  ograms twice daily (monitor plasma-calcium con-  centration and creatinine, consult product literature)   • By intravenous injection (or injection through catheter  after haemodialysis), hypocalcaemia in dialysis  patients with chronic renal failure, initially 500 nan-  ograms (approx. 10 nanograms/kg) 3 times a week,  increased if necessary in steps of 250-500 nanograms  at intervals of 2-4 weeks; usual dose 0.5-3 micr-  ograms 3 times a week; CHILD see BNF for Children  Moderate to severe secondary hyperparathyroidism  in dialysis patients, initially 0.5-4 micrograms 3 times  a week, increased if necessary in steps of 250-   Calcitriol (Non-proprietary) (Ml  Capsules, calcitriol 250 nanograms, net price 30-cap  pack = £18.04, 100-cap pack = £19.15; 500 nan-  ograms, 30-cap pack = £32.25, 100-cap pack = £25.76   Capsules, calcitriol 250 nanograms (red/white), net  price 100 = £18.04; 500 nanograms (red), 100 =  £32.25   Injection, calcitriol 1 microgram/mL, net price 1-mL  amp = £5.14; 2 micrograms/mL, 1-mL amp = £10.28   Indications see notes above  Cautions see under Ergocalciferol  Contra-indications see under Ergocalciferol  Pregnancy see under Ergocalciferol  Breast-feeding see under Ergocalciferol  Side-effects see under Ergocalciferol  Dose   Tablets (chewable) (lemon or tutti-frutti flavour),  calcium carbonate 1.5 g (calcium 600 mg or Ca 2+   15 mmol), colecalciferol 10 micrograms (400 units),  net price 56-tab pack = £3.89, 112-tab pack = £7.78.  Label: 24   Dissolve (effervescent tablets), lemon flavour, cal-  cium carbonate 1.5 g (calcium 600 mg or Ca 2+   Tablets (chewable), lemon flavour, calcium carbonate  1.25 g (calcium 500 mg or Ca 2+ 12.5 mmol), colecal-  ciferol 10 micrograms (400 units), net price 60-tab  pack = £3.62. Label: 24    Calcichew-D 3 ® Forte Tablets (chewable), lemon  flavour, calcium carbonate 1.25 g (calcium 500 mg or  Ca 2+ 12.5 mmol), colecalciferol 10 micrograms  (400 units), net price 60-tab pack = £4.32, 100-tab  pack = £7.21. Label: 24   Calcichew-D 3 ® 500 mg/400 unit caplets, f/c, lemon  flavour, calcium carbonate providing calcium 500 mg,  colecalciferol 10 micrograms (400 units), net price  100-tab pack = £7.57   Powder, lemon flavour, calcium phosphate 3.1 g  (calcium 1.2 g or Ca 2+ 30 mmol), colecalciferol  20 micrograms (800 units), net price 30-sachet pack =  £4.32. Label: 13, 21   Tablets (chewable), (aniseed, peppermint, and  molasses flavour), calcium carbonate 1.5 g (calcium  600 mg or Ca 2+ 15 mmol), colecalciferol 10 micr-  ograms (400 units), net price 60-tab pack = £3.63.  Label: 24   Sandocal® +D 600 tablets, effervescent, orange  flavour, calcium lactate gluconate 1.36 g, calcium  carbonate 1.05 g, providing calcium 600 mg (Ca 2+   15 mmol), colecalciferol concentrate 4 mg, providing  colecalciferol 10 micrograms (400 units), net price 60-  tab pack = £5.35, 100-tab pack = £8.75. Label: 13   Sandocal® +D 1200 tablets, effervescent, orange  flavour, calcium lactate gluconate 2.72 g, calcium  carbonate 2.1 g, providing calcium 1200 mg (Ca 2+   30 mmol), colecalciferol concentrate 8 mg, providing  colecalciferol 20 micrograms (800 units), net price 30-  tab pack = £4.32. Label: 13   Calcichew-D 3 ® Tablets (chewable), orange flavour,  calcium carbonate 1.25 g (calcium 500 mg or Ca 2+  12.5 mmol), colecalciferol 5 micrograms (200 units),  net price 100-tab pack = £7.68. Label: 24    Indications see notes above  Cautions see under Ergocalciferol  Contra-indications see under Ergocalciferol  Pregnancy see under Ergocalciferol  Breast-feeding see under Ergocalciferol  Side-effects see under Ergocalciferol   Dose acute, chronic, and latent forms of hypocalcaemic tetany  due to hypoparathyroidism, consult product literature   Indications see under preparations below  Cautions monitor plasma calcium and phosphate  during dose titration and at least monthly when sta-  bilised; monitor parathyroid hormone concentration;  interactions: Appendix 1 (vitamins)  Contra-indications see under Ergocalciferol  Pregnancy toxicity in animal studies — manufacturer  advises avoid unless potential benefit outweighs risk;  see also under Ergocalciferol  Breast-feeding manufacturer advises caution — no  information available; see also under Ergocalciferol  Side-effects see under Ergocalciferol; also dyspepsia,  taste disturbance, breast tenderness, acne, pruritus,  and rash  Dose   Capsules, paricalcitol 1 microgram (grey), net price  28-cap pack = £69.44; 2 micrograms (orange-brown),  28-cap pack = £138.88; 4 micrograms (gold), 28-cap  pack = £277.76    For prevention and treatment of secondary hyperparathyroidism  associated with chronic renal failure    Injection, paricalcitol 5 micrograms/mL, net price 1-  mL amp = £12.40, 2-mL amp = £24.80. For injection  via haemodialysis access   The daily requirement of vitamin E has not been well  defined but is probably about 3 to 15 mg daily. There is  little evidence that oral supplements of vitamin E are  essential in adults, even where there is fat malabsorp-  tion secondary to cholestasis. In young children with  congenital cholestasis, abnormally low vitamin E con-  centrations may be found in association with neuro-  muscular abnormalities, which usually respond only to  the parenteral administration of vitamin E.   Vitamin E has been tried for various other conditions  but there is little scientific evidence of its value.   Cautions predisposition to thrombosis; increased risk  of necrotising enterocolitis in neonate weighing less  than 1.5 kg; interactions: Appendix 1 (vitamins)  Pregnancy no evidence of safety of high doses  Breast-feeding excreted in milk; minimal risk,  although caution with large doses  Side-effects diarrhoea and abdominal pain with doses  more than 1 g daily   Dose malabsorption in cystic fibrosis, 100-200 mg daily; CHILD 1  month-1 year 50 mg daily; 1-12 years, 100 mg daily  Malabsorption in abetalipoproteinaemia, ADULT and CHILD 50-  100 mg/kg daily   Malabsorption in chronic cholestasis and severe liver disease,  CHILD see BNF for Children   Renal impairment manufacturer advises caution and  monitor closely; risk of renal toxicity due to poly-  ethylene glycol content   Pregnancy manufacturer advises caution, no evidence  of harm in animal studies   Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — no information  available   Side-effects diarrhoea; less commonly asthenia,  headache, disturbances in serum-potassium and  serum-sodium concentrations, alopecia, pruritus, and  rash   Vedrop® (Orphan Europe) T (Ml  Oral solution, yellow, D-alpha tocopherol (as toco-  fersolan) 50 mg/mL, net price 20 mL = £54.55, 60 mL  = £163.65 (all with oral syringe)   Note Tocofersolan is a water-soluble form of D-alpha tocopherol  Dose CHILD under 18 years, 17 mg/kg daily, adjusted as neces-  sary   Vitamin K is necessary for the production of blood  clotting factors and proteins necessary for the normal  calcification of bone.   Because vitamin K is fat soluble, patients with fat mal-  absorption, especially in biliary obstruction or hepatic  disease, may become deficient. Menadiol sodium  phosphate is a water-soluble synthetic vitamin K deri-  vative that can be given orally to prevent vitamin K  deficiency in malabsorption syndromes.    Oral coumarin anticoagulants act by interfering with  vitamin K metabolism in the hepatic cells and their  effects can be antagonised by giving vitamin K; for  advice on the use of vitamin K in haemorrhage, see  section 2.8.2.   Vitamin K deficiency bleeding Neonates are rela-  tively deficient in vitamin K and those who do not  receive supplements of vitamin K are at risk of serious  bleeding including intracranial bleeding. The Chief Med-  ical Officer and the Chief Nursing Officer have recom-  mended that all newborn babies should receive vitamin  K to prevent vitamin K deficiency bleeding (previously  termed haemorrhagic disease of the newborn). An  appropriate regimen should be selected after discussion  with parents in the antenatal period.   Vitamin K (as phytomenadione) 1 mg may be given by  a single intramuscular injection at birth; this prevents  vitamin K deficiency bleeding in virtually all babies. For  preterm neonates, see BNF for Children.   Alternatively, in healthy babies who are not at particular  risk of bleeding disorders, vitamin K may be given by  mouth, and arrangements must be in place to ensure the  appropriate regimen is followed. Two doses of a colloi-  dal (mixed micelle) preparation of phytomenadione  2 mg should be given by mouth in the first week, the  first dose being given at birth and the second dose at 4-  7 days. For exclusively breast-fed babies, a third dose of  colloidal phytomenadione 2 mg is given by mouth at 1  month of age; the third dose is omitted in formula-fed  babies because formula feeds contain adequate vitamin  K. An alternative regimen is to give one dose of phyto-  menadione 1 mg by mouth at birth (using the contents  of a phytomenadione capsule, see preparation below) to  protect from the risk of vitamin K deficiency bleeding in  the first week; for exclusively breast-fed babies, further  doses of phytomenadione 1 mg are given by mouth  (using the contents of a phytomenadione capsule) at  weekly intervals for 12 weeks.   Indications see notes above  Cautions G6PD deficiency (section 9.1.5) and vitamin  E deficiency (risk of haemolysis); interactions:  Appendix 1 (vitamins)   Contra-indications neonates and infants  Pregnancy avoid in late pregnancy and labour unless  benefit outweighs risk of neonatal haemolytic anae-  mia, hyperbilirubinaemia, and kernicterus in neonate  Dose   • 10-40 mg daily, adjusted as necessary; CHILD 1-12  years, 5-10 mg daily, adjusted as necessary, 12-18  years, 10-20 mg daily, adjusted as necessary   Tablets, menadiol sodium phosphate equivalent to  10 mg of menadiol phosphate, net price 100-tab pack  = £58.39   Cautions intravenous injections should be given very  slowly (see also below); interactions: Appendix 1  (vitamins)   Neokay® (Neoceuticals) (Ml  Capsules, brown, phytomenadione 1 mg in an oily  basis, net price 12-cap pack = £3.95; 100-cap pack =  £34.00   Note The contents of one capsule should be administered by  cutting the narrow tubular tip off and squeezing the liquid con-  tents into the mouth; if the baby spits out the dose or is sick within  three hours of administration a replacement dose should be given   Excipients include glycocholic acid 54.6mg/amp, lecithin  Cautions reduce dose in elderly; liver impairment (glycocholic  acid may displace bilirubin); reports of anaphylactoid reactions  Note Konakion ® MM may be administered by slow intravenous  injection or by intravenous infusion in glucose 5% (see Appendix  6); not for intramuscular injection   Excipients include glycocholic acid 10.9 mg/ amp, lecithin  Cautions parenteral administration in neonate of less than 2.5 kg  (increased risk of kernicterus)   Note Konakion ® MM Paediatric may be administered by mouth  or by intramuscular injection or by intravenous injection   Capsules, ascorbic acid 15 mg, nicotinamide 7.5 mg,  riboflavin 500 micrograms, thiamine hydrochloride  lmg, vitamin A 2500 units, vitamin D 300 units, net  price 28-cap pack = £1.50   Drops, vitamins A, B group, C, and D, net price 25 mL  (with dropper) = £2.20   Note Contains 1333 units of vitamin A (as palmitate) per 0.6-mL  dose   Oral drops, vitamins A, B group, C, and D, net price  25 mL = £2.98, 50 mL = £4.85  Note Contains 5000 units of vitamin A (as palmitate) per 0.6-  mL dose   Capsules, brown/red, vitamins (ascorbic acid 60 mg,  biotin 100 micrograms, cyanocobalamin 3 micr-  ograms, folic acid 400 micrograms, nicotinamide  18 mg, pantothenic acid 4 mg, pyridoxine 2 mg, ribo-  flavin 1.6 mg, thiamine 1.2 mg, vitamin A 2500 units,  vitamin D 2 400 units, vitamin E 10 mg, minerals and  trace elements (calcium 100 mg, chromium  200 micrograms, copper 2 mg, iodine 140 micr-  ograms, iron 12 mg, magnesium 30 mg, manganese    3 mg, molybdenum 250 micrograms, phosphorus  77 mg, potassium 4 mg, selenium 50 micrograms, zinc  15 mg), net price 15-cap pack = £2.83, 30-cap pack =  £5.19, 90-cap pack = £12.53. Label: 25  Dose vitamin and mineral deficiency and as adjunct in synthetic  diets, ADULT 1 capsule daily one hour after a meal   Junior capsules, brown, vitamins (ascorbic acid  25 mg, biotin 50 micrograms, cyanocobalamin  2 micrograms, folic acid 100 micrograms, nicotin-  amide 7.5 mg, pantothenic acid 2 mg, pyridoxine  1 mg, riboflavin 1 mg, thiamine 1.5 mg, vitamin A  1250 units, vitamin D 2 200 units, vitamin E 5 mg, vit-  amin Kj 25 micrograms), minerals and trace elements  (chromium 50 micrograms, copper lmg, iodine  75 micrograms, iron 5 mg, magnesium 1 mg, manga-  nese 1.25 mg, molybdenum 50 micrograms, selenium  25 micrograms, zinc 5 mg), net price 30-cap pack =  £3.52, 60-cap pack = £6.69   Tablets (Ml, yellow, ascorbic acid 16.6 mg, riboflavin  1 mg, thiamine hydrochloride 1 mg, pyridoxine  hydrochloride 330 micrograms, nicotinamide 3.3 mg,  calcium pantothenate 1.16 mg, alpha tocopheryl  acetate 5 mg, inositol 50 mg, biotin 170 micrograms,  folic acid 250 micrograms, acetomenaphthone  500 micrograms, net price 100-tab pack = £4.17  Dose prevention of vitamin deficiency in disorders of carbohy-  drate or amino-acid metabolism and adjunct in restricted, spe-  cialised, or synthetic diets, 1 tablet 3 times daily; use with  Ketovite ® Liquid for complete vitamin supplementation   Liquid, pink, sugar-free, vitamin A 2500 units, ergo-  calciferol 400 units, choline chloride 150 mg, cyano-  cobalamin 12.5 micrograms/5 mL, net price 150-mL  pack = £2.70   Dose prevention of vitamin deficiency in disorders of carbohy-  drate or amino-acid metabolism and adjunct in restricted, spe-  thetic diets, 5 mL daily; use with Ketovite ® Tablets  itamin supplementation    Mixtures containing simple and aromatic bitters are  traditional remedies for loss of appetite; there is no  evidence to support their use.   This section covers drugs used in metabolic disorders  and not readily classified elsewhere.   Penicillamine (see also section 10.1.3) is used in  Wilson’s disease (hepatolenticular degeneration) to aid   Trientine is used for the treatment of Wilson’s disease  only in patients intolerant of penicillamine; it is not an  alternative to penicillamine for rheumatoid arthritis or  cystinuria. Penicillamine-induced systemic lupus  erythematosus may not resolve on transfer to trientine.   Zinc prevents the absorption of copper in Wilson’s  disease. Symptomatic patients should be treated initially  with a chelating agent because zinc has a slow onset of  action. When transferring from chelating treatment to  zinc maintenance therapy, chelating treatment should  be co-administered for 2-3 weeks until zinc produces its  maximal effect.   • Wilson’s disease, 1.5-2 g daily in divided doses before  food; max. 2g daily for 1 year; maintenance 0.75-1 g  daily; ELDERLY 20 mg/kg daily in divided doses,  adjusted according to response; CHILD under 12 years  see BNF for Children   • Autoimmune hepatitis (used rarely; after disease  controlled with corticosteroids), initially 500 mg daily  in divided doses increased slowly over 3 months;  usual maintenance dose 1.25 g daily; ELDERLY not  recommended   • Cystinuria, therapeutic, 1-3 g daily in divided doses  before food, adjusted to maintain urinary cystine  below 200 mg/litre; prophylactic (maintain urinary  cystine below 300 mg/litre) 0.5-1 g at bedtime;  maintain adequate fluid intake (at least 3 litres daily);  CHILD and ELDERLY minimum dose to maintain urinary  cystine below 200 mg/litre   Pregnancy manufacturer advises use only if potential  benefit outweighs risk; monitor maternal and neonatal  serum-copper concentration; teratogenic in animal  studies   • ADULT and CHILD over 12 years, 1. 2-2.4 g daily in 2-4  divided doses before food; CHILD 2-12 years, initially  0.6-1. 5 g daily in 2-4 divided doses before food,  adjusted according to response   Trientine Dihydrochloride (Univar) Ml  Capsules, trientine dihydrochloride 300 mg. Label: 6,  22   Cautions portal hypertension (risk of hepatic decom-  pensation when switching from chelating agent);  monitor full blood count and serum cholesterol;  interactions: Appendix 1 (zinc)   Pregnancy reduce dose to 25 mg 3 times daily  adjusted according to plasma-copper concentration  and urinary copper excretion   Side-effects gastric irritation (usually transient; may  be reduced if first dose taken mid-moming or with a  little protein); less commonly sideroblastic anaemia  and leucopenia   • Wilson’s disease, 50 mg 3 times daily (max. 50 mg 5  times daily), adjusted according to response; CHILD 1-  6 years, 25 mg twice daily; 6-16 years, body-weight  under 57 kg, 25 mg 3 times daily, body-weight over  57 kg, 50 mg 3 times daily; ADOLESCENT 16-18 years,  50 mg 3 times daily   Wilzin® (Orphan Europe) (Ml  Capsules, zinc (as acetate) 25 mg (blue), net price  250-cap pack = £132.00; 50 mg (orange), 250-cap  pack = £242.00. Label: 23   Carnitine is available for the management of primary  carnitine deficiency due to inborn errors of metabolism  or of secondary deficiency in haemodialysis patients.   Cautions diabetes mellitus; monitoring of free and  acyl carnitine in blood and urine recommended   Renal impairment accumulation of metabolites may  occur with chronic oral administration in severe  impairment   Pregnancy appropriate to use; no evidence of terato-  genicity in animal studies   Side-effects nausea, vomiting, abdominal pain, diarr-  hoea, body odour; side-effects may be dose-related —  monitor tolerance during first week and after any dose  increase   • Primary deficiency, by mouth, up to 200 mg/kg daily  in 2-4 divided doses; higher doses of up to 400 mg/kg  daily occasionally required; usual max. 3 g daily; by    intravenous injection over 2-3 minutes, up to  100 mg/kg daily in 3-4 divided doses  • Secondary deficiency, by intravenous injection over  2-3 minutes, 20 mg/kg after each dialysis session  (dosage adjusted according to plasma-camitine con-  centration); maintenance (if benefit gained from first  intravenous course), by mouth, 1 g daily   Carnitor® (Sigma-Tau) (Ml  Tablets, L-camitine 330 mg, net price 90-tab pack =  £103.95   Chewable tablets, L-camitine 1 g, net price 10-tab  pack = £35.00   Oral liquid, L-camitine lOOmg/mL (10%), net price  10 x 10-mL (1-g) single-dose bottle = £35.00  Paediatric oral solution, L-camitine 300mg/mL  (30%), net price 20 mL = £21.00  Injection, L-camitine 200mg/mL, net price 5-mL  amp = £11.90   Agalsidase alfa and agalsidase beta, enzymes pro-  duced by recombinant DNA technology, are licensed  for long-term enzyme replacement therapy in Fabry’s  disease (a lysosomal storage disorder caused by defi-  ciency of alpha-galactosidase A).   Infusion-related reactions Infusion-related reactions very  common; manage by slowing the infusion rate or interrupt-  ing the infusion, or minimise by pre-treatment with an anti-  histamine, antipyretic, or corticosteroid — consult product  literature    Side-effects gastro-intestinal disturbances, taste dis-  turbances; tachycardia, bradycardia, palpitation,  hypertension, hypotension, chest pain, oedema,  flushing; dyspnoea, cough, rhinorrhoea; headache,  fatigue, dizziness, asthenia, paraesthesia, syncope,  neuropathic pain, tremor, sleep disturbances; influ-  enza-like symptoms, nasopharyngitis; muscle spasms,  myalgia, arthralgia; eye irritation; tinnitus; hyper-  sensitivity reactions, angioedema, pruritus, urticaria,  rash, acne; less commonly cold extremities, parosmia,  ear pain and swelling, skin discoloration, and injec-  tion-site reactions    Fabrazyme® (Genzyme) Ml  Intravenous infusion, powder for reconstitution,  agalsidase beta, net price 5-mg vial = £315.08; 35-mg  vial = £2196.59   Dose By intravenous infusion, ADULT and CHILD over 8 years  1 mg/kg every 2 weeks   Replagal® (Shire HGT) fMl  Concentrate for intravenous infusion, agalsidase  alfa 1 mg/mL, net price 1-mL vial = £356.85; 3. 5-mL  vial = £1068.64   Dose By intravenous infusion, ADULT and CHILD over 7 years  200 micrograms/kg every 2 weeks   Imiglucerase, an enzyme produced by recombinant  DNA technology, is administered as enzyme replace-  ment therapy for non-neurological manifestations of  type I or type III Gaucher’s disease, a familial disorder  affecting principally the liver, spleen, bone marrow, and  lymph nodes.   Velaglucerase alfa, an enzyme produced by recombi-  nant DNA technology, is administered as enzyme repla-  cement therapy for the treatment of type I Gaucher’s  disease.   Miglustat, an inhibitor of glucosylceramide synthase, is  licensed for the treatment of mild to moderate type I  Gaucher’s disease in patients for whom enzyme repla-  cement therapy is unsuitable; it is given by mouth; see  p. 627.    Indications (specialist use only) non-neurological  manifestations of type I or type III Gaucher’s disease  Cautions monitor for imiglucerase antibodies; when  stabilised, monitor all parameters and response to  treatment at intervals of 6-12 months  Pregnancy manufacturer advises use with caution —  limited information available  Breast-feeding no information available  Side-effects hypersensitivity reactions (including  urticaria, angioedema, cyanosis, hypotension, flush-  ing, tachycardia, paraesthesia, backache); less com-  monly nausea, vomiting, diarrhoea, abdominal  cramps, headache, dizziness, fatigue, fever, arthralgia,  and injection-site reactions  Dose   • By intravenous infusion, initially 60 units/kg once  every 2 weeks (doses as low as 15 units/kg once  every 2 weeks may improve haematological para-  meters and organomegaly, but not bone parameters);  maintenance, adjust dose according to response    Cerezyme® (Genzyme) (Mi  Intravenous infusion, powder for reconstitution,  imiglucerase, net price 200-unit vial = £535.65; 400-  unit vial = £1071.29   Cautions monitor immunoglobulin G (IgG) antibody  concentration in severe infusion-related reactions or if  there is a lack or loss of effect with velaglucerase alfa  Infusion-related reactions Infusion-related reactions very  common; manage by slowing the infusion rate, or inter-  rupting the infusion, or minimise by pre-treatment with an  antihistamine, antipyretic, or corticosteroid — consult pro-  duct literature   Side-effects nausea, abdominal pain, tachycardia,  hypertension, hypotension, flushing, headache, dizzi-  ness, malaise, pyrexia, arthralgia, bone pain, back  pain, hypersensitivity reactions, rash, urticaria   • By intravenous infusion, ADULT and CHILD over 4 years,  60 units/kg once every 2 weeks; adjusted according  to response to 15-60 units/kg once every 2 weeks   Intravenous infusion, powder for reconstitution,  velaglucerase alfa, net price 400-unit vial = £1410.20   Laronidase, an enzyme produced by recombinant DNA  technology, is licensed for long-term replacement ther-  apy in the treatment of non-neurological manifestations  of mucopolysaccharidosis I, a lysosomal storage disor-  der caused by deficiency of alpha-L-iduronidase.   Idursulfase, an enzyme produced by recombinant DNA  technology, is licensed for long-term replacement ther-  apy in mucopolysaccharidosis II (Hunter syndrome), a  lysosomal storage disorder caused by deficiency of  iduronate-2-sulfatase.   Galsulfase, a recombinant form of human N-acetylga-  lactosamine-4-sulfatase, is licensed for long-term repla-  cement therapy in mucopolysaccharidosis VI (Maro-  teaux-Lamy syndrome).   Infusion-related reactions Infusion-related reac-  tions often occur with administration of laronidase,  idursulfase, and galsulfase; they can be managed by  slowing the infusion rate or interrupting the infusion,  and can be minimised by pre-treatment with an anti-  histamine and an antipyretic. Recurrent infusion-related  reactions may require pre-treatment with a cortico-  steroid — consult product literature for details.   Side-effects abdominal pain, umbilical hernia, gas-  troenteritis; chest pain, hypertension; dyspnoea,  apnoea, nasal congestion; rigors, malaise, areflexia;  pharyngitis; conjunctivitis, corneal opacity; ear pain;  facial oedema  Dose   • By intravenous infusion, ADULT and CHILD over 5 years,  1 mg/kg once weekly   Naglazyme® (BioMarin) T (Ml  Concentrate for intravenous infusion, galsulfase  1 mg/mL, net price 5-mL vial = £982.00   Cautions severe respiratory disease; acute febrile  respiratory illness (consider delaying treatment)  Infusion-related reactions See notes above   Side-effects gastro-intestinal disturbances, swollen  tongue; arrhythmia, tachycardia, chest pain, cyanosis,  peripheral oedema, hypertension, hypotension,  flushing; bronchospasm, hypoxia, cough, wheezing,  tachypnoea, dyspnoea; headache, dizziness, tremor;  pyrexia; arthralgia; facial oedema, urticaria, pruritus,  rash, infusion-site swelling, erythema; pulmonary  embolism and anaphylaxis also reported  Dose   • By intravenous infusion, ADULT and CHILD over 5 years,  500 micrograms/kg once weekly   Elaprase® (Shire HGT) ▼ (Ml  Concentrate for intravenous infusion, idursulfase  2mg/mL, net price 3-mL vial = £1985.00   Indications (specialist use only) non-neurological  manifestations of mucopolysaccharidosis I  Cautions monitor immunoglobulin G (IgG) antibody  concentration; interactions: Appendix 1 (laronidase)  Infusion-related reactions See notes above  Pregnancy manufacturer advises avoid unless essen-  tial — no information available  Breast-feeding manufacturer advises avoid — no  information available   Side-effects nausea, vomiting, diarrhoea, abdominal  pain; cold extremities, pallor, flushing, tachycardia,  blood pressure changes; dyspnoea, cough, angio-  edema, anaphylaxis; headache, paraesthesia, dizzi-  ness, fatigue, restlessness; influenza-like symptoms;  musculoskeletal pain, pain in extremities; rash, pru-  ritus, urticaria, alopecia, infusion-site reactions;  bronchospasm and respiratory arrest also reported  Dose   Aldurazyme® (Genzyme) T (Ml  Concentrate for intravenous infusion, laronidase  lOOunits/mL, net price 5-mL vial = £444.70   Side-effects breath and body odour, nausea, vomi-  ting, diarrhoea, anorexia, lethargy, fever, rash; also  reported dehydration, hypertension, abdominal dis-  comfort, gastroenteritis, drowsiness, encephalopathy,  headache, nervousness, depression; anaemia, leuco-  penia; rarely gastro-intestinal ulceration and bleeding,  seizures, hallucinations, urticaria, interstitial nephritis  Dose   • Initial doses should be one-sixth to one-quarter of the  expected maintenance dose, increased gradually over  4-6 weeks   • Maintenance, ADULT and CHILD over 50 kg body-  weight, 2 g daily in 4 divided doses   CHILD up to 12 years, 1.3 g/m 2 (approx. 50 mg/kg)  daily in 4 divided doses   Cystagon® (Orphan Europe) (Ml  Capsules, mercaptamine (as bitartrate) 50 mg, net  price 100-cap pack = £70.00; 150 mg, 100-cap pack =  £190.00   Note CHILD under 6 years at risk of aspiration, capsules can be  opened and contents sprinkled on food (at a temperature suitable  for eating); avoid adding to acidic drinks (e.g. orange juice)   Alglucosidase alfa, an enzyme produced by recombi-  nant DNA technology, is licensed for long-term replace-  ment therapy in Pompe disease, a lysosomal storage  disorder caused by deficiency of acid alpha-glucosidase.   Infusion-related reactions Infusion-related reactions very  common, calling for use of antihistamine, antipyretic, or  corticosteroid; consult product literature for details  Pregnancy toxicity in animal studies, but treatment  should not be withheld    Side-effects nausea, vomiting, diarrhoea; flushing,  tachycardia, blood pressure changes, cold extremities,  cyanosis, facial oedema, chest discomfort; cough,  tachypnoea, bronchospasm; headache, agitation, tre-  mor, irritability, restlessness, paraesthesia, dizziness,  fatigue; pyrexia; antibody formation; myalgia, muscle  spasm; sweating, rash, pruritus, urticaria, injection-  site reactions; hypersensitivity reactions (including  anaphylaxis); severe skin reactions (including ulcer-  ative and necrotising skin lesions) also reported  Dose    • By intravenous infusion, ADULT and CHILD 20 mg/kg  every 2 weeks    Myozyme® (Genzyme) T (Ml  Intravenous infusion, powder for reconstitution,  alglucosidase alfa, net price 50-mg vial = £356.06   Nitisinone is licensed for the treatment of hereditary  tyrosinaemia type I in combination with dietary restric-  tion of tyrosine and phenylalanine.   Cautions slit-lamp examination of eyes recommended  before treatment; monitor liver function regularly;  monitor platelet and white blood cell count every 6  months   Side-effects thrombocytopenia, leucopenia, granulo-  cytopenia; conjunctivitis, photophobia, corneal opa-  city, keratitis, eye pain; less commonly leucocytosis,  blepharitis, pruritus, exfoliative dermatitis, and  erythematous rash   • ADULT and CHILD initially 500 micrograms /kg twice  daily, adjusted according to response; max. 2 mg/kg  daily   Note Capsules can be opened and the contents suspended in  a small amount of water or formula diet and taken immedi-  ately   Orfadin® (Swedish Orphan) (Ml  Capsules, nitisinone 2 mg, net price 60-cap pack =  £564.00; 5 mg, 60-cap pack = £1 127.00; 10 mg, 60-cap  pack = £2062.00   Sodium phenylbutyrate is used in the management of  urea cycle disorders. It is indicated as adjunctive ther-  apy in all patients with neonatal-onset disease and in  those with late-onset disease who have a history of  hyperammonaemic encephalopathy.    Carglumic acid is licensed for the treatment of hyper-  ammonaemia due to 7V-acetylglutamate synthase defi-  ciency.   • ADULT and CHILD initially 100-250 mg/kg daily in 2-4  divided doses immediately before food, adjusted  according to plasma-ammonia concentration; main-  tenance 10-100 mg/kg daily in 2-4 divided doses   Dispersible tablets, carglumic acid 200 mg, net price  5-tab pack = £299.00, 60-tab pack = £3499.00.   Indications adjunct in long-term treatment of urea  cycle disorders (under specialist supervision)  Cautions congestive heart failure; interactions:   Side-effects gastro-intestinal disturbances, weight  gain, taste disturbance, decreased appetite; syncope,  oedema; headache, depression, irritability; renal tub-  ular acidosis, menstrual disorders; blood disorders,  metabolic acidosis, alkalosis; rash, body odour; less  commonly rectal bleeding, peptic ulcer, pancreatitis,  and arrhythmias  Dose   • ADULT and CHILD body-weight over 20 kg, 9.9-13 g/m 2  daily in divided doses with meals (max. 20 g daily);  CHILD body-weight less than 20 kg, 450-600 mg/kg  daily in divided doses with meals   Betaine is licensed for the adjunctive treatment of  homocystinuria involving deficiencies or defects in  cystathionine beta-synthase, 5,10-methylene-tetrahy-  drofolate reductase, or cobalamin cofactor metabolism.  Betaine should be used in conjunction with dietary  restrictions and may be given with supplements of Vit-  amin B 12 , pyridoxine, and folate under specialist advice.   The Scottish Medicines Consortium (p. 4) has advised  (July 2010) that betaine anhydrous ( Cystadane ®) is  accepted for restricted use within NHS Scotland for the  adjunctive treatment of homocystinuria involving defi-  ciencies or defects in cystathionine beta-synthase, 5,10-  methylene-tetrahydrofolate reductase, or cobalamin  cofactor metabolism in patients who are not responsive  to pyridoxine treatment.   Cautions monitor plasma-methionine concentration  before and during treatment — interrupt treatment if  symptoms of cerebral oedema occur   Side-effects less commonly gastro-intestinal disor-  ders, anorexia, reversible cerebral oedema (see Cau-    tions), agitation, depression, personality disorder,  sleep disturbances, urinary incontinence, alopecia,  and urticaria   • ADULT and CHILD over 10 years, 3 g twice daily, adjusted  according to response; max. 20 g/day; CHILD under 10  years 50 mg/kg twice daily, dose and frequency  adjusted according to response; max. 75 mg/kg twice  daily   Cystadane® (Orphan Europe) (Ml  Powder, betaine (anhydrous), net price 180 g =  £347.00   Note Powder should be mixed with water, juice, milk, formula, or  food until completely dissolved and taken immediately; measuring  spoons are provided to measure 1 g, 150 mg, and 100 mg of  powder   Miglustat is available for the treatment of progressive  neurological manifestations of Niemann-Pick type C  disease, a neurodegenerative disorder characterised by  impaired intracellular lipid trafficking; it is also licensed  for the treatment of mild to moderate type 1 Gaucher’s  disease for whom imiglucerase is unsuitable, see also  p. 624.   Indications mild to moderate type I Gaucher’s disease  (specialist supervision only); Niemann-Pick type C  disease (specialist supervision only)   Cautions monitor cognitive and neurological function;  monitor growth and platelet count in Niemann-Pick  type C disease   1.73 m 2 ; initially 100 mg once daily if eGFR 30-  50mL/minute/1.73m 2 ; for Niemann-Pick type C  disease, initially 200 mg twice daily if eGFR 50-  70mL/minute/1.73m 2 ; initially 100 mg twice daily if  eGFR 30-50 mL/minute/ 1.73 m 2 ; child under 12  years — consult product literature; avoid if eGFR less  than 30 mL/minute/ 1.73 m 2   Pregnancy manufacturer advises avoid (toxicity in  animal studies) — effective contraception must be  used during treatment; also men should avoid  fathering a child during and for 3 months after treat-  ment   Side-effects diarrhoea, flatulence, abdominal pain,  dyspepsia, constipation, nausea, vomiting, anorexia,  weight changes; tremor, dizziness, headache, periph-  eral neuropathy, ataxia, hypoaesthesia, paraesthesia,  insomnia, fatigue, asthenia; decreased libido; throm-  bocytopenia; muscle spasm   • Gaucher’s disease, ADULT over 18 years, 100 mg 3  times daily; reduced if not tolerated to 100 mg 1-2  times daily   • Niemann-Pick type C disease, ADULT and CHILD over 12  years, 200 mg 3 times daily; CHILD 4-12 years, body  surface area less than 0.47 m 2 , 100 mg once daily;  body surface area 0.47-0.73 m 2 , 100 mg twice daily;    body surface area 0.73-0.88 m 2 , 100 mg three times  daily; body surface area 0.88-1.25 m 2 , 200 mg twice  daily; body surface area greater than 1.25 m 2 , adult  dose   The acute porphyrias (acute intermittent porphyria,  variegate porphyria, hereditary coproporphyria, and 5-  aminolaevulinic acid dehydratase deficiency porphyria)  are hereditary disorders of haem biosynthesis; they have  a prevalence of about 1 in 10 000 of the population.   Great care must be taken when prescribing for patients  with acute porphyria, since certain drugs can induce  acute porphyric crises. Since acute porphyrias are  hereditary, relatives of affected individuals should be  screened and advised about the potential danger of  certain drugs.   Treatment of serious or life-threatening conditions  should not be withheld from patients with acute por-  phyria. When there is no safe alternative, treatment  should be started and urinary porphobilinogen excre-  tion should be measured regularly; if it increases or  symptoms occur, the drug can be withdrawn and the  acute attack treated. If an acute attack of porphyria  occurs during pregnancy, contact an expert porphyria  service for further advice.   Haem arginate is administered by short intravenous  infusion as haem replacement in moderate, severe, or  unremitting acute porphyria crises.   Supplies of haem arginate may be obtained in an emer-  gency outside office hours from the on-call pharmacist  at:   Indications acute porphyrias (acute intermittent por-  phyria, porphyria variegata, hereditary copropor-  phyria)   Side-effects rarely hypersensitivity reactions and  fever; pain and thrombophlebitis at injection site   • By intravenous infusion, ADULT and CHILD 3 mg/kg  once daily (max. 250 mg daily) for 4 days; if response  inadequate, repeat 4-day course with close biochem-  ical monitoring   Normosang® (Orphan Europe) ▼ (Ml  Concentrate for intravenous infusion, haem arginate  25mg/mL, net price 10-mL amp = £434.25    The following list contains drugs on the UK market that  have been classified as ‘unsafe’ in porphyria because  they have been shown to be porphyrinogenic in animals  or in vitro, or have been associated with acute attacks in  patients. Absence of a drug from the following lists does  not necessarily imply that the drug is safe. For many  drugs no information about porphyria is available.   An up-to-date list of drugs considered safe in acute  porphyrias is available at www.wmic.wales.nhs.uk/  porphyria_info.php   Welsh Medicines Information Centre  University Hospital of Wales  Cardiff, CF14 4XW  Tel: (029) 2074 2979/3877   Note Quite modest changes in chemical structure can lead to  changes in porphyrinogenicity but where possible general  statements have been made about groups of drugs; these  should be checked first.   2. Includes tricyclic (and related) antidepressants and MAOIs; fluoxetine, venlafaxine, and mianserin thought to be safe.   3. Alimemazine, chlorphenamine, desloratadine, fexofenadine, ketotifen, loratadine, and promethazine thought to be safe.   6. Progestogens are more porphyrinogenic than oestrogens; oestrogens may be safe at least in replacement doses. Progestogens  should be avoided whenever possible by all women susceptible to acute porphyria; however, when non-hormonal  contraception is inappropriate, progestogens may be used with extreme caution if the potential benefit outweighs risk. The  risk of an acute attack is greatest in women who have had a previous attack or are aged under 30 years. Long-acting  progestogen preparations should never be used in those at risk of acute porphyria.   8. Applies to oral and intravenous use; topical antifungals are thought to be safe due to low systemic exposure.   15. When used for local anaesthesia, articaine, bupivacaine, lidocaine, prilocaine, and tetracaine are thought to be safe.   17. Buprenorphine, codeine, diamorphine, dihydrocodeine, fentanyl, methadone, morphine, pethidine, and tramadol are thought  to be safe.   18. Rifamycins have been used in a few patients without evidence of harm — use with caution if safer alternative not available.   Drugs for the relief of soft-tis-  sue inflammation and topical  pain relief    This chapter also includes advice on the drug man-  agement of the following:   myasthenia gravis, p. 657  osteoarthritis and soft-tissue disorders, below  rheumatoid arthritis and other inflammatory  disorders, below   A non-steroidal anti-inflammatory drug (NSAID) is  indicated for pain and stiffness resulting from inflamm-  atory rheumatic disease; analgesics such as paraceta-  mol or codeine can also be used. For advice on the  prophylaxis and treatment of NSAID-associated gastro-  intestinal ulcers, see p. 50.    Drugs are also used to influence the rheumatic disease  process itself (section 10.1.3). For rheumatoid arthritis  these disease-modifying antirheumatic drugs  (DMARDs) include methotrexate, cytokine modulators,  azathioprine, ciclosporin, cyclophosphamide, lefluno-  mide, penicillamine, gold, antimalarials (chloroquine  and hydroxychloroquine), and sulfasalazine. Corticos-  teroids also have a significant role in the management  of rheumatoid arthritis (section 10.1.2.1).   Drugs which may affect the disease process in psoriatic  arthritis include sulfasalazine, gold salts, azathioprine,  methotrexate, and cytokine modulators (section 10.1.3).  For long-term control of gout, uricosuric drugs and  allopurinol (section 10.1.4) can be used.   For pain relief in osteoarthritis and soft-tissue disorders,  paracetamol (section 4.7.1) should be used first and  may need to be taken regularly. A topical NSAID  (section 10.3.2) or topical capsaicin 0.025% (section  10.3.2) should also be considered, particularly in knee or  hand osteoarthritis. An oral NSAID (section 10.1.1) can  be substituted for, or used in addition to, paracetamol. If  further pain relief is required in osteoarthritis, then the  addition of an opioid analgesic (section 4.7.2) may be  considered, but with a substantial risk of adverse effects;  however, an opioid analgesic should be considered    before a NSAID in patients taking low-dose aspirin. For  advice on the prophylaxis and treatment of NSAID-  associated gastro-intestinal ulcers, see p. 50.  Intra-articular corticosteroid injections (section  10.1.2.2) may produce temporary benefit in osteoarth-  ritis, especially if associated with soft-tissue inflamma-  tion.   Non-drug measures, such as weight reduction and exer-  cise, should also be encouraged.   Glucosamine (section 10.1.5) and rubefacients (sec-  tion 10.3.2) are not recommended for the treatment of  osteoarthritis.   Hyaluronic acid and its derivatives are available for  osteoarthritis of the knee, but are not recommended.  Sodium hyaluronate ( Durolane ®, Euflexxa®,  Fermathron®, Hyalgan® {&&[ Orthovisc®, Ostenil®,  Suplasyn ® , Synocrom ® , Synopsis ®) or hylan G-F 20  ( Synvisc ®) is injected intra-articularly to supplement  natural hyaluronic acid in the synovial fluid. These  injections may reduce pain over 1-6 months, but are  associated with a short-term increase in knee inflam-  mation.   In single doses non-steroidal anti-inflammatory drugs  (NSAIDs) have analgesic activity comparable to that of  paracetamol (section 4.7.1), but paracetamol is pre-  ferred, particularly in the elderly (see also Prescribing  for the Elderly, p. 25).   In regular full dosage NSAIDs have both a lasting  analgesic and an anti-inflammatory effect which  makes them particularly useful for the treatment of  continuous or regular pain associated with inflamma-  tion. Therefore, although paracetamol often gives ade-  quate pain control in osteoarthritis, NSAIDs are more  appropriate than paracetamol or the opioid analgesics  in the inflammatory arthritides (e.g. rheumatoid arth-  ritis) and in some cases of advanced osteoarthritis.  NSAIDs can also be of benefit in the less well defined  conditions of back pain and soft-tissue disorders.   Choice Differences in anti-inflammatory activity  between NSAIDs are small, but there is considerable  variation in individual response and tolerance to these  drugs. About 60% of patients will respond to any  NSAID; of the others, those who do not respond to  one may well respond to another. Pain relief starts soon  after taking the first dose and a full analgesic effect  should normally be obtained within a week, whereas an  anti-inflammatory effect may not be achieved (or may  not be clinically assessable) for up to 3 weeks. If appro-  priate responses are not obtained within these times,  another NSAID should be tried.   NSAIDs reduce the production of prostaglandins by  inhibiting the enzyme cyclo-oxygenase. They vary in    their selectivity for inhibiting different types of cyclo-  oxygenase; selective inhibition of cyclo-oxygenase-2 is  associated with less gastro-intestinal intolerance. Sev-  eral other factors also influence susceptibility to gastro-  intestinal effects, and a NSAID should be chosen on the  basis of the incidence of gastro-intestinal and other side-  effects.   Ibuprofen is a propionic acid derivative with anti-  inflammatory, analgesic, and antipyretic properties. It  has fewer side-effects than other non-selective NSAIDs  but its anti-inflammatory properties are weaker. Doses  of 1.6 to 2.4 g daily are needed for rheumatoid arthritis  and it is unsuitable for conditions where inflammation is  prominent, such as acute gout. Dexibuprofen is the  active enantiomer of ibuprofen. It has similar properties  to ibuprofen and is licensed for the relief of mild to  moderate pain and inflammation.   Naproxen is one of the first choices because it com-  bines good efficacy with a low incidence of side-effects  (but more than ibuprofen, see CSM comment below).  Fenbufen is claimed to be associated with less gastro-  intestinal bleeding, but there is a high risk of rash (see  p. 635).   Fenoprofen is as effective as naproxen, and flurbipro-  fen may be slightly more effective. Both are associated  with slightly more gastro-intestinal side-effects than  ibuprofen.   Ketoprofen has anti-inflammatory properties similar to  ibuprofen and has more side-effects (see also CSM  advice below). Dexketoprofen, an isomer of ketopro-  fen, has been introduced for the short-term relief of mild  to moderate pain.   Tiaprofenic acid is as effective as naproxen; it has more  side-effects than ibuprofen (important: reports of  severe cystitis, see CSM advice on p. 640).   Diclofenac and aceclofenac have actions and side-  effects similar to those of naproxen.   Etodolac is comparable in efficacy to naproxen; it is  licensed for symptomatic relief of osteoarthritis and  rheumatoid arthritis.   Indometacin has an action equal to or superior to that  of naproxen, but with a high incidence of side-effects  including headache, dizziness, and gastro-intestinal dis-  turbances (see also CSM advice below).   Mefenamic acid has minor anti-inflammatory proper-  ties. It has occasionally been associated with diarrhoea  and haemolytic anaemia which require discontinuation  of treatment.   Meloxicam is licensed for the short-term relief of pain  in osteoarthritis and for long-term treatment of rheu-  matoid arthritis and ankylosing spondylitis.   Phenylbutazone is licensed for ankylosing spondylitis,  but is not recommended because it is associated with  serious side-effects, in particular haematological reac-  tions; it should be used only by a specialist in severe  cases where other treatments have been found unsui-  table.   Piroxicam is as effective as naproxen and has a long  duration of action which permits once-daily administra-    NSAIDs and cardiovascular events  Cyclo-oxygenase-2 selective inhibitors are asso-  ciated with an increased risk of thrombotic events  (e.g. myocardial infarction and stroke) and should  not be used in preference to non-selective NSAIDs  except when specifically indicated (i.e. for patients at  a particularly high risk of developing gastroduodenal  ulceration or bleeding) and after assessing their  cardiovascular risk.   Non-selective NSAIDs are also associated with a  small increased risk of thrombotic events even  when used short-term in those with no cardiovas-  cular risk factors. Diclofenac (150 mg daily) and  ibuprofen (2.4 g daily) are associated with an  increased risk of thrombotic events. The increased  risk for diclofenac is similar to that of licensed doses  of etoricoxib. Naproxen (lg daily) is associated  with a lower thrombotic risk, and low doses of ibu-  profen (1.2 g daily or less) have not been associated  with an increased risk of myocardial infarction.   The lowest effective dose of NS AID or cyclo-oxyge-  nase-2 selective inhibitor should be prescribed for  the shortest period to control symptoms and that the  need for long-term treatment should be reviewed  periodically.    The CSM has advised that non-selective NSAIDs are  contra-indicated in patients with previous or active  peptic ulceration and that selective inhibitors of cyclo-  oxygenase-2 are contra-indicated in active peptic ulcer-  ation (see also CSM advice below). While it is prefer-  able to avoid NSAIDs in patients with active or previous  gastro-intestinal ulceration or bleeding, and to withdraw  them if gastro-intestinal lesions develop, nevertheless  patients with serious rheumatic diseases (e.g. rheumat-  oid arthritis) are usually dependent on NSAIDs for  effective relief of pain and stiffness. Patients at risk of  gastro-intestinal ulceration (including the elderly), who  need NSAID treatment should receive gastroprotective  treatment; for advice on the prophylaxis and treatment  of NSAID-associated gastro-intestinal ulcers, see sec-  tion 1.3.   Hepatic impairment NSAIDs should be used with  caution in patients with hepatic impairment; there is an  increased risk of gastro-intestinal bleeding and fluid  retention. NSAIDs should be avoided in severe liver  disease; see also individual drugs.    Renal impairment NSAIDs should be avoided if  possible or used with caution in patients with renal  impairment; the lowest effective dose should be used  for the shortest possible duration, and renal function  should be monitored. Sodium and water retention may  occur and renal function may deteriorate, possibly lead-  ing to renal failure; deterioration in renal function has  also been reported after topical use; see also individual  drugs.    tion. However, it has more gastro-intestinal side-effects  than most other NSAIDs, and is associated with more  frequent serious skin reactions (important: see CHMP  advice, p. 639).   Sulindac is similar in tolerance to naproxen.  Tenoxicam is similar in activity and tolerance to nap-  roxen. Its long duration of action allows once-daily  administration.   Tolfenamic acid is licensed for the treatment of  migraine (section 4.7.4. 1).   Ketorolac and the selective inhibitor of cyclo-oxyge-  nase-2, parecoxib, are licensed for the short-term man-  agement of postoperative pain (section 15.1.4.2).   The selective inhibitors of cyclo-oxygenase-2, etoricox-  ib and celecoxib, are as effective as non-selective  NSAIDs such as diclofenac and naproxen. Short-term  data indicate that the risk of serious upper gastro-intes-  tinal events is lower with selective inhibitors compared  to non-selective NSAIDs; this advantage may be lost in  patients who require concomitant low-dose aspirin.  There are concerns about the cardiovascular safety of  cyclo-oxygenase-2 selective inhibitors (see below).   Celecoxib and etoricoxib are licensed for the relief of  pain in osteoarthritis, rheumatoid arthritis, and anky-  losing spondylitis; etoricoxib is also licensed for the  relief of pain from acute gout.    Dental and orofacial pain Most mild to moderate  dental pain and inflammation is effectively relieved by  NSAIDs. Those used for dental pain include ibuprofen  and diclofenac.   In an appraisal of the relative safety of 7 non-selective  NSAIDs, the CSM assessed ibuprofen to have the lowest  risk of serious gastro-intestinal side-effects (see p. 632).  For further information on the management of dental  and orofacial pain, see p. 257.    Cautions and contra-indications NSAIDs should be  used with caution in the elderly (risk of serious side-  effects and fatalities, see also Prescribing for the Elderly  p. 25), in allergic disorders (they are contra-indicated  in patients with a history of hypersensitivity to aspirin or  any other NSAID — which includes those in whom  attacks of asthma, angioedema, urticaria or rhinitis  have been precipitated by aspirin or any other  NSAID), and in coagulation defects. Long-term use of  some NSAIDs is associated with reduced female fertility,  which is reversible on stopping treatment. Caution is  also required in patients with connective-tissue disor-  ders, see Side-effects below.   In patients with cardiac impairment, caution is required  since NSAIDs may impair renal function (see also Side-  effects, below). All NSAIDs are contra-indicated in  severe heart failure. The selective inhibitors of cyclo-  oxygenase-2 (celecoxib, etoricoxib, and parecoxib) are  contra-indicated in ischaemic heart disease, cerebro-  vascular disease, peripheral arterial disease, and mod-  erate or severe heart failure. The selective inhibitors of  cyclo-oxygenase-2 should be used with caution in  patients with a history of cardiac failure, left ventricular  dysfunction, hypertension, in patients with oedema for  any other reason, and in patients with risk factors for  heart disease.    Pregnancy Most manufacturers advise avoiding the  use of NSAIDs during pregnancy or avoiding them  unless the potential benefit outweighs the risk. NSAIDs  should be avoided during the third trimester because  use is associated with a risk of closure of fetal ductus  arteriosus in utero and possibly persistent pulmonary  hypertension of the newborn. In addition, the onset of    Breast-feeding NSAIDs should be used with caution  during breast-feeding; see also individual drugs.   Side-effects Gastro-intestinal disturbances including  discomfort, nausea, diarrhoea, and occasionally bleed-  ing and ulceration occur (see also CSM advice below  and Cautions above). Systemic as well as local effects of  NSAIDs contribute to gastro-intestinal damage; taking  oral formulations with milk or food, or using enteric-  coated formulations, or changing the route of adminis-  tration may only partially reduce symptoms such as  dyspepsia.   All NSAIDs are associated with serious gastro-intes-  tinal toxicity; the risk is higher in the elderly. Evi-  dence on the relative safety of 7 non-selective  NSAIDs indicates differences in the risks of serious  upper gastro-intestinal side-effects. Azapropazone  is associated with the highest risk and ibuprofen  with the lowest, piroxicam, ketoprofen, indometa-  cin, naproxen and diclofenac are associated with  intermediate risks (possibly higher in the case of  piroxicam, see also CHMP advice, p. 639). Selective  inhibitors of cyclo-oxygenase-2 are associated  with a lower risk of serious upper gastro-intestinal  side-effects than non-selective NSAIDs.   Recommendations are that NSAIDs associated with  a low risk e.g. ibuprofen are generally preferred, to  start at the lowest recommended dose, not to use  more than one oral NSAID at a time, and to remem-  ber that all NSAIDs (including selective inhibitors of  cyclo-oxygenase-2) are contra-indicated in patients  with active peptic ulceration. The CSM also contra-  indicates non-selective NSAIDs in patients with a  history of peptic ulceration.   The combination of a NSAID and low-dose aspirin  can increase the risk of gastro-intestinal side-effects;  this combination should be used only if absolutely  necessary and the patient should be monitored  closely.    Other side-effects include hypersensitivity reactions  (particularly rashes, angioedema, and bronchospasm —  see below), headache, dizziness, nervousness, depres-  sion, drowsiness, insomnia, vertigo, hearing distur-  bances such as tinnitus, photosensitivity, and haematur-  ia. Blood disorders have also occurred. Fluid retention  may occur (rarely precipitating congestive heart failure);  blood pressure may be raised.   Any degree of worsening of asthma may be related  to the ingestion of NSAIDs, either prescribed or (in  the case of ibuprofen and others) purchased over the  counter.    Hepatic damage, alveolitis, pulmonary eosinophilia,  pancreatitis, visual disturbances, Stevens- Johnson  syndrome, and toxic epidermal necrolysis are other  rare side-effects. Induction of or exacerbation of colitis  or Crohn’s disease has been reported. Aseptic mening-  itis has been reported rarely with NSAIDs — patients  with connective-tissue disorders such as systemic  lupus erythematosus may be especially susceptible.  Overdosage: see Emergency Treatment of Poisoning,  p. 34.   Indications pain and inflammation in rheumatoid  arthritis, osteoarthritis and ankylosing spondylitis  Cautions see notes above; avoid in acute porphyria  (section 9.8.2)   Aceclofenac (Non-proprietary) [Ml  Tablets, aceclofenac 100 mg, net price 60-tab pack =  £10.48. Label: 21   Preservex® (Almirall) (Ml  Tablets, f/c, aceclofenac 100 mg, net price 60-tab  pack = £9.45. Label: 21   Indications pain and inflammation in rheumatic dis-  ease and other musculoskeletal disorders; postoper-  ative analgesia   Cautions see under Indometacin and notes above  Driving Dizziness may affect performance of skilled tasks  (e g. driving)   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   • 120 mg daily in divided doses with food, increased if  necessary to 180 mg daily; CHILD not recommended   Emflex® (Merck Serono) (Ml  Capsules, yellow/orange, acemetacin 60 mg, net  price 90-cap pack = £28.20. Label: 21, counselling,  driving    Renal failure may be provoked by NSAIDs, especially in  patients with pre-existing renal impairment (important,  see Renal impairment, above). Rarely, papillary necrosis  or interstitial fibrosis associated with NSAIDs can lead  to renal failure.   Indications short-term treatment of mild to moderate  pain including dysmenorrhoea  Cautions see notes above  Contra-indications see notes above  Hepatic impairment reduce initial dose to max.   50 mg daily in mild to moderate impairment; see also  notes above   Renal impairment reduce initial dose to 50 mg daily;  avoid in moderate to severe impairment; see also  notes above   • 12.5 mg every 4-6 hours or 25 mg every 8 hours; max.  75 mg daily; ELDERLY initially max. 50 mg daily; CHILD  not recommended   Tablets, f/c, scored, dexketoprofen (as trometamol)  25 mg, net price 20-tab pack = £3.67, 50-tab pack =  £9.18. Label: 22   Indications pain and inflammation in rheumatic dis-  ease and other musculoskeletal disorders; acute gout;  postoperative pain; migraine  Cautions see notes above; avoid in acute porphyria  (section 9.8.2)   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment avoid in severe impairment; see  also notes above  Pregnancy see notes above  Breast-feeding amount in milk too small to be  harmful; see also notes above  Side-effects see notes above  Dose   • Rheumatic disease, musculoskeletal disorders, acute  gout, postoperative pain, 75-150 mg daily in 2-3  divided doses; CHILD over 14 years, 75-100 mg daily in  2-3 divided doses   • Migraine, 50 mg at onset, repeated after 2 hours if  necessary then after 4-6 hours; max. 200 mg in 24  hours; CHILD not recommended    Diclofenac Potassium (Non-proprietary) (Ml  Tablets, diclofenac potassium 25 mg, net price 28-tab  pack = 81p; 50 mg, 28-tab pack = £1.55. Label: 21   Contra-indications see notes above; sulphonamide  sensitivity; inflammatory bowel disease  Hepatic impairment in pain and inflammation, halve  initial dose in moderate impairment; in familial ade-  nomatous polyposis, halve dose in moderate impair-  ment and avoid in severe impairment; see also notes  above   Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2 ; see also notes above  Pregnancy avoid (teratogenic in animal studies); see  also notes above   Breast-feeding avoid — present in milk in animal  studies; see also notes above  Side-effects see notes above; dyspnoea, influenza-  like symptoms; less commonly stomatitis, palpitation,  dysphonia, cerebral infarction, fatigue, paraesthesia,  lipoma, muscle cramps; rarely taste disturbance, alo-  pecia; very rarely seizures; also reported chest pain   4Pain and inflammation  Celebrex® (Pharmacia) Ml  Capsules, celecoxib 100 mg (white/blue), net price  60-cap pack = £21.55; 200 mg (white/gold), 30-cap  pack = £21.55   Dose osteoarthritis, 200 mg daily in 1-2 divided doses, increased  if necessary to max. 200 mg twice daily; CHILD not recommended  Rheumatoid arthritis, 100 mg twice daily, increased if necessary to  200 mg twice daily; CHILD not recommended  Ankylosing spondylitis, 200 mg daily in 1-2 divided doses,  increased if necessary to max. 400 mg daily in 1-2 divided doses;  CHILD not recommended   Indications pain and inflammation associated with  osteoarthritis and other musculoskeletal disorders;  mild to moderate pain and inflammation including  dysmenorrhoea and dental pain  Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment reduce initial dose; avoid if eGFR  less than 30 mL/minute/ 1.73m 2 ; see also notes above  Pregnancy see notes above  Breast-feeding present in milk — but risk to infant  minimal; see also notes above  Side-effects see notes above  Dose   • 600-900 mg daily in up to 3 divided doses; increased if  necessary to max. 1.2 g daily (900 mg daily for dys-  menorrhoea); max. single dose 400 mg (300 mg for  dysmenorrhoea); CHILD not recommended   Tablets, f/c, dexibuprofen 300 mg, net price 60-tab  pack = £9.47; 400 mg (scored) 60-tab pack = £9.47.  Label: 21    'Voltarol® Rapid (Novartis) Ml  Tablets, s/c, diclofenac potassium 25 mg (red), net  price 30-tab pack = £3.46; 50 mg (brown), 30-tab pack  = £6.62. Label: 21   1. 12.5 mg tablets can be sold to the public for the treatment of  headache, dental pain, period pain, rheumatic and muscular  pain, backache and the symptoms of cold and flu (including  fever), in patients aged over 14 years subject to max. single  dose of 25 mg, max. daily dose of 75 mg for max. 3 days, and  max. pack size of 18 x 12.5 mg   Indications pain and inflammation in rheumatic dis-  ease (including juvenile idiopathic arthritis) and other  musculoskeletal disorders; acute gout; postoperative  pain   Contra-indications see notes above; avoid injections  containing benzyl alcohol in neonates (see prepara-  tions below)   Intravenous use Additional contra-indications include con-  comitant NSAID or anticoagulant use (including low-dose  heparins), history of haemorrhagic diathesis, history of con-  firmed or suspected cerebrovascular bleeding, operations  with high risk of haemorrhage, history of asthma, moderate  or severe renal impairment (see also Renal impairment  below), hypovolaemia, dehydration;   Renal impairment avoid in severe impairment; avoid  intravenous use if serum creatinine greater than  160micromol/litre; see also notes above   Breast-feeding amount in milk too small to be  harmful; see also notes above   Side-effects see notes above; suppositories may  cause rectal irritation; injection site reactions  Dose   • By rectum in suppositories, 75-150 mg daily in divided  doses   • Postoperative pain, CHILD 6-12 years, by rectum, 1-  2 mg/kg (max. 150 mg) daily in divided doses  (12.5 mg and 25 mg suppositories only) for max. 4  days    Diclofenac Sodium (Non-proprietary) (Ml  Tablets, e/c, diclofenac sodium 25 mg, net price 84-  tab pack =£1.14; 50mg, 84-tab pack = £1.31. Label: 5,  25   Brands include Defenac ®, Dicloj lex 9 , Diclozip ®, Fenactol ® ,  Flamrase ®   Dose by deep intramuscular injection into the gluteal muscle,  acute exacerbations of pain and postoperative pain, 75 mg once  daily (twice daily in severe cases) for max. 2 days  Ureteric colic, 75 mg then a further 75 mg after 30 minutes if  necessary   By intravenous injection (in supervised settings), acute post-  operative pain, 75 mg repeated after 4-6 hours if necessary; max.  150 mg in 24 hours for 2 days   Prevention of postoperative pain, 25-50 mg after surgery; further  doses given after 4-6 hours if necessary; max. 150 mg in 24 hours  for 2 days   Note The Scottish Medicines Consortium (p. 4) has advised (Feb-  ruary 2008) that Dyloject® is accepted for restricted use within  NHS Scotland for the treatment or prevention of postoperative  pain by intravenous injection in supervised healthcare settings   Tablets, e/c, diclofenac sodium 25 mg (yellow), net  price 84-tab pack = £2.94; 50 mg (brown), 84-tab pack  = £4.57. Label: 5, 25   Dispersible tablets, sugar-free, pink, diclofenac,  equivalent to diclofenac sodium 50 mg, net price 21-  tab pack = £6.19. Label: 13,21   Note Voltarol Dispersible tablets are more suitable for short-term  use in acute conditions for which treatment required for no more  than 3 months (no information on use beyond 3 months)   Excipients include benzyl alcohol (avoid in neonates unless there is no  safer alternative, see Excipients, p. 2), propylene glycol  Dose by deep intramuscular injection into the gluteal muscle,  acute exacerbations of pain and postoperative pain, 75 mg once  daily (twice daily in severe cases) for max. 2 days; CHILD 2-18  years, see BNF for Children   Ureteric colic, 75 mg then a further 75 mg after 30 minutes if  necessary   By intravenous infusion (in hospital setting), acute postoperative  pain, 75 mg repeated if necessary after 4-6 hours; max. 150 mg in  24 hours for 2 days; CHILD 2-18 years, see BNF for Children  Prevention of postoperative pain, initially after surgery 25-50 mg  over 15-60 minutes then 5 mg/hour; max. 150 mg in 24 hours for  2 days   Suppositories, diclofenac sodium 12.5 mg, net price  10 = 58p; 25 mg, 10 = £1.03; 50 mg, 10 = £1.70;   Diclomax SR® (Galen) (Ml  Capsules, m/r, yellow, diclofenac sodium 75 mg, net  price 56-cap pack = £11.40. Label: 21, 25  Dose 1 capsule 1-2 times daily or 2 capsules once daily, pre-  ferably with food; CHILD not recommended   Capsules, m/r, diclofenac sodium 100 mg, net price  28-cap pack = £8.20. Label: 21, 25  Dose 1 capsule daily preferably with food; CHILD not recom-  mended   Motifene® 75 mg (Daiichi Sankyo) (Ml  Capsules, e/c, m/r, diclofenac sodium 75 mg  (enclosing e/c pellets containing diclofenac sodium  25 mg and m/r pellets containing diclofenac sodium  50 mg), net price 56-cap pack = £8.00. Label: 25  Dose 1 capsule 1-2 times daily; CHILD not recommended   Voltarol® 75 mg SR (Novartis) (Ml  Tablets, m/r, f/c, pink, diclofenac sodium 75 mg, net  price 28-tab pack = £6.46; 56-tab pack = £12.92.  Label: 21, 25   Dose 75 mg 1-2 times daily preferably with food; CHILD not  recommended   Note Other brands of modified-release tablets containing diclo-  fenac sodium 75 mg include Defenac® SR, Dexomon ® 75 SR,  Dicloflex ® 75 SR, Fenactol ® 75 mg SR, Flamatak® 75 MR,  Flamrase ® SR, Flexotard® MR 75, Rheumatac ® Retard 75,  Rhumalgan ® CR, Slofenac® SR, Volsaid® Retard 75   Voltarol® Retard (Novartis) (Ml  Tablets, m/r, f/c, red, diclofenac sodium 100 mg. Net  price 28-tab pack = £9.47. Label: 21, 25  Dose 1 tablet daily preferably with food; CHILD not recom-  mended   Note Other brands of modified-release tablets containing diclo-  fenac sodium 100 mg include Defenac® Retard, Dexomon®  Retard 100, Dicloflex® Retard, Fenactol® Retard 100 mg,  Flamatak ® 100 MR, Flamrase® SR, Rhumalgan® CR, Slofenac®  SR, Volsaid® Retard 100   Arthrotec® (Pharmacia) (Ml  Arthrotec® 50 tablets, diclofenac sodium (in e/c  core) 50 mg, misoprostol 200 micrograms, net price  60-tab pack = £11.98; Label: 21, 25  Dose prophylaxis against NSAID-induced gastroduodenal  ulceration in patients requiring diclofenac for rheumatoid arthritis  or osteoarthritis, 1 tablet 2-3 times daily with food; CHILD not  recommended   Arthrotec® 75 tablets, diclofenac sodium (in e/c  core) 75 mg, misoprostol 200 micrograms, net price  60-tab pack = £15.83. Label: 21, 25  Dose prophylaxis against NSAID-induced gastroduodenal  ulceration in patients requiring diclofenac for rheumatoid arthritis  or osteoarthritis, 1 tablet twice daily with food; CHILD not  recommended   Note The BNF recommends a higher starting dose of misoprostol for  prophylaxis against NSAID-induced gastroduodenal ulceration than  that provided by Arthrotec 9 (see section 1.3.4)   Side-effects see notes above; also stomatitis, vascu-  litis, palpitation, dyspnoea, confusion, fatigue,  paraesthesia, tremor, urinary frequency, dysuria,  pyrexia, and pruritus   • ADULT over 18 years, 600 mg daily in 1-2 divided doses   Etodolac (Non-proprietary) (Ml  Capsules, etodolac 300 mg, net price 60-cap pack =  £8.14   Tablets, m/r, f/c, light-grey, etodolac 600 mg, net  price 30-tab pack = £15.50. Label: 25  Dose 1 tablet daily; CHILD not recommended   Indications pain and inflammation in osteoarthritis,  rheumatoid arthritis, and ankylosing spondylitis;  acute gout   Cautions see notes above; also dehydration; monitor  blood pressure before treatment, 2 weeks after  initiation and periodically during treatment    Contra-indications see notes above; inflammatory  bowel disease; uncontrolled hypertension (persis-  tently above 140/90 mmHg)   Hepatic impairment max. 60 mg daily in mild  impairment; max. 60 mg on alternate days or 30 mg  once daily in moderate impairment; see also notes  above   Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2 ; see also notes above  Pregnancy manufacturer advises avoid (teratogenic in  animal studies); see also notes above  Breast-feeding manufacturer advises avoid — present  in milk in animal studies; see also notes above  Side-effects see notes above; also palpitation, fatigue,  influenza-like symptoms, ecchymosis; less commonly  dry mouth, taste disturbance, mouth ulcer, appetite  and weight change, atrial fibrillation, transient  ischaemic attack, chest pain, flushing, cough, dys-  pnoea, epistaxis, anxiety, mental acuity impaired,  paraesthesia, electrolyte disturbance, myalgia and  arthralgia; very rarely confusion and hallucinations  Dose   • Osteoarthritis, ADULT and CHILD over 16 years, 30 mg  once daily, increased if necessary to 60 mg once daily   • Rheumatoid arthritis and ankylosing spondylitis,  ADULT and CHILD over 16 years, 90 mg once daily   • Acute gout, ADULT and CHILD over 16 years, 120 mg  once daily for max. 8 days   Tablets, f/c, etoricoxib 30 mg (blue-green), net price  28-tab pack = £13.99; 60 mg (dark green), 28-tab pack  = £20.11; 90 mg (white), 28-tab pack = £22.96; 120 mg  (pale green), 7-tab pack = £6.03, 28-tab pack = £24.11   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above  Breast-feeding small amount present in milk — man-  ufacturer advises avoid; see also notes above   Side-effects see notes above, but also high risk of  rashes especially in seronegative rheumatoid arthritis,  psoriatic arthritis and in women (discontinue imme-  diately); also allergic interstitial lung disorders (may  follow rashes)    • 300 mg in the morning and 600 mg at bed-time or  450 mg twice daily; CHILD under 14 years not recom-  mended    Fenbufen (Non-proprietary) (Ml  Capsules, fenbufen 300 mg, net price 84-cap pack =  £20.71. Label: 21   Tablets, fenbufen 300 mg, net price 84-tab pack =  £6.00; 450 mg, 56-tab pack = £6.49. Label: 21   Indications pain and inflammation in rheumatic dis-  ease and other musculoskeletal disorders; mild to  moderate pain   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment see notes above  Pregnancy see notes above   Breast-feeding amount too small to be harmful; see  also notes above   Side-effects see notes above; upper respiratory-tract  infection, nasopharyngitis, and cystitis also reported   • 300-600 mg 3-4 times daily with food; max. 3 g daily;  CHILD not recommended   Tablets, orange, fenoprofen (as calcium salt) 300 mg,  net price 100-tab pack = £9.45 Label: 21   Indications pain and inflammation in rheumatic dis-  ease and other musculoskeletal disorders; mild to  moderate pain including dysmenorrhoea; migraine;  postoperative analgesia; sore throat (section 12.3.1)  Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment avoid in severe impairment; see  also notes above  Pregnancy see notes above  Breast-feeding small amount present in milk — man-  ufacturer advises avoid; see also notes above  Side-effects see notes above; also stomatitis; less  commonly paraesthesia, confusion, hallucinations,  and fatigue  Dose   • ADULT and CHILD over 12 years, 150-200 mg daily in 2-  4 divided doses, increased in acute conditions to  300 mg daily   • Dysmenorrhoea, ADULT and CHILD over 12 years,  initially 100 mg, then 50-100 mg every 4-6 hours;  max. 300 mg daily   Flurbiprofen (Non-proprietary) [Ml  Tablets, flurbiprofen 50 mg, net price 100 = £14.36;  100 mg, 100 = £29.00. Label: 21   Tablets, yellow, s/c, flurbiprofen 50 mg, net price 100  = £9.24; 100 mg, 100 = £17.51. Label: 21   Breast-feeding amount too small to be harmful but  some manufacturers advise avoid (including topical  use); see also notes above   • ADULT and CHILD over 12 years, initially 300-400 mg 3-   4 times daily; increased if necessary to max. 2.4 g  daily; maintenance dose of 0.6-1.2g daily may be  adequate   • Pain and fever in children, CHILD 1-3 months, see BNF  for Children', CHILD 3-6 months (body-weight over   5 kg), 50 mg 3 times daily (max. 30 mg/kg daily in 3-4  divided doses); CHILD 6 months-1 year, 50 mg 3-4  times daily (max. 30 mg/kg daily in 3-4 divided  doses); CHILD 1-4 years, 100 mg 3 times daily (max.  30 mg/kg daily in 3-4 divided doses); CHILD 4-7 years,  150 mg 3 times daily (max. 30 mg/kg daily in 3-4  divided doses); CHILD 7-10 years, 200 mg 3 times daily  (up to 30 mg/kg daily (max. 2.4 g) in 3-4 divided  doses); CHILD 10-12 years, 300 mg 3 times daily (up to  30 mg/kg daily (max. 2.4 g) in 3-4 divided doses)   • Rheumatic disease in children (including juvenile  idiopathic arthritis), CHILD 3 months-1 8 years (body-  weight over 5 kg), 30-40 mg/kg (max. 2.4 g) daily in  3-4 divided doses; in systemic juvenile idiopathic  arthritis up to 60 mg/kg (max. 2.4 g) daily [unlicensed]  in 4-6 divided doses   Tablets, coated, ibuprofen 200 mg, net price 84-tab  pack = £1.62; 400 mg, 84-tab pack = £1.72; 600 mg,  84-tab pack = £4.06. Label: 21  Brands include Arthrofen ®, Ebufac ® , Rimafen ®   Dental prescribing on NHS Ibuprofen Tablets maybe prescribed  Oral suspension, ibuprofen 100 mg/5 mL, net price  100 mL = £1.48, 150mL = £2.71, 500 mL = £8.88.  Label: 21   Note Sugar-free versions are available and can be ordered by  specifying ‘sugar-free’ on the prescription  Brands include Calprofen ® , Feverfen ® , Nurofen ® for Children,  Orbifen ® for Children   Dental prescribing on NHS Ibuprofen Oral Suspension Sugar-free  may be prescribed   1 . Can be sold to the public in certain circumstances; for  exemptions see Medicines, Ethics and Practice, No. 34,  London, Pharmaceutical Press, 2010 (and subsequent  editions as available)   Capsules, m/r, yellow, flurbiprofen 200 mg, net price  30-cap pack = £7.53. Label: 21, 25  Dose ADULT and CHILD over 12 years, 1 capsule daily, preferably  in the evening   Indications pain and inflammation in rheumatic dis-  ease (including juvenile idiopathic arthritis) and other  musculoskeletal disorders; mild to moderate pain  including dysmenorrhoea; postoperative analgesia;  migraine; dental pain; fever with discomfort and pain  in children; post-immunisation pyrexia (section 14.1)  Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above   Tablets, f/c, ibuprofen 200 mg, net price 100-tab pack  = £3.92; 400 mg, 100-tab pack = £8.16; 600 mg, 100-  tab pack = £12.24. Label: 21  Syrup, orange, ibuprofen 100 mg/ 5 mL, net price  500 mL (orange-flavoured) = £8.88. Label: 21  Granules, effervescent, ibuprofen 600 mg/sachet, net  price 20-sachet pack = £6.53. Label: 13, 21   Dose ADULT and CHILD over 12 years, 2 tablets daily as a single  dose, preferably in the early evening, increased in severe cases to  3 tablets daily in 2 divided doses    Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment avoid in severe impairment; see  also notes above  Pregnancy see notes above  Breast-feeding amount probably too small to be  harmful but manufacturer advises avoid unless  essential; see also notes above  Side-effects see notes above; pain may occur at  injection site (occasionally tissue damage); supposi-  tories may cause rectal irritation  Dose   • By mouth, rheumatic disease, 100-200 mg daily in 2-4  divided doses; CHILD not recommended   Pain and dysmenorrhoea, 50 mg up to 3 times daily;  CHILD not recommended   Combined oral and rectal treatment, max. total daily  dose 200 mg   • By deep intramuscular injection into the gluteal  muscle, 50-100 mg every 4 hours (max. 200 mg in 24  hours) for up to 3 days; CHILD not recommended   Ketoprofen (Non-proprietary) (Ml  Capsules, ketoprofen 50 mg, net price 28-cap pack =  £9.32; 100 mg, 56-cap pack = £6.66. Label: 21   Orudis® (Sanofi-Aventis) tMl  Capsules, ketoprofen 50 mg (green/purple), net price  112-cap pack = £15.14; 100 mg (pink), 56-cap pack =  £15.49. Label: 21   Oruvail® (Sanofi-Aventis) (Ml  Injection, ketoprofen 50 mg /mL. Net price 2-mL amp  = £1.07   Capsules, m/r, enclosing white pellets, ketoprofen  100 mg (pink/purple), net price 56-cap pack = £23.93;  150 mg (pink), 28-cap pack = £13.66; 200 mg (pink/  white), 28-cap pack = £23.85. Label: 21, 25  Dose 100-200 mg once daily with food; CHILD not recom-  mended   Note Other brands of modified-release capsules containing keto-  profen 100 mg and 200 mg include Ketocid ® 200 mg, Ketovail ®,  Tiloket 8 CR   Spansule® (= capsule m/r), maroon/pink, enclosing  off-white pellets, ibuprofen 300 mg, net price 120-cap  pack = £9.64. Label: 25   Dose ADULT and CHILD over 12 years, initially 2 capsules twice  daily, increased in severe cases to 3 capsules twice daily; then 1-2  capsules twice daily   Indications pain and moderate to severe inflamma-  tion in rheumatic disease and other acute musculo-  skeletal disorders; acute gout; dysmenorrhoea; pre-  mature labour (section 7.1.3)   Cautions see notes above; also epilepsy, parkinson-  ism, psychiatric disturbances; during prolonged ther-  apy ophthalmic and blood examinations particularly  advisable; avoid rectal administration in proctitis and  haemorrhoids   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment avoid in severe impairment; see  also notes above  Pregnancy see notes above  Breast-feeding amount probably too small to be  harmful — manufacturers advise avoid; see also notes  above   Side-effects see notes above; rarely confusion, con-  vulsions, psychiatric disturbances, syncope, blood  disorders (particularly thrombocytopenia), hyper-  glycaemia, peripheral neuropathy, and intestinal  strictures; suppositories may cause rectal irritation  and occasional bleeding  Dose   • By mouth, rheumatic disease, 50-200 mg daily in  divided doses; CHILD see BNF for Children  Acute gout, 150-200 mg daily in divided doses  Dysmenorrhoea, up to 75 mg daily   • By rectum in suppositories, 100 mg at night and in the  morning if required; CHILD not recommended  Combined oral and rectal treatment, max. total daily  dose 150-200 mg   Indometacin (Non-proprietary) 2°M1  Capsules, indometacin 25 mg, net price 28-cap pack  = £2.33; 50 mg, 28-cap pack = £2.29. Label: 21,  counselling, driving, see above   Suppositories, indometacin 100 mg, net price 10 =  £20.07. Counselling, driving, see above   Dose 75 mg 1-2 times daily (once daily in dysmenorrhoea);  CHILD not recommended   Indications pain and mild inflammation in rheumatic  disease and other musculoskeletal disorders, and after  orthopaedic surgery; acute gout; dysmenorrhoea   Capsules, m/r, ketoprofen 100 mg, omeprazole  20 mg (yeUow/ white), net price 30-cap pack = £13.80;  ketoprofen 200 mg, omeprazole 20 mg (white), 30-cap  pack = £13.80. Label: 21, 25   Note Capsules enclose microgranules containing modified-  release ketoprofen and gastro-resistant omperazole  Dose (expressed as ketoprofen) patients requiring ketoprofen for  osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis,  who are at risk of NSAID-associated duodenal or gastric ulcer or  gastroduodenal erosions, ADULT and CHILD over 15 years, 100 mg  (with omeprazole 20 mg) once daily increased to 200 mg (with  omeprazole 20 mg) once daily depending on severity of symptoms   Indications pain and inflammation in rheumatoid  arthritis and osteoarthritis; postoperative pain; mild to  moderate pain; dysmenorrhoea and menorrhagia  Cautions see notes above; epilepsy; acute porphyria  (section 9.8.2)   Hepatic impairment see notes above  Renal impairment avoid in severe impairment; see  also notes above  Pregnancy see notes above  Breast-feeding amount too small to be harmful but  manufacturer advises avoid; see also notes above  Side-effects see notes above; also diarrhoea or rashes  (withdraw treatment), stomatitis; less commonly  paraesthesia and fatigue; rarely hypotension, palpita-  tion, glucose intolerance, thrombocytopenia, haemo-  lytic anaemia (positive Coombs’ test), and aplastic  anaemia  Dose   • CHILD 12-18 years, acute pain including dysmenorr-  hoea, menorrhagia, 500 mg 3 times daily   Tablets, mefenamic acid 500 mg, net price 28-tab  pack = £2.20. Label: 21   Suspension, mefenamic acid 50mg/5mL, net price  125 mL = £79.98. Label: 21   Ponstan® (Chemidex) (Ml  Capsules, blue/ivory, mefenamic acid 250 mg, net  price 100-cap pack = £8.17. Label: 21  Forte tablets, yellow, mefenamic acid 500 mg, net  price 100-tab pack = £15.72. Label: 21   Indications pain and inflammation in rheumatic dis-  ease; exacerbation of osteoarthritis (short-term);  ankylosing spondylitis   Cautions see notes above; avoid rectal administration  in proctitis or haemorrhoids  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment avoid if eGFR less than 25 mL/  minute/ 1.73m 2 ; see also notes above  Pregnancy see notes above  Breast-feeding present in milk in animal studies —  manufacturer advises avoid; see also notes above  Side-effects see notes above  Dose   • By mouth, osteoarthritis, ADULT and CHILD over 16  years, 7.5 mg once daily, increased if necessary to  max. 15 mg once daily   Rheumatoid arthritis, ankylosing spondylitis, ADULT  and CHILD over 16 years, 15 mg once daily, may be  reduced to 7.5 mg once daily; ELDERLY 7.5 mg daily   • By rectum, in suppositories, rheumatoid arthritis,  ankylosing spondylitis, ADULT and CHILD over 16 years,  15 mg once daily, may be reduced to 7.5 mg once  daily; ELDERLY 7.5 mg once daily [but Mobic® 7.5 mg  suppositories discontinued]   Meloxicam (Non-proprietary) LmD  Tablets, meloxicam 7.5 mg, net price 30-tab pack =  £1.36; 15 mg, 30-tab pack = £1.62. Label: 21   Tablets, yellow, scored, meloxicam 7.5 mg, net price  30-tab pack = £9.30; 15 mg, 30-tab pack = £12.93.  Label: 21   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment avoid in severe impairment; see  also notes above  Pregnancy see notes above   • 1 g at night; severe or persistent symptoms 0.5-1 g in  morning and 1 g at night; ELDERLY 0.5-1 g daily; CHILD  not recommended   Tablets, nabumetone 500 mg, net price 56-tab pack =  £5.75. Label: 21   Tablets, red, f/c, nabumetone 500 mg. Net price 56-  tab pack = £6.18. Label: 21  Suspension, sugar-free, nabumetone 500 mg/5 mL.  Net price 300-mL pack = £24.08. Label: 21   Indications pain and inflammation in rheumatic dis-  ease (including juvenile idiopathic arthritis) and other  musculoskeletal disorders; dysmenorrhoea; acute  gout   Cautions see notes above  Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2 ; see also notes above  Pregnancy see notes above  Breast-feeding amount too small to be harmful but  manufacturer advises avoid; see also notes above  Side-effects see notes above  Dose   • Rheumatic disease, 0.5-1 g daily in 1-2 divided doses;  CHILD 2-18 years, juvenile idiopathic arthritis, see  BNF for Children   • Acute musculoskeletal disorders and dysmenorrhoea,  500 mg initially, then 250 mg every 6-8 hours as  required; max. dose after first day 1.25 g daily; CHILD  under 18 years, see BNF for Children   • Acute gout, 750 mg initially, then 250 mg every 8  hours until attack has passed; CHILD under 16 years  not recommended    Naproxen (Non-proprietary) [Ml  Tablets, naproxen 250 mg, net price 28-tab pack =  £1.35; 500 mg, 28-tab pack = £1.72. Label: 21  Brands include Arthroxen ®   Tablets, e/c, naproxen 250 mg, net price 56-tab pack  = £3. 18; 375 mg, 56-tab pack = £26.82; 500 mg, 56-tab  pack = £4.83. Label: 5, 25  1. Can be sold to the public for the treatment of primary  dysmenorrhoea in women aged 15-50 years subject to max.  single dose of 500 mg, max. daily dose of 750 mg for max. 3  days, and a max. pack size of 9 x 250 mg tablets   Tablets, yellow, scored, naproxen 250 mg, net price  56-tab pack = £4.29; 500 mg, 56-tab pack = £8.56.  Label: 21   Tablets, e/c, [Naprosyn EC®), naproxen 250 mg, net  price 56-tab pack = £4.29; 375 mg, 56-tab pack =  £6.42; 500 mg, 56-tab pack = £8.56. Label: 5, 25   550 mg twice daily when necessary, preferably after food; max.  1.1 g daily; CHILD under 16 years not recommended  Dysmenorrhoea and acute gout, initially 550 mg then 275 mg  every 6-8 hours as required; max. of 1.375 g on first day and 1.1 g  daily thereafter; CHILD under 16 years not recommended  Migraine, 825 mg at onset, then 275-550 mg at least 30 minutes  after initial dose; max. 1.375 g in 24 hours; CHILD under 16 years  not recommended   Breast-feeding amount too small to be harmful; see  also notes above   The CHMP has recommended restrictions on the use  of piroxicam because of the increased risk of gastro-  intestinal side effects and serious skin reactions. The  CHMP has advised that:   • piroxicam should be initiated only by physicians experi-  enced in treating inflammatory or degenerative rheumatic  diseases   • in adults, use of piroxicam should be limited to the symp-  tomatic relief of osteoarthritis, rheumatoid arthritis, and  ankylosing spondylitis   • piroxicam should no longer be used for the treatment of  acute painful and inflammatory conditions   • treatment should be reviewed 2 weeks after initiating  piroxicam, and periodically thereafter   • concomitant administration of a gastro-protective agent  (section 1.3) should be considered   Note Topical preparations containing piroxicam are not  affected by these restrictions    Piroxicam (Non-proprietary) (Ml  Capsules, piroxicam 10 mg, net price 56-cap pack =  £16.62; 20 mg, 28-cap pack = £22.45. Label: 21  Dispersible tablets, piroxicam 10 mg, net price 56-  tab pack = £9.96; 20 mg, 28-tab pack = £32.41.   Tablets, yellow, scored, piroxicam (as betadex) 20 mg,  net price 30-tab pack = £13.82. Label: 21  Dose osteoarthritis, rheumatic disease and acute musculo-  skeletal disorders, 1 tablet daily (may be halved in elderly); CHILD  not recommended   Capsules, piroxicam 10 mg (red/blue), net price 30-  cap pack = £3.86; 20 mg (white), 30-cap pack = £7.71.  Label: 21   Tablets, [Feldene Melt®), piroxicam 20 mg, net price  28-tab pack = £9.83. Label: 10, patient information  leaflet, 21   Excipients include aspartame equivalent to phenylalanine 140 micr-  ograms/tablet (section 9.4.1)   Note Feldene Melt ® tablets can be taken by placing on tongue or  by swallowing   Vimovo® (AstraZeneca) T (Ml  Tablets, f/c, m/r, naproxen 500 mg, esomeprazole (as  magnesium trihydrate) 20 mg, net price 60-tab pack =  £14.95. Label: 22, 25  Note Naproxen component is gastro-resistant  Dose patients requiring naproxen for osteoarthritis, rheumatoid  arthritis, or ankylosing spondylitis, who are at risk of NSAID-  associated duodenal or gastric ulcer and when treatment with  lower doses of naproxen or other NSAIDs ineffective, ADULT over  18 years, 1 tablet twice daily   Napratec® (Pharmacia) (Ml  Combination pack, 56 yellow scored tablets, nap-  roxen 500 mg; 56 white scored tablets, misoprostol  200 micrograms. Net price = £23.76. Label: 21  Dose patients requiring naproxen for rheumatoid arthritis,  osteoarthritis, or ankylosing spondylitis, with prophylaxis against  NSAID-induced gastroduodenal ulceration, 1 naproxen 500-mg  tablet and 1 misoprostol 200-microgram tablet taken together  twice daily with food; CHILD not recommended  Note The BNF recommends a higher starting dose of misoprostol  for prophylaxis against NSAID-induced gastroduodenal ulceration  than that provided by Napratec :® (see section 1.3.4)   Indications rheumatoid arthritis, osteoarthritis, and  ankylosing spondylitis (see also CHMP advice below)   Indications pain and inflammation in rheumatic dis-  ease and other musculoskeletal disorders; acute gout  Cautions see notes above; also history of renal stones  and ensure adequate hydration   Contra-indications see notes above  Hepatic impairment see notes above  Renal impairment avoid in severe impairment; see  also notes above  Pregnancy see notes above   Side-effects see notes above; jaundice with fever,  cholestasis, hepatitis, hepatic failure; also urine dis-  coloration occasionally reported   • 200 mg twice daily (may be reduced according to  response); max. 400 mg daily; acute gout should  respond within 7 days; limit treatment of peri-articular  disorders to 7-10 days; CHILD not recommended   Sulindac (Non-proprietary) (Ml  Tablets, sulindac 100 mg, net price 56-tab pack =  £18.20; 200 mg, 56-tab pack = £33.34. Label: 21   Indications pain and inflammation in rheumatic dis-  ease and other musculoskeletal disorders   Breast-feeding present in milk in animal studies; see  also notes above   Acute musculoskeletal disorders, ADULT over 18 years,  20 mg daily for 7 days; max. duration of treatment 14  days (including treatment by intravenous or intra-  muscular injection)   • By intravenous or intramuscular injection, ADULT over  18 years, initial treatment for 1-2 days if oral admin-  istration not possible, 20 mg once daily   Tenoxicam (Non-proprietary) (Ml  Tablets, f/c, tenoxicam 20 mg, net price 28-tab pack  = £14.13. Label: 21   Indications pain and inflammation in rheumatic dis-  ease and other musculoskeletal disorders  Cautions see notes above  Contra-indications see notes above; also active  bladder or prostate disease (or symptoms) and history  of recurrent urinary-tract disorders — if urinary  symptoms develop discontinue immediately and  perform urine tests and culture; see also CSM advice  below   Following reports of severe cystitis the CSM has  recommended that tiaprofenic acid should not be  given to patients with urinary-tract disorders and  should be stopped if urinary symptoms develop.  Patients should be advised to stop taking tiaprofenic  acid and to report to their doctor promptly if they  develop urinary-tract symptoms (such as increased  frequency, nocturia, urgency, pain on urinating, or  blood in urine)   Renal impairment reduce dose in mild or moderate  impairment; avoid in severe impairment; see also  notes above   Breast-feeding amount too small to be harmful; see  also notes above   Surgam® (Sanofi-Aventis) (Ml  Tablets, tiaprofenic acid 300 mg, net price 56-tab pack  = £14.95. Label: 21   Aspirin (section 4.7.1) has been used in high doses to  treat rheumatoid arthritis, but other NSAIDs are now  preferred.   The general actions, uses, and cautions of corticoster-  oids are described in section 6.3. Short-term treatment  with corticosteroids can help to rapidly improve symp-  toms of rheumatoid arthritis. Long-term treatment in  rheumatoid arthritis should be considered only after  evaluating the risks and all other treatment options  have been considered. Corticosteroids can induce  osteoporosis, and prophylaxis should be considered on  long-term treatment (section 6.6).   In severe, possibly life-threatening, situations a high  initial dose of corticosteroid is given to induce remission  and the dose is then reduced gradually and discontinued  altogether. Relapse may occur as the dose of cortico-  steroid is reduced, particularly if the reduction is too  rapid. The tendency is therefore to increase the main-  tenance dose and consequently the patient becomes  dependent on corticosteroids. For this reason pulse  doses of corticosteroids (e.g. methylprednisolone up to  1 g intravenously on 3 consecutive days) are used to  suppress highly active inflammatory disease while long-  er-term treatment with a disease-modifying drug is  commenced.   Prednisolone 7.5 mg daily may reduce the rate of joint  destruction in moderate to severe rheumatoid arthritis  of less than 2 years’ duration. The reduction in joint  destruction must be distinguished from mere sympto-  matic improvement (which lasts only 6 to 12 months at  this dose) and care should be taken to avoid increasing  the dose above 7.5 mg daily. Evidence supports main-  tenance of this anti-erosive dose for 2-4 years only after  which treatment should be tapered off to reduce long-  term adverse effects.   A modified-release preparation of prednisone (section  6.3.2) is also available for the treatment of moderate to  severe rheumatoid arthritis.   Polymyalgia rheumatica and giant cell (temporal)  arteritis are always treated with corticosteroids. The  usual initial dose of prednisolone in polymyalgia rheu-  matica is 10-15 mg daily and in giant cell arteritis 40-  60 mg daily (the higher dose being used if visual symp-    toms occur). Treatment should be continued until  remission of disease activity and doses are then reduced  gradually to about 7.5 -10 mg daily for maintenance.  Relapse is common if therapy is stopped prematurely.  Many patients require treatment for at least 2 years and  in some patients it may be necessary to continue long-  term low-dose corticosteroid treatment.   Polyarteritis nodosa and polymyositis are usually trea-  ted with corticosteroids. An initial dose of 60 mg of  prednisolone daily is often used and reduced to a main-  tenance dose of 10-15 mg daily.   Systemic lupus erythematosus is treated with corticos-  teroids when necessary using a similar dosage regimen  to that for polyarteritis nodosa and polymyositis  (above). Patients with pleurisy, pericarditis, or other  systemic manifestations will respond to corticosteroids.  It may then be possible to reduce the dosage; alternate-  day treatment is sometimes adequate, and the drug may  be gradually withdrawn. In some mild cases cortico-  steroid treatment may be stopped after a few months.  Many mild cases of systemic lupus erythematosus do  not require corticosteroid treatment. Alternative treat-  ment with anti-inflammatory analgesics, and possibly  chloroquine or hydroxychloroquine, should be consid-  ered.   Ankylosing spondylitis should not be treated with long-  term corticosteroids; rarely, pulse doses may be needed  and may be useful in extremely active disease that does  not respond to conventional treatment.    Corticosteroids are injected locally for an anti-inflamm-  atory effect. In inflammatory conditions of the joints,  particularly in rheumatoid arthritis, they are given by  intra-articular injection to relieve pain, increase mobi-  lity, and reduce deformity in one or a few joints. Full  aseptic precautions are essential; infected areas should  be avoided. Occasionally an acute inflammatory reac-  tion develops after an intra-articular or soft-tissue injec-  tion of a corticosteroid. This may be a reaction to the  microcrystalline suspension of the corticosteroid used,  but must be distinguished from sepsis introduced into  the injection site.    Smaller amounts of corticosteroids may also be injected  directly into soft tissues for the relief of inflammation in  conditions such as tennis or golfer’s elbow or compres-  sion neuropathies. In tendinitis, injections should be  made into the tendon sheath and not directly into the  tendon (due to the absence of a true tendon sheath and  a high risk of rupture, the Achilles tendon should not be  injected).    Hydrocortisone acetate or one of the synthetic analo-  gues is generally used for local injection. Intra-articular  corticosteroid injections can cause flushing and may  affect the hyaline cartilage. Each joint should usually be  treated no more than 3 times in one year.    Corticosteroid injections are also injected into soft tis-  sues for the treatment of skin lesions (see section 13.4).    Contra-indications see notes above and consult pro-  duct literature; avoid injections containing benzyl  alcohol in neonates (see preparations below)  Side-effects see notes above and consult product  literature  Dose   ^ Betamethasone  Betnesol® (UCB Pharma) (Ml  Injection, betamethasone (as sodium phosphate)  4mg/mL, net price 1-mL amp = £1.17.   ^Dexamethasone  Dexamethasone (Non-proprietary) (Ml  Injection, dexamethasone (as sodium phosphate)  4mg/mL, net price 1-mL amp = 83p, 2-mL vial =  £1.27   Dose by intra-articular injection (for details consult product  literature), 0.3-3 mg according to size; where appropriate may be  repeated at intervals of 3-21 days according to response   3.3 mg/mL, net price 1-mL amp = £1.00, 2-mL vial =  £1.98   Dose by intra-articular injection (for details consult product  literature), 0.33-3.3 mg according to size (by soft-tissue infiltra-  tion 1.7-5 mg); where appropriate may be repeated at intervals of  3-21 days   ^ Hydrocortisone acetate  Hydrocortistab® (Sovereign) Ml  Injection (aqueous suspension), hydrocortisone  acetate 25 mg/mL, net price 1-mL amp = £5.72  Dose by intra-articular injection (for details consult product  literature), 5-50 mg according to size; where appropriate may be  repeated at intervals of 21 days; not more than 3 joints should be  treated on any one day; CHILD 5-30 mg (divided)    ^ Methylprednisolone acetate  Depo-Medrone® (Pharmacia) M  Injection (aqueous suspension), methylprednisolone  acetate 40 mg/mL, net price 1-mL vial = £2.87; 2-mL  vial = £5.15; 3-mL vial = £7.47  Dose by intra-articular injection (for details consult product  literature), 4-80 mg, according to size; where appropriate may be  repeated at intervals of 7-35 days; also for intralesional injection   Depo-Medrone® with Lidocaine (Pharmacia) Ml  Injection (aqueous suspension), methylprednisolone  acetate 40 mg, lidocaine hydrochloride 10 mg/mL,  net price 1-mL vial = £3.28; 2-mL vial = £5.88  Dose by intra-articular injection (for details consult product  literature), 4-80 mg, according to size; where appropriate may be  repeated at intervals of 7-35 days   Deltastab® (Sovereign) M  Injection (aqueous suspension), prednisolone acetate  25 mg/mL, net price 1-mL amp = £5.73  Dose by intra-articular injection (for details consult product  literature), 5-25 mg according to size; not more than 3 joints  should be treated on any one day; where appropriate may be  repeated when relapse occurs  For intramuscular injection, see section 6.3.2    ^Triamcinolone acetonide  Adcortyl® Intra-articular/lntradermal (Squibb) M  Injection (aqueous suspension), triamcinolone  acetonide 10 mg/mL, net price 1-mL amp = 90p; 5-  mL vial = £3.63   Dose by intra-articular injection (for details consult product  literature), 2.5-15 mg according to size (for larger doses use    Kenalog ®); where appropriate may be repeated when relapse  occurs; CHILD under 18 years see BNF for Children  By intradermal injection, (for details consult product literature): 2-  3 mg; max. 5 mg at any one site (total max. 30 mg); where  appropriate may be repeated at intervals of 1-2 weeks; CHILD  under 6 years not recommended   Kenalog® Intra-articular/lntramuscular (Squibb) (Ml  Injection (aqueous suspension), triamcinolone  acetonide 40mg/mL, net price 1-mL vial = £1.49  Dose by intra-articular injection (for details consult product  literature), 5-40 mg according to size; total max. 80 mg (for doses  below 5 mg use Adcortyl® Intra-articular / Intradermal)', where  appropriate may be repeated when relapse occurs; CHILD under  18 years see BNF for Children  For intramuscular injection, see section 6.3.2   Certain drugs such as those affecting the immune  response can suppress the disease process in rheumat-  oid arthritis and psoriatic arthritis', gold, penicillamine,  hydroxychloroquine, chloroquine, and sulfasalazine can  also suppress the disease process in rheumatoid arth-  ritis while sulfasalazine and possibly gold can suppress  the disease process in psoriatic arthritis. Unlike  NSAIDs, disease-modifying anti-rheumatic drugs  (DMARDs) can affect the progression of disease but  may require 2-6 months of treatment for a full thera-  peutic response. Since in the first few months of treat-  ment, the course of rheumatoid arthritis is unpredictable  and the diagnosis uncertain, it is usual to start treatment  with an NSAID alone. However, disease-modifying anti-  rheumatic drugs should be initiated by specialists as  soon as diagnosis, progression, and severity of the  disease have been confirmed. Response to a disease-  modifying anti-rheumatic drug may allow the dose of  the NSAID to be reduced.   Disease-modifying antirheumatic drugs can improve  not only the symptoms of inflammatory joint disease  but also extra-articular manifestations such as vasculitis.  They reduce the erythrocyte sedimentation rate, C-  reactive protein, and sometimes the titre of rheumatoid  factor; some also retard erosive damage as judged  radiologically.   Choice The choice of a disease-modifying anti-  rheumatic drug should take into account co-morbidity  and patient preference. Methotrexate, sulfasalazine,  intramuscular gold, and penicillamine are similar in  efficacy. However, methotrexate or sulfasalazine  may be better tolerated.   A combination of DMARDs (including methotrexate  and at least one other DMARD) and a short-term  corticosteroid (section 10.1.2), should be given to  patients with newly diagnosed active rheumatoid arth-  ritis, ideally within 3 months of the onset of persistent  symptoms. If the use of particular DMARDs is contra-  indicated and combination therapy is not possible,  monotherapy with a suitable DMARD should be given  and the dose rapidly increased until clinically effective.  In patients with established and stable rheumatoid arth-  ritis, cautiously reduce drug doses to the lowest that are  clinically effective. Response to drug treatment often  produces a reduction in requirements of both corticos-  teroids and other drugs.    Gold and penicillamine are effective in palindromic  rheumatism. Systemic and discoid lupus erythematosus  are sometimes treated with chloroquine or hydroxy-  chloroquine.   If a disease-modifying anti-rheumatic drug does not  lead to an objective benefit within 6 months, it should  be replaced by a different one.   Juvenile idiopathic arthritis Many children with  juvenile idiopathic arthritis (juvenile chronic arthritis)  do not require disease-modifying antirheumatic drugs.  Methotrexate is effective [unlicensed indication]; sulfa-  salazine is an alternative [unlicensed indication] but it  should be avoided in systemic-onset juvenile idiopathic  arthritis. Gold and penicillamine are no longer used. For  the role of cytokine modulators in polyarticular juvenile  idiopathic arthritis, see p. 647.   Gold can be given as sodium aurothiomalate for active  progressive rheumatoid arthritis; it must be given by  deep intramuscular injection and the area gently mas-  saged. A test dose of 10 mg must be given followed by  doses of 50 mg at weekly intervals until there is definite  evidence of remission. Benefit is not to be expected until  about 300-500 mg has been given; it should be discon-  tinued if there is no remission after 1 g has been given.  In patients who do respond, the interval between injec-  tions is then gradually increased to 4 weeks and treat-  ment is continued for up to 5 years after complete  remission. If relapse occurs the dosage frequency may  be immediately increased to 50 mg weekly and only  once control has been obtained again should the dosage  frequency be decreased; if no response is seen within 2  months, alternative treatment should be sought. It is  important to avoid complete relapse since second  courses of gold are not usually effective.   Sodium aurothiomalate should be discontinued in the  presence of blood disorders, gastro-intestinal bleeding  (associated with ulcerative enterocolitis), or unex-  plained proteinuria (associated with immune complex  nephritis) which is repeatedly above 300 mg/litre. Urine  tests and full blood counts (including total and differ-  ential white cell and platelet counts) must therefore be  performed before starting treatment and before each  intramuscular injection. Rashes with pruritus often  occur after 2 to 6 months of treatment and may neces-  sitate discontinuation.   Indications active progressive rheumatoid arthritis  Cautions see notes above; elderly, history of urticaria,  eczema, colitis; monitor for pulmonary fibrosis with  annual chest X-ray; interactions: Appendix 1 (sodium  aurothiomalate)   Counselling Patients should be advised to seek prompt  medical attention if diarrhoea, sore throat, fever, infection,  non-specific illness, unexplained bleeding and bruising,  purpura, mouth ulcers, metallic taste, rash, breathlessness, or  cough develop   Contra-indications history of blood disorders or bone  marrow aplasia, exfoliative dermatitis, systemic lupus  erythematosus, necrotising enterocolitis, pulmonary  fibrosis; acute porphyria (section 9.8.2)   Hepatic impairment caution in mild to moderate  impairment, avoid in severe impairment    Renal impairment caution in mild to moderate  impairment; avoid in severe impairment   Side-effects see notes above; also severe anaphylac-  tic reactions; stomatitis, taste disturbances, colitis,  hepatotoxicity with cholestatic jaundice, pulmonary  fibrosis, peripheral neuropathy, mouth ulcers, protei-  nuria, blood disorders (sometimes sudden and fatal),  nephrotic syndrome, gold deposits in eye, alopecia,  and skin reactions (including, on prolonged parenteral  treatment, irreversible pigmentation in sun-exposed  areas)   Myocrisin® (Sanofi-Aventis) tMl  Injection, sodium aurothiomalate 20mg/mL, net  price 0.5-mL (10-mg) amp = £3.80; lOOmg/mL, 0.5-  mL (50-mg) amp = £11.23. Label: 11, counselling,  blood disorder symptoms   Penicillamine has a similar action to gold. More  patients are able to continue treatment than with gold  but side-effects are common.   Patients should be warned not to expect improvement  for at least 6 to 12 weeks after treatment is initiated.  Penicillamine should be discontinued if there is no  improvement within 1 year.   Blood counts, including platelets, and urine examina-  tions should be carried out before starting treatment and  then every 1 or 2 weeks for the first 2 months then every  4 weeks to detect blood disorders and proteinuria (they  should also be carried out in the week after any dose  increase). A reduction in platelet count calls for discon-  tinuation with subsequent re-introduction at a lower  dosage and then, if possible, gradual increase. Protei-  nuria, associated with immune complex nephritis,  occurs in up to 30% of patients, but may resolve despite  continuation of treatment; treatment may be continued  provided that renal function tests remain normal,  oedema is absent, and the 24-hour urinary excretion  of protein does not exceed 2 g.   Nausea may occur but is not usually a problem provided  that penicillamine is taken before food or on retiring and  that low initial doses are used and only gradually  increased. Loss of taste can occur about 6 weeks after  treatment is started but usually returns 6 weeks later  irrespective of whether treatment is discontinued;  mineral supplements are not recommended. Rashes  are a common side-effect. Those that occur in the first  few months of treatment disappear when the drug is  stopped and treatment may then be re-introduced at a  lower dose level and gradually increased. Late rashes  are more resistant and often necessitate discontinuation  of treatment.   Patients who are hypersensitive to penicillin may react  rarely to penicillamine.    Cautions see notes above; concomitant nephrotoxic  drugs (increased risk of toxicity); gold treatment  (avoid concomitant use if adverse reactions to gold);  interactions: Appendix 1 (penicillamine)   Blood counts and urine tests See notes above. Longer  intervals maybe adequate in cystinuria and Wilson’s disease.  Consider withdrawal if platelet count falls below 120 000/  mm 3 or white blood cells below 2500/mm 3 or if 3 successive  falls within reference range (can restart at reduced dose  when counts return to within reference range but permanent  withdrawal necessary if recurrence of leucopenia or throm-  bocytopenia)   Counselling Warn patient to tell doctor promptly if sore  throat, fever, infection, non-specific illness, unexplained  bleeding and bruising, purpura, mouth ulcers, or rashes  develop    Side-effects (see also notes above) initially nausea,  anorexia, fever, and skin reactions; taste loss (mineral  supplements not recommended); blood disorders  including thrombocytopenia, leucopenia, agranulo-  cytosis and aplastic anaemia; proteinuria, rarely hae-  maturia (withdraw immediately and seek specialist  advice); haemolytic anaemia, pancreatitis, cholestatic  jaundice, nephrotic syndrome, lupus erythematosus-  like syndrome, myasthenia gravis-like syndrome,  neuropathy, polymyositis (rarely with cardiac invol-  vement), dermatomyositis, mouth ulcers, stomatitis,  alopecia, bronchiolitis and pneumonitis, pemphigus,  Goodpasture’s syndrome, and Stevens- Johnson  syndrome also reported; male and female breast  enlargement reported; in non-rheumatoid conditions  rheumatoid arthritis-like syndrome also reported; late  rashes (consider withdrawing treatment)   250 mg daily for 1 month increased by similar  amounts at intervals of not less than 4 weeks to usual  maintenance of 500-750 mg daily in divided doses;  max. 1.5 g daily; if remission sustained for 6 months,  reduction of daily dose by 125-250 mg every 12  weeks may be attempted; ELDERLY initially up to   125 mg daily for 1 month increased by similar  amounts at intervals of not less than 4 weeks; max. 1 g  daily    Penicillamine (Non-proprietary) (Ml  Tablets, penicillamine 125 mg, net price 56-tab pack  = £16.66; 250 mg, 56-tab pack = £25.00. Label: 6, 22,  counselling, blood disorder symptoms (see above)   Tablets, f/c, penicillamine 125 mg, net price 100-tab  pack = £10.34; 250 mg, 100-tab pack= £17.78.   The antimalarial hydroxychloroquine is used to treat  rheumatoid arthritis of moderate inflammatory activity;  chloroquine is also licensed for treating inflammatory  disorders but is used much less frequently and is gen-  erally reserved for use if other drugs have failed. Chloro-  quine and hydroxychloroquine are effective for mild  systemic lupus erythematosus, particularly involving  the skin and joints. These drugs should not be used  for psoriatic arthritis.   Chloroquine and hydroxychloroquine are better toler-  ated than gold or penicillamine. Retinopathy (see below)  rarely occurs provided that the recommended doses are  not exceeded; in the elderly it is difficult to distinguish  drug-induced retinopathy from changes of ageing.   Mepacrine (section 5.4.4) is sometimes used in discoid  lupus erythematosus [unlicensed].    Cautions Manufacturers recommend regular ophthal-  mological examination but the evidence of practical  value is unsatisfactory (see advice of the Royal College  of Ophthalmologists, below). Chloroquine and hydroxy-  chloroquine should be used with caution in neurological  disorders (especially in those with a history of epilepsy),  in severe gastro-intestinal disorders, in G6PD deficiency  (section 9.1.5), in acute porphyria, and in the elderly  (see also above). Chloroquine and hydroxychloroquine  may exacerbate psoriasis and aggravate myasthenia  gravis. Concurrent use of hepatotoxic drugs should be  avoided; other interactions: Appendix 1 (chloroquine  and hydroxychloroquine).    • Refer to ophthalmologist if visual acuity  changes or if vision blurred and warn patient  to seek prescribing doctor’s advice about stop-  ping treatment   • A child treated for juvenile idiopathic arthritis  should receive slit-lamp examination routinely  to check for uveitis   • If long-term treatment is required (more than 5  years), individual arrangement should be  agreed with the local ophthalmologist   To avoid excessive dosage in obese patients, the  doses of hydroxychloroquine and chloroquine  should be calculated on the basis of ideal body-  weight. Ocular toxicity is unlikely if the dose of  chloroquine phosphate does not exceed 4 mg/kg  daily (equivalent to chloroquine base approx.  2.5 mg/kg daily)    Hepatic impairment Chloroquine and hydroxy-  chloroquine should be used with caution in moderate  to severe hepatic impairment.   Pregnancy It is not necessary to withdraw an anti-  malarial drug during pregnancy if the rheumatic disease  is well controlled; however, the manufacturer of  hydroxychloroquine advises avoiding use.   Breast-feeding Chloroquine and hydroxychloroquine  are present in breast milk and breast-feeding should be  avoided when they are used to treat rheumatic disease.   Screening for ocular toxicity A review group convened  by the Royal College of Ophthalmologists has updated  guidelines for screening to prevent ocular toxicity on  long-term treatment with chloroquine and hydroxy-  chloroquine [Hydroxychloroquine and Ocular Toxicity:  Recommendations on Screening 2009). Chloroquine  should be considered (for treating chronic inflammatory  conditions) only if other drugs have failed. All patients  taking chloroquine should receive ocular examination  according to a protocol arranged locally between the  prescriber and the ophthalmologist. The following  recommendations relate to hydroxychloroquine, which  is only rarely associated with toxicity.   • Ask patient about visual impairment (not cor-  rected by glasses). If impairment or eye disease  present, assessment by an optometrist is  advised and any abnormality should be referred  to an ophthalmologist   • Record near visual acuity of each eye (with  glasses where appropriate) using a standard  reading chart   • Initiate hydroxychloroquine treatment if no  abnormality detected (at a dose not exceeding  hydroxychloroquine sulphate 6.5 mg/kg daily)    • Ask patient about visual symptoms and monitor  visual acuity annually using the standard read-  ing chart    Side-effects The side-effects of chloroquine and  hydroxychloroquine include gastro-intestinal distur-  bances, headache and skin reactions (rashes, pruritus);  those occurring less frequently include ECG changes,  convulsions, visual changes, retinal damage (see above),  keratopathy, ototoxicity, hair depigmentation, hair loss,  and discoloration of skin, nails, and mucous mem-  branes. Side-effects that occur rarely include blood  disorders (including thrombocytopenia, agranulocyto-  sis, and aplastic anaemia), mental changes (including  emotional disturbances and psychosis), myopathy  (including cardiomyopathy and neuromyopathy), acute  generalised exanthematous pustulosis, exfoliative  dermatitis, Stevens- Johnson syndrome, photosensit-  ivity, and hepatic damage; angioedema has also been  reported. Important: very toxic in overdosage —  immediate advice from poisons centres essential (see  also p. 37).   Indications active rheumatoid arthritis, systemic and  discoid lupus erythematosus; malaria (section 5.4.1)  Cautions see notes above   Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above   • Administered on expert advice, by mouth, ADULT over  18 years, chloroquine (base) 150 mg daily; max.   2.5 mg/kg daily based on ideal body-weight, see also  recommendations above   Note Chloroquine base 150 mg = chloroquine sulphate  200 mg = chloroquine phosphate 250 mg (approx.).   Indications active rheumatoid arthritis (including  juvenile idiopathic arthritis), systemic and discoid  lupus erythematosus; dermatological conditions  caused or aggravated by sunlight   Renal impairment manufacturer advises caution and  monitoring of plasma-hydroxychloroquine concen-  tration in severe impairment   • Administered on expert advice, 200-400 mg daily (but  not exceeding 6.5 mg/kg daily based on ideal body-  weight, see also recommendations above); CHILD 1  month- 18 years see BNF for Children   Hydroxychloroquine (Non-proprietary) (Ml  Tablets, hydroxychloroquine sulphate 200 mg, net  price 60-tab pack = £5.25. Label: 5, 21   Plaquenil® (Sanofi-Aventis) (Ml  Tablets, f/c, hydroxychloroquine sulphate 200 mg,  net price 60-tab pack = £5.25. Label: 5, 21   Methotrexate is a disease-modifying antirheumatic  drug suitable for moderate to severe rheumatoid arth-  ritis. Azathioprine, ciclosporin, cyclophosphamide,  leflunomide, and the cytokine modulators are consid-  ered more toxic and they are used in cases that have not  responded to other disease-modifying drugs.  Methotrexate is usually given in an initial dose of  7.5 mg by mouth once a week, adjusted according to  response to a maximum of 1 5 mg once a week (occa-  sionally 20 mg once a week). Regular full blood counts  (including differential white cell count and platelet  count), renal and liver function tests are required. In  patients who experience mucosal or gastro-intestinal  side-effects with methotrexate, folic acid 5 mg every  week [unlicensed indication], on a different day from  the methotrexate, may help to reduce the frequency of  such side-effects.   Azathioprine is usually given in a dose of up to 2.5 mg/  kg daily in divided doses. Blood counts are needed to  detect possible neutropenia or thrombocytopenia  (usually resolved by reducing the dose). Nausea, vomi-  ting, and diarrhoea may occur, usually starting early    during the course of treatment, and may necessitate  withdrawal of the drug; herpes zoster infection may also  occur.    Leflunomide acts on the immune system as a disease-  modifying antirheumatic drug. Its therapeutic effect  starts after 4-6 weeks and improvement may continue  for a further 4-6 months. Leflunomide, which is similar  in efficacy to sulfasalazine and methotrexate, may be  chosen when these drugs cannot be used. The active  metabolite of leflunomide persists for a long period;  active procedures to wash the drug out are required in  case of serious adverse effects, or before starting treat-  ment with another disease-modifying antirheumatic  drug, or, in men or women, before conception. Side-  effects of leflunomide include bone-marrow toxicity; its  immunosuppressive effects increase the risk of infection  and malignancy.    Ciclosporin is licensed for severe active rheumatoid  arthritis when conventional second-line therapy is inap-  propriate or ineffective. There is some evidence that  ciclosporin may retard the rate of erosive progression  and improve symptom control in those who respond  only partially to methotrexate.   Cyclophosphamide (section 8.1.1) may be used at a  dose of 1 to 1.5 mg/kg daily by mouth for rheumatoid  arthritis with severe systemic manifestations [unli-  censed indication]; it is toxic and regular blood counts  (including platelet counts) should be carried out. Cyclo-  phosphamide can also be given intravenously in a dose  of 0.5 to 1 g (with prophylactic mesna) for severe sys-  temic rheumatoid arthritis and for other connective  tissue diseases (especially with active vasculitis),  repeated initially at fortnightly then at monthly intervals  (according to clinical response and haematological  monitoring).    Drugs that affect the immune response are also used in  the management of severe cases of systemic lupus  erythematosus and other connective tissue disorders.  They are often given in conjunction with corticosteroids  for patients with severe or progressive renal disease.  They may be used in cases of polymyositis that are  resistant to corticosteroids. They are used for their  corticosteroid-sparing effect in patients whose cortico-  steroid requirements are excessive. Azathioprine is  usually used.   Azathioprine and methotrexate are used in the treat-  ment of psoriatic arthropathy [unlicensed indication]  for severe or progressive cases that are not controlled  with anti-inflammatory drugs.   Indications see notes above; inflammatory bowel  disease [unlicensed indication] (section 1.5.3); auto-  immune conditions and prophylaxis of transplantation  rejection (section 8.2.1); severe refractory eczema  [unlicensed indication] (section 13.5.3)   Cautions section 8.2.1  Contra-indications section 8.2.1  Hepatic impairment section 8.2.1  Renal impairment section 8.2.1  Pregnancy section 8.2.1  Breast-feeding section 8.2.1  Side-effects section 8.2.1   • By mouth, initially, rarely more than 3 mg/kg daily,  reduced according to response; maintenance 1-3 mg/  kg daily; consider withdrawal if no improvement  within 3 months   Indications severe active rheumatoid arthritis when  conventional second-line therapy inappropriate or  ineffective; severe acute ulcerative colitis [unlicensed  indication] (section 1.5.3); graft-versus-host disease  (section 8.2.2); atopic dermatitis and psoriasis (sec-  tion 13.5.3)   Additional cautions in rheumatoid arthritis Contra-  indicated in abnormal renal function, uncontrolled hyper-  tension (see also below), uncontrolled infections, and  malignancy. Measure serum creatinine at least twice before  treatment and monitor every 2 weeks for first 3 months, then  every 4 weeks (or more frequently if dose increased or  concomitant NSAIDs introduced or increased (see also  interactions: Appendix 1 (ciclosporin)), reduce dose if serum  creatinine increases more than 30% above baseline in more  than 1 measurement; if above 50%, reduce dose by 50%  (even if within normal range) and discontinue if reduction  not successful within 1 month; monitor blood pressure (dis-  continue if hypertension develops that cannot be controlled  by antihypertensive therapy); monitor hepatic function if  concomitant NSAIDs given.   Hepatic impairment section 8.2.2  Renal impairment see Cautions above  Pregnancy see section 8.2.2  Breast-feeding section 8.2.2  Side-effects section 8.2.2  Dose   • By mouth, administered in accordance with expert  advice, initially 2.5 mg/kg daily in 2 divided doses, if  necessary increased gradually after 6 weeks; max.   4 mg/kg daily (discontinue if response insufficient  after 3 months); dose adjusted according to response  for maintenance and treatment reviewed after 6  months (continue only if benefits outweigh risks);  CHILD and under 18 years, not recommended  Important For preparations and counselling and for advice  on conversion between the preparations, see section 8.2.2   Indications (specialist use only) moderate to severe  active rheumatoid arthritis; active psoriatic arthritis  Cautions impaired bone-marrow function including  anaemia, leucopenia or thrombocytopenia (avoid if  significant and due to causes other than rheumatoid  arthritis); recent treatment with other hepatotoxic or  myelotoxic disease-modifying antirheumatic drugs;  washout procedures recommended for serious  adverse effects or before switching to other disease-  modifying antirheumatic drugs (consult product lit-    erature and see Washout Procedure, below); history of  tuberculosis; exclude pregnancy before treatment;  effective contraception essential during treatment  and for at least 2 years after treatment in women and  at least 3 months after treatment in men (plasma  concentration monitoring required; waiting time  before conception may be reduced with washout  procedure — consult product literature and see Wash-  out Procedure, below); monitor full blood count  (including differential white cell count and platelet  count) before treatment and every 2 weeks for 6  months then every 8 weeks; monitor liver function —  see Hepatotoxicity, below; monitor blood pressure;  interactions: Appendix 1 (leflunomide)  Hepatotoxicity Potentially life-threatening hepatotoxicity  reported usually in the first 6 months; monitor liver func-  tion before treatment and every 2 weeks for first 6 months  then every 8 weeks. Discontinue treatment (and institute  washout procedure — consult product literature and see  Washout Procedure below) or reduce dose according to  liver-function abnormality; if liver-function abnormality  persists after dose reduction, discontinue treatment and  institute washout procedure   Washout procedure To aid drug elimination in case of  serious adverse effect, or before starting another disease-  modifying antirheumatic drug, or before conception (see also  Pregnancy below), stop treatment and give either colestyr-  amine 8 g 3 times daily for 1 1 days or activated charcoal 50 g  4 times daily for 1 1 days; the concentration of the active  metabolite after washout should be less than 20 micr-  ograms/litre (measured on 2 occasions 14 days apart) in  men or women before conception — consult product litera-  ture. Procedure may be repeated as necessary   Pregnancy avoid — active metabolite teratogenic in  animal studies; effective contraception essential dur-  ing treatment and for at least 2 years after treatment  in women and at least 3 months after treatment in  men (see also Cautions above)   Side-effects diarrhoea, nausea, vomiting, anorexia,  oral mucosal disorders, abdominal pain; increased  blood pressure; headache, dizziness, asthenia,  paraesthesia; leucopenia; tenosynovitis; alopecia,  rash, dry skin, pruritus; less commonly taste distur-  bance, anxiety, hyperlipidaemia, hypokalaemia,  hypophosphataemia, anaemia, thrombocytopenia,  and tendon rupture; rarely hepatitis, jaundice (see  Hepatotoxicity, above), interstitial lung disease,  severe infection, eosinophilia, and pancytopenia; very  rarely pancreatitis, hepatic failure (see Hepatotoxicity,  above), peripheral neuropathy, vasculitis, progressive  multifocal leucoencephalopathy, Stevens- Johnson  syndrome, and toxic epidermal necrolysis; hypouri-  caemia, reduced sperm count, and renal failure also  reported; important: discontinue treatment and  institute washout procedure (see Washout Procedure  under Cautions) in case of serious side-effect  Dose   • Rheumatoid arthritis, ADULT over 18 years, initially  100 mg once daily for 3 days, then 10-20 mg once  daily   • Psoriatic arthritis, ADULT over 18 years, initially 100 mg  once daily for 3 days, then 20 mg once daily    Leflunomide (Non-proprietary) [Ml  Tablets, leflunomide, 10 mg, net price 30-tab pack =  £46.00; 20 mg, 30-tab pack = £46.00. Label: 4   Arava® (Sanofi-Aventis) (Ml  Tablets, f/c, leflunomide 10 mg (white), net price 30-  tab pack = £51.13; 20 mg (yellow), 30-tab pack =  £61.36; 100 mg (white), 3-tab pack = £30.67. Label: 4   Indications moderate to severe active rheumatoid  arthritis; Crohn’s disease [unlicensed indication]  (section 1.5.3); malignant disease (section 8.1.3);  psoriasis (section 13.5.3)   Cautions section 8.1; see CSM advice below (blood  count, liver and pulmonary toxicity); extreme caution  in blood disorders (avoid if severe); peptic ulceration,  ulcerative colitis, diarrhoea and ulcerative stomatitis  (withdraw if stomatitis develops — may be first sign of  gastro-intestinal toxicity); risk of accumulation in  pleural effusion or ascites — drain before treatment;  acute porphyria (section 9.8.2); interactions: see  below and Appendix 1 (methotrexate)   In view of reports of blood dyscrasias (including fatal-  ities) and liver cirrhosis with low-dose methotrexate,  the CSM has advised:   • full blood count and renal and liver function tests before  starting treatment and repeated weekly until therapy sta-  bilised, thereafter patients should be monitored every 2-3  months   • that patients should be advised to report all symptoms and  signs suggestive of infection, especially sore throat   Treatment with folinic acid (as calcium folinate, sec-  tion 8.1) may be required in acute toxicity   Blood count Bone marrow suppression can occur abruptly;  factors likely to increase toxicity include advanced age, renal  impairment, and concomitant use with another anti-folate  drug. A clinically significant drop in white cell count or  platelet count calls for immediate withdrawal of metho-  trexate and introduction of supportive therapy  Liver toxicity Liver cirrhosis reported. Treatment should  not be started or should be discontinued if any abnormality  of liver function tests or liver biopsy is present or develops  during therapy. Abnormalities can return to normal within 2  weeks after which treatment maybe recommenced if judged  appropriate   Pulmonary toxicity Pulmonary toxicity may be a special  problem in rheumatoid arthritis (patient to seek medical  attention if dyspnoea, cough or fever); monitor for symptoms  at each visit — discontinue if pneumonitis suspected.   Aspirin and other NSAIDs If aspirin or other NSAIDs are  given concurrently the dose of methotrexate should be  carefully monitored. Patients should be advised to avoid self-  medication with over-the-counter aspirin or ibuprofen  Contra-indications see Cautions above; active infec-  tion and immunodeficiency syndromes  Hepatic impairment avoid — dose-related toxicity;  see also Cautions above   Renal impairment reduce dose; risk of nephrotoxicity  at high doses; avoid in severe impairment  Pregnancy avoid (teratogenic; fertility may be reduced  during therapy but this may be reversible); effective  contraception required during and for at least 3  months after treatment in men or women; see also  section 8.1    and bleeding, diarrhoea, toxic megacolon, hepato-  toxicity (see Cautions above); hypotension, pericard-  itis, pericardial tamponade; pulmonary oedema,  pleuritic pain, pulmonary fibrosis, interstitial pneu-  monitis (see also Pulmonary Toxicity above); ana-  phylactic reactions, urticaria; dizziness, fatigue, chills,  fever, drowsiness, malaise, headache, mood changes,  neurotoxicity, confusion, paraesthesia; precipitation of  diabetes; menstrual disturbances, vaginitis, cystitis,  reduced libido, impotence; blood disorders; haema-  turia, dysuria, renal failure; osteoporosis, arthralgia,  myalgia, vasculitis; conjunctivitis, visual disturbance;  rash, pruritus, Stevens-Johnson syndrome, toxic epi-  dermal necrolysis, photosensitivity, changes in nail  and skin pigmentation, telangiectasia, acne, furunco-  losis, ecchymosis; injection-site reactions  Dose   • Moderate to severe active rheumatoid arthritis, by  mouth, 7.5 mg once weekly, adjusted according to  response; max. weekly dose 20 mg   • Severe active rheumatoid arthritis, by subcutaneous  or by intramuscular or by intravenous injection,   7.5 mg once weekly, increased according to response  by 2.5 mg weekly; max. weekly dose 25 mg   Note that the above dose is a weekly dose. To avoid  error with low-dose methotrexate, it is recommended  that:   • the patient is carefully advised of the dose and frequency  and the reason for taking methotrexate and any other  prescribed medicine (e.g. folic acid);   • only one strength of methotrexate tablet (usually 2.5 mg) is  prescribed and dispensed;   • the prescription and the dispensing label clearly show the  dose and frequency of methotrexate administration;   • the patient is warned to report immediately the onset of  any feature of blood disorders (e.g. sore throat, bruising,  and mouth ulcers), liver toxicity (e.g. nausea, vomiting,  abdominal discomfort, and dark urine), and respiratory  effects (e.g. shortness of breath).    Methotrexate (Non-proprietary) (Ml  Tablets, yellow, methotrexate 2.5 mg, net price 28-tab  pack = £3.27. Counselling, dose, NSAIDs  Brands include Maxtrex ®   Metoject® (Medac) (Ml  Injection, prefilled syringe, methotrexate (as  disodium salt) 50mg/mL, net price 0.15 mL (7.5 mg)  = £14.85, 0.2 mL (10 mg) = £15.29, 0.3 mL (15 mg) =  £16.57, 0.4 mL (20 mg) = £17.84, 0.5 mL (25 mg) =  £18.48, 0.6 mL (30 mg) = £18.95   Adalimumab, certolizumab pegol, etanercept, golimu-  mab, and infliximab inhibit the activity of tumour necro-  sis factor alpha (TNF-a).    Side-effects section 8.1; also anorexia, abdominal Adalimumab is licensed for moderate to severe active  discomfort, dyspepsia, gastro-intestinal ulceration rheumatoid arthritis when response to other disease-    modifying antirheumatic drugs (including methotrexate)  has been inadequate (see also NICE guidance October  2007, below and August 2010, p. 649); it can also be  used for severe, active, and progressive disease in adults  not previously treated with methotrexate. It is also  licensed for active polyarticular juvenile idiopathic  arthritis in adolescents who have not responded ade-  quately to one or more disease-modifying antirheumatic  drugs. In the treatment of rheumatoid arthritis and  polyarticular juvenile idiopathic arthritis, adalimumab  should be used in combination with methotrexate, but it  can be given alone if methotrexate is inappropriate.  Adalimumab is also licensed for the treatment of active  and progressive psoriatic arthritis (see also NICE gui-  dance, p. 649) and severe active ankylosing spondylitis  (see also NICE guidance, p. 649) that have not  responded adequately to other disease-modifying anti-  rheumatic drugs. For the role of adalimumab in Crohn’s  disease, see section 1.5.3. For the role of adalimumab in  plaque psoriasis, see section 13.5.3.   Certolizumab pegol is licensed for use in patients with  moderate to severe active rheumatoid arthritis when  response to disease-modifying antirheumatic drugs  (including methotrexate) has been inadequate (see  also NICE guidance, below). Certolizumab pegol can  be used in combination with methotrexate, or as a  monotherapy if methotrexate is not tolerated or is  contra-indicated.   Certolizumab pegol for the treatment of  rheumatoid arthritis (February 2010)  Certolizumab pegol is recommended as an option  for the treatment of patients with rheumatoid arth-  ritis only if:   • certolizumab pegol is used as described in the  NICE guidance (October 2007) for other tumour  necrosis factor (TNF) inhibitor treatments, (see  Adalimumab, Etanercept and Infliximab for the  treatment of Rheumatoid Arthritis, below) and   • the manufacturer provides the first 12 weeks of  certolizumab pegol (10 prefilled 200-mg syr-  inges) free of charge to all patients starting  treatment.    Etanercept is licensed for the treatment of moderate to  severe active rheumatoid arthritis either alone or in  combination with methotrexate when the response to  other disease-modifying antirheumatic drugs is inade-  quate and in severe, active and progressive rheumatoid  arthritis in patients not previously treated with metho-  trexate (see also NICE guidance October 2007, below  and August 2010, p. 649). It is also licensed for the  treatment of active polyarticular juvenile idiopathic  arthritis in children who have not responded adequately  to or are intolerant of methotrexate (see also NICE  guidance, p. 649), active and progressive psoriatic arth-  ritis inadequately responsive to other disease-modifying  antirheumatic drugs (see also NICE guidance, p. 649),  and for severe ankylosing spondylitis inadequately  responsive to conventional therapy (see also NICE  guidance, p. 649). For the role of etanercept in plaque  psoriasis, see section 13.5.3.   Golimumab is licensed in combination with metho-  trexate for the treatment of moderate to severe active  rheumatoid arthritis when response to disease-modify-    ing antirheumatic drug (DMARD) therapy (including  methotrexate) has been inadequate. Golimumab is  also licensed for the treatment of active and progressive  psoriatic arthritis, as monotherapy or in combination  with methotrexate, when response to DMARD therapy  has been inadequate; it is also licensed for the treatment  of severe active ankylosing spondylitis when there is an  inadequate response to conventional treatment.  Infliximab is licensed for the treatment of active rheu-  matoid arthritis in combination with methotrexate  when the response to other disease-modifying anti-  rheumatic drugs, including methotrexate, is inadequate  (see also NICE guidance October 2007, below and  August 2010, p. 649); it is also licensed in combination  with methotrexate for patients not previously treated  with methotrexate or other DMARDs who have severe,  active, and progressive rheumatoid arthritis. Infliximab  is also licensed for the treatment of ankylosing spondyl-  itis, in patients with severe axial symptoms who have  not responded adequately to conventional therapy (but  see also NICE guidance, p. 649) and in combination  with methotrexate (or alone if methotrexate is not  tolerated or is contra-indicated) for the treatment of  active and progressive psoriatic arthritis which has  not responded adequately to disease-modifying anti-  rheumatic drugs (see also NICE guidance, p. 649).  Rituximab is licensed in combination with metho-  trexate for the treatment of severe active rheumatoid  arthritis in patients whose condition has not responded  adequately to other disease-modifying antirheumatic  drugs (including one or more tumour necrosis factor  inhibitors) or who are intolerant of them (see also NICE  guidance, p. 649). For the role of rituximab in malignant  disease, see section 8.2.3.   Adalimumab, etanercept, and infliximab for  the treatment of rheumatoid arthritis  (October 2007)   The tumour necrosis factor alpha (TNF-a) inhibitors  adalimumab, etanercept, and infliximab are options  for the treatment of adults with active rheumatoid  arthritis who have failed to respond to at least 2  disease-modifying antirheumatic drugs (DMARDs),  including methotrexate (unless contra-indicated).  TNF-a inhibitors should be given in combination  with methotrexate; however, when methotrexate  cannot be used because of intolerance or contra-  indications, adalimumab or etanercept can be given  as monotherapy.   Adalimumab, etanercept, and infliximab should be  withdrawn if response is not adequate within 6  months. Response to treatment should be monitored  at least every 6 months in patients who respond  initially; treatment should be withdrawn if response  is not maintained. An alternative TNF-a inhibitor  may be considered for patients in whom treatment is  withdrawn because of intolerance before the initial  6-month assessment of efficacy.   Use of TNF-a inhibitors for the treatment of severe,  active, and progressive rheumatoid arthritis in adults  not previously treated with methotrexate or other  DMARDs is not recommended.   Adalimumab, etanercept, infliximab,  rituximab, and abatacept for the treatment  of rheumatoid arthritis after the failure of a  TNF inhibitor (August 2010)   Rituximab, in combination with methotrexate, is an  option for the treatment of severe active rheumatoid  arthritis in adults who have had an inadequate  response to, or are intolerant of, other disease-mod-  ifying antirheumatic drugs (DMARDs), including at  least 1 tumour necrosis factor (TNF) inhibitor.  Repeat courses of rituximab should be given no  more frequently than every 6 months, and should  only be continued if an adequate response is  achieved and maintained.   Adalimumab, etanercept, infliximab, or abatacept, in  combination with methotrexate, are options for the  treatment of severe active rheumatoid arthritis in  adults who have had an inadequate response to, or  have an intolerance of, other DMARDs including at  least 1 TNF inhibitor, and who cannot use rituximab  because of contra-indications or intolerance. In  patients who cannot use methotrexate because of  intolerance or contra-indications, adalimumab or  etanercept can be given as monotherapy. Treatment  should be continued only if there is adequate  response. Patients should be monitored at least  every 6 months.   Adalimumab, etanercept, and infliximab for  the treatment of ankylosing spondylitis (May  2008)   Adalimumab or etanercept are recommended as  treatment options for adults with severe active anky-  losing spondylitis whose disease satisfies specific  criteria for diagnosis where there is confirmation of  sustained active spinal disease, and where treatment  with two or more NSAIDs taken sequentially at  maximum tolerated or recommended doses for 4  weeks has failed to control symptoms.   Response to adalimumab or etanercept treatment  should be assessed at 12-week intervals and con-  tinued only if response is adequate. If response to  treatment is not maintained, a repeat assessment  should be made after a further 6 weeks and treat-  ment discontinued if there is an inadequate  response. Patients who are intolerant of adalimumab  or etanercept during the initial 12 weeks may receive  the alternative TNF-a inhibitor (adalimumab or eta-  nercept). However an alternative TNF-a inhibitor is  not recommended in patients who fail to respond  initially or fail to maintain an adequate response.  Infliximab is not recommended for the treatment of  ankylosing spondylitis. Patients who are already  receiving infliximab for the treatment of ankylosing  spondylitis can continue treatment until they and  their specialist consider it appropriate to stop.   See full NICE guidance for specific criteria to diag-  nose severe active ankylosing spondylitis, confirm  sustained active spinal disease, and assess response  to treatment.   Etanercept is recommended in children aged 4-17  years with active polyarticular-course juvenile idio-  pathic arthritis who have not responded adequately  to methotrexate or who are intolerant of it. Etaner-  cept should be used under specialist supervision  according to the guidelines of the British Society  for Paediatric and Adolescent Rheumatology [pre-  viously the British Paediatric Rheumatology Group].   Etanercept should be withdrawn if severe side-  effects develop or if there is no response after 6  months or if the initial response is not maintained.  There is no evidence to support treatment for longer  than 2 years; a decision to continue therapy should  be based on disease activity and clinical effective-  ness in individual cases.   Prescribes of etanercept should register consenting  patients with the Biologies Registry of the British  Society for Paediatric and Adolescent Rheumatol-  ogy-   Etanercept, infliximab, and adalimumab for  the treatment of psoriatic arthritis (August  2010)   Etanercept, infliximab, or adalimumab are recom-  mended for the treatment of active and progressive  psoriatic arthritis in adults who have peripheral arth-  ritis with at least 3 tender joints and at least 3  swollen joints, and who have not responded ade-  quately to at least 2 standard disease-modifying  antirheumatic drugs (used alone or in combination).    Etanercept, infliximab, and adalimumab should be  discontinued if there is an inadequate response at 12  weeks.    Side-effects Adalimumab, certolizumab pegol, eta-  nercept, golimumab, infliximab, and rituximab have  been associated with infections, sometimes severe,  including tuberculosis, septicaemia, and hepatitis B  reactivation. Other side-effects include nausea, abdo-  minal pain, worsening heart failure, hypersensitivity  reactions, fever, headache, depression, antibody forma-  tion (including lupus erythematosus-like syndrome),  pruritus, injection-site reactions, and blood disorders  (including anaemia, leucopenia, thrombocytopenia,  pancytopenia, and aplastic anaemia).   Abatacept prevents the full activation of T-lympho-  cytes. It is licensed for moderate to severe active rheu-  matoid arthritis in combination with methotrexate, in  patients unresponsive to other disease-modifying anti-  rheumatic drugs (including methotrexate or a tumour  necrosis factor (TNF) inhibitor); see also NICE guidance,  above. It is also licensed for the treatment of moderate  to severe active polyarticular juvenile idiopathic arth-  ritis (in combination with methotrexate) in children who  have not responded adequately to other disease-mod-  ifying antirheumatic drugs (including at least one  tumour necrosis factor (TNF) inhibitor). Abatacept is  not recommended for use in combination with TNF  inhibitors.    The Scottish Medicines Consortium (p. 4) has advised  (August 2007) that abatacept is not recommended for  the treatment of moderate to severe active rheumatoid  arthritis within NHS Scotland.   Anakinra inhibits the activity of interleukin- 1. Anakinra  (in combination with methotrexate) is licensed for the  treatment of rheumatoid arthritis which has not  responded to methotrexate alone; it is not, however,  recommended for routine management of rheumatoid  arthritis, see NICE guidance below.   The Scottish Medicines Consortium (p. 4) has advised  (July 2002) that anakinra is not recommended for the  treatment of rheumatoid arthritis within NHS Scotland.   Anakinra is not recommended for the treatment of  rheumatoid arthritis except when used in a con-  trolled long-term clinical study. Patients who are  already receiving anakinra for rheumatoid arthritis  should continue treatment until they and their spe-  cialist consider it appropriate to stop.    Tocilizumab antagonises the actions of interleukin-6.  Tocilizumab is licensed for use in patients with moder-  ate to severe active rheumatoid arthritis when response  to at least one disease-modifying antirheumatic drug or  tumour necrosis factor inhibitor has been inadequate, or  in those who are intolerant of these drugs. Tocilizumab  can be used in combination with methotrexate, or as  monotherapy if methotrexate is not tolerated or is  contra-indicated (see also NICE guidance below).   Tocilizumab, in combination with methotrexate, is  recommended for the treatment of moderate to  severe active rheumatoid arthritis in patients who  have had an inadequate response to 1 or more  tumour necrosis factor alpha inhibitors and:   Cautions predisposition to infection (screen for latent  tuberculosis and viral hepatitis); do not initiate until  active infections are controlled; children should be  brought up to date with current immunisation sche-  dule (section 14.1) before initiating therapy; progres-  sive multifocal leucoencephalopathy — discontinue  treatment if neurological symptoms present; elderly  (increased risk of side-effects); interactions: Appen-  dix 1 (abatacept)   Breast-feeding present in milk in animal studies —  manufacturer advises avoid breast-feeding during  treatment and for 14 weeks after last dose    Side-effects abdominal pain, diarrhoea, dyspepsia,  nausea; flushing, hypertension; cough; dizziness, fati-  gue, headache; infection, rhinitis; rash; less commonly  gastritis, stomatitis, tachycardia, bradycardia, palpi-  tation, hypotension, dyspnoea, paraesthesia, weight  gain, depression, anxiety, amenorrhoea, basal cell  carcinoma, thrombocytopenia, leucopenia, arthralgia,  pain in extremities, conjunctivitis, visual disturbance,  vertigo, bruising, alopecia, and dry skin   • By intravenous infusion, rheumatoid arthritis (see  notes above), ADULT over 18 years, body-weight less  than 60 kg, 500 mg, repeated 2 weeks and 4 weeks  after initial infusion, then every 4 weeks; body-weight  60-100 kg, 750 mg repeated 2 weeks and 4 weeks  after initial infusion, then every 4 weeks; body-weight  over 100 kg, 1 g repeated 2 weeks and 4 weeks after  initial infusion, then every 4 weeks  Polyarticular juvenile idiopathic arthritis (see notes  above), CHILD 6-17 years, body-weight less than 75 kg,  10 mg/kg, repeated 2 weeks and 4 weeks after initial  infusion, then every 4 weeks; body-weight 75-100 kg,  750 mg, repeated 2 weeks and 4 weeks after initial  infusion, then every 4 weeks; body-weight over  100 kg, 1 g, repeated 2 weeks and 4 weeks after initial  infusion, then every 4 weeks  Note Review treatment if no response within 6 months   Cautions predisposition to infection; monitor for  infections before, during, and for 5 months after  treatment (see also Tuberculosis below); do not initi-  ate until active infections are controlled; discontinue if  new serious infection develops; hepatitis B virus —  monitor for active infection; children should be  brought up to date with current immunisation sche-  dule (section 14.1) before initiating therapy; mild heart  failure (discontinue if symptoms develop or worsen —  avoid in moderate or severe heart failure); demyeli-  nating CNS disorders (risk of exacerbation); history of  malignancy; monitor for non-melanoma skin cancer  before and during treatment, especially in patients  with a history of PUVA treatment for psoriasis or  extensive immunosuppressant therapy; interactions:  Appendix 1 (adalimumab)   Tuberculosis Patients should be evaluated for tuberculosis  before treatment. Active tuberculosis should be treated with  standard treatment (section 5.1.9) for at least 2 months  before starting adalimumab. Patients who have previously  received adequate treatment for tuberculosis can start ada-  limumab but should be monitored every 3 months for  possible recurrence. In patients without active tuberculosis  but who were previously not treated adequately, chemo-  prophylaxis should ideally be completed before starting  adalimumab. In patients at high risk of tuberculosis who  cannot be assessed by tuberculin skin test, chemoprophy-  laxis can be given concurrently with adalimumab. Patients  should be advised to seek medical attention if symptoms  suggestive of tuberculosis (e.g. persistent cough, weight loss,  and fever) develop    Kineret® (Swedish Orphan) (Ml  Injection, anakinra, net price 100-mg prefilled syringe  = £26.23. Counselling, blood disorder symptoms    Pregnancy avoid; manufacturer advises effective  contraception required during treatment and for at  least 5 months after last dose  Breast-feeding avoid; manufacturer advises avoid for  at least 5 months after last dose  Side-effects see under Cytokine Modulators (p. 649)  and Cautions above; also vomiting, dyspepsia, gastro-  intestinal haemorrhage; dizziness, hyperlipidaemia,  hypertension, oedema, flushing, chest pain, tachy-  cardia; cough, dyspnoea; mood changes, sleep dis-  turbances, anxiety, paraesthesia; haematuria, renal  impairment; benign tumours, non-melanoma skin  cancers; electrolyte disturbances, hyperuricaemia;  musculoskeletal pain; eye disorders; rash, dermatitis,  onycholysis, impaired healing; less commonly dys-  phagia, pancreatitis, cholelithiasis, hepatic steatosis,  cholecystitis, arrhythmias, interstitial lung disease,  pneumonitis, tremor, erectile dysfunction, nocturia,  malignancy, rhabdomyolysis, hearing loss, tinnitus;  rarely vascular occlusion, myocardial infarction,  demyelinating disorders, pulmonary embolism,  pleural effusion, Stevens-Johnson syndrome, cuta-  neous vasculitis, new onset or worsening psoriasis,  and hepatosplenic T-cell lymphoma also reported  Dose   • By subcutaneous injection, rheumatoid arthritis,  ADULT over 18 years, 40 mg on alternate weeks; if  necessary increased to 40 mg weekly in patients  receiving adalimumab alone; review treatment if no  response within 12 weeks   Polyarticular juvenile idiopathic arthritis, CHILD 13-17  years, 40 mg on alternate weeks; review treatment if  no response within 12 weeks  Psoriatic arthritis, ankylosing spondylitis, ADULT over  18 years, 40 mg on alternate weeks; discontinue  treatment if no response within 12 weeks   Indications see under Cytokine Modulators above  Cautions predisposition to infections; history of  asthma (risk of serious infection); interactions:  Appendix 1 (anakinra)   Blood disorders Neutropenia reported commonly. Monitor  neutrophil count before treatment, then every month for 6  months, then every 3 months — discontinue if neutropenia  develops. Patients should be instructed to seek medical  advice if symptoms suggestive of neutropenia (such as fever,  sore throat, infection) develop  Contra-indications neutropenia  Renal impairment caution if eGFR 30-50 mL/min-  ute/ 1.73 m 2 ; avoid if eGFR less than 30mL/minute/  1.73 m 2   Side-effects injection-site reactions; headache; infec-  tions, neutropenia (see also Cautions), and antibody  formation; also reported malignancy   Cautions predisposition to infection; monitor for  infections before, during, and for 5 months after  treatment (see also Tuberculosis below); do not initi-  ate until active infections are controlled; discontinue if  new serious infection develops until infection con-  trolled; hepatitis B virus — monitor for active infection;  mild heart failure (discontinue if symptoms develop or  worsen — avoid in moderate to severe heart failure);  demyelinating CNS disorders (risk of exacerbation);  history or development of malignancy; interactions:  Appendix 1 (certolizumab pegol)   Tuberculosis Patients should be evaluated for tuberculosis  before treatment. Active tuberculosis should be treated with  standard treatment (section 5.1.9) for at least 2 months  before starting certolizumab pegol. Patients who have pre-  viously received adequate treatment for tuberculosis can  start certolizumab pegol but should be monitored every 3  months for possible recurrence. In patients without active  tuberculosis but who were previously not treated adequately  chemoprophylaxis should ideally be completed before  starting certolizumab pegol. In patients at high risk of  tuberculosis who cannot be assessed by tuberculin skin test,  chemoprophylaxis can be given concurrently with certoli-  zumab pegol. Patients should be advised to seek medical  attention if symptoms suggestive of tuberculosis (e.g. per-  sistent cough, weight loss, and fever) develop  Blood disorders Patients should be advised to seek medical  attention if symptoms suggestive of blood disorders (such as  fever, sore throat, bruising, or bleeding) develop   Pregnancy avoid; manufacturer advises adequate  contraception during treatment and for at least 5  months after last dose    Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — no information  available   Side-effects see under Cytokine Modulators (p. 649)  and Cautions above; hypertension; sensory abnorm-  alities; rash; less commonly ascites, cholestasis, gas-  trointestinal disorders (including perforation and  ulcer), hepatic disorders, appetite disorders; cardio-  myopathies (including heart failure), dyslipidaemia,  syncope, oedema, dizziness, ischaemic coronary  artery disorders, arrhythmias; asthma, pleural effu-  sion, cough; peripheral neuropathy, tremor, anxiety,  mood disorders; influenza-like illness; menstrual dis-  orders, renal impairment, haematuria; malignancy,  non-melanoma skin cancer, benign tumours;  haemorrhage, electrolyte disorders; muscle disorders;  visual disturbance, ocular inflammation; ecchymosis,  impaired healing, alopecia, photosensitivity, acne, skin  discoloration, nail disorders, psoriasis, dermatitis;  rarely cholelithiasis, splenomegaly, atrioventricular  block, cerebrovascular accident, Raynaud’s phenom-  enon, interstitial lung disease, impaired coordination,  trigeminal neuralgia, thyroid disorders, sexual dys-  function, nephropathy, tinnitus; multiple sclerosis also  reported  Dose   400 mg, repeated 2 weeks and 4 weeks after initial  injection, then 200 mg every 2 weeks; review treat-  ment if no response within 12 weeks    Active polyarticular juvenile idiopathic arthritis, CHILD  4-17 years, 400 micrograms/kg (max. 25 mg) twice  weekly, with an interval of 3-4 days between doses   Cautions predisposition to infection (avoid if predis-  position to septicaemia); significant exposure to  herpes zoster virus — interrupt treatment and consider  varicella-zoster immunoglobulin; hepatitis B virus —  monitor for active infection; monitor for worsening  hepatitis C infection; children should be brought up to  date with current immunisation schedule (section  14.1) before initiating therapy; heart failure (risk of  exacerbation); demyelinating CNS disorders (risk of  exacerbation); history of malignancy; monitor for  non-melanoma skin cancer before and during treat-  ment in those at risk, including patients with psoriasis  or a history of PUVA treatment; history of blood  disorders; diabetes mellitus; interactions: Appendix 1  (etanercept)   Tuberculosis Patients should be evaluated for tuberculosis  before treatment. Active tuberculosis should be treated with  standard treatment (section 5.1.9) for at least 2 months  before starting etanercept. Patients who have previously  received adequate treatment for tuberculosis can start eta-  nercept but should be monitored every 3 months for possible  recurrence. In patients without active tuberculosis but who  were previously not treated adequately, chemoprophylaxis  should ideally be completed before starting etanercept. In  patients at high risk of tuberculosis who cannot be assessed  by tuberculin skin test, chemoprophylaxis can be given  concurrently with etanercept. Patients should be advised to  seek medical attention if symptoms suggestive of tuber-  culosis (e.g. persistent cough, weight loss, and fever) develop  Blood disorders Patients should be advised to seek medical  attention if symptoms suggestive of blood disorders (such as  fever, sore throat, bruising, or bleeding) develop   Contra-indications active infection; avoid injections  containing benzyl alcohol in neonates (see prepara-  tions below)   Hepatic impairment use with caution in moderate to  severe alcoholic hepatitis   Side-effects see under Cytokine Modulators (p. 649);  also less commonly interstitial lung disease, non-  melanoma skin cancer, rash, psoriasis (including new  onset); rarely demyelinating disorders, seizures, Ste-  vens- Johnson syndrome, and cutaneous vasculitis;  very rarely toxic epidermal necrolysis; also reported  appendicitis, cholecystitis, gastritis, gastro-intestinal  haemorrhage, intestinal obstruction, liver damage,  oesophagitis, pancreatitis, ulcerative colitis, vomiting,  cerebral ischaemia, hypertension, hypotension, myo-  cardial infarction, thrombophlebitis, thromboembo-  lism, asthma, dyspnoea, aseptic meningitis, confusion,  paresis, paraesthesia, vertigo, lymphadenopathy, dia-  betes mellitus, haematuria, malignancy, renal calculi,  renal impairment, bone fracture, bursitis, polymyos-  itis, scleritis, and cutaneous ulcer   • By subcutaneous injection, rheumatoid arthritis,  psoriatic arthritis, ankylosing spondylitis, ADULT over  18 years, 25 mg twice weekly or 50 mg once weekly   Injection, etanercept, net price 25-mg prefilled  syringe = £89.38; 50-mg prefilled pen or prefilled  syringe = £178.75. Label: 10, alert card, counselling,  tuberculosis and blood disorders   Cautions predisposition to infection; monitor for  infections before, during, and for 5 months after  treatment (see also Tuberculosis below); do not initi-  ate until active infections are controlled; discontinue if  new serious infection develops until infection con-  trolled; hepatitis B virus — monitor for active infection;  mild heart failure (discontinue if symptoms develop or  worsen); demyelinating CNS disorders (risk of  exacerbation); history or development of malignancy;  interactions: Appendix 1 (golimumab)   Tuberculosis Patients should be evaluated for tuberculosis  before treatment. Active tuberculosis should be treated with  standard treatment (section 5.1.9) for at least 2 months  before starting golimumab. Patients who have previously  received adequate treatment for tuberculosis can start goli-  mumab but should be monitored every 3 months for possible  recurrence. In patients without active tuberculosis but who  were previously not treated adequately, chemoprophylaxis  should ideally be completed before starting golimumab. In  patients at high risk of tuberculosis who cannot be assessed  by tuberculin skin test, chemoprophylaxis can be given  concurrently with golimumab. Patients should be advised to  seek medical attention if symptoms suggestive of tuber-  culosis (e.g. persistent cough, weight loss, and fever) develop  Blood disorders Patients should be advised to seek medical  attention if symptoms suggestive of blood disorders (such as  fever, sore throat, bruising, or bleeding) develop   Contra-indications severe active infection (see also  Cautions); moderate or severe heart failure   Pregnancy use only if essential; manufacturer advises  adequate contraception during treatment and for at  least 6 months after last dose   Breast-feeding manufacturer advises avoid during  and for at least 6 months after treatment — present in  milk in animal studies   Side-effects see under Cytokine Modulators (p. 649)  and under Cautions above; also constipation, dys-  pepsia, hypertension, insomnia, dizziness, paraes-  thesia, asthenia, alopecia, dermatitis; less commonly  taste disturbance, gastritis, colitis, stomatitis, gastro-  oesophageal reflux disease, cholelithiasis, hepatic  disorders, hyperlipidaemia, arrhythmia, ischaemic  coronary artery disorders, Raynaud’s syndrome, heart  failure, thrombosis, flushing, bronchospasm, demye-  linating disorders, hyperglycaemia, thyroid disorders,  menstrual disorders, malignancy, bone fractures,    visual disturbance, eye irritation, new onset or wor-  sening psoriasis; rarely interstitial lung disease, renal  impairment   50 mg once a month on the same date each month,  review treatment if no response after 3-4 doses; body-  weight over 100 kg, if inadequate response to 3-4  doses of 50 mg once a month, dose can be increased  to 100 mg once a month, review treatment if inade-  quate response to this higher dose after 3-4 doses  Note If dose administered more than 2 weeks late, subse-  quent doses should be administered on the new monthly due  date   Indications see under Cytokine Modulators above;  inflammatory bowel disease (section 1.5.3); psoriasis  (section 13.5.3)   Cautions predisposition to infection; monitor for  infections before, during, and for 6 months after  treatment (see also Tuberculosis below); discontinue  if new serious infection develops; hepatitis B virus —  monitor for active infection; heart failure (discontinue  if symptoms develop or worsen; avoid in moderate or  severe heart failure); demyelinating CNS disorders  (risk of exacerbation); history of malignancy (consider  discontinuing treatment if malignancy develops); his-  tory of prolonged immunosuppressant or PUVA  treatment in patients with psoriasis; interactions:  Appendix 1 (infliximab)   Tuberculosis Patients should be evaluated for tuberculosis  before treatment. Active tuberculosis should be treated with  standard treatment (section 5.1.9) for at least 2 months  before starting infliximab. Patients who have previously  received adequate treatment for tuberculosis can start  infliximab but should be monitored every 3 months for  possible recurrence. In patients without active tuberculosis  but who were previously not treated adequately, chemo-  prophylaxis should ideally be completed before starting  infliximab. In patients at high risk of tuberculosis who cannot  be assessed by tuberculin skin test, chemoprophylaxis can be  given concurrently with infliximab. Patients should be  advised to seek medical attention if symptoms suggestive of  tuberculosis (e.g. persistent cough, weight loss, and fever)  develop   Hypersensitivity reactions Hypersensitivity reactions  (including fever, chest pain, hypotension, hypertension,  dyspnoea, pruritus, urticaria, serum sickness-like reactions,  angioedema, anaphylaxis) reported during or within 1-2  hours after infusion (risk greatest during first or second  infusion or in patients who discontinue other immuno-  suppressants). All patients should be observed carefully for  1-2 hours after infiision and resuscitation equipment should  be available for immediate use. Prophylactic antipyretics,  antihistamines, or hydrocortisone may be administered.  Monitor for symptoms of delayed hypersensitivity if read-  ministered after a prolonged period. Patients should be  advised to keep Alert card with them at all times and seek  medical advice if symptoms of delayed hypersensitivity  develop   Pregnancy use only if essential; manufacturer advises  adequate contraception during and for at least 6  months after last dose    Side-effects see under Cytokine Modulators (p. 649)  and under Cautions above; also diarrhoea, dyspepsia,  hepatic impairment; flushing, chest pain; dyspnoea;  dizziness, fatigue; sinusitis; rash, sweating, dry skin;  less commonly constipation, gastro-oesophageal  reflux, diverticulitis, cholecystitis, palpitation,  arrhythmia, hypertension, hypotension, vasospasm,  cyanosis, bradycardia, syncope, oedema, thrombo-  phlebitis, epistaxis, bronchospasm, pleurisy, confu-  sion, agitation, nervousness, amnesia, sleep distur-  bances, vaginitis, demyelinating disorders, antibody  formation, pyelonephritis, myalgia, arthralgia, eye  disorders, abnormal skin pigmentation, ecchymosis,  cheilitis, and alopecia; rarely hepatitis, intestinal ste-  nosis, intestinal perforation, gastro-intestinal  haemorrhage, and circulatory failure, meningitis, sei-  zure, pancreatitis, lymphoma; very rarely pericardial  and pleural effusion, and skin reactions (including  Stevens- Johnson syndrome, toxic epidermal necro-  lysis); neuropathy, paraesthesia, and transverse mye-  litis; interstitial lung disease, new onset or worsening  psoriasis also reported  Dose   • By intravenous infusion, rheumatoid arthritis (in  combination with methotrexate), ADULT over 18 years,  3 mg/kg, repeated 2 weeks and 6 weeks after initial  infusion, then every 8 weeks; if response inadequate  after 12 weeks, dose may be increased in steps of  1.5 mg/kg every 8 weeks, up to max. 7.5 mg/kg every  8 weeks; alternatively, 3 mg/kg may be given every 4  weeks; discontinue if no response by 12 weeks of  initial infusion or after dose adjustment  Ankylosing spondylitis, ADULT over 18 years, 5 mg/kg,  repeated 2 weeks and 6 weeks after initial infusion,  then every 6-8 weeks; discontinue if no response by 6  weeks of initial infusion   Psoriatic arthritis (in combination with methotrexate),  ADULT over 18 years, 5 mg/kg, repeated 2 weeks and 6  weeks after initial infusion, then every 8 weeks    Remicade® (Schering-Plough) (Ml  Intravenous infusion, powder for reconstitution,  infliximab, net price 100-mg vial = £419.62. Label: 10,  alert card, counselling, tuberculosis and hypersensi-  tivity reactions   Cautions section 8.2.3; predisposition to infection;  hepatitis B virus — monitor for active infection  Alert card Patients with rheumatoid arthritis should be  provided with the patient alert card before administration  Contra-indications section 8.2.3; severe infection  Pregnancy section 8.2.3  Breast-feeding section 8.2.3  Side-effects section 8.2.3 and under Cytokine Mod-  ulators (p. 649); also dyspepsia; hypertension, hypo-  tension; rhinitis, sore throat; asthenia, paraesthesia,  migraine; arthralgia, muscle spasm; urticaria  Dose   • By intravenous infusion, rheumatoid arthritis (in  combination with methotrexate), 1 g, repeated 2  weeks after initial infusion; CHILD not recommended   Cautions predisposition to infection or history of  recurrent or chronic infection; interrupt treatment if  serious infection occurs; history of intestinal ulcer-  ation or diverticulitis; monitor hepatic transaminases  every 4-8 weeks for first 6 months, then every 12  weeks; monitor neutrophil and platelet counts 4-8  weeks after starting treatment and then as indicated;  low platelet or absolute neutrophil count (avoid if  absolute neutrophil count less than 0.5 x 1 0 9 /litre or  platelet count less than 50 x 10 3 /microlitre); monitor  lipid profile 4-8 weeks after starting treatment and  then as indicated; monitor for demyelinating disor-  ders; interactions: Appendix 1 (tocilizumab)  Tuberculosis Patients should be evaluated for tuberculosis  before treatment. Patients with latent tuberculosis should be  treated with standard therapy (section 5.1.9) before starting  tocilizumab   Counselling Patients should be advised to seek immediate  medical attention if symptoms of infection occur, or if  symptoms of diverticular perforation such as abdominal  pain, haemorrhage, or fever accompanying change in bowel  habits occur    Pregnancy manufacturer advises avoid unless essen-  tial (toxicity in animal studies); effective contra-  ception required during and for 6 months after treat-  ment   Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — no information  available   Side-effects abdominal pain, mouth ulceration, gas-  tritis, raised hepatic transaminases; dizziness, periph-  eral oedema, hypertension, hypercholesterolaemia;  headache; infection (including upper respiratory-tract  infection); antibody formation, hypersensitivity,  leucopenia, neutropenia; rash, pruritus; less com-  monly gastric ulcer, gastro-intestinal perforation,  hypertriglyceridaemia, hypothyroidism, nephrolithia-  sis, infusion related reactions, anaphylaxis, and  thrombocytopenia also reported    • By intravenous infusion, ADULT over 18 years, 8 mg/kg  (max. 800 mg) once every 4 weeks; for details of dose  adjustment in patients with liver enzyme abnormal-  ities, or low absolute neutrophil or platelet count,  consult product literature    RoActemra® (Roche) ▼ IMl  Concentrate for intravenous infusion, tocilizumab  20mg/mL, net price 4mL (80-mg) vial = £102.40,   10 mL (200-mg) vial = £256.00, 20 mL (400-mg) vial =  £512.00. Alert card, counselling, see above   Sulfasalazine has a beneficial effect in suppressing the  inflammatory activity of rheumatoid arthritis. Side-  effects include rashes, gastro-intestinal intolerance  and, especially in patients with rheumatoid arthritis,  occasional leucopenia, neutropenia, and thrombocyto-    penia. These haematological abnormalities occur usual-  ly in the first 3 to 6 months of treatment and are  reversible on cessation of treatment. Close monitoring  of full blood counts (including differential white cell  count and platelet count) is necessary initially, and at  monthly intervals during the first 3 months (liver func-  tion tests also being performed at monthly intervals for  the first 3 months). Although the manufacturer recom-  mends renal function tests, evidence of practical value is  unsatisfactory.   Indications active rheumatoid arthritis; inflammatory  bowel disease, see section 1.5.1 and notes above  Cautions see section 1.5.1 and notes above  Blood disorders Patients should be advised to report any  unexplained bleeding, bruising, purpura, sore throat, fever or  malaise. A blood count should be performed and the drug  stopped immediately if there is suspicion of a blood dys-  crasia.   • By mouth, administered on expert advice, as enteric-  coated tablets, initially 500 mg daily, increased by  500 mg at intervals of 1 week to a max. of 2-3 g daily  in divided doses   Salazopyrin EN-Tabs® (Pharmacia) (Ml  Tablets, e/c, yellow, f/c, sulfasalazine 500 mg, net  price 112-tab pack = £8.43. Label: 5, 14, 25, coun-  selling, blood disorder symptoms (see recommenda-  tion above), contact lenses may be stained   It is important to distinguish drugs used for the treat-  ment of acute attacks of gout from those used in the  long-term control of the disease. The latter exacerbate  and prolong the acute manifestations if started during  an attack.   Acute attacks of gout are usually treated with high doses  of NSAIDs such as diclofenac, etoricoxib, indometacin,  ketoprofen, naproxen, or sulindac (section 10.1.1). Col-  chicine is an alternative in patients in whom NSAIDs  are contra-indicated. Aspirin is not indicated in gout.  Allopurinol, febuxostat, and uricosurics are not effective  in treating an acute attack and may prolong it indefi-  nitely if started during the acute episode.    The use of colchicine is limited by the development of  toxicity at higher doses, but it is of value in patients with  heart failure since, unlike NSAIDs, it does not induce  fluid retention; moreover, it can be given to patients  receiving anticoagulants.   Oral or parenteral corticosteroids are an effective  alternative in those who cannot tolerate NSAIDs or  who are resistant to other treatments. Intra-articular  injection of a corticosteroid can be used in acute mono-  articular gout [unlicensed indication], A corticosteroid  by intramuscular injection can be effective in podagra.   Indications acute gout; short-term prophylaxis during  initial therapy with allopurinol and uricosuric drugs;  prophylaxis of familial Mediterranean fever (recurrent  polyserositis)   Cautions see notes above; also elderly; gastro-intes-  tinal disease; cardiac disease; interactions: Appendix  1 (colchicine)   Contra-indications blood disorders  Hepatic impairment use with caution  Renal impairment reduce dose or increase dosage  interval if eGFR 10-50 mL/minute/ 1.73 m 2 ; avoid if  eGFR less than 10 mL/minute/ 1.73 m 2  Pregnancy avoid — teratogenicity in animal studies  Breast-feeding present in milk but no adverse effects  reported; manufacturers advise caution  Side-effects nausea, vomiting, and abdominal pain;  excessive doses may cause profuse diarrhoea, gastro-  intestinal haemorrhage, rash, renal and hepatic  damage; rarely peripheral neuritis, inhibition of sper-  matogenesis, myopathy, alopecia, and with prolonged  treatment blood disorders  Dose   • Acute gout, 500 micrograms 2-4 times daily until  symptoms relieved, max. 6 mg per course; course not  to be repeated within 3 days   • Prevention of gout attacks during initial treatment  with allopurinol or uricosuric drugs, 500 micrograms  twice daily   • Prophylaxis of familial Mediterranean fever [unli-  censed], 0.5-2 mg once daily   Note BNF doses may differ from those in the product literature   Colchicine (Non-proprietary) (Ml  Tablets, colchicine 500 micrograms, net price 100 =  £31.33    and continued for at least one month after the hyper-  uricaemia has been corrected. However, if an acute  attack develops during treatment, then the treatment  should continue at the same dosage and the acute attack  treated in its own right.   Allopurinol is widely used and is especially useful in  patients with renal impairment or urate stones when  uricosuric drugs cannot be used; it is not indicated for  the treatment of asymptomatic hyperuricaemia. It can  cause rashes.    Febuxostat is licensed for the treatment of chronic  hyperuricaemia where urate deposition has already  occurred; it is not indicated for patients in whom the  rate of urate formation is greatly increased, such as in  malignant disease or in Lesch-Nyhan syndrome.   Febuxostat for the management of  hyperuricaemia in patients with gout  (December 2008)   Febuxostat is recommended as an option for the  management of chronic hyperuricaemia in gout only  for patients who are intolerant of allopurinol or for  whom allopurinol is contra-indicated.   For the purposes of this guidance, intolerance of  allopurinol is defined as adverse effects that are  sufficiently severe to warrant discontinuation, or to  prevent full dose escalation for optimal effective-    Sulfinpyrazone can be used instead of allopurinol, or in  conjunction with it in cases that are resistant to treat-  ment.   Probenecid (available from ‘special-order’ manufac-  turers or specialist importing companies, see p. 988) is  a uricosuric drug used to prevent nephrotoxicity asso-  ciated with cidofovir (section 5. 3. 2. 2).   Benzbromarone (available from ‘special-order’ manu-  facturers or specialist importing companies, see p. 988)  is a uricosuric drug that can be used in patients with  mild renal impairment.   Crystallisation of urate in the urine can occur with the  uricosuric drugs and it is important to ensure an ade-  quate urine output especially in the first few weeks of  treatment. As an additional precaution the urine may be  rendered alkaline.   Aspirin and other salicylates antagonise the uricosuric  drugs; they do not antagonise allopurinol but are never-  theless not indicated in gout.   Frequent recurrence of acute attacks of gout, the pre-  sence of tophi, or signs of chronic gouty arthritis may  call for the initiation of long-term (‘interval’) treatment.  For long-term control of gout the formation of uric acid  from purines may be reduced with the xanthine-oxidase  inhibitors allopurinol or febuxostat; alternatively the  uricosuric drug sulfinpyrazone may be used to increase  the excretion of uric acid in the urine. Treatment should  be continued indefinitely to prevent further attacks of  gout by correcting the hyperuricaemia. These drugs  should never be started during an acute attack; they  are usually started 1-2 weeks after the attack has  settled. The initiation of treatment may precipitate an  acute attack, and therefore an anti-inflammatory  analgesic or colchicine should be used as a prophylactic   Indications prophylaxis of gout and of uric acid and  calcium oxalate renal stones; prophylaxis of hyper-  uricaemia associated with cancer chemotherapy   Cautions administer prophylactic NSAID ( not aspirin  or salicylates) or colchicine until at least 1 month after  hyperuricaemia corrected (usually for first 3 months)  to avoid precipitating an acute attack; ensure ade-  quate fluid intake (2-3 litres/day); for hyperuricaemia  associated with cancer therapy, allopurinol treatment  should be started before cancer therapy; interactions:  Appendix 1 (allopurinol)    Contra-indications not a treatment for acute gout but  continue if attack develops when already receiving  allopurinol, and treat attack separately (see notes  above)   Renal impairment max. 100 mg daily, increased only  if response inadequate; in severe impairment, reduce  daily dose below 100 mg, or increase dose interval; if  facilities available, adjust dose to maintain plasma-  oxipurinol concentration below lOOmicromol/litre   Pregnancy toxicity not reported; manufacturer  advises use only if no safer alternative and disease  carries risk for mother or child   Side-effects rashes (withdraw therapy; if rash mild  re-introduce cautiously but discontinue promptly if  recurrence — hypersensitivity reactions occur rarely  and include exfoliation, fever, lymphadenopathy,  arthralgia, and eosinophilia resembling Stevens-  Johnson syndrome or toxic epidermal necrolysis,  vasculitis, hepatitis, renal impairment, and very rarely  seizures); gastro-intestinal disorders; rarely malaise,  headache, vertigo, drowsiness, visual and taste dis-  turbances, hypertension, alopecia, hepatotoxicity,  paraesthesia and neuropathy, gynaecomastia, blood  disorders (including leucopenia, thrombocytopenia,  haemolytic anaemia and aplastic anaemia)   • Initially 100 mg daily, preferably after food, then  adjusted according to plasma or urinary uric acid  concentration; usual maintenance dose in mild con-  ditions 100-200 mg daily, in moderately severe con-  ditions 300-600 mg daily, in severe conditions 700-  900 mg daily; doses over 300 mg daily given in divided  doses; CHILD under 15 years, (in neoplastic conditions,  enzyme disorders) 10-20 mg/kg daily (max. 400 mg  daily)   Allopurinol (Non-proprietary) tMl  Tablets, allopurinol 100 mg, net price 28-tab pack =  £1.18; 300 mg, 28-tab pack = £1.32. Label: 8, 21, 27   Tablets, allopurinol 100 mg, net price 100-tab pack =  £10.19; 300 mg, 28-tab pack = £7.31. Label: 8, 21, 27   Indications treatment of chronic hyperuricaemia in  gout (but see also NICE guidance above)   Cautions administer prophylactic NSAID ( not aspirin  or salicylates) or colchicine for at least 6 months after  starting febuxostat to avoid precipitating an acute  attack; transplant recipients; monitor liver function  tests before and periodically during treatment as  indicated; thyroid disorders; interactions: Appendix 1  (febuxostat)   Contra-indications not a treatment for acute gout but  continue if attack develops when already receiving  febuxostat, and treat attack separately (see notes  above); ischaemic heart disease; congestive heart  failure   Hepatic impairment max. 80 mg daily in mild  impairment; no dose information available in moder-  ate or severe impairment   Renal impairment use with caution if eGFR less than  30 mL/minute/ 1.73 m 2 — no information available   Side-effects gastro-intestinal disturbances, abnormal  liver function tests; headache; rash; less commonly  taste disturbances, increased appetite; hypertension,  oedema, flushing; dizziness, paraesthesia, drowsiness;  influenza-like symptoms; haematuria, nephrolithiasis,  increased urinary frequency, decreased libido; myal-  gia; dermatitis, pruritus, urticaria; rarely thirst, palpi-  tation, asthenia, nervousness, insomnia, and renal  impairment  Dose   • ADULT over 18 years, 80 mg once daily, if after 2-4  weeks serum uric acid greater than 6mg/100mL,  increase to 120 mg once daily   Tablets, both yellow, f/c, febuxostat 80 mg, net price  28-tab pack = £24.36; 120 mg 28-tab pack = £24.36   Indications prevention of nephrotoxicity associated  with cidofovir (section 5. 3. 2. 2)   Cautions ensure adequate fluid intake (about 2-3 litres  daily) and render urine alkaline if uric acid overload is  high; peptic ulceration; transient false-positive Bene-  dict’s test; G6PD-deficiency (section 9.1.5); interac-  tions: Appendix 1 (probenecid)   Contra-indications history of blood disorders,  nephrolithiasis, acute porphyria (section 9.8.2), acute  gout attack; avoid aspirin and salicylates  Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73m 2   Breast-feeding present in milk  Side-effects gastro-intestinal disturbances; less com-  monly sore gums, flushing, headache, dizziness,  urinary frequency, anaemia, alopecia; hepatic necro-  sis, hypersensitivity reactions (including anaphylaxis,  pruritus, urticaria, fever, and Stevens- Johnson  syndrome), nephrotic syndrome, haemolytic anaemia,  leucopenia, and aplastic anaemia also reported  Dose   Indications gout prophylaxis, hyperuricaemia  Cautions see under Probenecid; regular blood counts  advisable; cardiac disease (may cause salt and water  retention); interactions: Appendix 1 (sulfinpyrazone)  Contra-indications see under Probenecid; avoid in  hypersensitivity to NSAIDs  Hepatic impairment avoid in severe impairment  Renal impairment reduce dose; avoid in severe  impairment    Breast-feeding no information available  Side-effects gastro-intestinal disturbances, occasion-  ally allergic skin reactions, salt and water retention;  rarely blood disorders, gastro-intestinal ulceration and  bleeding, acute renal failure, raised liver enzymes,  jaundice and hepatitis  Dose   • Initially 100-200 mg daily with food (or milk)  increasing over 2-3 weeks to 600 mg daily (rarely  800 mg daily), continued until serum uric acid con-  centration normal then reduced for maintenance  (maintenance dose may be as low as 200 mg daily)   Sulfinpyrazone (Non-proprietary) £mD  Tablets, sulfinpyrazone 100 mg, net price 84-tab pack  = £13.09; 200 mg, 84-tab pack = £25.07. Label: 12, 21   Allopurinol is used to prevent hyperuricaemia asso-  ciated with cytotoxic drugs — see section 8.1 (Hyper-  uricaemia) and Allopurinol above.   Rasburicase is licensed for the prophylaxis and treat-  ment of acute hyperuricaemia, before and during initia-  tion of chemotherapy, in patients with haematological  malignancy and a high tumour burden at risk of rapid  lysis.   Side-effects fever; less commonly nausea, vomiting,  diarrhoea, headache, hypersensitivity reactions  (including rash, bronchospasm and anaphylaxis);  haemolytic anaemia, methaemoglobinaemia   • By intravenous infusion, 200 micrograms/kg once  daily for up to 7 days according to plasma-uric acid  concentration   Intravenous infusion, powder for reconstitution,  rasburicase, net price 1.5-mg vial (with solvent) =  £57.88; 7.5-mg vial (with solvent) = £241.20   Glucosamine is a natural substance found in mucopo-  lysaccharides, mucoproteins, and chitin. It is licensed for  symptomatic relief of mild to moderate osteoarthritis of  the knee, but is not recommended. The mechanism of    action is not understood and there is limited evidence to  show it is effective.   The Scottish Medicines Consortium (p. 4) has advised  (May 2008) that glucosamine ( Alateris ®) is not  recommended for use within NHS Scotland for the  symptomatic relief of mild to moderate osteoarthritis of  the knee.   Indications symptomatic relief of mild to moderate  osteoarthritis of the knee   Cautions impaired glucose tolerance (monitor blood-  glucose concentration before treatment and periodi-  cally thereafter); predisposition to cardiovascular dis-  ease (monitor cholesterol); asthma; interactions:  Appendix 1 (glucosamine)   Side-effects nausea, abdominal pain, dyspepsia,  flatulence, diarrhoea, constipation, drowsiness,  headache, fatigue; less commonly flushing, rash, pru-  ritus; also reported hypercholesterolaemia, visual  disturbances, hair loss  Dose   Dose ADULT over 18 years, 1.25 g once daily; review treatment if  no benefit after 2-3 months   Oral powder, sugar-free, glucosamine sulphate (as  sodium chloride) 1.5g/sachet, net price 30-sachet  pack = £18.40. Label: 13   Dose ADULT over 18 years, 1 sachet (dissolved in at least 250 mL  of water) once daily; review treatment if no benefit after 2-3  months   Anticholinesterases are used as first-line treatment in  ocular myasthenia gravis and as an adjunct to immu-  nosuppressant therapy for generalised myasthenia  gravis.   Corticosteroids are used when anticholinesterases do  not control symptoms completely. A second-line immu-  nosuppressant such as azathioprine is frequently used to  reduce the dose of corticosteroid.    Plasmapheresis or infusion of intravenous immuno-  globulin [unlicensed indication] may induce temporary  remission in severe relapses, particularly where bulbar  or respiratory function is compromised or before thy-  mectomy.    Anticholinesterase drugs enhance neuromuscular trans-  mission in voluntary and involuntary muscle in myas-  thenia gravis. They prolong the action of acetylcholine  by inhibiting the action of the enzyme acetylcholines-  terase. Excessive dosage of these drugs can impair  neuromuscular transmission and precipitate cholinergic  crises by causing a depolarising block. This may be  difficult to distinguish from a worsening myasthenic  state.    Muscarinic side-effects of anticholinesterases include  increased sweating, increased salivary and gastric secre-  tions, increased gastro-intestinal and uterine motility,  and bradycardia. These parasympathomimetic effects  are antagonised by atropine.   Edrophonium has a very brief action and it is therefore  used mainly for the diagnosis of myasthenia gravis.  However, such testing should be performed only by  those experienced in its use; other means of establishing  the diagnosis are available. A single test-dose usually  causes substantial improvement in muscle power (last-  ing about 5 minutes) in patients with the disease (if  respiration already impaired, only in conjunction with  someone skilled at intubation).   Edrophonium can also be used to determine whether a  patient with myasthenia is receiving inadequate or  excessive treatment with cholinergic drugs. If treatment  is excessive an injection of edrophonium will either have  no effect or will intensify symptoms (if respiration  already impaired, give only in conjunction with some-  one skilled at intubation). Conversely, transient  improvement may be seen if the patient is being inade-  quately treated. The test is best performed just before  the next dose of anticholinesterase.    Neostigmine produces a therapeutic effect for up to 4  hours. Its pronounced muscarinic action is a disadvan-  tage, and simultaneous administration of an anti-  muscarinic drug such as atropine or propantheline  may be required to prevent colic, excessive salivation,  or diarrhoea. In severe disease neostigmine can be  given every 2 hours. The maximum that most patients  can tolerate is 180 mg daily.   Pyridostigmine is less powerful and slower in action  than neostigmine but it has a longer duration of action.  It is preferable to neostigmine because of its smoother  action and the need for less frequent dosage. It is  particularly preferred in patients whose muscles are  weak on waking. It has a comparatively mild gastro-  intestinal effect but an antimuscarinic drug may still be  required. It is inadvisable to exceed a total daily dose of  450 mg in order to avoid acetylcholine receptor down-  regulation; patients requiring doses exceeding 450 mg  daily will usually require input from a specialised neuro-  muscular service. Immunosuppressant therapy is usual-  ly considered if the dose of pyridostigmine exceeds  360 mg daily   Distigmine has the longest action but the danger of a  cholinergic crisis caused by accumulation of the drug is    greater than with shorter-acting drugs; it is rarely used  in the management of myasthenia gravis.   Neostigmine and edrophonium are also used to reverse  the actions of the non-depolarising neuromuscular  blocking drugs (see section 15.1.6).   Cautions asthma ( extreme caution), bradycardia,  arrhythmias, recent myocardial infarction, epilepsy,  hypotension, parkinsonism, vagotonia, peptic ulcer-  ation, hyperthyroidism; atropine or other antidote to  muscarinic effects may be necessary (particularly  when neostigmine is given by injection), but not given  routinely because it may mask signs of overdosage;  interactions: Appendix 1 (parasympathomimetics)   Side-effects nausea, vomiting, increased salivation,  diarrhoea, abdominal cramps (more marked with  higher doses); signs of overdosage include broncho-  constriction, increased bronchial secretions, lacrima-  tion, excessive sweating, involuntary defaecation and  micturition, miosis, nystagmus, bradycardia, heart  block, arrhythmias, hypotension, agitation, excessive  dreaming, and weakness eventually leading to fasci-  culation and paralysis   • By mouth, neostigmine bromide 15-30 mg at suitable  intervals throughout day, total daily dose 75-300 mg  (but see also notes above); NEONATE 1-5 mg every 4  hours, half an hour before feeds; CHILD up to 6 years  initially 7.5 mg, 6-12 years initially 15 mg, usual total  daily dose 15-90 mg   • By subcutaneous or intramuscular injection, ADULT  and CHILD over 12 years, neostigmine metilsulfate 1-  2.5 mg at suitable intervals throughout day (usual total  daily dose 5-20 mg); NEONATE 150 micrograms/kg  every 6-8 hours 30 minutes before feeds, increased to  max. 300 micrograms/kg every 4 hours, if necessary  [unlicensed]; CHILD 1 month-12 years 200-500 micr-  ograms as required   Neostigmine (Non-proprietary) (Mi  Tablets, scored, neostigmine bromide 15 mg, net  price 140 = £56.10   Cautions see under Neostigmine; have resuscitation  facilities; extreme caution in respiratory distress (see  notes above) and in asthma   Note Severe cholinergic reactions can be counteracted by  injection of atropine sulphate (which should always be  available)   • Diagnosis of myasthenia gravis, by intravenous  injection, 2 mg followed after 30 seconds (if no  adverse reaction has occurred) by 8 mg; in adults  without suitable veins, by intramuscular injection,   • Detection of overdosage or underdosage of cholin-  ergic drugs, by intravenous injection, 2 mg (preferably  just before next dose of anticholinesterase, see notes  above); CHILD under 12 years see BNF for Children   Edrophonium (Non-proprietary) [Ml  Injection, edrophonium chloride 10 mg/mL, net price  1-mL amp = £19.50   Contra-indications see under Neostigmine  Renal impairment reduce dose; excreted by kidney  Pregnancy see under Neostigmine  Breast-feeding see under Neostigmine  Side-effects see under Neostigmine  Dose   • By mouth, 30-120 mg at suitable intervals throughout  day, total daily dose 0.3-1. 2 g (but see also notes  above); CHILD under 18 years, see BNF for Children   Tablets, scored, pyridostigmine (as bromide) 60 mg,  net price 200 = £45.33   Corticosteroids (section 6.3) are established as treat-  ment for myasthenia gravis; although they are com-  monly given on alternate days there is little evidence  of benefit over daily administration. Corticosteroid  treatment is usually initiated under in-patient supervi-  sion and all patients should receive osteoporosis  prophylaxis (section 6.6).   In generalised myasthenia gravis small initial doses of  prednisolone (10 mg on alternate days) are increased in  steps of 10 mg on alternate days to 1-1.5 mg/kg (max.  100 mg) on alternate days. When given daily, predniso-  lone is started at 5 mg daily and then increased in steps  of 5 mg daily to 60 mg daily or occasionally up to 80 mg  daily (0.75-1 mg/kg daily). About 10% of patients  experience a transient but very serious worsening of  symptoms in the first 2-3 weeks, especially if the  corticosteroid is started at a high dose. However, venti-  lated patients may be started on 1.5 mg/kg (max.  100 mg) on alternate days. Smaller doses of cortico-  steroid are usually required in ocular myasthenia. Once  clinical remission has occurred (usually after 2-6  months), the dose of prednisolone should be reduced  slowly to the minimum effective dose (usually 10-40 mg  on alternate days).   In generalised myasthenia gravis azathioprine (section  8.2.1) is usually started at the same time as the cortico-  steroid and it allows a lower maintenance dose of the  corticosteroid to be used; azathioprine is initiated at a    dose of 0.5-1 mg/kg daily, which is increased over 3-4  weeks to 2-2.5 mg/kg daily. Ciclosporin (section 8.2.2),  methotrexate (section 8.1.3), or mycophenolate mofe-  til (section 8.2.1) can be used in patients unresponsive  or intolerant to other treatments [unlicensed indica-  tions].   Amifampridine is licensed for the symptomatic treat-  ment of Lambert-Eaton myasthenic syndrome (LEMS),  a rare disorder of neuromuscular transmission.    Indications (specialist use only) symptomatic treat-  ment of Lambert-Eaton myasthenic syndrome  Cautions concomitant use of drugs that lower con-  vulsive threshold; non-paraneoplastic form of Lam-  bert-Eaton myasthenic syndrome; clinical and ECG  monitoring required at treatment initiation and yearly  thereafter    Contra-indications epilepsy; uncontrolled asthma;  congenital QT syndromes; avoid concomitant use of  drugs that prolong QT interval; avoid concomitant  use of drugs with a narrow therapeutic index   Hepatic impairment use with caution; in mild  impairment reduce initial dose to 10 mg daily in  divided doses, increased in steps of 5 mg every 7 days;  in moderate or severe impairment reduce initial dose  to 5 mg daily in divided doses, increased in steps of  5 mg every 7 days   Renal impairment use with caution; in mild impair-  ment reduce initial dose to 10 mg daily in divided  doses, increased in steps of 5 mg every 7 days; in  moderate or severe impairment reduce initial dose to  5 mg daily divided doses, increased in steps of 5 mg  every 7 days    Side-effects gastro-intestinal disorders; paraesthesia;  palpitations, arrhythmias, Raynaud’s syndrome,  cough, bronchial hypersecretion, exacerbation or  precipitation of asthma, sleep disturbances, con-  vulsions, anxiety, drowsiness, dizziness, weakness,  headache, chorea, myoclonia, and blurred vision also  reported  Dose    • ADULT over 18 years, initially 15 mg daily in 3 divided  doses, increased in steps of 5 mg every 4-5 days, to  max. 60 mg daily in 3-4 divided doses; max. single  dose 20 mg    Firdapse® (BioMarin) T (Ml  Tablets, scored, amifampridine (as phosphate) 10 mg,  net price 100-tab pack = £1815.00. Label: 3, 21   The drugs described below are used for the relief of  chronic muscle spasm or spasticity associated with  multiple sclerosis or other neurological damage; they  are not indicated for spasm associated with minor    injuries. Baclofen, diazepam, and tizanidine act princi-  pally on the central nervous system. Dantrolene, has a  peripheral site of action; cannabis extract has both a  central and a peripheral action. Skeletal muscle relax-  ants differ in action from the muscle relaxants used in  anaesthesia (section 15.1.5), which block transmission  at the neuromuscular junction.   The underlying cause of spasticity should be treated and  any aggravating factors (e.g. pressure sores, infection)  remedied. Skeletal muscle relaxants are effective in  most forms of spasticity except the rare alpha variety.  The major disadvantage of treatment with these drugs is  that reduction in muscle tone can cause a loss of  splinting action of the spastic leg and trunk muscles  and sometimes lead to an increase in disability.  Baclofen inhibits transmission at spinal level and also  depresses the central nervous system. The dose should  be increased slowly to avoid the major side-effects of  sedation and muscular hypotonia (other adverse events  are uncommon).   A cannabis extract containing dronabinol (delta-9-tet-  rahydrocannabinol) and cannabidiol is licensed as an  adjunct treatment for moderate to severe spasticity  associated with multiple sclerosis in patients who have  not responded adequately to other skeletal muscle  relaxants. The dose should be titrated over 2 weeks;  response to treatment should be reviewed after 4 weeks  and treatment stopped if an adequate response is not  achieved.    Dantrolene acts directly on skeletal muscle and pro-  duces fewer central adverse effects making it a drug of  choice. The dose should be increased slowly.    Diazepam can also be used. Sedation and occasionally  extensor hypotonus are disadvantages. Other benzo-  diazepines also have muscle-relaxant properties.  Muscle-relaxant doses of benzodiazepines are similar  to anxiolytic doses (section 4.1.2).   Tizanidine is an alpha 2 -adrenoceptor agonist indicated  for spasticity associated with multiple sclerosis or spinal  cord injury.    Indications chronic severe spasticity resulting from  disorders such as multiple sclerosis or traumatic par-  tial section of spinal cord   Cautions psychiatric illness, Parkinson’s disease,  cerebrovascular disease, elderly; respiratory impair-  ment; epilepsy; history of peptic ulcer (avoid oral  route in active peptic ulceration); diabetes; hypertonic  bladder sphincter; avoid abrupt withdrawal (risk of  hyperactive state, may exacerbate spasticity, and  precipitate autonomic dysfunction including hyper-  thermia, psychiatric reactions and convulsions, see  also under Withdrawal below); interactions: Appen-  dix 1 (muscle relaxants)   Withdrawal Serious side-effects can occur on abrupt with-  drawal; to minimise risk, discontinue by gradual dose  reduction over at least 1-2 weeks (longer if symptoms occur)  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced   Renal impairment risk of toxicity — use smaller doses  (e.g. 5 mg daily by mouth) and if necessary increase  dosage interval; if eGFR less than 15mL/minute/  1.73m 2 manufacturer advises use by mouth only if  potential benefit outweighs risk; excreted by kidney    Pregnancy manufacturer advises use only if potential  benefit outweighs risk (toxicity in animal studies)   Side-effects gastro-intestinal disturbances, dry  mouth; hypotension, respiratory or cardiovascular  depression; sedation, drowsiness, confusion, dizzi-  ness, ataxia, hallucinations, nightmares, headache,  euphoria, insomnia, depression, anxiety, agitation,  tremor; seizure; urinary disturbances; myalgia; visual  disorders; rash, hyperhidrosis; rarely taste distur-  bances, abdominal pain, changes in hepatic function,  paraesthesia, erectile dysfunction, dysarthria; very  rarely hypothermia   • By mouth, ADULT and CHILD over 10 years, initially 5 mg  3 times daily, gradually increased; usual maintenance  dose up to 60 mg daily in divided doses (max. 100 mg  daily); CHILD 1-2 years, initially 300 micrograms/kg  daily in 4 divided doses, increased gradually to usual  maintenance dose 0.75-2 mg/kg daily in divided  doses (or 10-20 mg daily in divided doses); CHILD 2-6  years, initially 300 micrograms/kg daily in 4 divided  doses, increased gradually to usual maintenance dose  of 0.75-2 mg/kg daily in divided doses (or 20-30 mg  daily in divided doses); CHILD 6-8 years, initially  300 micrograms/kg daily in 4 divided doses,  increased gradually to usual maintenance dose of  0.75-2 mg/kg daily in divided doses (or 30-40 mg  daily in divided doses); CHILD 8-10 years, initially  300 micrograms/kg daily in 4 divided doses,  increased gradually to usual maintenance dose of  0.75-2 mg/kg daily in divided doses (or up to 60 mg  daily in divided doses)   Baclofen (Non-proprietary) (Ml  Tablets, baclofen 10 mg, net price 84-tab pack =  £1.58. Label: 2, 8, 21   Oral solution, baclofen 5 mg/5 mL, net price 300 mL  = £9.26. Label: 2, 8, 21  Brands include Lyflex ® (sugar-free)   Liquid, sugar-free, raspberry-flavoured, baclofen  5mg/5mL, net price 300 mL = £7.16. Label: 2, 8, 21   Intrathecal injection, baclofen, 50 micrograms/mL,  net price 1-mL amp (for test dose) = £2.19;   500 micrograms/mL, 20-mL amp (for use with  implantable pump) = £48.62; 2 mg/mL, 5-mL amp  (for use with implantable pump) = £48.62  Important Consult product literature for details on test dose and  titration — important to monitor patients closely in appropriately  equipped and staffed environment during screening and imme-  diately after pump implantation. Resuscitation equipment must be  available for immediate use   Dose by intrathecal injection, specialist use only, severe chronic  spasticity unresponsive to oral antispastic drugs (or where side-  effects of oral therapy unacceptable) or as alternative to ablative  neurosurgical procedures, initial test dose 25-50 micrograms over  at least 1 minute via catheter or lumbar puncture, increased in 25-  microgram steps (not more often than every 24 hours) to max.  100 micrograms to determine appropriate dose then dose-titration  phase, most often using infusion pump (implanted into chest wall  or abdominal wall tissues) to establish maintenance dose (ranging    from 12 micrograms to 2 mg daily for spasticity of spinal origin or  22 micrograms to 1.4 mg daily for spasticity of cerebral origin)  retaining some spasticity to avoid sensation of paralysis; CHILD 4-  18 years (spasticity of cerebral origin only), initial test dose  25 micrograms then titrated as for ADULT to maintenance dose  (ranging from 24 micrograms to 1.2 mg daily in children under 12  years)   Indications adjunct in moderate to severe spasticity in  multiple sclerosis (specialist use only)   Driving May affect performance of skilled tasks (e.g. driv-  ing); effects of alcohol may be enhanced  Contra-indications personal or family history of psy-  chosis; history of other severe psychiatric disorder  Hepatic impairment manufacturer advises more fre-  quent monitoring in significant impairment — possible  risk of prolonged or enhanced effect  Renal impairment manufacturer advises more fre-  quent monitoring in significant impairment — possible  risk of prolonged or enhanced effect  Pregnancy manufacturer advises use only if potential  benefit outweighs risks, and recommends effective  contraception during and for 3 months after treatment  in men and women   Breast-feeding avoid — present in milk  Side-effects increased or decreased appetite, taste  disturbance, constipation, diarrhoea, nausea, vomi-  ting, dry mouth, mouth ulcers, oral pain, dizziness,  vertigo, malaise, depression, disorientation, dissocia-  tion, mood disturbance, amnesia, impaired attention,  drowsiness, dysarthria, blurred vision; less commonly  abdominal pain, oromucosal and tooth discoloration,  stomatitis, palpitation, tachycardia, hypertension,  pharyngitis, syncope, hallucinations, paranoia, delu-  sions, suicidal thoughts; also reported anxiety, sei-  zures  Dose   'Satlvex® (Bayer Schering) T GS  Oromucosal spray, Cannabis sativa extract (con-  taining dronabinol (delta-9-tetrahydrocannabinol)   27 mg and cannabidiol 25 mg/mL), net price 3x10-  mL units = £375.00. Counselling, driving see above   Indications chronic severe spasticity of voluntary  muscle; malignant hyperthermia (section 15.1.8)  Cautions impaired cardiac and pulmonary function;  therapeutic effect may take a few weeks to develop —  discontinue if no response within 45 days; interac-  tions: Appendix 1 (muscle relaxants).   Hepatotoxicity Potentially life-threatening hepatotoxicity  reported, usually if doses greater than 400 mg daily used,  in females, patients over 30 years, if history of liver disorders,  or concomitant use of hepatotoxic drugs; test liver function  before and at intervals during therapy — discontinue if  abnormal liver function tests or symptoms of liver disorder   Counselling Patients should be told how to recognise signs  of liver disorder and advised to seek prompt medical atten-  tion if symptoms such as anorexia, nausea, vomiting, fatigue,  abdominal pain, dark urine, or pruritus develop  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced  Contra-indications acute muscle spasm; avoid when  spasticity is useful, for example, locomotion  Hepatic impairment avoid — may cause severe liver  damage; injection may be used in an emergency for  malignant hyperthermia   Breast-feeding present in milk — manufacturer  advises avoid use in chronic spasticity  Side-effects diarrhoea (withdraw if severe, discon-  tinue treatment if recurs on re-introduction), nausea,  vomiting, anorexia, hepatotoxicity (see above),  abdominal pain; pericarditis; pleural effusion, respir-  atory depression; headache, drowsiness, dizziness,  asthenia, fatigue, seizures, fever, chills; speech and  visual disturbances; rash; less commonly dysphagia,  constipation, exacerbation of cardiac insufficiency,  tachycardia, erratic blood pressure, dyspnoea,  depression, confusion, nervousness, insomnia,  increased urinary frequency, urinary incontinence or  retention, haematuria, crystalluria, and increased  sweating  Dose   • Initially 25 mg daily, may be increased at weekly  intervals to max. 100 mg 4 times daily; usual dose  75 mg 3 times daily; CHILD 5-18 years see BNF for  Children   Capsules, orange/brown, dantrolene sodium 25 mg,  net price 100 =£16.87; 100 mg, 100 = £43.07. Label: 2,  counselling, driving, hepatotoxicity   Indications muscle spasm of varied aetiology, includ-  ing tetanus; other indications (section 4.1.2, section  4.8, section 15.1.4.1)   Cautions section 4.1.2; special precautions for intra-  venous injection (section 4.8.2)   • Muscle spasm, by mouth, 2-15 mg daily in divided  doses, increased if necessary in spastic conditions to  60 mg daily according to response  Cerebral spasticity in selected cases, CHILD 2-40 mg  daily in divided doses   By intramuscular or by slow intravenous injection  (into a large vein at a rate of not more than 5 mg/  minute), in acute muscle spasm, 10 mg repeated if  necessary after 4 hours   Note Only use intramuscular route when oral and intra-  venous routes not possible; emulsion formulation preferred  for intravenous injection; special precautions for intravenous  injection, see section 4.8.2    • Tetanus, ADULT and CHILD, by intravenous injection  (emulsion preparation preferred), 100-300 micr-  ograms/kg repeated every 1-4 hours; by intravenous  infusion (or by nasoduodenal tube), 3-10 mg/kg over  24 hours, adjusted according to response    Indications spasticity associated with multiple  sclerosis or spinal cord injury or disease  Cautions elderly; monitor liver function monthly for  first 4 months and in those who develop unexplained  nausea, anorexia or fatigue; concomitant administra-  tion of drugs that prolong QT interval; avoid abrupt  withdrawal (risk of rebound hypertension and tachy-  cardia, see under Withdrawal, below); interactions:  Appendix 1 (muscle relaxants)   Withdrawal Rebound hypertension and tachycardia can  occur on abrupt withdrawal; to minimise risk, discontinue  gradually and monitor blood pressure  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced  Hepatic impairment avoid in severe impairment  Renal impairment manufacturer advises caution  Pregnancy manufacturer advises use only if potential  benefit outweighs risk — no information available  Breast-feeding manufacturer advises use only if  potential benefit outweighs risk — no information  available   Side-effects drowsiness, fatigue, dizziness, dry mouth,  nausea, gastro-intestinal disturbances, hypotension;  also reported, bradycardia, insomnia, hallucinations  and altered liver enzymes (discontinue if persistently  raised — consult product literature); rarely acute  hepatitis  Dose   • ADULT over 18 years, initially 2 mg daily as a single  dose increased according to response at intervals of at  least 3-4 days in steps of 2 mg daily (and given in  divided doses) usually up to 24 mg daily in 3-4 divided  doses; max. 36 mg daily   Tablets, tizanidine (as hydrochloride) 2 mg net price  120-tab pack = £6.22; 4 mg, 120-tab pack = £8.64.  Label: 2, 8    Zanaflex® (Cephalon) (Ml  Tablets, scored, tizanidine (as hydrochloride) 2 mg,  net price 120-tab pack = £63.00; 4 mg, 120-tab pack =  £80.00. Label: 2, 8   The clinical efficacy of methocarbamol and mepro-  bamate (section 4.1.2) as muscle relaxants is not well  established, although they have been included in com-  pound analgesic preparations.   Indications short-term symptomatic relief of muscle  spasm (but see notes above)   Cautions interactions: Appendix 1 (muscle relaxants)  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced    Contra-indications coma or pre-coma, brain damage,  epilepsy, myasthenia gravis  Hepatic impairment manufacturer advises caution;   Breast-feeding present in milk in animal studies —  manufacturer advises caution  Side-effects nausea, vomiting, dyspepsia; hyper-  sensitivity reactions (including urticaria, angioedema,  anaphylaxis); fever, headache, drowsiness, dizziness,  hypotension, bradycardia, confusion, amnesia, rest-  lessness, anxiety, tremor, seizures; blurred vision,  nasal congestion; rash, pruritus; leucopenia, chole-  static jaundice  Dose   • 1.5 g 4 times daily; may be reduced to 750 mg 3 times  daily; ELDERLY up to 750 mg 4 times daily may be  sufficient; CHILD not recommended   Quinine salts (section 5.4.1), such as quinine sulphate  200-300 mg at bedtime, are effective in reducing the  frequency of nocturnal leg cramps by about 25% in  ambulatory patients; however, because of potential  toxicity, quinine is not recommended for routine treat-  ment and should not be used unless cramps cause  regular disruption to sleep. Quinine should only be  considered when cramps are very painful or frequent;  when other treatable causes of cramp have been  excluded; and when non-pharmacological treatments  have not worked (e.g. passive stretching exercises). It  may take up to 4 weeks for improvement to become  apparent; if there is benefit, quinine treatment can be  continued. Patients should be monitored closely during  the early stages for adverse effects as well as for benefit.  Treatment should be interrupted at intervals of approxi-  mately 3 months to assess the need for further quinine  treatment. In patients taking quinine long term, a trial  discontinuation may be considered. Quinine is toxic in  overdosage and accidental fatalities have occurred (see  also below).   Indications see notes above; malaria (section 5.4.1)  Cautions see section 5.4.1 and notes above   Drugs for the relief of  soft-tissue inflammation  and topical pain relief   Local guidelines for the management of extravasa-  tion should be followed where they exist or specialist  advice sought.    Extravasation injury follows leakage of drugs or intra-  venous fluids from the veins or inadvertent administra-  tion into the subcutaneous or subdermal tissue. It must  be dealt with promptly to prevent tissue necrosis.  Acidic or alkaline preparations and those with an osmo-  larity greater than that of plasma can cause extravasa-  tion injury; excipients including alcohol and polyethy-  lene glycol have also been implicated. Cytotoxic drugs  commonly cause extravasation injury. In addition, cer-  tain patients such as the very young and the elderly are  at increased risk. Those receiving anticoagulants are  more likely to lose blood into surrounding tissues if  extravasation occurs, while those receiving sedatives  or analgesics may not notice the early signs or symp-  toms of extravasation.   Prevention of extravasation Precautions should be  taken to avoid extravasation; ideally, drugs likely to  cause extravasation injury should be given through a  central line and patients receiving repeated doses of  hazardous drugs peripherally should have the cannula  resited at regular intervals. Attention should be paid to  the manufacturers’ recommendations for administra-  tion. Placing a glyceryl trinitrate patch (section 2.6.1)  distal to the cannula may improve the patency of the  vessel in patients with small veins or in those whose  veins are prone to collapse.   Patients should be asked to report any pain or burning at  the site of injection immediately.   Management of extravasation If extravasation is  suspected the infusion should be stopped immediately  but the cannula should not be removed until after an  attempt has been made to aspirate the area (through the  cannula) in order to remove as much of the drug as  possible. Aspiration is sometimes possible if the extra-  vasation presents with a raised bleb or blister at the  injection site and is surrounded by hardened tissue, but  it is often unsuccessful if the tissue is soft or soggy.  Corticosteroids are usually given to treat inflammation,  although there is little evidence to support their use in  extravasation. Hydrocortisone or dexamethasone (sec-  tion 6.3.2) can be given either locally by subcutaneous  injection or intravenously at a site distant from the  injury. Antihistamines (section 3.4.1) and analgesics  (section 4.7) may be required for symptom relief.   The management of extravasation beyond these mea-  sures is not well standardised and calls for specialist    advice. Treatment depends on the nature of the offend-  ing substance; one approach is to localise and neutralise  the substance whereas another is to spread and dilute it.  The first method may be appropriate following extra-  vasation of vesicant drugs and involves administration  of an antidote (if available) and the application of cold  compresses 3-4 times a day (consult specialist literature  for details of specific antidotes). Spreading and diluting  the offending substance involves infiltrating the area  with physiological saline, applying warm compresses,  elevating the affected limb, and administering hyal-  uronidase (section 10.3.1). A saline flush-out technique  (involving flushing the subcutaneous tissue with physio-  logical saline) may be effective but requires specialist  advice. Hyaluronidase should not be administered fol-  lowing extravasation of vesicant drugs (unless it is either  specifically indicated or used in the saline flush-out  technique). Dexrazoxane (section 8.1) is licensed for  the treatment of anthracycline-induced extravasation.   Hyaluronidase is used to render the tissues more  readily permeable to injected fluids, e.g. for introduction  of fluids by subcutaneous infusion (termed hypodermo-  clysis).    Indications enhance permeation of subcutaneous or  intramuscular injections, local anaesthetics and sub-  cutaneous infusions; promote resorption of excess  fluids and blood   Contra-indications do not apply direct to cornea;  avoid sites where infection or malignancy; not for  anaesthesia in unexplained premature labour; not to  be used to reduce swelling of bites or stings; not for  intravenous administration   Side-effects oedema; rarely local irritation, infection,  bleeding, bruising; occasional severe allergy (includ-  ing anaphylaxis)   • With local anaesthetics, 1500 units mixed with local  anaesthetic solution (ophthalmology, 1 5 units/mL)   • Hypodermoclysis, 1500 units dissolved in lmL water  for injections or 0.9% sodium chloride injection,  administered before start of 500-1 000 mL infusion  fluid   1500 units dissolved in 1 mL water for injections or  0.9% sodium chloride injection, infiltrated into  affected area (as soon as possible after extravasation)   act by counter-irritation. Pain, whether  superficial or deep-seated, is relieved by any method  that itself produces irritation of the skin. Topical rubefa-  cient preparations may contain nicotinate and salicylate  compounds, essential oils, capsicum, and camphor. The  evidence available does not support the use of topical  rubefacients in acute or chronic musculoskeletal pain.   The use of a NSAID by mouth is effective for relieving  musculoskeletal pain. Topical NSAIDs (e.g. felbinac,  ibuprofen, ketoprofen, and piroxicam) may provide  some relief of pain in musculoskeletal conditions; they  can be considered as an adjunctive treatment in knee or  hand osteoarthritis (see section 10.1).   Cautions Apply with gentle massage only. Avoid con-  tact with eyes, mucous membranes, and inflamed or  broken skin; discontinue if rash develops. Hands should  be washed immediately after use. Not for use with  occlusive dressings. Topical application of large  amounts can result in systemic effects (see section  10.1.1), including hypersensitivity and asthma (renal  disease has also been reported). Not generally suitable  for children. Patient packs carry a warning to avoid  during pregnancy or breast-feeding.   Dose apply up to 4 times daily; therapy should be reviewed after  14 days   1 . Smaller pack sizes available on sale to the public   Ibugel® Forte (Dermal) (Ml  Forte gel, ibuprofen 10%, net price 100 g = £5.87   Dose apply 4-5 sprays up to 3 times daily; therapy should be  reviewed after 7 days   1 . Smaller pack sizes available on sale to the public   1 Oruvail® (Sanofi-Aventis) (Ml  Gel, ketoprofen 2.5%, net price 100 g = £6.84   Dose apply 2-4 times daily for up to 7 days (usual recommended  dose 15 g daily)   1 . Smaller pack sizes available on sale to the public  Powergel® (Menarini) (Ml   Gel, ketoprofen 2.5%, net price 50 g = £3.06; 100 g =  £5.89   Dose apply 2-3 times daily for up to max. 10 days   Dose apply 2-4 times daily; max. 25 g daily; therapy should be    Photosensitivity Patients should be advised against  excessive exposure to sunlight of area treated in order  to avoid possibility of photosensitivity; patients using  preparations containing ketoprofen should be advised to  avoid exposure to sunlight of the area treated, and for  two weeks after stopping treatment.   Ketoprofen (Non-proprietary) (Ml  Gel, ketoprofen 2.5%, net price 30 g = £3.22, 50 g =  £2.83, 100 g = £2.63   Dose apply 2-4 times daily for up to 7 days (usual max. 15 g  daily)   Piroxicam (Non-proprietary) (Ml  Gel, piroxicam 0.5%, net price 60 g = £2.01; 1 12 g =  £2.93   Dose apply 3-4 times daily; therapy should be reviewed after 4   Gel, diclofenac diethylammonium salt 1.16%  (equivalent to diclofenac sodium 1%), net price 20 g  (hosp. only) = £1.55; 100 g = £7.00   Dose apply 3-4 times daily; therapy should be reviewed after 14   1 . Various pack sizes available on sale to the public   Voltarol Gel Patch® (Novartis) fRi  Gel patch, diclofenac epolamine (equivalent to  140 mg diclofenac sodium per patch), net price 10-  patch pack = £14.09   Excipients include hydroxybenzoates (parabens), propylene glycol  Dose AD U LT and CH I LD over 1 5 years, ankle sprain, apply 1 patch  daily for up to 3 days; epicondylitis, apply 1 patch twice daily for  up to 14 days   A preparation containing capsaicin 0.025% can be con-  sidered as an adjunct in hand or knee osteoarthritis (see  section 10.1). It may need to be used for 1-2 weeks  before pain is relieved.   A capsaicin 0.075% cream is licensed for the sympto-  matic relief of postherpetic neuralgia (section 4.7.3)  after lesions have healed, and for the relief of painful  diabetic neuropathy (section 6.1.5).   A self-adhesive patch containing capsaicin 8% is  licensed for the treatment of peripheral neuropathic  pain in non-diabetic patients.   Excipients include benzyl alcohol, cetyl alcohol  Cautions avoid contact with eyes, inflamed or broken skin; wash  hands immediately after use (or wash hands 30 minutes after  application if hands treated); not to be used under tight bandages;  avoid hot shower or bath just before or after application (burning  sensation enhanced); avoid inhalation of vapours  Side-effects transient burning sensation during initial treatment  (particularly if too much used or if administered less than 4 times  daily); rarely cough, sneezing, eye irritation; dyspnoea and  exacerbation of asthma also reported   Dose symptomatic relief in osteoarthritis, apply sparingly 4 times  daily (not more often than every 4 hours)   avoid hot shower or bath just before or after application (burning   (particularly if too much used or if administered less than 3-4   healed), apply sparingly up to 3-4 times daily (not more often than   Painful diabetic neuropathy, under specialist supervision, apply  sparingly 3-4 times daily (not more often than every 4 hours) for 8  weeks then review   Patches, self-adhesive, capsaicin 179 mg (8%), net  price 1 x 280 cm 2 patch (with cleansing gel) =  £ 210 . 00 .   Excipients include butylated hydroxyanisole in cleansing gel (see sec-  tion 13.1.3)   Cautions avoid holding near eyes or mucous membranes; avoid  contact with inflamed or broken skin, the face, scalp or in  proximity to mucous membranes; monitor blood pressure during  treatment procedure; uncontrolled hypertension; recent cardio-  vascular events   Side-effects application site reactions including transient burn-  ing, erythema, pruritus; less commonly nausea; peripheral  oedema, first degree AV block, tachycardia, palpitations, hyper-  tension; cough, throat irritation; hypoaesthesia, burning sensation,  dysgeusia; pain in extremities, muscle spasm; eye irritation; pru-  ritus   Note Nitrile gloves to be worn while handling patches and clean-  ing treatment areas (latex gloves do not provide adequate pro-  tection)   Poultice, heavy kaolin 52.7%, thymol 0.05%, boric  acid 4.5%, peppermint oil 0.05%, methyl salicylate  0.2%, glycerol 42.5%. Net price 200 g = £2.93  Dose warm and apply directly or between layers of muslin; avoid  application of overheated poultice    Kaolin Poultice K/L Pack® (K/L) CM  Kaolin poultice Net price 4 x 100-g pouches = £6.40   Drugs are most commonly administered to the eye by  topical application as eye drops or eye ointments. When  a higher drug concentration is required within the eye, a  local injection may be necessary.   Eye-drop dispenser devices are available to aid the  instillation of eye drops from plastic bottles; they are  particularly useful for the elderly, visually impaired,  arthritic, or otherwise physically limited patients.   Eye drops and eye ointments Eye drops are gen-  erally instilled into the pocket formed by gently pulling  down the lower eyelid and keeping the eye closed for as  long as possible after application; one drop is all that is  needed. Instillation of more than one drop should be  discouraged because it may increase systemic side-  effects. A small amount of eye ointment is applied  similarly; the ointment melts rapidly and blinking  helps to spread it.   When two different eye-drop preparations are used at  the same time of day, dilution and overflow may occur  when one immediately follows the other. The patient  should therefore leave an interval of at least 5 minutes  between the two.   Systemic effects may arise from absorption of drugs into  the general circulation from conjunctival vessels or from  the nasal mucosa after the excess preparation has  drained down through the tear ducts. The extent of  systemic absorption following ocular administration is  highly variable; nasal drainage of drugs is associated  with eye drops much more often than with eye oint-  ments. Pressure on the lacrimal punctum for at least a  minute after applying eye drops reduces nasolacrimal  drainage and therefore decreases systemic absorption  from the nasal mucosa.   Patients should be warned not to drive or perform other  skilled tasks until vision is clear after using eye drops or  eye ointments.   For warnings relating to eye drops and contact lenses,  see section 11.9.   Eye lotions These are solutions for the irrigation of the  conjunctival sac. They act mechanically to flush out  irritants or foreign bodies as a first-aid treatment. Sterile  sodium chloride 0.9% solution (section 11.8.1) is usually  used. Clean water will suffice in an emergency.   Other preparations Subconjunctival injection may be  used to administer anti-infective drugs, mydriatics, or  corticosteroids for conditions not responding to topical  therapy. The drug diffuses through the cornea and sclera  to the anterior and posterior chambers and vitreous  humour. However, because the dose-volume is limited  (usually not more than 1 mL), this route is suitable only  for drugs which are readily soluble.    Drugs such as antimicrobials and corticosteroids may  be administered systemically to treat susceptible eye  conditions.   Preservatives and sensitisers Information on pre-  servatives and on substances identified as skin sensiti-  sers (see section 13.1.3) is provided under preparation  entries.   Preparations for the eye should be sterile when issued.  Eye drops in multiple-application containers include a  preservative but care should nevertheless be taken to  avoid contamination of the contents during use.   Eye drops in multiple-application containers for dom-  iciliary use should not be used for more than 4 weeks  after first opening (unless otherwise stated).   Eye drops for use in hospital wards are normally dis-  carded 1 week after first opening. Individual containers  should be provided for each patient. A separate bottle  should be supplied for each eye only if there are special  concerns about contamination. Containers used before  an eye operation should be discarded at the time of the  operation and fresh containers supplied. A fresh supply  should also be provided upon discharge from hospital;  in specialist ophthalmology units, it may be acceptable  to issue eye-drop bottles that have been dispensed to  the patient on the day of discharge.   In out-patient departments single-application packs  should preferably be used; if multiple-application  packs are used, they should be discarded at the end of  each day. In clinics for eye diseases and in accident and  emergency departments, where the dangers of infection  are high, single-application packs should be used; if a  multiple-application pack is used, it should be discarded  after single use.   Diagnostic dyes (e.g. fluorescein) should be used only  from single-application packs.   In eye surgery single-application containers should be  used if possible; if a multiple-application pack is used, it  should be discarded after single use. Preparations used  during intra-ocular procedures and others that may  penetrate into the anterior chamber must be isotonic  and without preservatives and buffered if necessary to a  neutral pH. Specially formulated fluids should be used  for intra-ocular surgery; intravenous infusion prepara-  tions are not suitable for this purpose. For all surgical  procedures, a previously unopened container is used for  each patient.    Bacterial blepharitis is treated by application of an anti-  bacterial eye ointment to the conjunctival sac or to the  lid margins. Systemic treatment may occasionally be  required and is usually undertaken after culturing organ-  isms from the lid margin and determining their anti-  microbial sensitivity; antibiotics such as the tetracy-  clines given for 3 months or longer may be appropriate.  Most cases of acute bacterial conjunctivitis are self-  limiting; where treatment is appropriate, antibacterial  eye drops or an eye ointment are used. A poor response  might indicate viral or allergic conjunctivitis. Gonococ-  cal conjunctivitis is treated with systemic and topical  antibacterials.   Corneal ulcer and keratitis require specialist treatment  and may call for hospital admission for intensive ther-  apy-   Endophthalmitis is a medical emergency which also  calls for specialist management and often requires par-  enteral, subconjunctival, or intra-ocular administration  of antimicrobials.    Bacterial eye infections are generally treated topically  with eye drops and eye ointments. Systemic adminis-  tration is sometimes appropriate in blepharitis.    Chloramphenicol has a broad spectrum of activity and  is the drug of choice for superficial eye infections.  Chloramphenicol eye drops are well tolerated and the  recommendation that chloramphenicol eye drops  should be avoided because of an increased risk of  aplastic anaemia is not well founded.    Other antibacterials with a broad spectrum of activity  include the quinolones, ciprofloxacin, levofloxacin,  moxifloxacin, and ofloxacin; the aminoglycosides,  gentamicin, neomycin [unlicensed], and tobramycin  are also active against a wide variety of bacteria. Genta-  micin, quinolones (except moxifloxacin), and poly-  myxin B are effective for infections caused by Pseudo-  monas aeruginosa.   Ciprofloxacin eye drops are licensed for corneal ulcers', v?  intensive application (especially in the first 2 days) is n  required throughout the day and night.   Trachoma which results from chronic infection with  Chlamydia trachomatis can be treated with azithro-  mycin by mouth [unlicensed indication].    Propamidine isetionate is of little value in bacterial  infections but is specific for the rare but potentially  sight-threatening condition of acanthamoeba keratitis  [unlicensed indication] (see also section 11.9).    With corticosteroids Many antibacterial prepara-  tions also incorporate a corticosteroid but such mix-  tures should not be used unless a patient is under close  specialist supervision. In particular they should not be  prescribed for undiagnosed ‘red eye’ which is some-  times caused by the herpes simplex virus and may be  difficult to diagnose (section 11.4).    Eye infections Most acute superficial eye infections  can be treated topically. Blepharitis and conjunctivitis  are often caused by staphylococci; keratitis and  endophthalmitis may be bacterial, viral, or fungal.    Administration Frequency of application depends on  the severity of the infection and the potential for irre-  versible ocular damage; antibacterial eye preparations  are usually administered as follows:    Eye drops Apply 1 drop at least every 2 hours then  reduce frequency as infection is controlled and continue  for 48 hours after healing.   Eye ointment Apply either at night (if eye drops used  during the day) or 3-4 times daily (if eye ointment used  alone).   Note Chloramphenicol 0.5% eye drops (in max. pack size  10 mL) and 1% eye ointment (in max. pack size 4 g) can be  sold to the public for treatment of acute bacterial conjunctivitis  in adults and children over 2 years; max. duration of treatment  5 days   Ophthalmic ointment (= eye ointment), chloram-  phenicol 1%. Net price 4g = £1.08   Minims® Chloramphenicol (Bausch & Lomb) (Ml  Eye drops, chloramphenicol 0.5%. Net price 20 x  0.5 mL = £9.17   Cautions not recommended for children under 1 year  Pregnancy manufacturer advises use only if potential  benefit outweighs risk   Breast-feeding manufacturer advises caution  Side-effects local burning and itching; lid margin  crusting; hyperaemia; taste disturbances; corneal  staining, keratitis, lid oedema, lacrimation, photo-  phobia, corneal infiltrates; nausea and visual distur-  bances reported  Dose   • Comeal ulcer, apply eye drops throughout day and  night, day 1 apply every 15 minutes for 6 hours then  every 30 minutes, day 2 apply every hour, days 3-14  apply every 4 hours (max. duration of treatment 21  days)   Apply eye ointment throughout day and night; apply  1.25 cm ointment every 1-2 hours for 2 days then  every 4 hours for next 12 days   Ophthalmic solution (= eye drops), ciprofloxacin (as  hydrochloride) 0.3%. Net price 5 mL = £4.70   Eye drops, m/r, fusidic acid 1% in gel basis (liquifies  on contact with eye). Net price 5 g = £1.96   Cautions not recommended for children under 1 year  Pregnancy manufacturer advises avoid — systemic  quinolones have caused arthropathy in animal studies  Breast-feeding manufacturer advises avoid  Side-effects transient ocular irritation, visual distur-  bances, lid margin crusting, lid or conjunctival  oedema, hyperaemia, conjunctival follicles, photo-  phobia, headache, rhinitis  Dose   Indications see notes above  Cautions not recommended for neonates  Side-effects taste disturbances, ocular discomfort  (including pain, irritation and dryness), hyperaemia;  less commonly vomiting, headache, paraesthesia,  corneal disorders (including keratitis, erosion, and  staining), conjunctival haemorrhage, eyelid erythema,  visual disturbances, nasal discomfort, pharyngolar-  yngeal pain; also reported nausea, palpitation, dys-  pnoea, dizziness, raised intra-ocular pressure, photo-  phobia, rash, pruritus  Dose   • ADULT and CHILD over 1 month, apply 3 times daily  (continue treatment for 2-3 days after infection clears;  review if no improvement within 5 days)    Neomycin (Non-proprietary) (Ml  Eye drops, neomycin sulphate 0.5% (3500units/mL).  Net price 10 mL = £3.11   Eye ointment, neomycin sulphate 0.5% (3500 units/  g). Net price 3 g = £2.44   Indications see notes above  Pregnancy manufacturer advises use only if benefit  outweighs risk; systemic quinolones have caused  arthropathy in animal studies  Breast-feeding manufacturer advises avoid  Side-effects local irritation including photophobia;   • Apply every 2-4 hours for the first 2 days then reduce  frequency to 4 times daily (max. 10 days treatment)   Eye ointment, polymyxin B sulphate 10 000 units,  bacitracin zinc 500units/g. Net price 4g = £3.26   Eye drops, propamidine isetionate 0.1%. Net price  10 mL = £2.80   Note Eye drops containing propamidine isetionate 0.1% also  available from Typharm ( Golden Eye Drops)   Eye ointment, dibrompropamidine isetionate 0.15%.  Net price 5 g = £2.92  Dose apply 1-2 times daily   Note Eye ointment containing dibrompropamidine isetionate  0.15% also available from Typharm ( Golden Eye Ointment)   • ADULT and CHILD over 1 year, apply twice daily for 6-8  days; in severe infection, apply 4 times daily on the  first day, then twice daily for 5-7 days    Fungal infections of the cornea are rare but can occur  after agricultural injuries, especially in hot and humid  climates. Orbital mycosis is rarer, and when it occurs it  is usually because of direct spread of infection from the  paranasal sinuses. Increasing age, debility, or immuno-  suppression can encourage fungal proliferation. The  spread of infection through blood occasionally produces  metastatic endophthalmitis.    Many different fungi are capable of producing ocular  infection; they can be identified by appropriate labora-  tory procedures.    Antifungal preparations for the eye are not generally  available. Treatment will normally be carried out at  specialist centres, but requests for information about  supplies of preparations not available commercially  should be addressed to the Strategic Health Authority  (or equivalent), or to the nearest hospital ophthalmology  unit, or to Moorfields Eye Hospital, 162 City Road,  London EC1V 2PD (tel. (020) 7253 3411) or  www.moorfields.nhs.uk    Herpes simplex infections producing, for example,  dendritic corneal ulcers can be treated with aciclovir  or ganciclovir. Aciclovir eye ointment is used in com-  bination with systemic treatment for ophthalmic zoster  (section 5.3.2).    Slow-release ocular implants containing ganciclovir  (available on a named-patient basis from specialist  importing companies, see p. 988) may be inserted sur-  gically to treat immediate sight-threatening CMV reti-  nitis. Local treatments do not protect against systemic  infection or infection in the other eye. For systemic  treatment of CMV retinitis, see section 5. 3.2.2.   Side-effects local irritation and inflammation, super-  ficial punctate keratopathy; rarely blepharitis; very  rarely hypersensitivity reactions including angio-  edema   • Apply 5 times daily (continue for at least 3 days after  complete healing)   • Apply 5 times daily until healing complete, then apply  3 times daily for a further 7 days   Corticosteroids administered locally to the eye or given  by mouth are effective for treating anterior segment  inflammation, including that which results from surgery.  Topical corticosteroids are applied frequently for the  first 24-48 hours; once inflammation is controlled, the  frequency of application is reduced. They should nor-  mally only be used under expert supervision; three main  dangers are associated with their use:   • a ‘red eye’, when the diagnosis is unconfirmed, may  be due to herpes simplex virus, and a corticosteroid  may aggravate the condition, leading to corneal  ulceration, with possible damage to vision and  even loss of the eye. Bacterial, fungal, and amoebic  infections pose a similar hazard;   Other side-effects of ocular corticosteroids include thin-  ning of the cornea and sclera.   Combination products containing a corticosteroid with  an anti-infective drug are sometimes used after ocular  surgery to reduce inflammation and prevent infection;  use of combination products is otherwise rarely justified.  Systemic corticosteroids (section 6.3.2) may be useful  for ocular conditions. The risk of producing a ‘steroid  >s cataract’ increases with the dose and duration of  J corticosteroid use.   • Apply eye drops every 1-2 hours until controlled then  reduce frequency; apply eye ointment 2-4 times daily  or at night when used with eye drops   Betnesol® (UCB Pharma) (Ml  Drops (for ear, eye, or nose), betamethasone sodium  phosphate 0.1%. Net price 10 mL = £2.23   Vistamethasone® (Martindale) Ml  Drops (for ear, eye, or nose), betamethasone sodium  phosphate 0.1%. Net price 5mL = £1.02; 10 mL =  £1.16   dWith neomycin  Betnesol-N® (UCB Pharma) (MCM  Drops (for ear, eye, or nose), see section 12.1.1  Dose apply up to 6 times daily   • Apply eye drops every 30-60 minutes until controlled  then reduce frequency to 4-6 times daily   Eye drops, dexamethasone 0.1%, hypromellose 0.5%.  Net price 5 mL = £1.42; 10 mL = £2.80   Minims® Dexamethasone (Bausch & Lomb) (Ml  Eye drops, dexamethasone sodium phosphate 0.1%.  Net price 20 x 0.5 mL = £9.38   Eye drops, dexamethasone 0.1%, neomycin 0.35% (as  sulphate), polymyxin B sulphate 6000 units/mL. Net  price 5mL = £1.68   Eye ointment, dexamethasone 0.1%, neomycin  0.35% (as sulphate), polymyxin B sulphate  6000units/g. Net price 3.5 g = £1.44   Dose apply 3-4 times daily or at night when used with eye drops   Sofradex® (Sanofi-Aventis) [Ml M  Drops (for ear or eye), see section 12.1.1   Tobradex® (Alcon) (Ml CM  Eye drops, dexamethasone 0.1%, tobramycin 0.3%.  Net price 5 mL = £5.37   • Apply every hour for 24-48 hours then reduce fre-  quency to 2-4 times daily   Ophthalmic suspension (= eye drops), fluoro-  metholone 0.1%, polyvinyl alcohol (Liquifilm®) 1.4%.  Net price 5 mL = £1.71; 10mL = £2.95   • Apply eye drops every 30-60 minutes until controlled  then reduce frequency to every 4 hours   Hydrocortisone (Non-proprietary) [Ml  Eye drops, hydrocortisone acetate 1%. Net price  10 mL = £3.21   Eye ointment, hydrocortisone acetate 0.5%, net price  3g = £2.88; 1%, 3 g = £6.71   Indications treatment of post-operative inflammation  following ocular surgery  Cautions see notes above  Side-effects see notes above   • Apply 4 times daily starting 24 hours after surgery;  max. duration of treatment 14 days   Lotemax® (Bausch & Lomb) ▼ (Ml  Opthalmic suspension (= eye drops), loteprednol  etabonate 0.5%, net price 5mL = £5.50   Eye drops, prednisolone acetate 1%. Net price 5 mL =  £1.52; lOmL = £3.05   • Postoperative inflammation, apply 4 times daily for 2  weeks, beginning 24 hours after surgery   • Steroid-responsive inflammation, apply at least 4  times daily for up to 4 weeks   • Uveitis, apply every hour during daytime in week 1,  then every 2 hours in week 2, then 4 times daily in  week 3, then twice daily for first 4 days of week 4, then  once daily for remaining 3 days of week 4   An intravitreal implant containing dexamethasone  ( Ozurdex ®) is licensed for the treatment of adults with  macular oedema following either branch retinal vein    occlusion or central retinal vein occlusion; it should be  administered by specialists experienced in the use of  intravitreal injections.   Indications see notes above — specialist use only  Cautions monitor intra-ocular pressure and for signs  of ocular infection; history of ocular herpes simplex;  aphakia; retinal vein occlusion with significant retinal  ischaemia; concomitant administration of anti-  coagulant or antiplatelet drugs  Contra-indications active or suspected ocular or peri-  ocular infection; uncontrolled advanced glaucoma  Pregnancy manufacturer advises avoid unless poten-  tial benefit outweighs risk — no information available  Breast-feeding manufacturer advises avoid unless  potential benefit outweighs risk — no information  available   Side-effects raised intra-ocular pressure, vitreous  detachment, cataract, visual disturbance; less com-  monly headache; also reported glaucoma, ocular  infection   Other preparations used for the topical treatment of  inflammation and allergic conjunctivitis include antihist-  amines, lodoxamide, and sodium cromoglicate.   Eye drops containing antihistamines, such as antaz-  oline (with xylometazoline as Otrivine-Antistin®),  azelastine, epinastine, ketotifen, and olopatadine,  can be used for allergic conjunctivitis.   Sodium cromoglicate (sodium cromoglycate) and  nedocromil sodium eye drops can be useful for vernal  keratoconjunctivitis and other allergic forms of con-  junctivitis.   Lodoxamide eye drops are used for allergic conjuncti-  val conditions including seasonal allergic conjunctivitis.    Diclofenac eye drops (section 11.8.2) and emedastine  eye drops are also licensed for seasonal allergic con-  junctivitis.   Eye drops, antazoline sulphate 0.5%, xylometazoline  hydrochloride 0.05%. Net price 10 mL = £2.35   Excipients include benzalkonium chloride, disodium edetate  Dose ADULT and CHILD over 12 years apply 2-3 times daily (max.  7 days)   Note Xylometazoline is a sympathomimetic; it should be used  with caution in patients susceptible to angle-closure glaucoma;  absorption of antazoline and xylometazoline may result in sys-  temic side-effects and the possibility of interaction with other  drugs   • Seasonal allergic conjunctivitis, ADULT and CHILD over  4 years, apply twice daily, increased if necessary to 4  times daily   • Perennial conjunctivitis, ADULT and CHILD over 12  years, apply twice daily, increased if necessary to 4  times daily; max. duration of treatment 6 weeks   Indications seasonal allergic conjunctivitis  Side-effects transient burning or stinging; blurred  vision, local oedema, keratitis, irritation, dry eye,  lacrimation, corneal infiltrates (discontinue) and  staining; photophobia; headache, and rhinitis occa-  sionally reported  Dose   • ADULT and CHILD over 3 years, apply twice daily  Emadine® (Alcon) ®   Eye drops, emedastine 0.05% (as difumarate), net  price 5mL = £7.31   Side-effects burning; less commonly dry mouth, taste  disturbance; nasal irritation, rhinitis; headache, ble-  pharoptosis, conjunctival oedema and hyperaemia,  dry eye, local irritation, photophobia, visual distur-  bance; pruritus   • ADULT and ADOLESCENT over 12 years, apply twice  daily; max. duration of treatment 8 weeks   Indications seasonal allergic conjunctivitis  Side-effects burning or stinging, punctate corneal  epithelial erosion; less commonly dry eye, subcon-  junctival haemorrhage, photophobia; headache,  drowsiness, skin reactions, and dry mouth also  reported  Dose   • ADULT and CHILD over 3 years, apply twice daily  Zaditen® (Novartis) (Ml   Eye drops, ketotifen (as fumarate) 250 micrograms/  mL, net price 5 mL = £7.80   Indications allergic conjunctivitis  Side-effects burning, stinging, itching, blurred vision,  tear production disturbance, and ocular discomfort;  less commonly flushing, nasal dryness, dizziness,  drowsiness, headache, blepharitis and keratitis  Dose   • ADULT and CHILD over 4 years, apply 4 times daily;  improvement of symptoms may sometimes require  treatment for up to 4 weeks   Ophthalmic solution (= eye drops), lodoxamide 0.1%  (as trometamol). Net price 10 mL = £5.21   Excipients include benzalkonium chloride, disodium edetate  Note Lodoxamide 0.1% eye drops can be sold to the public  for treatment of allergic conjunctivitis in adults and children  over 4 years   • Seasonal and perennial conjunctivitis, ADULT and CHILD  over 6 years, apply twice daily increased if necessary  to 4 times daily; max. 12 weeks treatment for seasonal  allergic conjunctivitis   • Seasonal keratoconjunctivitis, ADULT and CHILD over 6  years, apply 4 times daily   Rapitil® (Sanofi-Aventis) tMl  Eye drops, nedocromil sodium 2%. Net price 5 mL =  £4.92   Indications seasonal allergic conjunctivitis  Side-effects local irritation; less commonly keratitis,  dry eye, local oedema, photophobia; headache, asth-  enia, dizziness; dry nose also reported   • ADULT and CHILD over 3 years, apply twice daily; max.  duration of treatment 4 months   Eye drops, olopatadine (as hydrochloride) 1 mg/mL,  net price 5 mL = £3.91   Sodium Cromoglicate (Non-proprietary) (Ml  Eye drops, sodium cromoglicate 2%. Net price  13.5 mL = £1.79   Brands include Hay-Crom ® Aqueous , Opticrom ® Aqueous,  Vividrin ®   Note Sodium cromoglicate 2% eye drops can be sold to the  public (in max. pack size of 10 mL) for treatment of acute  seasonal and perennial allergic conjunctivitis   Eye drops, sodium cromoglicate 2%, net price 30 x  0.3 mL = £8.99   Antimuscarinics dilate the pupil and paralyse the ciliary  muscle; they vary in potency and duration of action.  Short-acting, relatively weak mydriatics, such as tropic-  amide 0.5% (action lasts for 4-6 hours), facilitate the  examination of the fundus of the eye. Cyclopentolate  1% (action up to 24 hours) or atropine (action up to 7  days) are preferable for producing cycloplegia for  refraction in young children. Atropine ointment 1% is  sometimes preferred for children aged under 5 years  because the ointment formulation reduces systemic  absorption.   Mydriatics and cycloplegics are used in the treatment of  anterior uveitis, usually as an adjunct to corticosteroids  (section 11.4.1). Atropine is used in anterior uveitis  mainly to prevent posterior synechiae and to relieve  ciliary spasm, often in combination with phenylephrine  eye drops; cyclopentolate or homatropine (action up to  3 days) can also be used and may be preferred because  they have a shorter duration of action.   Phenylephrine is used for mydriasis in diagnostic or  therapeutic procedures; mydriasis occurs within 60-90  minutes and lasts up to 5-7 hours. Phenylephrine 10%  drops are contra-indicated in children and the elderly  owing to the risk of systemic effects.   Cautions Darkly pigmented iris is more resistant to  pupillary dilatation and caution should be exercised to  avoid overdosage. Mydriasis can precipitate acute  angle-closure glaucoma in a few patients, usually aged  over 60 years and hypermetropic (long-sighted), who  are predisposed to the condition because of a shallow  anterior chamber. Phenylephrine may interact with sys-  temically administered monoamine-oxidase inhibitors;  other interactions: Appendix 1 (sympathomimetics).   Driving Patients should be warned not to drive until vision is  clear after mydriasis.   Side-effects Ocular side-effects of mydriatics and  cycloplegics include transient stinging and raised  intra-ocular pressure; on prolonged administration,  local irritation, hyperaemia, oedema and conjunctivitis  can occur. Contact dermatitis can occur with the anti-  muscarinic mydriatic drugs, especially atropine.  Systemic side-effects of atropine and cyclopentolate can  occur, particularly in children and the elderly; see sec-  tion 1.2 for systemic side-effects of antimuscarinic  drugs.    Atropine (Non-proprietary) (M  Eye drops, atropine sulphate 0.5%, net price 10 mL =  £2.78   Indications see notes above  Cautions see notes above  Side-effects see notes above   Mydrilate® (Intrapharm) (Ml  Eye drops, cyclopentolate hydrochloride 0.5%, net  price 5mL = £6.73; 1%, 5mL = £6.73   Eye drops, cyclopentolate hydrochloride 0.5% and  1%. Net price 20 x 0.5 mL (both) = £9.64   Indications see notes above  Cautions see notes above  Side-effects see notes above   Homatropine (Non-proprietary) (Ml  Eye drops, homatropine hydrobromide 1%, net price  10 mL = £2.57; 2%, 10 mL = £2.71   Indications see notes above  Cautions see notes above  Side-effects see notes above  Mydriacyl® (Alcon) (Ml   Minims® Tropicamide (Bausch & Lomb) (Ml  Eye drops, tropicamide 0.5% and 1%. Net price 20 x  0.5 mL (both) =£9.01   Cautions children and elderly (avoid 10% strength);  cardiovascular disease (avoid or use 2.5% strength  only); tachycardia; hyperthyroidism; diabetes; see also  notes above   Side-effects eye pain and stinging; blurred vision,  photophobia; systemic effects include palpitations,  arrhythmias, hypertension, coronary artery spasm;  very rarely angle-closure glaucoma   Eye drops, phenylephrine hydrochloride 2.5%, net  price 20 x 0.5 mL = £9.53; 10%, 20 x 0.5 mL = £9.53    Glaucoma describes a group of disorders characterised  by a loss of visual field associated with cupping of the  optic disc and optic nerve damage. While glaucoma is  generally associated with raised intra-ocular pressure, it  can occur when the intra-ocular pressure is within the  normal range.   The commonest form of glaucoma is primary open-  angle glaucoma (chronic simple glaucoma; wide-angle  glaucoma), where the obstruction is in the trabecular  meshwork. The condition is often asymptomatic and the  patient may present with significant loss of visual-field.  Primary angle-closure glaucoma (acute closed-angle  glaucoma, narrow-angle glaucoma) results from block-  age of aqueous humour flow into the anterior chamber  and is a medical emergency.   Drugs that reduce intra-ocular pressure by different  mechanisms are available for managing glaucoma. A  topical beta-blocker or a prostaglandin analogue is  usually the drug of first choice. It may be necessary to  combine these drugs or add others, such as miotics,  sympathomimetics, or carbonic anhydrase inhibitors, to  control intra-ocular pressure.   For urgent reduction of intra-ocular pressure and before  surgery, mannitol 20% (up to 500 mL) is given by slow  intravenous infusion until the intra-ocular pressure has  been satisfactorily reduced. Acetazolamide by intra-  venous injection can also be used for the emergency  management of raised intra-ocular pressure.   Standard antiglaucoma therapy is used if supplementary  lu treatment is required after iridotomy, iridectomy, or a   D drainage operation in either primary open-angle or  primary angle-closure glaucoma.   Topical application of a beta-blocker to the eye reduces  intra-ocular pressure effectively in primary open-angle  glaucoma, probably by reducing the rate of production  of aqueous humour. Administration by mouth also  reduces intra-ocular pressure but this route is not used  since side-effects may be troublesome.   Beta-blockers used as eye drops include betaxolol,  carteolol, levobunolol, metipranolol, and timolol.   Systemic absorption can follow topical application to  the eyes; therefore, eye drops containing a beta-blocker  are contra-indicated in patients with bradycardia, heart  block, or uncontrolled heart failure. Important: for a  warning to avoid in asthma see below. Consider also  other cautions, contra-indications, and side-effects of  beta-blockers (p. 97). Local side-effects of eye drops  include ocular stinging, burning, pain, itching, erythema,  dry eyes and allergic reactions including anaphylaxis  and blepharoconjunctivitis; occasionally corneal disor-  ders have been reported.   Important Beta-blockers, even those with apparent cardios-  electivity, should not be used in patients with asthma or a    history of obstructive airways disease, unless no alternative  treatment is available. In such cases the risk of inducing  bronchospasm should be appreciated and appropriate pre-  cautions taken.   Interactions Since systemic absorption may follow  topical application the possibility of interactions, in  particular, with drugs such as verapamil should be  borne in mind. See also Appendix 1 (beta-blockers).   Betaxolol (Non-proprietary) £mD  Eye drops, solution, betaxolol (as hydrochloride)  0.5%, net price 5 mL = £1.90   Ophthalmic solution (= eye drops), betaxolol (as  hydrochloride) 0.5%, net price 5mL = £1.90   Ophthalmic suspension (= eye drops), betaxolol (as  hydrochloride) 0.25%, net price 5mL = £2.66   Unit dose eye drop suspension, betaxolol (as  hydrochloride) 0.25%, net price 50 x 0.25 mL =  £13.77   Teoptic® (Spectrum Thea) (Ml  Eye drops, carteolol hydrochloride 1%, net price 5 mL  = £7.60; 2%, 5mL = £8.40   Levobunolol (Non-proprietary) tMl  Eye drops, levobunolol hydrochloride 0.5%. Net price  5 mL = £3.05   Eye drops, levobunolol hydrochloride 0.5%, polyvinyl  alcohol ( Liquifilm ®) 1.4%. Net price 5-mL = £1.85   Unit dose eye drops, levobunolol hydrochloride  0.5%, polyvinyl alcohol ( Liquifilm ®) 1.4%. Net price  30 x 0.4 mL = £9.98   Indications see notes above but in chronic open-angle  glaucoma restricted to patients allergic to preserva-  tives or to those wearing soft contact lenses (in whom  benzalkonium chloride should be avoided)   Cautions see notes above  Contra-indications see notes above  Side-effects see notes above; granulomatous anterior  uveitis reported (discontinue treatment)   Minims® Metipranolol (Bausch & Lomb) (Ml  Eye drops, metipranolol 0.1%, net price 20 x 0.5 mL  = £11.77   Timolol (Non-proprietary) (Ml  Eye drops, timolol (as maleate) 0.25%, net price 5 mL  = £1.56; 0.5%, 5mL = £1.56  Timoptol® (MSD) ®   Eye drops, in Ocumeter® metered-dose unit, timolol  (as maleate) 0.25%, net price 5mL = £3.12; 0.5%,   Unit dose eye drops, timolol (as maleate) 0.25%, net  price 30 x 0.2 mL = £8.45; 0.5%, 30 x 0.2 mL = £9.65   Eye gel (= eye drops), timolol (as maleate) 0.1%, net  price 5g = £2.85   Ophthalmic gel-forming solution (= eye drops),  timolol (as maleate) 0.25%, net price 2.5 mL = £3.12;  0.5%, 2.5 mL = £3.12    prost, increase uveoscleral outflow and subsequently  reduce intra-ocular pressure. They are used to reduce  intra-ocular pressure in ocular hypertension or open-  angle glaucoma.   Cautions Before initiating treatment, patients should  be monitored for possible change in eye colour since an  increase in the brown pigment in the iris may occur;  particular care is required in those with mixed coloured  irides and those receiving treatment to one eye only.  Use with caution in patients with aphakia, pseudophakia  with tom posterior lens capsule or anterior chamber  lenses, and in those with known risk factors for cystoid  macular oedema, iritis, or uveitis. Care is also needed in  patients with brittle or severe asthma. Do not use within  5 minutes of thiomersal-containing preparations. For  use in contact lens wearers see Contact Lenses, p. 684.   Side-effects Side-effects of prostaglandin analogues  and prostamides include brown pigmentation particu-  larly in those with mixed-colour irides, blepharitis, ocu-  lar irritation and pain, conjunctival hyperaemia, transi-  ent punctate epithelial erosion, skin rash, dry eyes,  headache, and photophobia; they may also cause, dar-  kening, thickening and lengthening of eye lashes. Less  frequent side-effects include eyelid oedema and rash,  keratitis, blurred vision, and conjunctivitis. There have  been rare reports of dyspnoea, exacerbation of asthma,  dizziness, arthralgia, myalgia, iritis, uveitis, local  oedema, darkening of palpebral skin. Very rarely chest  pain, palpitations, and exacerbation of angina has also  been reported.   • Apply once daily, preferably in the evening; CHILD  under 18 years, not recommended   Lumigan® (Allergan) (Ml  Eye drops, bimatoprost lOOmicrograms/mL, net  price 3mL = £12.43, triple pack (3x3 mL) = £37.29;  300 micrograms/mL, 3mL = £10.30, triple pack (3 x  3 mL) =£30.90   The prostaglandin analogues latanoprost, tafluprost,  and travoprost, and the synthetic prostamide, bimato-   Eye drops, bimatoprost 300 micrograms/mL, timolol  (as maleate) 5mg/mL, net price 3-mL = £13.95   Dose for raised intra-ocular pressure in patients with open-angle  glaucoma or ocular hypertension when beta-blocker or prosta-  glandin analogue alone not adequate; apply once daily, preferably  in the morning   • Apply once daily, preferably in the evening; CHILD not  recommended   Eye drops, latanoprost 50 micrograms/mL, net price  2.5 mL = £12.48   Xalacom® (Pharmacia) tMl  Eye drops, latanoprost 50 micrograms, timolol (as  maleate) 5mg/mL, net price 2.5 mL = £14.32   Dose for raised intra-ocular pressure in patients with open-angle  glaucoma and ocular hypertension when beta-blocker alone not  adequate; apply once daily   • Apply once daily, preferably in the evening; CHILD  under 18 years, not recommended   Unit dose eye drops, tafluprost 15 micrograms/mL,  net price 30 x 0.3 mL = £17.41   • Apply once daily, preferably in the evening; CHILD  under 18 years, not recommended   Eye drops, travoprost 40 micrograms, timolol (as  maleate) 5mg/mL, net price 2.5 mL = £12.54   Excipients include benzalkonium chloride, disodium edetate  Dose for raised intra-ocular pressure in patients with open-angle  glaucoma or ocular hypertension when beta-blocker or prosta-  glandin analogue alone not adequate; apply once daily; CHILD and  ADOLESCENT under 18 years, not recommended   Brimonidine, a selective alpha 2 -adrenoceptor agonist,  is licensed for the reduction of intra-ocular pressure in  open-angle glaucoma or ocular hypertension in patients  for whom beta-blockers are inappropriate; it may also  be used as adjunctive therapy when intra-ocular pres-  sure is inadequately controlled by other antiglaucoma  therapy.   Apraclonidine (section 11.8.2) is another alpha 2 -  adrenoceptor agonist. Eye drops containing apracloni-  dine 0.5% are used for a short term to delay laser  treatment or surgery for glaucoma in patients not ade-  quately controlled by another drug; eye drops contain-  ing 1% are used for control of intra-ocular pressure after  anterior segment laser surgery.   Cautions severe cardiovascular disease; cerebral or  coronary insufficiency, Raynaud’s syndrome, throm-  boangiitis obliterans, postural hypotension, depres-  sion; children 2-12 years (increased risk of drowsi-  ness); interactions: Appendix 1 (brimonidine)   Driving Drowsiness may affect performance of skilled tasks  (e g. driving)   Side-effects dry mouth, gastro-intestinal distur-  bances, taste disturbances, upper respiratory symp-  toms, headache, drowsiness, dizziness, malaise, ocular  disturbances (including hyperaemia, burning, stinging,  pruritus, pain and dryness), visual disturbances, eyelid  inflammation, photophobia, corneal erosion and  staining, conjunctival disturbances (including blanch-  ing, follicles, and infection); less commonly palpita-  tion, arrhythmia, bradycardia, tachycardia, depres-  sion, nasal dryness; rarely dyspnoea; very rarely  hypertension, hypotension, syncope, insomnia, iritis,  miosis    Brimonidine Tartrate (Non-proprietary) (Ml  Eye drops, brimonidine tartrate 0.2%, net price 5mL  = £6.55   Eye drops, brimonidine tartrate 0.2%, net price 5 mL  = £6.85   Combigan® (Allergan) (Ml  Eye drops, brimonidine tartrate 0.2%, timolol (as  maleate) 0.5%, net price 5-mL = £10.00   Excipients include benzalkonium chloride  Dose for raised intra-ocular pressure in open-angle glaucoma  and for ocular hypertension when beta-blocker alone not ade-  quate, apply twice daily   The carbonic anhydrase inhibitors, acetazolamide,  brinzolamide, and dorzolamide, reduce intra-ocular  pressure by reducing aqueous humour production. Sys-  temic use also produces weak diuresis.   Acetazolamide is given by mouth or by intravenous  injection (intramuscular injections are painful because  of the alkaline pH of the solution). It is used as an  adjunct to other treatment for reducing intra-ocular  pressure. Acetazolamide is a sulphonamide; blood dis-  orders, rashes, and other sulphonamide-related side-  effects occur occasionally; patients should be told to  report any unusual skin rash. It is not generally recom-  mended for long-term use; electrolyte disturbances and  metabolic acidosis that occur can be corrected by  administering potassium bicarbonate (as effervescent  potassium tablets, section 9.2. 1.3).   Dorzolamide and brinzolamide are topical carbonic  anhydrase inhibitors. They are licensed for use in  patients resistant to beta-blockers or those in whom  beta-blockers are contra-indicated. They are used alone  or as an adjunct to a topical beta-blocker. Systemic  absorption can rarely cause sulphonamide-like side-  effects and may require discontinuation if severe.   The osmotic diuretics, intravenous hypertonic manni-  tol (section 2.2.5) or glycerol by mouth are useful short-  term ocular hypotensive drugs.   Indications reduction of intra-ocular pressure in open-  angle glaucoma, secondary glaucoma, and peri-  operatively in angle-closure glaucoma; diuresis (sec-  tion 2.2.7); epilepsy   Cautions not generally recommended for prolonged  use but if given monitor blood count and plasma-  electrolyte concentration; pulmonary obstruction and  impaired alveolar ventilation (risk of acidosis); elderly;  diabetes mellitus; renal calculi; avoid extravasation at  injection site (risk of necrosis); interactions: Appen-  dix 1 (diuretics)   Contra-indications hypokalaemia, hyponatraemia,  hyperchloraemic acidosis; adrenocortical insuffi-  ciency; long-term administration in chronic angle-  closure glaucoma; sulfonamide hypersensitivity  Hepatic impairment manufacturer advises avoid    Renal impairment avoid — risk of metabolic acidosis  Pregnancy manufacturer advises avoid, especially in  first trimester (toxicity in animal studies)  Breast-feeding amount too small to be harmful  Side-effects see notes above; also nausea, vomiting,  diarrhoea, taste disturbance, loss of appetite, paraes-  thesia, flushing, headache, dizziness, fatigue, irritabil-  ity, excitement, ataxia, depression; thirst, polyuria,  reduced libido, less commonly melaena, drowsiness,  confusion, hearing disturbances, fever, glycosuria,  metabolic acidosis and electrolyte disturbances on  long-term therapy, haematuria, crystalluria, renal and  ureteric colic, renal lesions or calculi, renal failure,  blood disorders, bone marrow suppression, rash  (including Stevens- Johnson syndrome and toxic epi-  dermal necrosis); rarely fulminant hepatic necrosis,  hepatitis, cholestatic jaundice, flaccid paralysis, con-  vulsions, photosensitivity; also reported transient  myopia  Dose   • Glaucoma, by mouth or by intravenous injection,  0.25-1 g daily in divided doses   • Epilepsy, by mouth or by intravenous injection, 0.25-  1 g daily in divided doses; CHILD 8-30 mg/kg daily,  max. 750 mg daily   Note Dose by intramuscular injection, as for intravenous  injection but preferably avoided because of alkalinity   4 Modified release  Diamox® SR (Goldshield) (Ml  Capsules, m/r, orange, enclosing orange f/c pellets,  acetazolamide 250 mg. Net price 30-cap pack =  £13.88. Label: 3, 25  Dose glaucoma, 1-2 capsules daily   Indications adjunct to beta-blockers or used alone in  raised intra-ocular pressure in ocular hypertension  and in open-angle glaucoma if beta-blocker alone  inadequate or inappropriate  Cautions systemic absorption follows topical applica-  tion; interactions: Appendix 1 (brinzolamide)  Contra-indications hyperchloraemic acidosis  Hepatic impairment manufacturer advises avoid  Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2   Pregnancy manufacturer advises avoid unless essen-  tial — toxicity in animal studies  Breast-feeding manufacturer advises avoid  Side-effects local irritation, taste disturbance; less  commonly nausea, dyspepsia, dry mouth, chest pain,  epistaxis, haemoptysis, dyspnoea, rhinitis, pharyng-  itis, bronchitis, paraesthesia, depression, dizziness,  headache, dermatitis, alopecia, comeal erosion  Dose   • Apply twice daily increased to 3 times daily if neces-  sary   Eye drops, brinzolamide 10 mg/mL, net price 5 mL =  £6.56   Ophthalmic suspension (= eye drops), brinzolamide  10 mg, timolol (as maleate) 5mg/mL, net price 5mL  = £11.05   Excipients include benzalkonium chloride, disodium edetate  Dose for raised intra-ocular pressure in open-angle glaucoma or  ocular hypertension when beta-blocker alone not adequate, ADULT  over 18 years apply twice daily   Indications raised intra-ocular pressure in ocular  hypertension, open-angle glaucoma, pseudo-exfol-  iative glaucoma either as adjunct to beta-blocker or  used alone in patients unresponsive to beta-blockers  or if beta-blockers contra-indicated  Cautions systemic absorption follows topical applica-  tion; history of renal calculi; chronic corneal defects,  history of intra-ocular surgery; interactions: Appen-  dix 1 (dorzolamide)   Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m 2   Side-effects nausea, bitter taste, dry mouth; head-  ache, asthenia; ocular irritation, blurred vision, lacri-  mation, conjunctivitis, superficial punctuate keratitis,  eyelid inflammation; less commonly iridocyclitis;  rarely hypersensitivity reactions (including urticaria,  angioedema, bronchospasm), dizziness, paraesthesia,  urolithiasis, eyelid crusting, transient myopia, corneal  oedema, epistaxis, throat irritation  Dose   Dorzolamide (Non-proprietary) (Ml  Eye drops, dorzolamide (as hydrochloride) 2%, net  price 5 mL = £5.61   Ophthalmic solution (= eye drops), in Ocumeter ®  Plus metered-dose unit, dorzolamide (as hydro-  chloride) 2%, net price 5 mL = £6.33   Unit dose eye drops, dorzolamide (as hydrochloride)  2%, net price 60 x 0.2 mL = £24.18   Dorzolamide with Timolol (Non-proprietary) (Ml  Eye drops, dorzolamide (as hydrochloride) 2%,  timolol (as maleate) 0.5%, net price 5mL = £10.05   Ophthalmic solution (= eye drops), in Ocumeter®  Plus metered-dose unit, dorzolamide (as hydro-  chloride) 2%, timolol (as maleate) 0.5%, net price  5 mL = £10.05    Unit dose eye drops, dorzolamide (as hydrochloride)  2%, timolol (as maleate) 0.5%, net price 60 x 0.2 mL =  £28.59   The small pupil is an unfortunate side-effect of these  drugs (except when pilocarpine is used temporarily  before an operation for angle-closure glaucoma ). They  act by opening up the inefficient drainage channels in  the trabecular meshwork resulting from contraction or  spasm of the ciliary muscle.   Pilocarpine, a miotic, is used in the management of  raised intra-ocular pressure.   Cautions A darkly pigmented iris may require higher  concentration of the miotic or more frequent adminis-  tration and care should be taken to avoid overdosage.  Retinal detachment has occurred in susceptible indivi-  duals and those with retinal disease; therefore fundus  examination is advised before starting treatment with a  miotic. Care is also required in conjunctival or corneal  damage. Intra-ocular pressure and visual fields should  be monitored in those with chronic simple glaucoma  and those receiving long-term treatment with a miotic.  Miotics should be used with caution in patients with  peptic ulceration, gastro-intestinal spasm, cardiac dis-  ease, hypertension, hypotension, marked vasomotor  instability, asthma, epilepsy, Parkinson’s disease, hyper-  thyroidism, and urinary-tract obstruction.   Counselling Blurred vision may affect performance of skilled  tasks (e.g. driving) particularly at night or in reduced lighting   Contra-indications Miotics are contra-indicated in  conditions where pupillary constriction is undesirable  such as acute iritis, anterior uveitis and some forms of  secondary glaucoma. They should be avoided in acute  inflammatory disease of the anterior segment.   Side-effects Ciliary spasm leads to headache and  browache which may be more severe in the initial 2-4  weeks of treatment (a particular disadvantage in  patients under 40 years of age). Ocular side-effects  include burning, itching, smarting, blurred vision, con-  junctival vascular congestion, myopia, lens changes  with chronic use, vitreous haemorrhage, and pupillary  block. Systemic side-effects (see under Parasympatho-  mimetics, section 7.4.1) are rare following application to  the eye.   • Apply up to 4 times daily; long-acting preparations,  see under preparations below    Pilocarpine Hydrochloride (Non-proprietary) (Ml  Eye drops, pilocarpine hydrochloride 1%, net price  10 mL = £3.00; 2%, 10 mL = £2.87; 4%, 10 mL = £3.83   Minims® Pilocarpine Nitrate (Bausch & Lomb) (M)  Eye drops, pilocarpine nitrate 2%, net price 20 x  0.5 mL = £10.04   Excipients include benzalkonium chloride, disodium edetate  Dose apply 1-1.5 cm gel once daily at bedtime   Oxybuprocaine and tetracaine (amethocaine) are  widely used topical local anaesthetics. Proxymetacaine  causes less initial stinging and is useful for children.  Oxybuprocaine or a combined preparation of lidocaine  and fluorescein is used for tonometry. Tetracaine pro-  duces a more profound anaesthesia and is suitable for  use before minor surgical procedures, such as the  removal of corneal sutures. It has a temporary disrup-  tive effect on the corneal epithelium. Lidocaine, with or  without adrenaline (epinephrine), is injected into the  eyelids for minor surgery, while retrobulbar or peribul-  bar injections are used for surgery of the globe itself.  Local anaesthetics should never be used for the man-  agement of ocular symptoms.   Local anaesthetic eye drops should be avoided in pre-  term neonates because of the immaturity of the meta-  bolising enzyme system.   Eye drops, lidocaine hydrochloride 4%, fluorescein  sodium 0.25%. Net price 20 x 0.5 mL = £10.61   Eye drops, oxybuprocaine hydrochloride 0.4%. Net  price 20 x 0.5 mL = £8.92   Minims® Proxymetacaine (Bausch & Lomb) (Ml  Eye drops, proxymetacaine hydrochloride 0.5%. Net  price 20 x 0.5 mL = £9.51   Eye drops, proxymetacaine hydrochloride 0.5%,  fluorescein sodium 0.25%. Net price 20 x 0.5 mL =  £10.59   Eye drops, tetracaine hydrochloride 0.5% and 1%.  Net price 20 x 0.5 mL (both) = £8.93   Certain eye drops, e.g. amphotericin, ceftazidime, cefur-  oxime, colistin, desferrioxamine, dexamethasone,  gentamicin, and vancomycin can be prepared asepti-  cally from material supplied for injection.    Chronic soreness of the eyes associated with reduced or  abnormal tear secretion (e.g. in Sjogren’s syndrome)  often responds to tear replacement therapy or pilo-  carpine given by mouth (section 12.3.5). The severity  of the condition and patient preference will often guide  the choice of preparation.   Hypromellose is the traditional choice of treatment for  tear deficiency. It may need to be instilled frequently n  (e.g. hourly) for adequate relief. Ocular surface mucin is  often abnormal in tear deficiency and the combination  of hypromellose with a mucolytic such as acetylcys-  teine can be helpful.    The ability of carbomers to cling to the eye surface may  help reduce frequency of application to 4 times daily.    Polyvinyl alcohol increases the persistence of the tear  film and is useful when the ocular surface mucin is  reduced.    Povidone and sodium hyaluronate eye drops are also  used in the management of tear deficiency.   Sodium chloride 0.9% drops are sometimes useful in  tear deficiency, and can be used as ‘comfort drops’ by  contact lens wearers, and to facilitate lens removal.  Special presentations of sodium chloride 0.9% and  other irrigation solutions are used routinely for intra-  ocular surgery.   Eye ointments containing a paraffin can be used to  lubricate the eye surface, especially in cases of recurrent  corneal epithelial erosion. They may cause temporary  visual disturbance and are best suited for application    before sleep. Ointments should not be used during  contact lens wear.   Eye drops, acetylcysteine 5%, hypromellose 0.35%.  Net price 10 mL = £4.40   Note Synthetic high molecular weight polymers of acrylic  acid cross-linked with either allyl ethers of sucrose or allyl  ethers of pentaerithrityl   Gel (= eye drops), carbomer 980 (polyacrylic acid)  0.2%, net price 10 g = £1.49   Gel (= eye drops), carbomer 980 (polyacrylic acid)  0.2%, net price 10 g = £2.80   Gel (= eye drops), carbomer 980 (polyacrylic acid)  0.2%, net price 10 g = £2.96   Gel (= eye drops), carbomer 974P (polyacrylic acid)  0.25%, net price 10 g = £4.50   Gel (= eye drops), carbomer 980 (polyacrylic acid)  0.2%, net price 10 g = £2.10   Liquid gel (= eye drops), carbomer 980 (polyacrylic  acid) 0.2%, net price 10 g = £2.94   Liquid gel (= eye drops), carbomer 980 (polyacrylic  acid) 0.2%, net price 30 x 0.6-mL single-dose units =  £5.42   Eye drops, carmellose sodium 0.5%, glycerol, net  price 10 mL = £7.49   Eye drops, carmellose sodium 0.5%, net price 30 x  0.4 mL = £5.75, 90 x 0.4 mL = £15.53; 1%, 30 x  0.4 mL = £3.00, 60 x 0.4 mL = £10.99   Eye drops, hydroxyethylcellulose 0.44%, sodium  chloride 0.35%. Net price 20 x 0.5 mL = £8.21   Indications tear deficiency  Note The Royal Pharmaceutical Society has stated that  where it is not possible to ascertain the strength of hypro-  mellose prescribed, the prescriber should be contacted to  clarify the strength intended.   Excipients may include benzalkonium chloride  Brands include Artelac ®, Lumecare ® Hypromellose   Eye drops, hypromellose 0.5%, net price 10 mL = 8 lp   Eye drops, hypromellose 0.32%, net price 30 x  0.5 mL =£16.95   Eye drops, hypromellose 0.3%, net price 30 x 0.4 mL  = £5.75   Lumecare® Preservative Free Tear Drops (Medicom)  Eye drops, hypromellose 0.3%, net price 30 x 0.5 mL  = £5.72   Eye ointment, white soft paraffin 57.3%, liquid par-  affin 42.5%, wool alcohols 0.2%. Net price 3.5 g =  £2.51, 5g = £3.32   Ointment, liquid paraffin 10%, wool fat 10%, in yellow  soft paraffin. Net price 4 g = £3.06   Ophthalmic solution (= eye drops), polyvinyl alcohol  1.4%, povidone 0.6%. Net price 30 x 0.4 mL = £5.35   Solution (sterile), sodium chloride 0.64%, sodium  acetate 0.39%, sodium citrate 0.17%, calcium chloride  0.048%, magnesium chloride 0.03%, potassium  chloride 0.075%   For intra-ocular or topical irrigation during surgical procedures  Brands include Iocare ®   Eye drops, sodium hyaluronate 0.1%, dexpanthenol  2%, net price 10 mL = £10.30   Eye drops, sodium hyaluronate 0.4%, net price 30 x  0.5 mL =£5.70   Note Each unit is resealable for up to 12 hours  Ocusan® (Agepha)   Eye drops, sodium hyaluronate 0.2%, net price 20 x  0.5 mL =£5.25   Fluorescein sodium is used in diagnostic procedures  and for locating damaged areas of the cornea due to  injury or disease.   Eye drops, fluorescein sodium 1% or 2%. Net price 20  x 0.5 mL (both) =£7.53   Drugs used to prepare the eye for surgery, drugs that are  injected into the anterior chamber at the time of surgery,  and those used after eye surgery, are included here.  Non-steroidal anti-inflammatory eye drops such as  diclofenac, flurbiprofen, ketorolac, and nepafenac,  are used for the prophylaxis and treatment of inflam-  mation, pain, and other symptoms associated with  ocular surgery or laser treatment of the eye. Diclofenac  and flurbiprofen are also used to prevent miosis during  ocular surgery.   Apraclonidine, an alpha 2 -adrenoreceptor agonist,  reduces intra-ocular pressure possibly by reducing the  production of aqueous humour. It is used to control  increases in intra-ocular pressure associated with ocular  surgery and as short-term treatment to reduce intra-  ocular pressure prior to surgery.   Acetylcholine, instilled into the anterior chamber of the  eye during surgery, rapidly produces miosis which lasts  approximately 20 minutes. If prolonged miosis is  required, it can be applied again.    Intra-ocular sodium hyaluronate and balanced salt  solution (section 11.8.1) are used during surgical proce-  dures on the eye.   Indications cataract surgery, penetrating keratoplasty,  iridectomy, and other anterior segment surgery  requiring rapid complete miosis  Cautions gastro-intestinal spasm, peptic ulcer; heart  failure; asthma; hyperthyroidism, urinary-tract  obstruction; parkinsonism   Pregnancy avoid unless potential benefit outweighs  risk — no information available  Breast-feeding avoid unless potential benefit out-  weighs risk — no information available  Side-effects rarely bradycardia, hypotension, breath-  ing difficulty, sweating, flushing   Miochol-E® (Novartis) (MI  Intra-ocular irrigation, powder for reconstitution,  acetylcholine chloride lOmg/mL (1%) when recon-  stituted, net price 20-mg vial (with solvent) = £7.28   Note Apraclonidine is a derivative of clonidine  Indications control of intra-ocular pressure  Cautions history of angina, severe coronary insuffi-  ciency, recent myocardial infarction, heart failure,  cerebrovascular disease, vasovagal attack, chronic  renal failure; depression; monitor intra-ocular pres-  sure and visual fields; loss of effect may occur over  time; suspend treatment if reduction in vision occurs  in end-stage glaucoma; monitor for excessive reduc-  tion in intra-ocular pressure following peri-operative  use; interactions: Appendix 1 (apraclonidine)   Side-effects dry mouth, taste disturbance; hyperae-  mia, ocular pruritus, discomfort and lacrimation  (withdraw if ocular intolerance including oedema of  lids and conjunctiva); headache, asthenia, dry nose;  lid retraction, conjunctival blanching and mydriasis  reported after peri-operative use; since absorption  may follow topical application systemic effects (see  Clonidine, section 2.5.2) may occur  Dose   Ophthalmic solution (= eye drops), apraclonidine 1%  (as hydrochloride), net price 12x2 single use 0.25-  mL units = £77.81   Dose control or prevention of postoperative elevation of intra-  ocular pressure after anterior segment laser surgery, apply 1 drop  1 hour before laser procedure then 1 drop immediately after  completion of procedure; CHILD not recommended    lopidine 0.5% ophthalmic solution (= eye drops),  apraclonidine 0.5% (as hydrochloride), net price 5 mL  = £ 10.88   Excipients include benzalkonium chloride  Dose short-term adjunctive treatment of chronic glaucoma in  patients not adequately controlled by another drug (see note  below), apply 1 drop 3 times daily usually for max. 1 month; CHILD  not recommended   Note May not provide additional benefit if patient already using  two drugs that suppress the production of aqueous humour   Indications inhibition of intra-operative miosis during  cataract surgery (but does not possess intrinsic  mydriatic properties); postoperative inflammation in  cataract surgery, strabismus surgery or argon laser  trabeculoplasty; pain in corneal epithelial defects after  photorefractive keratectomy, radial keratotomy or  accidental trauma; seasonal allergic conjunctivitis  (section 11.4.2)   Voltarol® Ophtha Multidose (Novartis) (Ml  Eye drops, diclofenac sodium 0.1%, net price 5 mL =  £ 6.68   Eye drops, diclofenac sodium 0.1%, net price pack of  5 single-dose units = £4.00, 40 single-dose units =  £32.00   Indications inhibition of intra-operative miosis (but  does not possess intrinsic mydriatic properties);  anterior segment inflammation following postoper-  ative and post-laser trabeculoplasty when corticos-  teroids contra-indicated  Ocufen® (Allergan) (Ml   Ophthalmic solution (= eye drops), flurbiprofen  sodium 0.03%, polyvinyl alcohol ( Liquifilm ®) 1.4%,  net price 40 x 0.4 mL = £37.15   Indications prophylaxis and reduction of inflamma-  tion and associated symptoms following ocular sur-  gery   Eye drops, ketorolac trometamol 0.5%, net price 5 mL  = £3.00   Indications prophylaxis and treatment of postoper-  ative pain and inflammation associated with cataract  surgery   Cautions avoid sunlight; discontinue immediately if  evidence of corneal epithelial breakdown  Side-effects headache; punctuate keratitis, blurred  vision, eye pruritus, dry eye; less commonly nausea,  dry mouth; iritis; keratitis, comeal deposits, choroidal  effusion, allergic conjunctivitis, increased lacrimation,  photophobia, conjunctival hyperaemia   Ophthalmic suspension (= eye drops), nepafenac  1 mg/mL, net price 5 mL= £14.92   Pegaptanib and ranibizumab are vascular endothelial  growth factor inhibitors licensed for the treatment of  neovascular (wet) age-related macular degeneration;  they are given by intravitreal injection by specialists  experienced in the management of this condition.   Ranibizumab and pegaptanib for the  treatment of wet age-related macular  degeneration (August 2008)   Ranibizumab is recommended for the treatment of  wet age-related macular degeneration if all of the  following apply:   • the best corrected visual acuity is between 6/12  and 6/96;   • there is no permanent structural damage to the  central fovea;   • the lesion size is less than or equal to 12 disc  areas in greatest linear dimension;   • the cost of ranibizumab beyond 14 injections is  met by the manufacturer.   Ranibizumab should only be continued in patients  who maintain adequate response to therapy.  Pegaptanib is not recommended for the treatment of  wet age-related macular degeneration; patients cur-  rently receiving pegaptanib for any lesion type can  continue therapy until they and their specialist con-  sider it appropriate to stop.    Verteporfin is licensed for use in the photodynamic  treatment of age-related macular degeneration asso-  ciated with predominantly classic subfoveal choroidal  neovascularisation or with pathological myopia (see  NICE guidance below). Following intravenous infusion,  verteporfin is activated by local irradiation using non-  thermal red light to produce cytotoxic derivatives. Only  specialists experienced in the management of these  conditions should use it.   Photodynamic therapy for wet age-related  macular degeneration (September 2003)  Photodynamic therapy is recommended for wet age-  related macular degeneration with a confirmed diag-  nosis of classic (no occult) subfoveal choroidal neo-  vascularisation and best-corrected visual acuity of  6/60 or better.   Photodynamic therapy is not recommended for wet  age-related macular degeneration with predomi-  nantly classic but partly occult subfoveal choroidal  neovascularisation except in clinical studies.    Side-effects rhinorrhoea; headache; eye pain, anterior  chamber inflammation, raised intra-ocular pressure,  punctate keratitis, vitreous floaters, cataract, con-  junctival and retinal haemorrhage, local oedema,  conjunctivitis, corneal dystrophy, dry eye,  endophthalmitis, eye discharge, eye irritation, macu-  lar degeneration, mydriasis, periorbital haematoma,  photophobia, flashing lights, vitreous disorders; less  commonly vomiting, dyspepsia, palpitation, chest  pain, hypertension, aortic aneurysm, influenza-like  symptoms, nightmares, depression, back pain, asthe-  nopia, blepharitis, corneal deposits, vitreous  haemorrhage, chalazion, retinal exudates, eyelid pto-  sis, decreased intra-ocular pressure, injection-site  reactions, retinal detachment, occlusion of retinal  blood vessels, ectropion, eye movement disorder,  pupillary disorder, iritis, optic nerve cupping, naso-  pharyngitis, deafness, vertigo, eczema, changes in hair  colour, rash, pruritus, night sweats  Dose   • By intravitreal injection, 300 micrograms once every 6  weeks into the affected eye   Solution for intravitreal injection, pegaptanib (as  sodium salt), net price 300-microgram vial = £514.00   Side-effects nausea; headache; nasopharyngitis,  cough; anxiety; anaemia; arthralgia; raised intra-ocu-  lar pressure, visual disturbance, conjuctival retinal  and vitreous disorders, eye inflammation and irrita-  tion, eye haemorrhage; allergic skin reactions; less  commonly atrial fibrillation, blindness, corneal disor-  ders, iris adhesion, injection site reactions  Dose   • By intravitreal injection, initially 500 micrograms once  a month for 3 months into the affected eye, thereafter  monitor visual acuity once a month; if necessary  subsequent doses may be given at least 1 month apart  Note For further information on administration, consult  product literature   Antimicrobial eye drops should be administered into the  affected eye for 3 days before and 3 days after each injection   Contra-indications acute porphyria  Hepatic impairment use with caution in moderate  impairment; avoid in severe impairment  Pregnancy manufacturer advises use only if potential  benefit outweighs risk (teratogenic in animal studies)  Breast-feeding no information available — manufac-  turer advises avoid breast-feeding for 48 hours after  administration   Side-effects nausea, hypercholesterolaemia, malaise,  back pain, photosensitivity, visual disturbances  (including reduced visual acuity, flashing lights,  visual-field defects), less commonly hypertension,  hyperaesthesia, pyrexia, retinal detachment,  haemorrhage, rarely retinal or choroidal vessel non-  perfusion; also reported chest pain, myocardial  infarction  Dose    used in conjunction with contact lens wear; oily eye  drops should also be avoided.   Many drugs given systemically can also have adverse  effects on contact lens wear. These include oral contra-  ceptives (particularly those with a higher oestrogen  content), drugs which reduce blink rate (e.g. anxiolytics,  hypnotics, antihistamines, and muscle relaxants), drugs  which reduce lacrimation (e.g. antihistamines, anti-  muscarinics, phenothiazines and related drugs, some  beta-blockers, diuretics, and tricyclic antidepressants),  and drugs which increase lacrimation (including ephe-  drine and hydralazine). Other drugs that may affect  contact lens wear are isotretinoin (can cause conjuncti-  val inflammation), aspirin (salicylic acid appears in tears  and can be absorbed by contact lenses — leading to  irritation), and rifampicin and sulfasalazine (can disco-  lour lenses).    For cosmetic reasons many people prefer to wear con-  tact lenses rather than spectacles; contact lenses are  also sometimes required for medical indications. Visual  defects are corrected by either rigid (‘hard’ or gas  permeable) lenses or soft (hydrogel or silicone hydrogel)  lenses; soft lenses are the most popular type, because  they are initially the most comfortable, but they may not  give the best vision. Lenses should usually be worn for a  >, specified number of hours each day and removed for  ^ sleeping. Continuous (extended) wear involves much   D greater risks to eye health and is not generally recom-  mended except where medically indicated.   Contact lenses require meticulous care. Poor compli-  ance with directions for use, and with daily cleaning and  disinfection, can result in complications including ulcer-  ative keratitis or conjunctivitis. One-day disposable  lenses, which are worn only once and therefore require  no disinfection or cleaning, are becoming increasingly  popular.   Acanthamoeba keratitis, a painful and sight-threatening  condition, is associated with ineffective lens cleaning  and disinfection, the use of contaminated lens cases, or  tap water coming into contact with the lenses. The  condition is especially associated with the use of soft  lenses (including frequently replaced lenses) and should  be treated by specialists.    Contact lenses and drug treatment Special care is  required in prescribing eye preparations for contact lens  users. Some drugs and preservatives in eye preparations  can accumulate in hydrogel lenses and may induce toxic  reactions. Therefore, unless medically indicated, the  lenses should be removed before drop instillation and  not worn during the period of treatment. Alternatively,  unpreserved drops can be used. Eye drops may, how-  ever, be instilled while patients are wearing rigid corneal  contact lenses. Ointment preparations should never be    This chapter also includes advice on the drug man-  agement of the following:  allergic rhinitis, p. 689  nasal polyps, p. 689  oropharyngeal infections, p. 695  periodontitis, p. 693    Otitis externa is an inflammatory reaction of the meatal  skin. It is important to exclude an underlying chronic  otitis media before treatment is commenced. Many  cases recover after thorough cleansing of the external  ear canal by suction or dry mopping. A frequent pro-  blem in resistant cases is the difficulty in applying  lotions and ointments satisfactorily to the relatively  inaccessible affected skin. The most effective method  is to introduce a ribbon gauze dressing or sponge wick  soaked with corticosteroid ear drops or with an astrin-  gent such as aluminium acetate solution. When this is  not practical, the ear should be gently cleansed with a  probe covered in cotton wool and the patient encour-  aged to lie with the affected ear uppermost for ten  minutes after the canal has been filled with a liberal  quantity of the appropriate solution.    If infection is present, a topical anti-infective which is  not used systemically (such as neomycin or clioquinol)  may be used, but for only about a week as excessive use  may result in fungal infections; these may be difficult to  treat and require expert advice. Sensitivity to the anti-  infective or solvent may occur and resistance to anti-  bacterials is a possibility with prolonged use. Aluminium  acetate ear drops are also effective against bacterial  infection and inflammation of the ear. Chlorampheni-  col may be used but the ear drops contain propylene  glycol and cause hypersensitivity reactions in about  10% of patients. Solutions containing an anti-infective  and a corticosteroid (such as Locorten-Vioform ®) are  used for treating cases where infection is present with  inflammation and eczema.   In view of reports of ototoxicity in patients with a  perforated tympanic membrane (eardrum), manufac-  turers contra-indicate treatment with a topical amino-  glycoside antibiotic in those with a tympanic perfora-  tion. However, many specialists do use these drops  cautiously in the presence of a perforation in patients  with otitis media (section 12.1.2) and when other mea-  sures have failed for otitis externa.    A solution of acetic acid 2% acts as an antifungal and  antibacterial in the external ear canal. It may be used to  treat mild otitis externa but in severe cases an anti-  inflammatory preparation with or without an anti-infec-  tive drug is required. A proprietary preparation contain-  ing acetic acid 2% [EarCalm® spray) is on sale to the  public.   For severe pain associated with otitis externa, a simple  analgesic, such as paracetamol (section 4.7.1) or ibu-    profen (section 10.1.1), can be used. A systemic anti-  bacterial (Table 1, section 5.1) can be used if there is  spreading cellulitis or if the patient is systemically  unwell. When a resistant staphylococcal infection (a  boil) is present in the external auditory meatus, fluclox-  acillin is the drug of choice; ciprofloxacin (or an  aminoglycoside) may be needed in pseudomonal infec-  tions which may occur if the patient has diabetes or is  immunocompromised.   The skin of the pinna adjacent to the ear canal is often  affected by eczema. Topical corticosteroid creams and  ointments (section 13.4) are then required, but pro-  longed use should be avoided.   Drops (for ear, eye, or nose), betamethasone sodium  phosphate 0.1%. Net price 5mL = £1.02; 10 mL =  £1.16   Excipients include benzalkonium chloride, disodium edetate  Dose ear, apply 2-3 drops every 3-4 hours; reduce frequency  when relief obtained; eye, section 11.4.1; nose, section 12.2.1   4With antibacterial  Betnesol-N® (UCB Pharma) (Ml  Drops (for ear, eye, or nose), betamethasone sodium  phosphate 0.1%, neomycin sulphate 0.5%. Net price  10 mL = £2.30   Excipients include benzalkonium chloride, disodium edetate  Dose ear, apply 2-3 drops 3-4 times daily; eye, section 11.4.1;  nose, section 12.2.3   • Insert into meatus or apply on a ribbon gauze dressing  or sponge wick which should be kept saturated with  the ear drops    Topical corticosteroids are used to treat inflammation  and eczema in otitis externa.   Cautions Prolonged use of topical corticosteroid ear  preparations should be avoided.    Contra-indications Corticosteroid ear preparations  should be avoided in the presence of an untreated ear  infection. If infection is present, the corticosteroid  should be used in combination with a suitable anti-  infective (see notes above).   Betnesol® (UCB Pharma) (Ml  Drops (for ear, eye, or nose), betamethasone sodium  phosphate 0.1%. Net price 10 mL = £2.23   Excipients include benzalkonium chloride, disodium edetate  Dose ear, apply 2-3 drops every 2-3 hours; reduce frequency  when relief obtained; eye, section 11.4.1; nose, section 12.2.1   4With antibacterial  Otomize® (GSK Consumer Healthcare) [Ml  Ear spray, dexamethasone 0.1%, neomycin sulphate  3250 units/mL, glacial acetic acid 2%. Net price 5-mL  pump-action aerosol unit = £3.71   Sofradex® (Sanofi-Aventis) (Ml  Drops (for ear or eye), dexamethasone (as sodium  metasulphobenzoate) 0.05%, framycetin sulphate  0.5%, gramicidin 0.005%. Net price 10 mL = £6.25   Dose ear, apply 2-3 drops 3-4 times daily; eye, section 11.4.1   Dose ADULT and CHILD over 2 years apply 2-3 drops into the ear    4With antibacterial  Gentisone® HC (Amdipharm) (Ml  Ear drops, hydrocortisone acetate 1%, gentamicin  0.3% (as sulphate). Net price 10 mL = £3.92   Excipients include benzalkonium chloride, disodium edetate  Dose ear, apply 2-4 drops 3-4 times daily and at night   Ear drops, hydrocortisone 1%, neomycin sulphate  3400 units, polymyxin B sulphate lOOOOunits/mL.  Net price 5mL = £2.00; 10 mL = £4.00   Dose ADULT and CHILD over 3 years, ear, apply 3 drops 3-4 times  daily   Excipients include benzalkonium chloride, disodium edetate  Dose ear, apply 2-3 drops every 2-3 hours; reduce frequency  when relief obtained; eye, section 11.4.1   Drops (for ear or eye), prednisolone sodium phos-  phate 0.5%, neomycin sulphate 0.5%. Net price 10 mL  = £2.27   Excipients include benzalkonium chloride, disodium edetate  Dose ear, apply 2-3 drops 3-4 times daily; eye, section 11.4.1   Chloramphenicol (Non-proprietary) (S  Ear drops, chloramphenicol in propylene glycol, net  price 5%, 10 mL = £6.22; 10%, 10 mL = £5.62  Dose ear, apply 2-3 drops 2-3 times daily   Indications mild bacterial or fungal infections in otitis  externa (see notes above)   Cautions avoid prolonged use (see notes above);  manufacturer advises avoid in perforated tympanic  membrane (but used by specialists for short periods)  Side-effects local sensitivity; stains skin and clothing   Solution, clotrimazole 1% in polyethylene glycol 400  (macrogol 400). Net price 20 mL = £2.43  Dose ear, apply 2-3 times daily continuing for at least 14 days  after disappearance of infection; skin, section 13.10.2   Cautions avoid prolonged use (see notes above)  Contra-indications perforated tympanic membrane  (see p. 685)   Cautions avoid prolonged use (see notes above)  Contra-indications perforated tympanic membrane  (but see also p. 685 and section 12.1.2)   Dose ear, apply 2-3 drops 3-4 times daily and at night; eye,   Cautions avoid prolonged use (see notes above)  Contra-indications perforated tympanic membrane  (see p. 685)    Acute otitis media Acute otitis media is the com-  monest cause of severe aural pain in small children.  Many infections, especially those accompanying coryza,    are caused by viruses. Most uncomplicated cases  resolve without antibacterial treatment and a simple  analgesic, such as paracetamol, may be sufficient. In  children without systemic features, a systemic anti-  bacterial (Table 1, section 5.1) may be started after  72 hours if there is no improvement, or earlier if there is  deterioration, if the patient is systemically unwell, if the  patient is at high risk of serious complications (e.g. in  immunosuppression, cystic fibrosis), if mastoiditis is  present, or in children under 2 years of age with bilateral  otitis media. Perforation of the tympanic membrane in  patients with acute otitis media usually heals sponta-  neously without treatment; if there is no improvement,  e.g. pain or discharge persists, a systemic antibacterial  (Table 1, section 5.1) can be given. Topical treatment of  acute otitis media is ineffective and there is no place for  drops containing a local anaesthetic.   Otitis media with effusion Otitis media with effu-  sion (‘glue ear’) occurs in about 10% of children and in  90% of children with cleft palates. Systemic antibac-  terials are not usually required. If ‘glue ear’ persists for  more than a month or two, the child should be referred  for assessment and follow up because of the risk of long-  term hearing impairment which can delay language  development. Untreated or resistant glue ear may be  responsible for some types of chronic otitis media.   Chronic otitis media Opportunistic organisms are  often present in the debris, keratin, and necrotic bone of  the middle ear and mastoid in patients with chronic  otitis media. The mainstay of treatment is thorough  cleansing with aural microsuction which may comple-  tely resolve long-standing infection. Local cleansing of  the meatal and middle ear may be followed by treatment  with a sponge wick or ribbon gauze dressing soaked  with corticosteroid ear drops or with an astringent such  as aluminium acetate solution; this is particularly ben-  eficial for discharging ears or infections of the mastoid  cavity. An antibacterial ear ointment may also be used.  Acute exacerbations of chronic infection may also  require systemic treatment with amoxicillin (or erythro-  mycin if penicillin-allergic); treatment is adjusted  according to the results of sensitivity testing. Parenteral  antibacterials are required if Pseudomonas aeruginosa  and Proteus spp. are present.   Manufacturers contra-indicate topical treatment with  ototoxic antibacterials in the presence of a perforation  (section 12.1.1). However, many specialists use ear  drops containing aminoglycosides (e.g. neomycin) or  polymyxins if the otitis media has failed to settle with  systemic antibacterials; it is considered that the pus in  the middle ear associated with otitis media carries a  higher risk of ototoxicity than the drops themselves.  Ciprofloxacin or ofloxacin ear drops [both unlicensed;  available from ‘special-order’ manufacturers or specia-  list importing companies, see p. 988] or eye drops used  in the ear [unlicensed indication] are an effective alter-  native to aminoglycoside ear drops for chronic otitis  media in patients with perforation of the tympanic  membrane.   Wax is a normal bodily secretion which provides a  protective film on the meatal skin and need only be  removed if it causes hearing loss or interferes with a  proper view of the ear drum.   Wax can be softened using simple remedies such as  olive oil ear drops or almond oil ear drops; sodium  bicarbonate ear drops are also effective, but may cause  dryness of the ear canal. If the wax is hard and  impacted, the drops can be used twice daily for several  days and this may reduce the need for mechanical  removal of the wax. The patient should lie with the  affected ear uppermost for 5 to 10 minutes after a  generous amount of the softening remedy has been  introduced into the ear. Some proprietary preparations  containing organic solvents can irritate the meatal skin,  and in most cases the simple remedies indicated above  are just as effective and less likely to cause irritation.  Docusate sodium or urea-hydrogen peroxide are ingre-  dients in a number of proprietary preparations for soft-  ening ear wax.   If necessary, wax may be removed by irrigation with  water (warmed to body temperature). Ear irrigation is  generally best avoided in young children, in patients  unable to co-operate with the procedure, in those with  otitis media in the last six weeks, in otitis externa, in  patients with cleft palate, a history of ear drum perfora-  tion, or previous ear surgery. A person who has hearing  in one ear only should not have that ear irrigated  because even a very slight risk of damage is unaccep-  table in this situation.   Ear drops, almond oil in a suitable container  Allow to warm to room temperature before use   Ear drops, olive oil in a suitable container  Allow to warm to room temperature before use   Ear drops, sodium bicarbonate 5%, net price 10 mL =  £1.25   Ear drops, chlorobutanol 5%, arachis (peanut) oil  57.3%. Net price 11 mL = £1.76   Drugs used in nasal allergy  Topical nasal decongestants  Nasal preparations for infection   Rhinitis is often self-limiting but bacterial sinusitis may  require treatment with antibacterials (Table 1, section  5.1). There are few indications for nasal sprays and  drops except in allergic rhinitis and perennial rhinitis  (section 12.2.1). Many nasal preparations contain sym-  pathomimetic drugs which may damage the nasal cilia    (section 12.2.2). Sodium chloride 0.9% solution maybe  used as a douche or ‘sniff following endonasal surgery.   Nasal polyps Short-term use of corticosteroid nasal  drops helps to shrink nasal polyps; to be effective, the  drops must be administered with the patient in the ‘head  down’ position. A short course of a systemic cortico-  steroid (section 6.3.2) may be required initially to shrink  large polyps. A corticosteroid nasal spray can be used to  maintain the reduction in swelling and also for the initial  treatment of small polyps.   Nasal spray, azelastine hydrochloride 140 micr-  ograms (0.14mL)/metered spray. Net price 22 mL  (157-spray unit with metered pump) = £10.45   Dose ADULT and CHILD over 5 years, 140 micrograms (1 spray)  into each nostril twice daily   Note Preparations of azelastine hydrochloride can be sold to the  public for nasal administration in aqueous form (other than by  aerosol) if supplied for the treatment of seasonal allergic rhinitis or  perennial allergic rhinitis in adults and children over 5 years,  subject to max. single dose of 140 micrograms per nostril, max.  daily dose of 280 micrograms per nostril, and a pack size limit of  36 doses   Mild allergic rhinitis is controlled by antihistamines  (see also section 3.4.1) or topical nasal corticosteroids;  systemic nasal decongestants are of doubtful value  (section 3.10). Topical nasal decongestants can be  used for a short period to relieve congestion and allow  penetration of a topical nasal corticosteroid.   More persistent symptoms and nasal congestion can be  relieved by topical nasal corticosteroids; cromoglicate  (cromoglycate) is an alternative, but may be less effec-  tive. The topical antihistamine azelastine is useful for  controlling breakthrough symptoms in allergic rhinitis.  Topical antihistamines are considered less effective than  topical corticosteroids but probably more effective than  cromoglicate. In seasonal allergic rhinitis (e.g. hay  fever), treatment should begin 2 to 3 weeks before the  season commences and may have to be continued for  several months; continuous treatment may be required  for years in perennial rhinitis.   Montelukast (section 3.3.2) is less effective than topical  nasal corticosteroids; montelukast can be used in  patients with seasonal allergic rhinitis and concomitant  asthma.   Sometimes allergic rhinitis is accompanied by vaso-  motor rhinitis. In this situation, the addition of topical  nasal ipratropium bromide (section 12.2.2) can reduce  watery rhinorrhoea.   Very disabling symptoms occasionally justify the use of  systemic corticosteroids for short periods (section  6.3), for example, in students taking important exam-  inations. They may also be used at the beginning of a  course of treatment with a corticosteroid spray to  relieve severe mucosal oedema and allow the spray to  penetrate the nasal cavity.   Pregnancy If a pregnant woman cannot tolerate the  symptoms of allergic rhinitis, treatment with nasal  beclometasone, budesonide, fluticasone, or sodium cro-  moglicate may be considered.   Nasal preparations containing corticosteroids (beclome-  tasone, betamethasone, budesonide, flunisolide, flutica-  sone, mometasone, and triamcinolone) have a useful  role in the prophylaxis and treatment of allergic rhinitis  (see notes above).   Cautions Corticosteroid nasal preparations should be  avoided in the presence of untreated nasal infections,  and also after nasal surgery (until healing has occurred);  they should also be avoided in pulmonary tuberculosis.  Patients transferred from systemic corticosteroids may  experience exacerbation of some symptoms. Systemic  absorption may follow nasal administration particularly  if high doses are used or if treatment is prolonged; for  cautions and side-effects of systemic corticosteroids,  see section 6.3.2. The risk of systemic effects may be  greater with nasal drops than with nasal sprays; drops  are administered incorrectly more often than sprays.  The height of children receiving prolonged treatment  with nasal corticosteroids should be monitored; if  growth is slowed, referral to a paediatrician should be  considered.    Side-effects Local side-effects include dryness, irrita-  tion of nose and throat, and epistaxis. Nasal ulceration  has been reported, but occurs commonly with nasal  preparations containing fluticasone furoate or mometa-  sone furoate. Nasal septal perforation (usually following  nasal surgery) occurs very rarely. Raised intra-ocular  pressure or glaucoma may occur rarely. Headache,  smell and taste disturbances may also occur. Hyper-  sensitivity reactions, including bronchospasm, have  been reported.   • ADULT and CHILD over 6 years, 100 micrograms (2  sprays) into each nostril twice daily; max. total  400 micrograms (8 sprays) daily; when symptoms  controlled, dose reduced to 50 micrograms (1 spray)  into each nostril twice daily    Beclometasone (Non-proprietary) [Ml  Nasal spray, beclometasone dipropionate 50 micr-  ograms/metered spray. Net price 200-spray unit =  £2.52   1 . Can be sold to the public for nasal administration (other than  by aerosol) if supplied for the prevention and treatment of  allergic rhinitis in adults over 18 years subject to max. single  dose of 100 micrograms per nostril, max. daily dose of  200 micrograms per nostril for max. 3 months, and a pack  size of 20 mg   Nasal spray (aqueous suspension), beclometasone  dipropionate 50 micrograms/metered spray. Net price  200-spray unit with applicator = £2.19   Betnesol® (UCB Pharma) (Ml  Drops (for ear, eye, or nose), betamethasone sodium  phosphate 0.1%, net price 10 mL = £2.23   Excipients include benzalkonium chloride, disodium edetate  Dose nose, 2-3 drops into each nostril 2-3 times daily; ear,  section 12.1.1; eye, section 11.4.1   Vistamethasone® (Martindale) [Ml  Drops (for ear, eye, or nose), betamethasone sodium  phosphate 0.1%. Net price 5mL = £1.02, 10 mL =  £1.16   Excipients include benzalkonium chloride, disodium edetate  Dose nose, 2-3 drops into each nostril twice daily; ear, section  12.1.1; eye, section 11.4.1   Indications prophylaxis and treatment of allergic and  vasomotor rhinitis; nasal polyps  Cautions see notes above; interactions: Appendix 1  (corticosteroids)    budesonide (Non-proprietary) (Ml  Nasal spray, budesonide 100 micrograms/metered  spray, net price 100-spray unit = £5.90  Dose rhinitis, ADULT and CHILD over 12 years, 200 micrograms (2  sprays) into each nostril once daily in the morning or 100 micr-  ograms (1 spray) into each nostril twice daily; when control  achieved reduce to 100 micrograms (1 spray) into each nostril  once daily   Nasal polyps, ADULT and CHILD over 12 years, 100 micrograms (1  spray) into each nostril twice daily for up to 3 months   1 . Can be sold to the public for nasal administration (other than  by aerosol) if supplied for the prevention and treatment of  seasonal allergic rhinitis in adults over 18 years subject to  max. single dose of 200 micrograms per nostril, max. daily  dose of 200 micrograms per nostril for max. period of 3  months, and a pack size of 10 mg   Rhinocort Aqua® (AstraZeneca) (MI  Nasal spray, budesonide 64 micrograms /metered  spray. Net price 120-spray unit = £2.49   Excipients include disodium edetate, polysorbate 80, potassium sorbate  Dose rhinitis, ADULT and CHILD over 12 years, 128 micrograms (2  sprays) into each nostril once daily in the morning or 64 micr-  ograms (1 spray) into each nostril twice daily; when control    achieved reduce to 64 micrograms (1 spray) into each nostril once  daily; max. duration of treatment 3 months  Nasal polyps, ADULT and CHILD over 12 years, 64 micrograms (1  spray) into each nostril twice daily for up to 3 months   Excipients include benzalkonium chloride, butylated hydroxytoluene,  disodium edetate, polysorbate 20, propylene glycol  Dose ADULT, 50 micrograms (2 sprays) into each nostril twice  daily, increased if necessary to max. 3 times daily then reduced for  maintenance; CHILD 5-14 years initially 25 micrograms (1 spray)  into each nostril up to 3 times daily   Indications prophylaxis and treatment of allergic  rhinitis and perennial rhinitis; nasal polyps  Cautions see notes above; interactions: Appendix 1  (corticosteroids)   • Rhinitis, 100 micrograms (2 sprays) into each nostril  once daily, preferably in the morning, increased to  max. twice daily if required; when control achieved  reduce to 50 micrograms (1 spray) into each nostril  once daily; CHILD 4-11 years, 50 micrograms (1 spray)  into each nostril once daily, preferably in the morning,  increased to max. twice daily if required   Excipients include benzalkonium chloride, polysorbate 80  Note Preparations of fluticasone propionate can be sold to  the public for nasal administration (other than by pressurised  nasal spray) if supplied for the prevention and treatment of  allergic rhinitis in adults over 18 years, subject to max. single  dose of 100 micrograms per nostril, max. daily dose of  200 micrograms per nostril for max. 3 months, and a pack  size of 3 mg   200 micrograms (approx. 6 drops) into each nostril once or twice  daily; consider alternative treatment if no improvement after 4-6  weeks   Aqueous nasal spray fluticasone propionate  50 micrograms /metered spray. Net price 150-spray  unit = £8.41   Nasal spray, fluticasone furoate 27.5 micrograms/  metered spray, net price 120-spray unit = £6.44   Dose prophylaxis and treatment of allergic rhinitis, ADULT and  CHILD over 12 years, 55 micrograms (2 sprays) into each nostril  once daily; when control achieved reduce to minimum effective  dose, 27.5 micrograms (1 spray) into each nostril once daily may  be sufficient; CHILD 6-12 years, 27.5 micrograms (1 spray) into  each nostril once daily, increased if necessary to 55 micrograms (2  sprays) into each nostril once daily; when control achieved reduce  to 27.5 micrograms (1 spray) into each nostril once daily   4% aqueous nasal spray, sodium cromoglicate 4%  (5.2 mg/spray). Net price 22 mL (150-spray unit with  pump) = £17.07   Excipients include benzalkonium chloride, disodium edetate  Dose ADULT and CHILD, 1 spray into each nostril 2-4 times daily   Nasal spray, sodium cromoglicate 2%. Net price  15 mL (approx. 110-spray unit) = £11.60   Excipients include benzalkonium chloride, edetic acid, polysorbate 80  Dose ADULT and CHILD, 1 spray into each nostril 4-6 times daily   Nasonex® (Schering-Plough) (Ml  Nasal spray, mometasone furoate 50 micrograms/  metered spray. Net price 140-spray unit = £7.68   Excipients include benzalkonium chloride, polysorbate 80  Dose prophylaxis and treatment of allergic rhinitis, ADULT and  CHILD over 12 years, 100 micrograms (2 sprays) into each nostril  once daily, increased if necessary to max. 200 micrograms (4  sprays) into each nostril once daily; when control achieved reduce  to 50 micrograms (1 spray) into each nostril once daily; CHILD 6-  11 years, 50 micrograms (1 spray) into each nostril once daily  Nasal polyps, ADULT over 18 years, 100 micrograms (2 sprays) into  each nostril once daily, increased if necessary after 5-6 weeks to  100 micrograms (2 sprays) into each nostril twice daily (consider  alternative treatment if no improvement after further 5-6 weeks);  reduce to the lowest effective dose when control achieved   Nasacort® (Sanofi-Aventis) Ml  Aqueous nasal spray, triamcinolone acetonide  55 micrograms /metered spray. Net price 120-spray  unit = £7.39   Dose ADULT and CHILD over 12 years, 110 micrograms (2 sprays)  into each nostril once daily; when control achieved, reduce to  55 micrograms (1 spray) into each nostril once daily; CHILD 6-12  years, 55 micrograms (1 spray) into each nostril once daily,  increased if necessary to 110 micrograms (2 sprays) into each  nostril once daily; when control achieved, reduce to 55 micr-  ograms (1 spray) into each nostril once daily; max. duration of  treatment 3 months; CHILD 2-6 years see BNF for Children  Note Preparations of triamcinolone acetonide can be sold to the  public for nasal administration as a non-pressurised nasal spray if  supplied for the symptomatic treatment of seasonal allergic  rhinitis in adults over 18 years, subject to max. daily dose of  110 micrograms per nostril for max. 3 months, and a pack size of  3.575 mg   The nasal mucosa is sensitive to changes in atmospheric  temperature and humidity and these alone may cause  slight nasal congestion. The nose and nasal sinuses  produce a litre of mucus in 24 hours and much of this  finds its way silently into the stomach via the nasophar-  ynx. Slight changes in the nasal airway, accompanied by  an awareness of mucus passing along the nasopharynx  causes some patients to be inaccurately diagnosed as  suffering from chronic sinusitis. These symptoms are  particularly noticeable in the later stages of the common  cold. Sodium chloride 0.9% given as nasal drops or  spray may relieve nasal congestion by helping to liquefy  mucous secretions.   Inhalation of warm moist air is useful in the treatment  of symptoms of acute infective conditions. The addition  of volatile substances such as menthol and eucalyptus  may encourage the use of warm moist air (section 3.8).    Symptoms of nasal congestion associated with vaso-  motor rhinitis and the common cold can be relieved by  the short-term use (usually not longer than 7 days) of  decongestant nasal drops and sprays. These all contain  sympathomimetic drugs which exert their effect by  vasoconstriction of the mucosal blood vessels which  in turn reduces oedema of the nasal mucosa. They are of  limited value because they can give rise to a rebound  congestion (rhinitis medicamentosa) on withdrawal, due  to a secondary vasodilatation with a subsequent tem-  porary increase in nasal congestion. This in turn tempts  the further use of the decongestant, leading to a vicious  cycle of events. Ephedrine nasal drops is the safest  sympathomimetic preparation and can give relief for  several hours. The more potent sympathomimetic drugs  oxymetazoline and xylometazoline are more likely to  cause a rebound effect. Sympathomimetics may cause a  hypertensive crisis if used during treatment with a  monoamine-oxidase inhibitor including moclobemide.   The CHM/MHRA has stated that non-prescription  cough and cold medicines containing ephedrine, oxy-  metazoline, or xylometazoline can be considered for up  to 5 days in children aged 6-12 years after basic  principles of best care have been tried; these medicines  should not be used in children under 6 years of age  (section 3.9.1).    Non-allergic watery rhinorrhoea often responds well to  treatment with the antimuscarinic ipratropium  bromide.    Sinusitis and oral pain Sinusitis affecting the max-  illary antrum can cause pain in the upper jaw. Where    this is associated with blockage of the opening from the  sinus into the nasal cavity, it may be helpful to relieve  the congestion with inhalation of warm moist air (sec-  tion 3.8) or with ephedrine nasal drops (see above).  For antibacterial treatment of sinusitis, see Table 1,  section 5.1.    Nasal spray, xylometazoline hydrochloride 0.1%, net  price 10 mL = £1.91   Dose 1 spray into each nostril 1-3 times daily when required;  max. duration 7 days; not recommended for children under 12  years   Indications nasal congestion  Cautions see section 3. 1.1.2 and notes above; also  avoid excessive or prolonged use; interactions:  Appendix 1 (sympathomimetics)   Pregnancy see section 3. 1.1.2  Breast-feeding see section 3. 1.1. 2  Side-effects local irritation, nausea, headache; after  excessive use tolerance with diminished effect,  rebound congestion; cardiovascular effects also  reported  Dose   Nasal drops, ephedrine hydrochloride 0.5%, net price  10 mL = £1.39; 1%, 10 mL = £1.63  Note The BP directs that if no strength is specified 0.5% drops  should be supplied   Dose ADULT and CHILD over 12 years, 1-2 drops into each nostril  up to 3 or 4 times daily when required, max. duration 7 days;  CHILD under 12 years see BNF for Children  Dental prescribing on NHS Ephedrine nasal drops may be  prescribed   1. Can be sold to the public provided no more than 180 mg of  ephedrine base (or salts) are supplied at one time, and  pseudoephedrine salts are not supplied at the same time; for  conditions that apply to supplies made at the request of a  patient, see Medicines, Ethics and Practice, No. 34, London,  Pharmaceutical Press, 2010 (and subsequent editions)   Pregnancy manufacturer advises avoid  Side-effects see under Ephedrine Hydrochloride and  notes above; in small children, also restlessness, sleep  disturbances, and hallucinations (discontinue treat-  ment)   Nasal drops, xylometazoline hydrochloride 0.1%, net  price 10 mL = £1.91   Dose 2-3 drops into each nostril 2-3 times daily when required;  max. duration 7 days; not recommended for children under 12  years   Paediatric nasal drops, xylometazoline hydro-  chloride 0.05%, net price 10 mL = £1.59  Dose CHILD 6-12 years 1-2 drops into each nostril 1-2 times  daily when required; max. duration 5 days  Brands include Otradrops ® , Otrivine®   Side-effects epistaxis, nasal dryness, and irritation;  less frequently nausea, headache, and pharyngitis;  very rarely antimuscarinic effects such as gastro-  intestinal motility disturbances, palpitations, and  urinary retention  Dose   • ADULT and CHILD over 12 years, 42 micrograms (2  sprays) into each nostril 2-3 times daily   Rinatec® (Boehringer Ingelheim) (Ml  Nasal spray 0.03%, ipratropium bromide 21 micr-  ograms/metered spray. Net price 180-dose unit =  £3.99   There is no evidence that topical anti-infective nasal  preparations have any therapeutic value in rhinitis or  sinusitis; for elimination of nasal staphylococci, see  below.   Drops (for ear, eye, or nose), betamethasone sodium  phosphate 0.1%, neomycin sulphate 0.5%. Net price  10 mL = £2.30   Excipients include benzalkonium chloride, disodium edetate  Dose nose, 2-3 drops into each nostril 2-3 times daily; eye,  section 11.4.1; ear, section 12.1.1   Elimination of organisms such as staphylococci from the  nasal vestibule can be achieved by the use of a cream  containing chlorhexidine and neomycin ( Naseptin ®),  but re-colonisation frequently occurs. Coagulase-posi-  tive staphylococci are present in the noses of 40% of the  population.   A nasal ointment containing mupirocin is also avail-  able; it should probably be held in reserve for resistant  cases. In hospital or in care establishments, mupirocin  nasal ointment should be reserved for the eradication  (in both patients and staff) of nasal carriage of meticillin-  resistant Staphylococcus aureus (MRS A). The ointment  should be applied 3 times daily for 5 days and a sample  taken 2 days after treatment to confirm eradication. The  course may be repeated if the sample is positive (and the  throat is not colonised). To avoid the development of  resistance, the treatment course should not exceed 7  days and the course should not be repeated on more    than one occasion. If the MRSA strain is mupirocin-  resistant or does not respond after 2 courses, consider  alternative products such as chlorhexidine and neo-  mycin cream.   Nasal ointment, mupirocin 2% (as calcium salt) in  white soft paraffin basis. Net price 3 g = £5.80  Dose for eradication of nasal carriage of staphylococci, including  meticillin-resistant Staphylococcus aureus (MRSA), apply 2-3  times daily to the inner surface of each nostril   Cream, chlorhexidine hydrochloride 0.1%, neomycin  sulphate 0.5%, net price 15 g = £1.90   Excipients include arachis (peanut) oil, cetostearyl alcohol  Dose for eradication of nasal carriage of staphylococci, apply to  nostrils 4 times daily for 10 days; for preventing nasal carriage of  staphylococci, apply to nostrils twice daily   Ulceration of the oral mucosa may be caused by trauma  (physical or chemical), recurrent aphthae, infections,  carcinoma, dermatological disorders, nutritional defi-  ciencies, gastro-intestinal disease, haematopoietic dis-  orders, and drug therapy (see also Chemotherapy-  induced mucositis and myelosuppression, section 8.1).  It is important to establish the diagnosis in each case as  the majority of these lesions require specific manage-  ment in addition to local treatment. Local treatment  aims to protect the ulcerated area, to relieve pain, to  reduce inflammation, or to control secondary infection.  Patients with an unexplained mouth ulcer of more than  3 weeks’ duration require urgent referral to hospital to  exclude oral cancer.   Simple mouthwashes A saline mouthwash (section  12.3.4) may relieve the pain of traumatic ulceration. The  mouthwash is made up with warm water and used at  frequent intervals until the discomfort and swelling  subsides.   mucosa, it is difficult to apply it effectively to the tongue  and oropharynx.    Corticosteroids Topical corticosteroid therapy may  be used for some forms of oral ulceration. In the case of  aphthous ulcers it is most effective if applied in the  ‘prodromal’ phase.   Thrush or other types of candidiasis are recognised  complications of corticosteroid treatment.   Hydrocortisone oromucosal tablets are allowed to  dissolve next to an ulcer and are useful in recurrent  aphthae and erosive lichenoid lesions.   Beclometasone dipropionate inhaler 50-100 micr-  ograms sprayed twice daily on the oral mucosa is  used to manage oral ulceration [unlicensed indication].  Alternatively, betamethasone soluble tablets dissolved  in water can be used as a mouthwash to treat oral  ulceration [unlicensed indication].   Systemic corticosteroid therapy (section 6.3.2) is  reserved for severe conditions such as pemphigus vul-  garis.    Local analgesics Local analgesics have a limited role  in the management of oral ulceration. When applied  topically their action is of a relatively short duration so  that analgesia cannot be maintained continuously  throughout the day. The main indication for a topical  local analgesic is to relieve the pain of otherwise intract-  able oral ulceration particularly when it is due to major  aphthae. For this purpose lidocaine 5% ointment or  lozenges containing a local anaesthetic are applied to  the ulcer. Lidocaine 10% solution as spray (section 15.2)  can be applied thinly to the ulcer [unlicensed indication]  using a cotton bud. When local anaesthetics are used in  the mouth care must be taken not to produce anaes-  thesia of the pharynx before meals as this might lead to  choking.    Benzydamine mouthwash or spray may be useful in  reducing the discomfort associated with a variety of  ulcerative conditions. It has also been found to be  effective in reducing the discomfort of post-irradiation  mucositis. Some patients find the full-strength  mouthwash causes some stinging and, for them, it  should be diluted with an equal volume of water.    Choline salicylate dental gel has some analgesic action  and may provide relief for recurrent aphthae, but exces-  sive application or confinement under a denture irritates  the mucosa and can itself cause ulceration.    Other preparations Doxycycline rinsed in the mouth  may be of value for recurrent aphthous ulceration.    Antiseptic mouthwashes Secondary bacterial infec-  tion may be a feature of any mucosal ulceration; it can  increase discomfort and delay healing. Use of chlor-  hexidine mouthwash (section 12.3.4) is often beneficial  and may accelerate healing of recurrent aphthae.   may relieve some discomfort arising from ulceration by  protecting the ulcer site. As the paste adheres to dry    Periodontitis Low-dose doxycycline ( Periostat ®) is  licensed as an adjunct to scaling and root planing for the  treatment of periodontitis; a low dose of doxycycline  reduces collagenase activity without inhibiting bacteria  associated with periodontitis. For anti-infectives used in  the treatment of destructive (refractory) forms of  periodontal disease, see section 12.3.2 and Table 1,  section 5.1. For mouthwashes used for oral hygiene and  plaque inhibition, see section 12.3.4.   Oral rinse, green, benzydamine hydrochloride 0.15%,  net price 200 mL [Difflam® Sore Throat Rinse) =  £2.50; 300 mL = £4.01   Dose ADULT and ADOLESCENT over 12 years, rinse or gargle,  using 15 mL (dilute with an equal volume of water if stinging  occurs) every 1 1/2-3 hours as required, usually for not more than 7  days   Dental prescribing on NHS May be prescribed as Benzydamine  Mouthwash 0.15%   Dose ADULT, 4-8 sprays onto affected area every l'/z-3 hours;  CHILD under 6 years 1 spray per 4 kg body-weight to max. 4 sprays  every l‘/z-3 hours; 6-12 years 4 sprays every 1 Vi— 3 hours  Dental prescribing on NHS May be prescribed as Benzydamine  Oromucosal Spray 0.15%   Contra-indications section 5.1.3  Hepatic impairment section 5.1.3  Renal impairment section 5.1.3  Pregnancy section 5.1.3   Note Doxycycline stains teeth; avoid in children under 12  years of age   Tablets, f/c, doxycycline (as hyclate) 20 mg, net price  56-tab pack = £16.50. Label: 6, 11, 27, counselling,  posture   Dose periodontitis (as an adjunct to gingival scaling and root  planing), 20 mg twice daily for 3 months; CHILD under 12 years not  recommended   Counselling Tablets should be swallowed whole with plenty of  fluid (at least 100 mL), while sitting or standing  Dental prescribing on NHS Maybe prescribed as Doxycy-  cline Tablets 20 mg   Protective paste (= oral paste), carmellose sodium  16.7%, pectin 16.7%, gelatin 16.7%, in Plastibase®.  Net price 30 g = £2.02; 100 g = £4.48  Dose apply a thin layer when necessary after meals  Dental prescribing on NHS May be prescribed as Carm-  ellose Gelatin Paste   Contra-indications untreated oral infection  Side-effects occasional exacerbation of local infec-  tion; thrush or other candidal infections   Mucoadhesive buccal tablets (= oromucosal  tablets), hydrocortisone 2.5 mg (as sodium succinate).  Net price 20 = £2.03   Dose ADULT and CHILD over 12 years, 1 lozenge 4 times daily,  allowed to dissolve slowly in the mouth in contact with the ulcer;  CHILD under 12 years, only on medical advice  Dental prescribing on NHS May be prescribed as Hydro-  cortisone Oromucosal Tablets    Betnesol® (UCB Pharma) (Ml  Soluble tablets, pink, scored, betamethasone  500 micrograms (as sodium phosphate), net price 100-  tab pack = £4.97. Label: 10, steroid card, 13, 21  Dose oral ulceration, [unlicensed indication] ADULT and CHILD  over 12 years, 500 micrograms dissolved in 20 mL water and  rinsed around the mouth 4 times daily; not to be swallowed  Dental prescribing on the NHS Maybe prescribed as Betametha-  sone Soluble Tablets 500 micrograms   Indications see preparations; oral herpes (section  12.3.2); other indications (section 5.1.3)   For recurrent aphthous ulceration, a 100 mg doxycy-  cline dispersible tablet can be stirred into a small  amount of water then rinsed around the mouth for  2-3 minutes 4 times daily usually for 3 days; it should  preferably not be swallowed [unlicensed indication].   Contra-indications section 10.1.1  Hepatic impairment section 10.1.1  Renal impairment section 10.1.1  Pregnancy section 10.1.1   Breast-feeding section 10.1.1  Side-effects taste disturbance, mouth ulcers (move  lozenge around mouth); see also section 10.1.1   Lozenges, flurbiprofen 8.75 mg, net price 16 = £2.24  Dose ADULT and CHILD over 12 years, allow 1 lozenge to dissolve  slowly in the mouth every 3-6 hours, max. 5 lozenges in 24 hours,  for max. 3 days   Hepatic impairment see Lidocaine section 15.2  Renal impairment see Lidocaine section 15.2  Pregnancy see Lidocaine section 15.2  Breast-feeding see Lidocaine section 15.2   Ointment, lidocaine 5% in a water-miscible basis, net  price 15 g = 80p    ^Preparations on sale to the public  Many mouth ulcer preparations, throat lozenges, and  throat sprays on sale to the public contain a local  anaesthetic. To identify the active ingredients in such  preparations, consult the product literature of the  manufacturer.   Note The correct proprietary name should be ascertained —  many products have very similar names but different active  ingredients   Cautions not to be applied to dentures — leave at least  30 minutes before re-insertion of dentures; frequent  application, especially in children, may give rise to  salicylate poisoning   Contra-indications children under 16 years  Reye’s syndrome The CHM has advised that topical oral  pain relief products containing salicylate salts should not be  used in children under 16 years, as a cautionary measure due  to the theoretical risk of Reye’s syndrome   Oral gel, choline salicylate 8.7% in a flavoured gel  basis, net price 15 g = £1.89  Brands include Bonjela ® (sugar-free)   Dose ADULT and CHILD over 16 years, apply Vi-inch of gel with  gentle massage not more often than every 3 hours  Dental prescribing on NHS Choline Salicylate Dental Gel  may be prescribed   Oral paint, brown, rhubarb extract (anthraquinone  glycosides 0.5%), salicylic acid 1%. Net price 10 mL  with brush = £3.25   Dose ADULT and CHILD over 16 years, apply 3-4 times daily   The most common cause of a sore throat is a viral  infection which does not benefit from anti-infective  treatment. Streptococcal sore throats require systemic  penicillin therapy (Table 1, section 5.1). Acute ulcer-  ative gingivitis (Vincent’s infection) responds to sys-  temic metronidazole (section 5.1.11).   Preparations administered in the dental surgery for the  local treatment of periodontal disease include gels of  metronidazole (Elyzol®, Colgate-Palmolive) and of  minocycline (Dentomycin ® , Blackwell).   Fungal infections of the mouth are usually caused by  Candida spp. (candidiasis or candidosis). Different  types of oropharyngeal candidiasis are managed as  follows:    Thrush Acute pseudomembranous candidiasis  (thrush), is usually an acute infection but it may persist  for months in patients receiving inhaled corticosteroids,  cytotoxics or broad-spectrum antibacterials. Thrush  also occurs in patients with serious systemic disease  associated with reduced immunity such as leukaemia,  other malignancies, and HIV infection. Any predispos-  ing condition should be managed appropriately. When  thrush is associated with corticosteroid inhalers, rinsing  the mouth with water (or cleaning a child’s teeth)  immediately after using the inhaler may avoid the  problem. Treatment with nystatin or miconazole  maybe needed. Fluconazole (section 5.2.1) is effective  for unresponsive infections or if a topical antifungal  drug cannot be used or if the patient has dry mouth.  Topical therapy may not be adequate in immunocom-  promised patients and an oral triazole antifungal is  preferred (section 5.2.1).   Acute erythematous candidiasis Acute erythema-  tous (atrophic) candidiasis is a relatively uncommon  condition associated with corticosteroid and broad-  spectrum antibacterial use and with HIV disease. It is  usually treated with fluconazole (section 5.2.1).    Denture stomatitis Patients with denture stomatitis  (chronic atrophic candidiasis), should cleanse their den-  tures thoroughly and leave them out as often as possible  during the treatment period. To prevent recurrence of  the problem, dentures should not normally be worn at  night. New dentures may be required if these measures  fail despite good compliance.    Miconazole oral gel can be applied to the fitting surface  of the denture before insertion (for short periods only).  Denture stomatitis is not always associated with candi-  diasis and other factors such as mechanical or chemical  irritation, bacterial infection, or rarely allergy to the  dental base material, may be the cause.   Chronic hyperplastic candidiasis Chronic hyper-  plastic candidiasis (candidal leucoplakia) carries an  increased risk of malignancy; biopsy is essential — this  type of candidiasis may be associated with varying  degrees of dysplasia, with oral cancer present in a  high proportion of cases. Chronic hyperplastic candi-  diasis is treated with a systemic antifungal such as  fluconazole (section 5.2.1) to eliminate candidal over-  lay. Patients should avoid the use of tobacco.   Angular cheilitis Angular cheilitis (angular stomatitis)  is characterised by soreness, erythema and Assuring at  the angles of the mouth. It is commonly associated with  denture stomatitis but may represent a nutritional defi-  ciency or it may be related to orofacial granulomatosis  or HIV infection. Both yeasts ( Candida spp.) and bac-  teria ( Staphylococcus aureus and beta-haemolytic  streptococci) are commonly involved as interacting,  infective factors. A reduction in facial height related to  ageing and tooth loss with maceration in the deep  occlusive folds that may subsequently arise, predisposes  to such infection. While the underlying cause is being  identified and treated, it is often helpful to apply micon-    azole cream (see p. 737) or sodium fusidate ointment  (see p. 735); if the angular cheilitis is unresponsive to  treatment, miconazole and hydrocortisone cream or  ointment (see p. 707) can be used.   Immunocompromised patients For advice on pre-  vention of fungal infections in immunocompromised  patients see p. 374.   Drugs used in oropharyngeal candidiasis Nys-  tatin is not absorbed from the gastro-intestinal tract and  is applied locally (as a suspension) to the mouth for  treating local fungal infections. Miconazole is applied  locally (as an oral gel) in the mouth but it is absorbed to  the extent that potential interactions need to be con-  sidered. Miconazole also has some activity against  Gram-positive bacteria including streptococci and sta-  phylococci. Fluconazole (section 5.2.1) is given by  mouth for infections that do not respond to topical  therapy or when topical therapy cannot be used. It is  reliably absorbed and effective. Itraconazole (section  5.2.1) can be used for fluconazole-resistant infections.   If candidal infection fails to respond to 1 to 2 weeks of  treatment with antifungal drugs the patient should be  sent for investigation to eliminate the possibility of  underlying disease. Persistent infection may also be  caused by reinfection from the genito-urinary or gas-  tro-intestinal tract. Infection can be eliminated from  these sources by appropriate anticandidal therapy; the  patient’s partner may also require treatment to prevent  reinfection.   For the role of antiseptic mouthwashes in the prevention  of oral candidiasis in immunocompromised patients and  treatment of denture stomatitis, see section 12.3.4.   interactions: Appendix 1 (antifungals, imidazole)  Contra-indications with oral gel, impaired swallow-  ing reflex in infants, first 5-6 months of life of an  infant born preterm  Hepatic impairment avoid  Pregnancy manufacturer advises avoid if possible —  toxicity at high doses in animal studies  Breast-feeding manufacturer advises caution — no  information available    Side-effects nausea, vomiting; rash; with buccal  tablets, abdominal pain, taste disturbance, burning  sensation at application site, pruritus, and oedema;  with oral gel, very rarely diarrhoea (usually on long-  term treatment), hepatitis, toxic epidermal necrolysis,  and Stevens- Johnson syndrome  Dose    ^aktarin® (Janssen-Cilag) (Ml  Oral gel, sugar-free, orange-flavoured, miconazole  24 mg/mL (20 mg/g). Net price 15-g tube = £2.85, 80-  g tube = £4.38. Label: 9, counselling, hold in mouth,  after food   Dose prevention and treatment of oral and intestinal fungal  infections, 5-10 mL in the mouth after food 4 times daily, retained  near oral lesions before swallowing; CHILD 4 months-2 years  2.5 mL twice daily, smeared around the mouth; 2-6 years 5 mL    twice daily, retained near lesions before swallowing; over 6 years  5 mL 4 times daily, retained near lesions before swallowing  Note Treatment should be continued for 48 hours after lesions  have healed   Localised lesions, ADULT and CHILD over 2 years, smear small  amount on affected area with clean finger 4 times daily for 5-7  days (dental prostheses should be removed at night and brushed  with gel); treatment continued for 48 hours after lesions have  healed   Dose oropharyngeal candidiasis in immunocompromised ADU LT,  50 mg daily preferably taken in the morning for 7 days; if no  improvement, continue treatment for a further 7 days  Counselling Place rounded side of tablet on upper gum above an  incisor tooth and hold upper lip firmly over the gum for 30  seconds using a finger. If tablet detaches within 6 hours, replace  with a new tablet. With each dose, use alternate sides of the gum  Note The Scottish Medicines Consortium (p. 4) has advised  (November 2008) that miconazole mucoadhesive buccal tablets  (Loramyc®) are not recommended for use within NHS Scotland.   • Treatment, ADULT and CHILD, 100 000 units 4 times  daily after food, usually for 7 days (continued for 48  hours after lesions have resolved)   The management of primary herpetic gingivostomatitis  is a soft diet, adequate fluid intake, and analgesics as  required, including local use of benzydamine (section  12.3.1). The use of chlorhexidine mouthwash (section  12.3.4) will control plaque accumulation if toothbrush-  ing is painful and will also help to control secondary  infection in general.   In the case of severe herpetic stomatitis, a systemic  antiviral such as aciclovir is required (section 5.3.2. 1).  Valaciclovir and famciclovir are suitable alternatives for  oral lesions associated with herpes zoster. Aciclovir and  valaciclovir are also used for the prevention of fre-  quently recurring herpes simplex lesions of the mouth,  particularly when implicated in the initiation of erythe-  ma multiforme. See section 13.10.3 for the treatment of  labial herpes simplex infections.   Herpes infections of the mouth may also respond to  rinsing the mouth with doxycycline, see p. 694.    There is no convincing evidence that antiseptic  lozenges and sprays have a beneficial action and they  sometimes irritate and cause sore tongue and sore lips.  Some of these preparations also contain local anaes-  thetics which relieve pain but may cause sensitisation.   Superficial infections of the mouth are often helped by  warm mouthwashes which have a mechanical cleansing  effect and cause some local hyperaemia. However, to be  effective, they must be used frequently and vigorously. A  warm saline mouthwash is ideal and can be prepared  either by dissolving half a teaspoonful of salt in a glassful  of warm water or by diluting compound sodium chlor-  ide mouthwash with an equal volume of warm water.  Mouthwash solution-tablets are used to remove  unpleasant tastes.   Mouthwashes containing an oxidising agent, such as  hydrogen peroxide, may be useful in the treatment of  acute ulcerative gingivitis (Vincent’s infection) since the  organisms involved are anaerobes. It also has a mechan-  ical cleansing effect arising from frothing when in con-  tact with oral debris.   Chlorhexidine is an effective antiseptic which has the  advantage of inhibiting plaque formation on the teeth. It  does not, however, completely control plaque deposi-  tion and is not a substitute for effective toothbrushing.  Moreover, chlorhexidine preparations do not penetrate  significantly into stagnation areas and are therefore of  little value in the control of dental caries or of period-  ontal disease once pocketing has developed. Chlorhexi-  dine mouthwash is used in the treatment of denture  stomatitis. It is also used in the prevention of oral  candidiasis in immunocompromised patients. Chlor-  hexidine mouthwash reduces the incidence of alveolar  osteitis following tooth extraction. Chlorhexidine  mouthwash should not be used for the prevention of  endocarditis in patients undergoing dental procedures.  Chlorhexidine can be used as a mouthwash, spray or gel  for secondary infection in mucosal ulceration and for  controlling gingivitis, as an adjunct to other oral hygiene  measures. These preparations may also be used instead  of toothbrushing where there is a painful periodontal  condition (e.g. primary herpetic stomatitis) or if the  patient has a haemorrhagic disorder, or is disabled.  Chlorhexidine preparations are of little value in the  control of acute necrotising ulcerative gingivitis.   Indications see under preparations below  Side-effects mucosal irritation (if desquamation  occurs, discontinue treatment or dilute mouthwash  with an equal volume of water); taste disturbance;  reversible brown staining of teeth, and of silicate or  composite restorations; tongue discoloration; parotid  gland swelling reported   Note Chlorhexidine gluconate may be incompatible with  some ingredients in toothpaste; leave an interval of at least  30 minutes between using mouthwash and toothpaste   Dose oral hygiene and plaque inhibition, oral candidiasis, gin-  givitis, and management of aphthous ulcers, rinse mouth with  10 mL for about 1 minute twice daily  Denture stomatitis, cleanse and soak dentures in mouthwash  solution for 15 minutes twice daily  Dental prescribing on NHS Chlorhexidine Mouthwash  may be prescribed   Dose oral hygiene and plaque inhibition and gingivitis, brush on  the teeth once or twice daily   Oral candidiasis and management of aphthous ulcers, apply to  affected areas once or twice daily   Mouthwash, chlorhexidine gluconate 0.2%. Net price  300 mL (original or mint) = £2.18, 600 mL (mint) =  £3.85   Dose oral hygiene and plaque inhibition, oral candidiasis, gin-  givitis, and management of aphthous ulcers, rinse mouth with  10 mL for about 1 minute twice daily  Denture stomatitis, cleanse and soak dentures in mouthwash  solution for 15 minutes twice daily  Oral spray, chlorhexidine gluconate 0.2% (mint-fla-  voured). Net price 60 mL = £4.10  Dose oral hygiene and plaque inhibition, oral candidiasis, gin-  givitis, and management of aphthous ulcers, apply as required to  tooth, gingival, or ulcer surfaces using up to 12 actuations  (approx. 0.14mL/actuation) twice daily  Dental prescribing on NHS May be prescribed as Chlor-  hexidine Oral Spray   Oromucosal solution, alcohol-free, chlorhexidine  gluconate 0.2%, net price 300 mL = £1.96  Dose short-term treatment of inflammation of gingival and oral  mucosa, ADULT and CHILD over 6 years, rinse mouth with 10 mL  for about 1 minute twice daily   Dental prescribing on NHS May be prescribed as Chlor-  hexidine Oromucosal Solution, Alcohol-free, 0.2%   Mouthwash or gargle, chlorhexidine gluconate 0.1%,  chlorobutanol 0.5% (mint-flavoured), net price 90 mL  = £1.36, 250 mL = £2.83, 500 mL = £5.06  Dose oral hygiene and plaque inhibition, use 10-15 mL (diluted  with warm water in measuring cup provided) 2-3 times daily  Denture disinfection, soak previously cleansed dentures in  mouthwash (diluted with 2 volumes of water) for 60 minutes   Mouthwash or gargle, red or blue-green (mint-fla-  voured), hexetidine 0.1%. Net price 100 mL = £1.31;  200 mL = £2.02   Dose ADULT and CHILD over 6 years, use 15 mL undiluted 2-3  times daily   Mouthwash, consists of Hydrogen Peroxide Solution  6% (= approx. 20 volume) BP   Dose rinse the mouth for 2-3 minutes with 15 mL diluted in half  a tumblerful of warm water 2-3 times daily  Dental prescribing on NHS Hydrogen Peroxide  Mouthwash may be prescribed   Dose rinse the mouth with 10 mL for about 1 minute up to 4  times daily (after meals and at bedtime)   Mouthwash, sodium bicarbonate 1%, sodium chlor-  ide 1.5% in a suitable vehicle with a peppermint  flavour.   Dose extemporaneous preparations should be prepared  according to the following formula: sodium chloride 1.5 g, sodium  bicarbonate 1 g, concentrated peppermint emulsion 2.5 mL, dou-  ble-strength chloroform water 50 mL, water to 100 mL  To be diluted with an equal volume of warm water  Dental prescribing on NHS Compound Sodium Chloride  Mouthwash may be prescribed   Consist of tablets which may contain antimicrobial,  colouring, and flavouring agents in a suitable soluble  effervescent basis to make a mouthwash suitable for  dental purposes. Net price 100-tab pack = £15.09  Dose dissolve 1 tablet in a tumblerful of warm water  Note Mouthwash solution tablets may contain ingredients such as  thymol    Dry mouth (xerostomia) may be caused by drugs with  antimuscarinic (anticholinergic) side-effects (e.g. anti-  spasmodics, tricyclic antidepressants, and some anti-  psychotics), by diuretics, by irradiation of the head and  neck region or by damage to or disease of the salivary  glands. Patients with a persistently dry mouth may  develop a burning or scalded sensation and have poor  oral hygiene; they may develop increased dental caries,  periodontal disease, intolerance of dentures, and oral  infections (particularly candidiasis). Dry mouth may be  relieved in many patients by simple measures such as  frequent sips of cool drinks or sucking pieces of ice or  sugar-free fruit pastilles. Sugar-free chewing gum stimu-  lates salivation in patients with residual salivary func-  tion.    Artificial saliva can provide useful relief of dry mouth.  A properly balanced artificial saliva should be of a  neutral pH and contain electrolytes (including fluoride)  to correspond approximately to the composition of  saliva. The acidic pH of some artificial saliva products  may be inappropriate. Of the proprietary preparations,  Salinum ® or Xerotin® can be used for any condition    giving rise to a dry mouth. Biotene Oralbalance ® ,  BioXtra®, Glandosane®, Saliva Orthana®, and Sal-  iveze®, have ACBS approval for dry mouth associated  only with radiotherapy or sicca syndrome. Salivix®  pastilles, which act locally as salivary stimulants, are  also available and have similar ACBS approval. SST  tablets may be prescribed for dry mouth in patients with  salivary gland impairment (and patent salivary ducts).  Pilocarpine tablets are licensed for the treatment of  xerostomia following irradiation for head and neck  cancer and for dry mouth and dry eyes (xerophthalmia)  in Sjogren’s syndrome. They are effective only in  patients who have some residual salivary gland func-  tion, and therefore should be withdrawn if there is no  response.   Oral spray, gastric mucin (porcine) 3.5%, xylitol 2%,  sodium fluoride 4.2 mg/litre, with preservatives and  flavouring agents, pH neutral. Net price 50-mL bottle  = £4.92; 450-mL refill = £34.27  Dose ACBS: patients suffering from dry mouth as a result of  having (or having undergone) radiotherapy, or sicca syndrome,  spray 2-3 times onto oral and pharyngeal mucosa, when required  Dental prescribing on NHS AS Saliva Orthana ® Oral  Spray may be prescribed   Lozenges, mucin 65 mg, xylitol 59 mg, in a sorbitol  basis, pH neutral. Net price 30-lozenge pack = £3.50  Dose ACBS: patients suffering from dry mouth as a result of  having (or having undergone) radiotherapy, or sicca syndrome  Note AS Saliva Orthana ® lozenges do not contain fluoride  Dental prescribing on NHSASSa/rva Orthana ® Lozenges  may be prescribed   Saliva replacement gel, lactoperoxidase, lactoferrin,  lysozyme, glucose oxidase, xylitol in a gel basis, net  price 50-g tube = £4.10, 24 x 12.4-mL tube = £30.40  (for hospital use)   Dose ACBS: patients suffering from dry mouth as a result of  having (or having undergone) radiotherapy, or sicca syndrome,  apply to gums and tongue as required   Gel, lactoperoxidase, lactoferrin, lysozyme, whey  colostrum, xylitol and other ingredients, net price 40-  mL tube = £3.94, 50-mL spray = £3.94  Dose ACBS: patients suffering from dry mouth as a result of  having (or having undergone) radiotherapy, or sicca syndrome,  apply to oral mucosa as required   Aerosol spray, carmellose sodium 500 mg, sorbitol  1.5 g, potassium chloride 60 mg, sodium chloride  42.2 mg, magnesium chloride 2.6 mg, calcium chlor-  ide 7.3 mg, and dipotassium hydrogen phosphate  17.1 mg/50 g, pH 5.75. Net price 50-mL unit (neutral,  lemon or peppermint flavoured) = £4.82  Dose ACBS: patients suffering from dry mouth as a result of  having (or having undergone) radiotherapy, or sicca syndrome,  spray onto oral and pharyngeal mucosa as required  Dental prescribing on NHS Glandosane ® Aerosol Spray  may be prescribed   Oral spray, carmellose sodium (sodium carboxy-  methylcellulose), calcium chloride, magnesium  chloride, potassium chloride, sodium chloride, and  dibasic sodium phosphate, pH neutral. Net price 50-  mL bottle (mint-flavoured) = £3.50  Dose ACBS: patients suffering from dry mouth as a result of  having (or having undergone) radiotherapy, or sicca syndrome, 1  spray onto oral mucosa as required   Pastilles, sugar-free, reddish-amber, acacia, malic  acid and other ingredients. Net price 50-pastille pack  = £3.50   Dose ACBS: patients suffering from dry mouth as a result of  having (or having undergone) radiotherapy, or sicca syndrome,  suck 1 pastille when required   Tablets, sugar-free, citric acid, malic acid and other  ingredients in a sorbitol base, net price 100-tab pack =  £4.86   Dose symptomatic treatment of dry mouth in patients with  impaired salivary gland function and patent salivary ducts, allow 1  tablet to dissolve slowly in the mouth when required  Dental prescribing on NHS May be prescribed as Saliva  Stimulating Tablets   Oral spray, sugar-free, water, sorbitol, carmellose  (carboxymethylcellulose), potassium chloride, sodium  chloride, potassium phosphate, magnesium chloride,  calcium chloride and other ingredients, pH neutral.  Net price 100-mL unit = £6.86  Dose symptomatic treatment of dry mouth, spray as required  Dental prescribing on NHS Xerotin ® Oral Spray may be  prescribed as Artificial Saliva Oral Spray   Indications xerostomia following irradiation for head  and neck cancer (see also notes above); dry mouth  and dry eyes in Sjogren’s syndrome  Cautions asthma and chronic obstructive pulmonary  disease (avoid if uncontrolled, see Contra-indica-  tions), cardiovascular disease (avoid if uncontrolled);  cholelithiasis or biliary-tract disease, peptic ulcer, risk  of increased urethral smooth muscle tone and renal  colic; maintain adequate fluid intake to avoid dehy-  dration associated with excessive sweating; cognitive  or psychiatric disturbances; susceptibility to angle-  closure glaucoma; interactions: Appendix 1 (para-  sympathomimetics)   Counselling Blurred vision or dizziness may affect perfor-  mance of skilled tasks (e.g. driving) particularly at night or in  reduced lighting   Contra-indications uncontrolled asthma and chronic  obstructive pulmonary disease (increased bronchial  secretions and increased airways resistance); uncon-  trolled cardiorenal disease; acute iritis  Hepatic impairment reduce initial oral dose in mod-  erate or severe cirrhosis   Side-effects dyspepsia, diarrhoea, abdominal pain,  nausea, vomiting, constipation; flushing, hyper-  tension, palpitation, headache, dizziness, asthenia,  influenza-like symptoms, sweating; increased urinary  frequency; visual disturbances, lacrimation, ocular  pain, conjunctivitis; rhinitis; rash, pruritus; less com-  monly flatulence, urinary urgency    • Xerostomia following irradiation for head and neck  cancer, 5 mg 3 times daily with or immediately after  meals (last dose always with evening meal); if toler-  ated but response insufficient after 4 weeks, may be  increased to max. 30 mg daily in divided doses; max.  therapeutic effect normally within 4-8 weeks; dis-  continue if no improvement after 2-3 months; CHILD  not recommended   • Dry mouth and dry eyes in Sjogren’s syndrome, 5 mg  4 times daily (with meals and at bedtime); if tolerated  but response insufficient, may be increased to max.  30 mg daily in divided doses; discontinue if no  improvement after 2-3 months; CHILD not recom-  mended    This chapter also includes advice on the drug man-  agement of the following:  candidiasis, p. 737  crab lice, p. 740  dermatophytoses, p. 736  head lice, p. 740  hirsutism, p. 733  nappy rash, p. 705  photodamage, p. 731  pityriasis versicolor, p. 736  scabies, p. 740    For information on wound management products and  elastic hosiery see Appendix 8, p. 935.   The British Association of Dermatologists list of pre-  ferred unlicensed dermatological preparations (spe-  cials) is available at http://www.bad.org.uk/site/  495/default.aspx   Both vehicle and active ingredients are important in the  treatment of skin conditions; the vehicle alone may have  more than a mere placebo effect. The vehicle affects the  degree of hydration of the skin, has a mild anti-inflamm-  atory effect, and aids the penetration of active drug.  Applications are usually viscous solutions, emulsions,  or suspensions for application to the skin (including the  scalp) or nails.   Collodions are painted on the skin and allowed to dry to  leave a flexible film over the site of application.  Creams are emulsions of oil and water and are generally  well absorbed into the skin. They may contain an anti-  microbial preservative unless the active ingredient or  basis is intrinsically bactericidal and fungicidal. Gener-  ally, creams are cosmetically more acceptable than  ointments because they are less greasy and easier to  apply.    Gels consist of active ingredients in suitable hydrophilic  or hydrophobic bases; they generally have a high water  content. Gels are particularly suitable for application to  the face and scalp.   Lotions have a cooling effect and may be preferred to  ointments or creams for application over a hairy area.  Lotions in alcoholic basis can sting if used on broken  skin. Shake lotions (such as calamine lotion) contain  insoluble powders which leave a deposit on the skin  surface.   Ointments are greasy preparations which are normally  anhydrous and insoluble in water, and are more occlu-  sive than creams. They are particularly suitable for  chronic, dry lesions. The most commonly used ointment  bases consist of soft paraffin or a combination of soft,  liquid and hard paraffin. Some ointment bases have both  hydrophilic and lipophilic properties; they may have  occlusive properties on the skin surface, encourage  hydration, and also be miscible with water; they often  have a mild anti-inflammatory effect. Water-soluble  ointments contain macrogols which are freely soluble  in water and are therefore readily washed off; they have  a limited but useful role where ready removal is desir-  able.   Pastes are stiff preparations containing a high propor-  tion of finely powdered solids such as zinc oxide and  starch suspended in an ointment. They are used for  circumscribed lesions such as those which occur in  lichen simplex, chronic eczema, or psoriasis. They are  less occlusive than ointments and can be used to protect  inflamed, lichenified, or excoriated skin.   Dusting powders are used only rarely. They reduce  friction between opposing skin surfaces. Dusting pow-  ders should not be applied to moist areas because they  can cake and abrade the skin. Talc is a lubricant but it  does not absorb moisture; it can cause respiratory  irritation. Starch is less lubricant but absorbs water.   Dilution The BP directs that creams and ointments  should not normally be diluted but that should dilution  be necessary care should be taken, in particular, to  prevent microbial contamination. The appropriate dilu-  ent should be used and heating should be avoided  during mixing; excessive dilution may affect the stability  of some creams. Diluted creams should normally be  used within 2 weeks of preparation.    These amounts are usually suitable for an adult for twice  daily application for 1 week. The recommendations do  not apply to corticosteroid preparations — for suitable  quantities of corticosteroid preparations see section  13.4.    Excipients in topical products rarely cause problems. If a  patch test indicates allergy to an excipient, products  containing the substance should be avoided (see also  Anaphylaxis, p. 197). The following excipients in topical  preparations are rarely associated with sensitisation; the  presence of these excipients is indicated in the entries  for topical products. See also Excipients, under General  Guidance, p. 2.    Beeswax  Benzyl alcohol  Butylated hydroxyanisole  Butylated hydroxytoluene  Cetostearyl alcohol (includ-  ing cetyl and stearyl  alcohol)   Borderline substances The preparations marked  ‘ACBS’ are regarded as drugs when prescribed in accor-  dance with the advice of the Advisory Committee on  Borderline Substances for the clinical conditions listed.  Prescriptions issued in accordance with this advice and  endorsed ACBS’ will normally not be investigated. See  Appendix 7 for listing by clinical condition.   Suitable quantities of dermatological pre-  parations to be prescribed for specific areas  of the body    Emollients soothe, smooth and hydrate the skin and are  indicated for all dry or scaling disorders. Their effects  are short-lived and they should be applied frequently  even after improvement occurs. They are useful in dry  and eczematous disorders, and to a lesser extent in  psoriasis (section 13.5.2). The choice of an appropriate  emollient will depend on the severity of the condition,  patient preference, and the site of application. Emolli-  ents should be applied in the direction of hair growth.  Ointments may exacerbate acne and folliculitis. Some  ingredients rarely cause sensitisation (section 13.1.3)  and this should be suspected if an eczematous reaction    occurs. The use of aqueous cream as a leave-on emoll-  ient may increase the risk of skin reactions, particularly  in eczema.   Fire hazard with paraffin-based emollients  Emulsifying ointment or 50% Liquid Paraffin and  50% White Soft Paraffin Ointment in contact with  dressings and clothing is easily ignited by a naked  flame. The risk is greater when these preparations  are applied to large areas of the body, and clothing or  dressings become soaked with the ointment.  Patients should be told to keep away from fire or  flames, and not to smoke when using these prepara-  tions. The risk of fire should be considered when  using large quantities of any paraffin-based emoll-  ient.    Preparations such as aqueous cream and emulsifying  ointment can be used as soap substitutes for hand  washing and in the bath; the preparation is rubbed on  the skin before rinsing off completely. The addition of a  bath oil (section 13.2.1.1) may also be helpful.   Preparations containing an antibacterial (section 13.10)  should be avoided unless infection is present or is a  frequent complication.   Urea is a hydrating agent used in the treatment of dry,  scaling conditions (including ichthyosis) and may be  useful in elderly patients. It is occasionally used with  other topical agents such as corticosteroids to enhance  penetration of the skin.   Cream, emulsifying ointment 30%, ^henoxyethanol  1% in freshly boiled and cooled purified water, net  price lOOg = £1.51, 500g = £1.86   Excipients include cetostearyl alcohol  l.The BP permits use of alternative antimicrobials provided  their identity and concentration are stated on the label   Cream, colloidal oatmeal in emollient basis, net price  100 mL = £3.78, 300-mL pump pack = £6.80   Excipients include benzyl alcohol, cetyl alcohol, isopropyl palmitate  ACBS: For endogenous and exogenous eczema, xeroderma,  ichthyosis, and senile pruritus (pruritus of the elderly) associated  with dry skin   Lotion, colloidal oatmeal in emollient basis, net price  400 mL = £6.42   Excipients include benzyl alcohol, cetyl alcohol, isopropyl palmitate  ACBS: as for Aveeno ® Cream   Emollient cream, white soft paraffin 13.2%, light liq-  uid paraffin 10.5%, net price 50-g pump pack = £1.40,  150-g pump pack = £3.98, 500-g pump pack = £5.99,  1.05-kg pump pack = £11.62   Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)  For inflamed, damaged, dry or chapped skin including eczema   Spray application, white soft paraffin 10% in a basis  containing liquid paraffin, fractionated coconut oil,  net price 250-mL pressurised aerosol unit = £5.97   For dry skin conditions including eczema, ichthyosis, pruritus of  the elderly  Note Flammable   Cream, cetomacrogol 2.25%, cetostearyl alcohol  7.2%, liquid paraffin 6%, white soft paraffin 15%,  water-miscible basis used for Diprosone® cream, net  price 50 g = £1.28; 500-g pump pack = £6.32   Ointment, liquid paraffin 5%, white soft paraffin 95%,  basis used for Diprosone® ointment, net price 50 g =  £1.28, 500 g = £5.99   Ointment, emulsifying wax 30%, white soft paraffin  50%, liquid paraffin 20%, net price 500 g = £2.22   Ointment, (oily cream), dried magnesium sulphate  0.5%, phenoxyethanol 1%, wool alcohols ointment  50%, in freshly boiled and cooled purified water, net  price 500 g = £2.92   Ointment, liquid paraffin 50%, white soft paraffin  50%, net price 500 g = £6.09   Gel, isopropyl myristate 15%, liquid paraffin 15%, net  price 100 g = £2.65, 500 g = £5.82   Cream, light liquid paraffin 12.6%, white soft paraffin  14.5%, hypoallergenic anhydrous wool fat (hypoal-  lergenic lanolin) 1% in self-emulsifying monostearin,  net price 50 g = £1.40, 125 g = £2.55, 350 g = £4.46,  500-g pump pack = £4.89   Lotion, light liquid paraffin 4%, cetomacrogol, white  soft paraffin 10%, hypoallergenic anhydrous wool fat  (hypoallergenic lanolin) 1% in glyceryl monostearate,  net price 200 mL = £2.40, 500-mL pump pack = £4.50   ACBS: for symptomatic relief of dry skin conditions, such as those  associated with atopic eczema and contact dermatitis   Cream, containing liquid paraffin, white soft paraffin,  net price 50 g = £1.22, 500-g pump pack = £6.40   Spray, liquid paraffin 50%, white soft paraffin 50% in  aerosol basis, net price 150 mL = £3.74, 240 mL =  £5.98   Cream, yellow soft paraffin 15%, liquid paraffin 10%,  emulsifying wax 5%, net price 50-g pump pack =  £1.60, 500-g pump pack = £6.55   Excipients include cetostearyl alcohol, chlorocresol  For use as an emollient or soap substitute  Ointment, emulsifying wax 30%, yellow soft paraffin  30%, liquid paraffin 40%, net price 125 g = £3.72,   Excipients include cetostearyl alcohol  For use as an emollient or soap substitute   Cream, sodium pidolate 2.5%, liquid paraffin 13.8%,  net price 50 g = £2.04, 100g = £3.80, 500 g = £11.09   Ointment, yellow soft paraffin 30%, emulsifying wax  30%, liquid paraffin 40%, net price 125 g = £2.79,   Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)  For dry skin conditions, also for use during treatment with topical  corticosteroid and as diluent for Locoid Lipocream ®   Cream, light liquid paraffin 6%, white soft paraffin  15%, net price 40 g = £1.30, 150 g = £2.46, 500-mL  pump pack = £4.99, 1.05-litre pump pack = £9.98   Oilatum® Junior Cream, light liquid paraffin 6%,  white soft paraffin 15%, 150 g = £3.38, 350 mL =  £4.65, 500 mL = £4.99, 1.05-litre pump pack = £9.98   Cream, glycerol 10%, light liquid paraffin 10%, white  soft paraffin 5%, net price 100 g = £1.95, 500 g = £5.60   Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)  For dry skin conditions including eczema, psoriasis, ichthyosis,  pruritus   Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)  For dry skin conditions including eczema, psoriasis, ichthyosis,  pruritus   Cream, water-miscible, containing liquid paraffin and  white soft paraffin, net price 50 g = £1.58, 500-g pump  pack = £16.23   Excipients include fragrance, hydroxybenzoates (parabens), disodium  edetate, stearyl alcohol  For dry skin conditions   Cream, containing saturated neutral oil, liquid par-  affin, white soft paraffin, net price 50 g = £1.41, 100 g  = £2.78, 200-mL pump pack = £5.50, 500 g = £8.48   Excipients include cetostearyl alcohol, polysorbate 40, propylene gly-  col, sorbic acid   Cream, liquid paraffin 11%, net price 50 g = £1.04,  500-g pump pack = £5.26   Cream, liquid paraffin 12.6%, white soft paraffin  14.5%, net price 50 g = £1.17, 500-g pump pack =  £4.08   Cream, light liquid paraffin 8%, white soft paraffin 4%,  refined soya bean oil 5%, net price 100 g = £2.33,  500 g = £7.07   Excipients include cetostearyl alcohol, polysorbate 40, propylene gly-  col, sorbic acid  For dry skin conditions   Cream, urea 5%, ceramide 0.1%, net price 50-g pump  pack = £2.80, 500-g pump pack = £9.80   Excipients include cetostearyl alcohol, polysorbates, propylene glycol  Dose for dry skin conditions, apply twice daily  Balneum® Plus Cream, urea 5%, lauromacrogols 3%,  net price 100 g = £3.29, 175-g pump pack = £8.33,  500-g pump pack = £16.42   Cream, urea 10%, lactic acid 5%, net price 100 g =  £5.70, 500-g pump pack = £27.42   Dose for dry, scaling and itching skin, apply a thick layer for 3-5  minutes, massage into area, and remove excess, usually twice  daily. Use half-strength cream for 1 week if stinging occurs  Note Can be diluted with aqueous cream (life of diluted cream 14  days)   Cream, urea 25%, net price 75 mL = £4.00, 200 mL =  £9.50   Dose for dry skin on soles of feet, apply twice daily   Cream, urea 5%, macrogol lauryl ether 3%, net price  50 g = £2.55, 100 g = £3.47, 500-g pump pack = £14.99   Excipients include benzyl alcohol, isopropyl palmitate, wool fat  Dose for dry skin conditions including eczema, ichthyosis, xer-  oderma, hyperkeratosis, apply thinly and rub into area twice daily   Excipients include benzyl alcohol, isopropyl palmitate  Dose for dry skin conditions including eczema, ichthyosis, xer-  oderma, hyperkeratosis, apply sparingly and rub into area twice  daily   Cream, urea 10%, net price 30 g = £1.64, 100 g = £4.37   Excipients include hydroxybenzoates (parabens), propylene glycol  Dose for dry, scaling and itching skin, apply 2-3 times daily   Cream, benzalkonium chloride 0.1%, chlorhexidine  hydrochloride 0.1%, isopropyl myristate 10%, liquid  paraffin 10%, net price 100-g tube = £2.86, 500-g  pump pack = £6.63   Dose for dry and pruritic skin conditions including eczema and  dermatitis, apply to skin or use as soap substitute   Dermol® 500 Lotion, benzalkonium chloride 0.1%,  chlorhexidine hydrochloride 0.1%, liquid paraffin  2.5%, isopropyl myristate 2.5%, net price 500-mL  pump pack = £6.03   Dose for dry and pruritic skin conditions including eczema and  dermatitis, apply to skin or use as soap substitute   Cream, chlorhexidine gluconate 1 % in emollient  basis, net price 250 mL = £3.70   Dose for dry and pruritic skin conditions including eczema and  dermatitis, apply to skin or use as soap substitute   Emollient bath additives should be added to bath water;  hydration can be improved by soaking in the bath for  10-20 minutes. Some bath emollients can be applied to  wet skin undiluted and rinsed off. In dry skin conditions  soap should be avoided (see section 13.2.1 for soap  substitutes). The quantities of bath additives recom-  mended for adults are suitable for an adult-size bath.  Proportionately less should be used for a child-size bath  or a washbasin; recommended bath additive quantities  for children reflect this.   Aveeno® Bath oil, colloidal oatmeal, white oat  fraction in emollient basis, net price 250 mL = £4.28   Dose ACBS: for endogenous and exogenous eczema, xeroderma,  ichthyosis, and senile pruritus (pruritus of the elderly) associated  with dry skin, add 20-30 mL/bath or apply to wet skin and rinse    Aveeno Colloidal® Bath additive, oatmeal, white oat  fraction in emollient basis, net price 10 x 50-g sachets  = £7.33; Baby Bath Additive, 10 x 15-g sachets =  £4.39   Balneum® bath oil, soya oil 84.75%, net price  200 mL = £2.48, 500 mL = £5.38, 1 litre = £10.39   Dose for dry skin conditions including those associated with  dermatitis and eczema; add 20-60 mL/bath (INFANT 5-15 mL); do  not use undiluted   Balneum Plus® bath oil, soya oil 82.95%, mixed  lauromacrogols 15%, net price 500 mL = £6.66   Dose for dry skin conditions including those associated with  dermatitis and eczema where pruritus also experienced; add  20 mL/bath (INFANT 5mL) or apply to wet skin and rinse   Emollient bath additive, light liquid paraffin 82.8%,  net price 500 mL = £5.75   Dose for dry skin conditions, including eczema, add 1-2 capfuls/  bath (CHILD !4-l capful) or apply to wet skin and rinse   Bath emollient, acetylated wool alcohols 5%, liquid  paraffin 65%, net price 500 mL = £3.44   Dose for dermatitis, dry skin conditions including ichthyosis and  pruritus of the elderly; add 15-20 mL/bath (INFANT and CHILD 5-  10 mL) or apply to wet skin and rinse   Bath additive, isopropyl myristate 39%, light liquid  paraffin 46%, net price 500 mL = £6.71   Emollient bath additive, liquid paraffin 65%, net  price 500 mL = £5.45   Dose for dry skin conditions including dermatitis, ichthyosis, and  pruritus of the elderly; add 15-20 mL/bath, (INFANT and CHILD 5-  10 mL)   Emollient shower gel, isopropyl myristate 15%, liquid  paraffin 15%, net price 200 g = £5.21   Emollient bath oil, cetyl dimeticone 5%, liquid par-  affin 91%, net price 250 mL = £3.19, 500 mL = £5.11   Dose ACBS: for endogenous and exogenous eczema, xeroderma,  ichthyosis, and senile pruritus (pruritus of the elderly) associated  with dry skin; add 15 mL/bath (CHILD 5-10 mL) or apply to wet  skin and rinse   Emollient wash cream, soap substitute, zinc oxide  5% in an emollient basis, net price 250-mL pump pack  = £3.19   Excipients none as listed in section 13.1.3  ACBS: for endogenous and exogenous eczema, xeroderma,  ichthyosis and senile pruritus (pruritus of the elderly) associated  with dry skin   Bath and shower emollient, isopropyl myristate  13%, light liquid paraffin 37.8%, net price 350 mL =  £3.61, 500 mL = £4.11, 1 litre = £8.19   Excipients none as listed in section 13.1.3  Dose for dry skin conditions including eczema, ichthyosis and  pruritus of the elderly; add 1-3 capfuls/bath (INFANT 14-2 capfuls)  or apply to wet skin and rinse   Emollient bath additive (emulsion), light liquid par-  affin 63.4%, net price 250 mL = £2.75, 500 mL = £4.57   Dose for dry skin conditions including dermatitis, pruritus of the  elderly and ichthyosis; add 1-3 capfuls/bath (INFANT 0.5-2 cap-  fuls) or apply to wet skin and rinse   Junior bath additive, light liquid paraffin 63.4%, net  price 150 mL = £2.82, 250 mL = £3.25, 300 mL =  £5.10, 600 mL = £5.89   Excipients include acetylated lanolin alcohols, isopropyl palmitate  Dose for dry skin conditions including dermatitis, pruritus of the  elderly and ichthyosis; add 1-3 capfuls/bath (INFANT 0.5-2 cap-  fuls) or apply to wet skin and rinse   Shower emollient (gel), light liquid paraffin 70%, net  price (with fragrance or fragrance-free) 150 g = £5.15  For dry skin conditions including dermatitis   Bath oil, light liquid paraffin 85.09%, net price 200 mL  = £2.20, 500 mL = £4.50   Dose for dry skin conditions including eczema, ichthyosis, and  pruritus of the elderly, add 10 mL/bath (CHILD 7 mL, INFANT 4 mL)  or apply to wet skin and rinse   For dry skin conditions including eczema, psoriasis, ichthyosis,  and pruritus, use as soap substitute   Emollient medicinal bath oil, liquid paraffin 65%,  acetylated wool alcohols 5%, net price 500 mL =  £4.79   Dose for dry skin conditions including dermatitis, pruritus of the  elderly, and ichthyosis, add 15-20 mL/bath (CHILD 5-10 mL)   Bath oil, refined soya bean oil 83.35%, net price  500 mL = £4.48   Dose for dry skin conditions including eczema and dermatitis,  add 20-60 mL/bath (CHILD 5-15 mL)   Bath additive, light liquid paraffin 51.66%, benz-  alkonium chloride 6%, triclosan 2%, net price 500 mL  = £5.81   Dose for prophylactic management of eczema at risk from  infection, add 1-2 capfuls/bath (INFANT over 6 months, 1 mL); do  not use undiluted    Barrier preparations often contain water-repellent sub-  stances such as dimeticone or other silicones. They are  used on the skin around stomas, bedsores, and pressure  areas in the elderly where the skin is intact. Where the  skin has broken down, barrier preparations have a  limited role in protecting adjacent skin. They are no  substitute for adequate nursing care and it is doubtful if  they are any more effective than zinc ointments.   Bath oil, refined soya bean oil 83.45%, macrogol 4-  lauryl ether 15%, net price 500 mL = £5.55   Dose for dry skin conditions including eczema and dermatitis,  add 20-60 mL/bath (CHILD 5-15 mL), or apply to wet skin and  rinse   Dermol 600® Bath Emollient, benzalkonium chloride  0.5%, liquid paraffin 25%, isopropyl myristate 25%,  net price 600 mL = £7.55   Dose for dry and pruritic skin conditions including eczema and  dermatitis, add up to 30 mL/bath (INFANT up to 15 mL); do not use  undiluted   Dermol® 200 Shower Emollient, benzalkonium  chloride 0.1%, chlorhexidine hydrochloride 0.1%,  liquid paraffin 2.5%, isopropyl myristate 2.5%, net  price 200 mL = £3.55   Dose for dry and pruritic skin conditions including eczema and  dermatitis, apply to skin or use as soap substitute   Liquid emulsion, liquid paraffin 25%, isopropyl myr-  istate 25%, benzalkonium chloride 0.5%, net price  300 mL (with 15-mL measure) = £3.85, 1 litre (with 30-  mL measure) = £12.00   Dose for dry skin conditions including eczema and ichthyosis;  add 7-30 mL/bath or rub into dry skin until absorbed   Bath additive, benzalkonium chloride 6%, triclosan  2%, light liquid paraffin 52.5%, net price 500 mL =  £6.98   Excipients include acetylated lanolin alcohols, isopropyl palmitate  Dose for topical treatment of eczema including eczema at risk  from infection; add 1-2 capfuls/bath (INFANT over 6 months  1 mL); do not use undiluted    Nappy rash Barrier creams and ointments are used for  protection against nappy rash which is usually a local  dermatitis. The first line of treatment is to ensure that  nappies are changed frequently and that tightly fitting  water-proof pants are avoided. The rash may clear when  left exposed to the air and a barrier preparation can be  helpful. If the rash is associated with a fungal infection,  an antifungal cream such as clotrimazole cream (section  13.10.2) is useful. A mild corticosteroid such as hydro-  cortisone 1% is useful in moderate to severe inflamma-  tion, but it should be avoided in neonates. The barrier  preparation is applied after the corticosteroid prepara-  tion to prevent further damage. Hydrocortisone can be  used in combination with antifungal and antibacterial  drugs (section 13.4) if there is considerable inflamma-  tion, erosion, and infection. Preparations containing  hydrocortisone should be applied for no more than a  week; the hydrocortisone should be discontinued as  soon as the inflammation subsides. The occlusive effect  of nappies and water-proof pants may increase absorp-  tion (for cautions, see p. 708).   Cream, zinc oxide 32%, arachis (peanut) oil 32%,  calcium hydroxide 0.045%, oleic acid 0.5%, wool fat  8%, in freshly boiled and cooled purified water, net  price 50 g = 75p   Ointment, zinc oxide 15%, in Simple Ointment BP  1988 (which contains wool fat 5%, hard paraffin 5%,  cetostearyl alcohol 5%, white soft paraffin 85%), net  price 25 g = 30p   Ointment, zinc oxide 7.5%, castor oil 50%, arachis  (peanut) oil 30.5%, white beeswax 10%, cetostearyl  alcohol 2%, net price 500 g = £2.93  For nappy and urinary rash   Excipients include cetostearyl alcohol, fragrance  For nappy and urinary rash and pressure sores   Cream, benzalkonium chloride 0.01%, cetrimide 0.2%  in a basis containing white soft paraffin, cetyl alcohol  and wool fat, net price 100 g = £1.54, 200 g = £2.50,  350 g = £3.75   Excipients include cetyl alcohol, chlorocresol, wool fat  For nappy and urinary rash; minor wounds   Cream, cetrimide 0.5% in a basis containing light  liquid paraffin, white soft paraffin, cetostearyl alcohol,  glyceryl monostearate, net price 50 g = £1.69   Pruritus may be caused by systemic disease (such as  obstructive jaundice, endocrine disease, chronic renal  disease, iron deficiency, and certain malignant diseases),  skin disease (e.g. psoriasis, eczema, urticaria, and  scabies), drug hypersensitivity, or as a side-effect of  opioid analgesics. Where possible the underlying causes  should be treated. An emollient (section 13.2.1) maybe  of value where the pruritus is associated with dry skin.  Pruritus that occurs in otherwise healthy elderly people  can also be treated with an emollient. Levomenthol  cream can be used to relieve pruritus; it exerts a cooling  effect on the skin. For advice on the treatment of pru-  ritus in palliative care, see p. 22.   Preparations containing crotamiton are sometimes  used but are of uncertain value. Preparations containing  calamine are often ineffective.   Ointment, titanium dioxide 20%, titanium peroxide  5%, titanium salicylate 3% in a basis containing  dimeticone, light liquid paraffin, white soft paraffin,  and benzoin tincture, net price 30 g = £2.01   Ointment, cod-liver oil 11.4%, zinc oxide 38%, in a  basis containing liquid paraffin and yellow soft par-  affin, net price 50 g = £1.91   For minor wounds, varicose ulcers, pressure sores, eczema and  nappy rash   Barrier cream, dimeticone ‘1000’ 10%, cetrimide  0.3%, arachis (peanut) oil, net price 50 g = £2.15    A topical preparation containing doxepin 5% is licensed  for the relief of pruritus in eczema; it can cause drowsi-  ness and there may be a risk of sensitisation.   Pruritus is common in biliary obstruction, especially in  primary biliary cirrhosis and drug-induced cholestasis.  Oral administration of colestyramine is the treatment  of choice (section 1.9.2).   Topical antihistamines and local anaesthetics are only  marginally effective and occasionally cause sensitisa-  tion. For insect stings and insect bites, a short course of a  topical corticosteroid is appropriate. Short-term treat-  ment with a sedating antihistamine (section 3.4.1) may  help in insect stings and in intractable pruritus where  sedation is desirable. Calamine preparations are of little  value for the treatment of insect stings or bites.   Spray application, dimeticone 1.04%, zinc oxide  12.5%, in a basis containing wool alcohols, cetostearyl  alcohol, dextran, white soft paraffin, liquid paraffin,  propellants, net price 1 15-g pressurised aerosol unit =  £3.54    For urinary rash, pressure sores, leg ulcers, moist eczema, fissures,  fistulae and ileostomy care  Note Flammable   Cream, benzyl alcohol 0.39%, benzyl benzoate 1.01%,  benzyl cinnamate 0.15%, hydrous wool fat (hypoal-  lergenic lanolin) 4%, zinc oxide 15.25%, net price 30 g  = £1.13, 60g = £1.25, 125 g = £1.84, 250g = £3.09,  400 g = £4.34   Barrier cream, dimeticone 20%, calamine 1.5%, zinc  oxide 7.5%, net price 100 g = £2.72   Aqueous cream, calamine 4%, zinc oxide 3%, liquid  paraffin 20%, self-emulsifying glyceryl monostearate  5%, cetomacrogol emulsifying wax 5%, phenox-  yethanol 0.5%, freshly boiled and cooled purified  water 62.5%, net price 100 mL = 84p  Lotion (= cutaneous suspension), calamine 15%, zinc  oxide 5%, glycerol 5%, bentonite 3%, sodium citrate  0.5%, liquefied phenol 0.5%, in freshly boiled and  cooled purified water, net price 200 mL = 63p  Oily lotion (BP 1980), calamine 5%, arachis (peanut)  oil 50%, oleic acid 0.5%, wool fat 1%, in calcium  hydroxide solution, net price 200 mL = £1.57   • Pruritus, apply 2-3 times daily; CHILD under 3 years,  apply once daily   Cream, crotamiton 10%, net price 30 g = £2.38, 100 g  = £4.15   Excipients include cetyl alcohol, fragrance, propylene glycol, sorbic  acid, stearyl alcohol   Cautions susceptibility to angle-closure glaucoma,  urinary retention, mania, cardiac arrhythmias, severe  heart disease; avoid application to large areas; inter-  actions: Appendix 1 (antidepressants, tricyclic)  Driving Drowsiness may affect performance of skilled tasks  (e.g. driving); effects of alcohol enhanced   Side-effects drowsiness; local burning, stinging, irri-  tation, tingling and rash; systemic side-effects such as  antimuscarinic effects, headache, fever, dizziness,  gastro-intestinal disturbances also reported  Dose   • ADULT and CHILD over 12 years, apply thinly 3-4 times  daily; usual max. 3 g per application; usual total max.  12 g daily; coverage should be less than 10% of body  surface area   Cream, doxepin hydrochloride 5%, net price 30 g =  £11.70. Label: 2, 10, patient information leaflet   Cream, levomenthol 0.5%, net price 500 g = £15.30;  1% 100 g = £3.67, 500 g = £15.30; 2% 50-mL pump  pack = £3.19, 500 g = £15.30  Dose apply 1-2 times daily   Indications relief of local pain, see notes above. See  section 15.2 for use in surface anaesthesia  Cautions occasionally cause hypersensitivity  Note Topical local anaesthetic preparations may be  absorbed, especially through mucosal surfaces, therefore  excessive application should be avoided and they should  preferably not be used for more than about 3 days; not  generally suitable for young children   Cautions may cause hypersensitivity; avoid in eczema;  photosensitivity (diphenhydramine); not recom-  mended for longer than 3 days    Topical corticosteroids are used for the treatment of  inflammatory conditions of the skin (other than those  arising from an infection), in particular eczema (section  13.5.1), contact dermatitis, insect stings (p. 42), and  eczema of scabies (section 13.10.4). Corticosteroids  suppress the inflammatory reaction during use; they  are not curative and on discontinuation a rebound  exacerbation of the condition may occur. They are  generally used to relieve symptoms and suppress  signs of the disorder when other measures such as  emollients are ineffective.    Topical corticosteroids are of no value in the treatment  of urticaria and they are contra-indicated in rosacea;  they may worsen ulcerated or secondarily infected  lesions. They should not be used indiscriminately in  pruritus (where they will only benefit if inflammation  is causing the itch) and are not recommended for acne  vulgaris.   Systemic or potent topical corticosteroids should be  avoided or given only under specialist supervision in  psoriasis because, although they may suppress the psor-  iasis in the short term, relapse or vigorous rebound  occurs on withdrawal (sometimes precipitating severe  pustular psoriasis). Topical use of potent corticosteroids  on widespread psoriasis can lead to systemic as well as  to local side-effects. It is reasonable, however, to pre-  scribe a mild to moderate topical corticosteroid for a  short period (2-4 weeks) for flexural and facial psoriasis  and to use a more potent corticosteroid such as beta-  methasone or fluocinonide for psoriasis of the scalp,  palms, or soles (see below for cautions in psoriasis).   In general, the most potent topical corticosteroids  should be reserved for recalcitrant dermatoses such as  chronic discoid lupus erythematosus, lichen simplex  chronicus, hypertrophic lichen planus, and palmoplan-  tar pustulosis. Potent corticosteroids should generally  be avoided on the face and skin flexures, but specialists  occasionally prescribe them for use on these areas in  certain circumstances.    When topical treatment has failed, intralesional cortico-  steroid injections (section 10.1.2.2) maybe used. These  are more effective than the very potent topical cortico-  steroid preparations and should be reserved for severe  cases where there are localised lesions such as keloid  scars, hypertrophic lichen planus, or localised alopecia  areata.   Perioral lesions Hydrocortisone cream 1% can be  used for up to 7 days to treat uninfected inflammatory  lesions on the lips. Hydrocortisone and miconazole  cream or ointment is useful where infection by suscep-  tible organisms and inflammation co-exist, particularly  for initial treatment (up to 7 days) e.g. in angular cheilitis  (see also p. 695). Organisms susceptible to miconazole  include Candida spp. and many Gram-positive bacteria  including streptococci and staphylococci.   Children Children, especially infants, are particularly  susceptible to side-effects. However, concern about the  safety of topical corticosteroids in children should not  result in the child being undertreated. The aim is to  control the condition as well as possible; inadequate  treatment will perpetuate the condition. A mild cortico-  steroid such as hydrocortisone 1% ointment or cream is  useful for treating nappy rash (section 13.2.2) and for    atopic eczema in childhood (section 13.5.1). A moder-  ately potent or potent corticosteroid may be appropriate  for severe atopic eczema on the limbs, for 1-2 weeks  only, switching to a less potent preparation as the  condition improves. In an acute flare-up of atopic ecz-  ema, it may be appropriate to use more potent formula-  tions of topical corticosteroids for a short period to  regain control of the condition. A very potent cortico-  steroid should be initiated under the supervision of a  specialist. Continuous daily application of a mild  corticosteroid such as hydrocortisone 1% is equivalent  to a potent corticosteroid such as betamethasone 0.1%  applied intermittently. Carers of young children should  be advised that treatment should not necessarily be  reserved to ‘treat only the worst areas’ and they may  need to be advised that patient information leaflets may  contain inappropriate advice for the patient’s condition.   Choice of formulation Water-miscible corticosteroid  creams are suitable for moist or weeping lesions  whereas ointments are generally chosen for dry, liche-  nified or scaly lesions or where a more occlusive effect  is required. Lotions may be useful when minimal appli-  cation to a large or hair-bearing area is required or for  the treatment of exudative lesions. Occlusive polythene  or hydrocolloid dressings increase absorption, but also  increase the risk of side-effects; they are therefore used  only under supervision on a short-term basis for areas of  very thick skin (such as the palms and soles). The  inclusion of urea or salicylic acid also increases the  penetration of the corticosteroid.    Cautions Avoid prolonged use of a topical cortico-  steroid on the face (and keep away from eyes). In  children avoid prolonged use and use potent or very  potent corticosteroids under specialist supervision;  extreme caution is required in dermatoses of infancy  including nappy rash — treatment should be limited to 5-  7 days.   Psoriasis The use of potent or very potent corticosteroids in  psoriasis can result in rebound relapse, development of gen-   In order to minimise the side-effects of a topical  corticosteroid, it is important to apply it thinly to  affected areas only, no more frequently than twice  daily, and to use the least potent formulation which  is fully effective.    Application Topical corticosteroid preparations  should be applied no more frequently than twice daily;  once daily is often sufficient.   Topical corticosteroids should be spread thinly on the  skin but in sufficient quantity to cover the affected areas.  The length of cream or ointment expelled from a tube  may be used to specify the quantity to be applied to a  given area of skin. This length can be measured in terms  of a fingertip unit (the distance from the tip of the adult  index finger to the first crease). One fingertip unit  (approximately 500 mg) is sufficient to cover an area  that is twice that of the flat adult palm.    Suitable quantities of corticosteroid pre-  parations to be prescribed for specific areas  of the body    These amounts are usually suitable for an adult for a  single daily application for 2 weeks    If a patient is using topical corticosteroids of different  potencies, the patient should be told when to use each  corticosteroid. The potency of each topical cortico-  steroid (see Topical Corticosteroid Preparation Poten-  cies, below) should be included on the label with the  directions for use. The label should be attached to the  container (for example, the tube) rather than the outer  packaging.   Mixing topical preparations on the skin should be  avoided where possible; several minutes should elapse  between application of different preparations.   Compound preparations The advantages of includ-  ing other substances (such as antibacterials or anti-  fungals) with corticosteroids in topical preparations  are uncertain, but such combinations may have a  place where inflammatory skin conditions are asso-  ciated with bacterial or fungal infection, such as infected  eczema. In these cases the antimicrobial drug should be  chosen according to the sensitivity of the infecting  organism and used regularly for a short period (typically  twice daily for 1 week). Longer use increases the like-  lihood of resistance and of sensitisation.   The keratolytic effect of salicylic acid facilitates the  absorption of topical corticosteroids; however, exces-  sive and prolonged use of topical preparations contain-  ing salicylic acid may cause salicylism.   Contra-indications Topical corticosteroids are con-  tra-indicated in untreated bacterial, fungal, or viral skin  lesions, in rosacea, and in perioral dermatitis; potent  corticosteroids are contra-indicated in widespread  plaque psoriasis (see notes above).   Side-effects Mild and moderately potent topical  corticosteroids are associated with few side-effects but  care is required in the use of potent and very potent  corticosteroids. Absorption through the skin can rarely  cause adrenal suppression and even Cushing’s  syndrome (section 6.3.2), depending on the area of the  body being treated and the duration of treatment.  Absorption is greatest where the skin is thin or raw,  and from intertriginous areas; it is increased by occlu-  sion. Local side-effects include:   • thinning of the skin which may be restored over a  period after stopping treatment but the original  structure may never return;   Potency of a topical corticosteroid preparation is a result of the  formulation as well as the corticosteroid. Therefore, proprie-  tary names are shown below.   • Mild with antimicrobials: Canesten HC, Daktacort,  Econacort, Fucidin H, Nystaform-HC, Timodine    years or for pregnant women; they should not be sold  for application to the face, anogenital region, broken  or infected skin (including cold sores, acne, and ath-  lete’s foot); over-the-counter hydrocortisone prepara-  tions containing clotrimazole or miconazole nitrate  can be sold to the public for athlete’s foot and candidal  intertrigo   Excipients include cetostearyl alcohol, propylene glycol  Note Although this contains only 0.1% hydrocortisone, the for-  mulation is designed to provide a clinical activity comparable to  that of Hydrocortisone Cream 1% BP   Betamethasone valerate 0.1%, Betacap, Betesil,  Bettamousse, Betnovate, Cutivate, Diprosone,  Elocon, Hydrocortisone butyrate, Locoid, Locoid  Crelo, Metosyn, Nerisone, Synalar   • Potent with antimicrobials: Aureocort, Betnovate-C,  Betnovate-N, Fucibet, Lotriderm, Synalar C,  Synalar N   Indications mild inflammatory skin disorders such as  eczemas (but for over-the-counter preparations, see  below); nappy rash, see notes above and section  13.2.2   Hydrocortisone (Non-proprietary) (Ml  Cream, hydrocortisone 0.5%, net price, 15 g = £1.92,  30 g = £5.19; 1%, 15 g = £1.64, 30 g = £1.99, 50 g =  £4.06; 2.5%, 15 g = £19.70. Label: 28, counselling,  application, see p. 708. Potency: mild  Dental prescribing on NHS Hydrocortisone Cream 1% 15 g may  be prescribed   Ointment, hydrocortisone 0.5%, net price 15 g =  £3.05, 30 g = £5.23; 1%, 15 g = £3.34, 30 g = £2.70,  50 g = £6.87; 2.5%, 15 g = £23.78. Label: 28, coun-  selling, application, see p. 708. Potency: mild  When hydrocortisone cream or ointment is prescribed and no  strength is stated, the 1% strength should be supplied   ^ Over-the-counter hydrocortisone preparations  Skin creams and ointments containing hydrocortisone  (alone or with other ingredients) can be sold to the  public for the treatment of allergic contact dermatitis,  irritant dermatitis, insect bite reactions and mild to  moderate eczema, to be applied sparingly over the  affected area 1-2 times daily for max. 1 week. Over-  the-counter hydrocortisone preparations should not  be sold without medical advice for children under 10    Alphaderm® (Alliance) (Ml  Cream, hydrocortisone 1%, urea 10%, net price 30 g =  £2.38; 100 g = £7.03. Label: 28, counselling, applica-  tion, see p. 708. Potency: moderate   Cream, hydrocortisone 1%, urea 10%, lactic acid 5%,  net price 30 g = £2.80, 50 g = £4.67. Label: 28, coun-  selling, application, see p. 708. Potency: moderate   Note If stinging occurs, manufacturer advises dilute to half-  strength with aqueous cream for 1 week then transfer to undi-  luted preparation (but see section 13.1.1 for advice to avoid  dilution where possible)    Cream, hydrocortisone 0.25%, crotamiton 10%, net  price 30 g = 87p. Label: 28, counselling, application,  see p. 708. Potency: mild   1. A 15-g tube is on sale to the public for treatment of contact  dermatitis and insect bites   Cream, hydrocortisone 1%, clotrimazole 1%, net price  30 g = £2.42. Label: 28, counselling, application, see  p. 708. Potency: mild   Excipients include benzyl alcohol, cetostearyl alcohol  1. A 15-g tube is on sale to the public for the treatment of  athlete’s foot and fungal infection of skin folds with  associated inflammation   Daktacort® (lanssen-Cilag) (Ml  Cream, hydrocortisone 1%, miconazole nitrate 2%,  net price 30 g = £2.28. Label: 28, counselling, appli-  cation, see p. 708. Potency: mild   Excipients include butylated hydroxyanisole, disodium edetate  Dental prescribing on NHS May be prescribed as Miconazole  and Hydrocortisone Cream for max. 7 days  Note A 15-g tube is on sale to the public for the treatment of  athlete’s foot and candidal intertrigo    Ointment, hydrocortisone 1%, miconazole nitrate 2%,  net price 30 g = £2.28. Label: 28, counselling, appli-  cation, see p. 708. Potency: mild   Cream, hydrocortisone acetate 1%, fusidic acid 2%,  net price 30 g = £4.99, 60 g = £9.98. Label: 28, coun-  selling, application, see p. 708. Potency: mild   Cream, hydrocortisone 0.5%, nystatin 100 000 units/  g, chlorhexidine hydrochloride 1%, net price 30 g =  £2.66. Label: 28, counselling, application, see p. 708.  Potency: mild   Ointment, hydrocortisone 1%, nystatin 100 000 units/  g, chlorhexidine acetate 1%, net price 30 g = £2.66.  Label: 28, counselling, application, see p. 708.  Potency: mild   Cream, hydrocortisone 0.5%, nystatin 100 000 units/  g, benzalkonium chloride solution 0.2%, dimeticone  ‘350’ 10%, net price 30 g = £2.03. Label: 28, counsel-  ling, application, see p. 708. Potency: mild   Excipients include butylated hydroxyanisole, cetostearyl alcohol,  hydroxybenzoates (parabens), sodium metabisulphite, sorbic acid   Indications severe inflammatory skin disorders such  as eczemas unresponsive to less potent corticoster-  oids; psoriasis, see notes above  Cautions see notes above   Cream, hydrocortisone butyrate 0.1%, net price 30 g =  £1.60, 100 g = £4.93. Label: 28, counselling, applica-  tion, see p. 708. Potency: potent   Lipocream, hydrocortisone butyrate 0.1%, net price  30 g = £1.69, 100 g = £5.17. Label: 28, counselling,  application, see p. 708. Potency: potent   Scalp lotion, hydrocortisone butyrate 0.1%, in an  aqueous isopropyl alcohol basis, net price 100 mL =  £6.83. Label: 15, 28, counselling, application, see  p. 708. Potency: potent   Locoid Crelo® (Astellas) (Ml  Lotion (topical emulsion), hydrocortisone butyrate  0.1% in a water-miscible basis, net price 100 g (with  applicator nozzle) = £5.91. Label: 28, counselling,  application, see p. 708. Potency: potent   Cream, alclometasone dipropionate 0.05%, net price  50 g = £2.68. Label: 28, counselling, application, see  p. 708. Potency: moderate   Ointment, alclometasone dipropionate 0.05%, net  price 50 g = £2.68. Label: 28, counselling, application,  see p. 708. Potency: moderate   Indications severe inflammatory skin disorders such  as eczemas unresponsive to less potent corticoster-  oids; psoriasis, see notes above  Cautions see notes above; use of more than 100 g per  week of 0.1% preparation likely to cause adrenal  suppression   Betamethasone Valerate (Non-proprietary) (Ml  Cream, betamethasone (as valerate) 0.1%, net price  30 g = £2.36, 100 g = £4.93. Label: 28, counselling,  application, see p. 708. Potency: potent  Ointment, betamethasone (as valerate) 0.1%, net  price 30 g = £2.27, 100 g = £4.67. Label: 28, counsel-  ling, application, see p. 708. Potency: potent   Scalp application, betamethasone (as valerate) 0.1%  in a water-miscible basis containing coconut oil deri-  vative, net price 100 mL = £3.75. Label: 15, 28,  counselling, application, see p. 708. Potency: potent   Excipients include disodium edetate, hydroxybenzoates (parabens)  Dose ADULT over 18 years, apply plaster to clean, dry skin once  daily; max. 6 plasters daily; max. duration of treatment 30 days  Counselling Leave at least 30 minutes between applications;  plasters may be cut; avoid water contact with plaster — take bath  or shower between applications; see also p. 708   Cream, betamethasone (as valerate) 0.1% in a water-  miscible basis, net price 30 g = £1.43, 100 g = £4.05.  Label: 28, counselling, application, see p. 708.  Potency: potent   Ointment, betamethasone (as valerate) 0.1% in an  anhydrous paraffin basis, net price 30g = £1.43, 100 g  = £4.05. Label: 28, counselling, application, see p. 708.  Potency: potent   Scalp application, betamethasone (as valerate) 0.1%  in a water-miscible basis, net price 100 mL = £4.99.  Label: 15, 28, counselling, application, see p. 708.  Potency: potent   Betnovate-RD® (GSK) (Ml  Cream, betamethasone (as valerate) 0.025% in a  water-miscible basis (1 in 4 dilution of Betnovate®  cream), net price 100 g = £3.15. Label: 28, counselling,  application, see p. 708. Potency: moderate   Ointment, betamethasone (as valerate) 0.025% in an  anhydrous paraffin basis (1 in 4 dilution of Betnovate®  ointment), net price 100 g = £3.15. Label: 28,  counselling, application, see p. 708. Potency: moder-  ate   Foam (= scalp application), betamethasone valerate  0.12% (= betamethasone 0.1%), net price 100 g =  £9.37. Label: 28, counselling, application, see p. 708.  Potency: potent   Excipients include cetyl alcohol, polysorbate 60, propylene glycol,  stearyl alcohol  Note Flammable   Diprosone® (Schering-Plough) (Ml  Cream, betamethasone (as dipropionate) 0.05%, net  price 30 g = £2.16, 100 g = £6.12. Label: 28, counsel-  ling, application, see p. 708. Potency: potent   Ointment, betamethasone (as dipropionate) 0.05%,  net price 30 g = £2.16, 100 g = £6.12. Label: 28,  counselling, application, see p. 708. Potency: potent   Lotion, betamethasone (as dipropionate) 0.05%, net  price 30 mL = £2.73, 100 mL = £7.80. Label: 28,  counselling, application, see p. 708. Potency: potent   Ointment, betamethasone (as dipropionate) 0.05%,  salicylic acid 3%, net price 30 g = £3.18, 100 g = £9.14.  Label: 28, counselling, application, see p. 708.  Potency: potent   Excipients none as listed in section 13.1.3  Dose apply thinly 1-2 times daily; max. 60 g per week  Scalp application, betamethasone (as dipropionate)  0.05%, salicylic acid 2%, in an alcoholic basis, net  price 100 mL = £10.10. Label: 28, counselling, appli-  cation, see p. 708. Potency: potent   Excipients include disodium edetate  Dose apply a few drops 1-2 times daily   Betnovate-C® (Chemidex) (Ml  Cream, betamethasone (as valerate) 0.1%, clioquinol  3%, net price 30 g = £1.76. Label: 28, counselling,  application, see p. 708. Potency: potent   Cream, betamethasone (as valerate) 0.1%, neomycin  sulphate 0.5%, net price 30 g = £1.76, 100 g = £4.88.  Label: 28, counselling, application, see p. 708.  Potency: potent   Ointment, betamethasone (as valerate) 0.1%, neo-  mycin sulphate 0.5%, net price 30 g = £1.76, 100 g =  £4.88. Label: 28, counselling, application, see p. 708.  Potency: potent   Cream, betamethasone (as valerate) 0.1%, fusidic acid  2%, net price 30 g = £5.29, 60 g = £10.58. Label: 28,  counselling, application, see p. 708. Potency: potent   Cream, betamethasone dipropionate 0.064% ( =  betamethasone 0.05%), clotrimazole 1%, net price  30 g = £6.34. Label: 28, counselling, application, see  p. 708. Potency: potent    Indications short-term treatment only of severe  resistant inflammatory skin disorders such as recal-  citrant eczemas unresponsive to less potent corti-  costeroids; psoriasis, see notes above  Cautions see notes above  Contra-indications see notes above  Side-effects see notes above  Dose    • Apply thinly 1-2 times daily for up to 4 weeks; max.  50 g of 0.05% preparation per week   Foam (= scalp application), clobetasol propionate  0.05%, net price 100 g = £11.06. Label: 15, 28, coun-  selling, application, see p. 708. Potency: very potent   Note Apply directly to scalp lesions (foam begins to subside  immediately on contact with skin)   Cream, clobetasol propionate 0.05%, net price 30 g =  £2.69, 100 g = £7.90. Label: 28, counselling, applica-  tion, see p. 708. Potency: very potent   Excipients include beeswax (or beeswax substitute), cetostearyl  alcohol, chlorocresol, propylene glycol   Ointment, clobetasol propionate 0.05%, net price 30 g  = £2.69, 100 g = £7.90. Label: 28, counselling, appli-  cation, see p. 708. Potency: very potent   Scalp application, clobetasol propionate 0.05%, in a  thickened alcoholic basis, net price 30 mL = £3.07,  100 mL = £10.42. Label: 15, 28, counselling, applica-  tion, see p. 708. Potency: very potent   Shampoo, clobetasol propionate 0.05%, net price  125 mL = £15.43. Label: 28, counselling, application,  see p. 708. Potency: very potent   Dose moderate scalp psoriasis, ADULT over 18 years, apply thinly  once daily, rinse off after 15 minutes; reduce frequency of appli-  cation after clinical improvement; max. duration of treatment 4  weeks   Cream, clobetasol propionate 0.05%, neomycin sul-  phate 0.5%, nystatin 100 000 units/g, net price 30 g =  £3.91. Label: 28, counselling, application, see p. 708.  Potency: very potent   Ointment, clobetasol propionate 0.05%, neomycin  sulphate 0.5%, nystatin 100 000 units/g, in a paraffin  basis, net price 30 g = £3.91. Label: 28, counselling,  application, see p. 708. Potency: very potent   Indications eczemas and dermatitis of all types;  maintenance between courses of more potent corti-  costeroids   Cream, clobetasone butyrate 0.05%, net price 30 g =  £1.86, 100 g = £5.44. Label: 28, counselling, applica-  tion, see p. 708. Potency: moderate    Ointment, clobetasone butyrate 0.05%, net price 30 g  = £1.86, 100 g = £5.44. Label: 28, counselling, appli-  cation, see p. 708. Potency: moderate   1 . Cream can be sold to the public for short-term symptomatic  treatment and control of patches of eczema and dermatitis  (but not seborrhoeic dermatitis) in adults and children over  12 years provided pack does not contain more than 15 g   Cream, clobetasone butyrate 0.05%, oxytetracycline  3% (as calcium salt), nystatin 100 000 units/g, net  price 30 g = £3.29. Label: 28, counselling, application,  see p. 708. Potency: moderate   Indications severe inflammatory skin disorders such  as eczemas unresponsive to less potent corticoster-  oids; high strength (0.3%), short-term treatment of  severe exacerbations; psoriasis, see notes above  Cautions see notes above  Contra-indications see notes above  Side-effects see notes above  Dose   • Apply thinly 1-2 times daily for up to 4 weeks (0.1%  preparations) or 2 weeks (0.3% preparations), redu-   Cream, diflucortolone valerate 0.1%, net price 30 g =  £1.59. Label: 28, counselling, application, see p. 708.  Potency: potent   Oily cream, diflucortolone valerate 0.1%, net price  30 g = £2.56. Label: 28, counselling, application, see  p. 708. Potency: potent   Ointment, diflucortolone valerate 0.1%, net price 30 g  = £1.59. Label: 28, counselling, application, see p. 708.  Potency: potent   Nerisone Forte® (Meadow) (Ml  Oily cream, diflucortolone valerate 0.3%, net price  15 g = £2.09. Label: 28, counselling, application, see  p. 708. Potency: very potent   Ointment, diflucortolone valerate 0.3%, net price 15 g  = £2.09. Label: 28, counselling, application, see p. 708.  Potency: very potent   Tape, polythene adhesive film impregnated with flu-  droxycortide 4 micrograms /cm 2 , net price 7.5 cm x  50 cm = £9.27, 7.5 cm x 200 cm = £24.95  Dose for chronic localised recalcitrant dermatoses (but not acute  or weeping), cut tape to fit lesion, apply to clean, dry skin shorn of  hair, usually for 12 hours daily   Indications inflammatory skin disorders such as  eczemas; psoriasis, see notes above  Cautions see notes above   Cream, fluocinolone acetonide 0.025%, net price 30 g  = £3.76, 100 g = £10.68. Label: 28, counselling,  application, see p. 708. Potency: potent    Gel, fluocinolone acetonide 0.025%, net price 30 g =  £5.56, 60 g = £10.02. For use on scalp and other hairy  areas. Label: 28, counselling, application, see p. 708.  Potency: potent   Ointment, fluocinolone acetonide 0.025%, net price  30 g = £3.76, 100 g = £10.68. Label: 28, counselling,  application, see p. 708. Potency: potent   Cream, fluocinolone acetonide 0.00625%, net price  50 g = £4.40. Label: 28, counselling, application, see  p. 708. Potency: moderate   Ointment, fluocinolone acetonide 0.00625%, net  price 50 g = £4.40. Label: 28, counselling, application,  see p. 708. Potency: moderate   Synalar 1 in 10 Dilution® (GP Pharma) (Mi  Cream, fluocinolone acetonide 0.0025%, net price  50 g = £4.16. Label: 28, counselling, application, see  p. 708. Potency: mild   Synalar C® (GP Pharma) (Mi  Cream, fluocinolone acetonide 0.025%, clioquinol  3%, net price 15 g = £2.42. Label: 28, counselling,  application, see p. 708. Potency: potent   Excipients include cetostearyl alcohol, disodium edetate, hydroxy-  benzoates (parabens), polysorbates, propylene glycol   Ointment, fluocinolone acetonide 0.025%, clioquinol  3%, net price 15 g = £2.42. Label: 28, counselling,  application, see p. 708. Potency: potent.   Synalar N® (GP Pharma) (Mi  Cream, fluocinolone acetonide 0.025%, neomycin  sulphate 0.5%, net price 30 g = £3.96. Label: 28,  counselling, application, see p. 708. Potency: potent   Ointment, fluocinolone acetonide 0.025%, neomycin  sulphate 0.5%, in a greasy basis, net price 30 g =  £3.96. Label: 28, counselling, application, see p. 708.  Potency: potent   Indications severe inflammatory skin disorders such  as eczemas unresponsive to less potent corticoster-  oids; psoriasis, see notes above  Cautions see notes above   FAPG cream, fluocinonide 0.05%, net price 25 g =  £3.30, 100 g = £11.12. Label: 28, counselling, appli-  cation, see p. 708. Potency: potent   Ointment, fluocinonide 0.05%, net price 25 g = £2.92,  100 g = £10.96. Label: 28, counselling, application, see  p. 708. Potency: potent   Indications severe inflammatory skin disorders such  as eczemas unresponsive to less potent corticoster-  oids; psoriasis, see notes above  Cautions see notes above   Ultralanum Plain® (Meadow) (Ml  Cream, fluocortolone caproate 0.25%, fluocortolone  pivalate 0.25%, net price 50 g = £2.95. Label: 28,  counselling, application, see p. 708. Potency: moder-  ate   Ointment, fluocortolone 0.25%, fluocortolone capro-  ate 0.25%, net price 50 g = £2.95. Label: 28, coun-  selling, application, see p. 708. Potency: moderate   Cream, fluticasone propionate 0.05%, net price 15 g =  £2.27, 30 g = £4.24. Label: 28, counselling, application,  see p. 708. Potency: potent   Ointment, fluticasone propionate 0.005%, net price  15 g = £2.27, 30 g = £4.24. Label: 28, counselling,  application, see p. 708. Potency: potent   Indications severe inflammatory skin disorders such  as eczemas unresponsive to less potent corticoster-  oids; psoriasis, see notes above  Cautions see notes above   • Apply thinly once daily (to scalp in case of lotion)   Cream, mometasone furoate 0.1%, net price 30 g =  £4.36, 100 g = £12.58. Label: 28, counselling, appli-  cation, see p. 708. Potency: potent   Ointment, mometasone furoate 0.1%, net price 30 g =  £4.32, 100 g = £12.44. Label: 28, counselling, appli-  cation, see p. 708. Potency: potent   Scalp lotion, mometasone furoate 0.1% in an  aqueous isopropyl alcohol basis, net price 30 mL =  £4.36. Label: 28, counselling, application, see p. 708.  Potency: potent   Indications severe inflammatory skin disorders such  as eczemas unresponsive to less potent corticoster-  oids; psoriasis, see notes above   Ointment, triamcinolone acetonide 0.1%, chlortetra-  cycline hydrochloride 3%, in an anhydrous greasy  basis containing wool fat and white soft paraffin, net  price 15 g = £2.70. Label: 28, counselling, application,  see p. 708. Potency: potent    Eczema (dermatitis) has several causes, which may  influence treatment. The main types of eczema are  irritant, allergic contact, atopic, venous and discoid;  different types may co-exist. Lichenification, due to  scratching and rubbing, may complicate any chronic  eczema. Atopic eczema is the most common type and it  usually involves dry skin as well as infection and liche-  nification.   Management of eczema involves the removal or treat-  ment of contributory factors including occupational and  domestic irritants. Known or suspected contact aller-  gens should be avoided. Rarely, ingredients in topical  medicinal products may sensitise the skin; the BNF lists  active ingredients together with excipients that have  been associated with skin sensitisation.    Skin dryness and the consequent irritant eczema  requires emollients (section 13.2.1) applied regularly  and liberally to the affected area; this can be supple-  mented with bath or shower emollients. The use of  emollients should continue even if the eczema improves  or if other treatment is being used.   Topical corticosteroids (section 13.4) are also required  in the management of eczema; the potency of the  corticosteroid should be appropriate to the severity  and site of the condition. Mild corticosteroids are gen-  erally used on the face and on flexures; potent corti-  costeroids are generally required for use on adults with  discoid or lichenified eczema or with eczema on the  scalp, limbs, and trunk. Treatment should be reviewed  regularly, especially if a potent corticosteroid is  required. In patients with frequent flares (2-3 per  month), a topical corticosteroid can be applied on 2  consecutive days each week to prevent further flares.    Bandages (including those containing zinc and ichth-  ammol) are sometimes applied over topical corticoster-  oids or emollients to treat eczema of the limbs.   For the role of topical pimecrolimus and tacrolimus in  atopic eczema see section 13.5.3.   Infection Bacterial infection (commonly with Staphy-  lococcus aureus and occasionally with Streptococcus  pyogenes ) can exacerbate eczema and requires treat-  ment with topical or systemic antibacterial drugs  (section 13.10.1 and section 5.1). Antibacterial drugs,  particularly fusidic acid, should be used in short courses  (typically 1 week) to reduce the risk of drug resistance or  skin sensitisation. Associated eczema is treated simul-  taneously with a topical corticosteroid usually of mod-  erate or high potency.   Eczema involving widespread or recurrent infection  requires the use of a systemic antibacterial that is active  against the infecting organism. Products that combine  an antiseptic with an emollient application (section   13.2.1) and with a bath emollient (section 13.2.1.1)  can also be used; antiseptic shampoos (section 13.9)  can be used on the scalp.   Intertriginous eczema commonly involves Candida and  bacteria; it is best treated with a mild or moderately  potent topical corticosteroid and a suitable anti-  microbial drug.   Widespread herpes simplex infection may complicate  atopic eczema and treatment with a systemic antiviral  drug (section 5.3.2. 1) is indicated.   Management of other features of eczema Liche-  nification, which results from repeated scratching is  treated initially with a potent corticosteroid. Bandages  containing ichthammol paste (to reduce pruritus) and  other substances such as zinc oxide can be applied over  the corticosteroid or emollient. Coal tar (section 13.5.2)  and ichthammol can be useful in some cases of chronic  eczema.   A non-sedating antihistamine (section 3.4.1) maybe of  some value in relieving severe itching or urticaria asso-  ciated with eczema. A sedating antihistamine (section   3.4.1) can be used if itching causes sleep disturbance.  Exudative Sweeping’) eczema requires a potent cortico-  steroid initially; infection may also be present and  require specific treatment (see above). Potassium per-  manganate solution (1 in 10 000) can be used in exu-  dating eczema for its antiseptic and astringent effects;  treatment should be stopped when exudation stops.   Severe refractory eczema Severe refractory eczema  is best managed under specialist supervision; it may  require phototherapy or drugs that act on the immune  system (section 13.5.3). Alitretinoin (see p. 715) is  licensed for the treatment of severe chronic hand ecz-  ema refractory to potent topical corticosteroids;  patients with hyperkeratotic features are more likely to  respond to alitretinoin than those with pompholyx.   Seborrhoeic dermatitis Seborrhoeic dermatitis  [seborrhoeic eczema) is associated with species of the  yeast Malassezia and affects the scalp, paranasal areas,  and eyebrows. Shampoos active against the yeast  (including those containing ketoconazole and coal tar,  section 13.9) and combinations of mild corticosteroids  with suitable antimicrobials (section 13.4) are used.   Cream, ichthammol 5%, cetostearyl alcohol 3%, wool  fat 10%, in zinc cream   The retinoid, alitretinoin, is licensed for the treatment  of severe chronic hand eczema refractory to potent  topical corticosteroids; patients with hyperkeratotic fea-  tures are more likely to respond to alitretinoin than  those with pompholyx.   Alitretinoin should be prescribed only by, or under the  supervision of, a consultant dermatologist.   Alitretinoin is teratogenic and must not be given to  women of child-bearing potential unless they practise  effective contraception and then only after detailed  assessment and explanation by the physician. See also  Pregnancy Prevention under Cautions, below.   Alitretinoin for the treatment of severe  chronic hand eczema in adults (August  2009)   Alitretinoin is recommended for the treatment of  severe chronic hand eczema that has not responded  to potent topical corticosteroids. Treatment should  be stopped as soon as an adequate response has  been achieved (hands clear or almost clear), or if the  eczema remains severe after 12 weeks, or if an  adequate response has not been achieved by 24  weeks.   Cautions avoid blood donation during treatment and  for at least 1 month after stopping treatment; monitor  serum lipids (more frequently in those with diabetes,  history of hyperlipidaemia, or risk factors for cardio-  vascular disease) — discontinue if uncontrolled hyper-  lipidaemia; history of depression; dry eye syndrome;  interactions: Appendix 1 (retinoids)   Pregnancy prevention In women of child-bearing poten-  tial, exclude pregnancy 1 month before treatment, up to 3  days before treatment, every month during treatment (unless  there are compelling reasons to indicate that there is no risk  of pregnancy), and 5 weeks after stopping treatment — per-  form pregnancy test in the first 3 days of the menstrual cycle.  Women must practise effective contraception for at least 1  month before starting treatment, during treatment, and for at  least 1 month after stopping treatment. Women should be    advised to use at least 1 method of contraception but ideally  they should use 2 methods of contraception. Oral proges-  togen-only contraceptives are not considered effective.  Barrier methods should not be used alone but can be used in  conjunction with other contraceptive methods. Each pre-  scription for alitretinoin should be limited to a supply of up to  30 days’ treatment and dispensed within 7 days of the date  stated on the prescription. Women should be advised to  discontinue treatment and to seek prompt medical attention  if they become pregnant during treatment or within 1 month  of stopping treatment   Breast-feeding manufacturer advises avoid  Side-effects raised serum concentration of tri-  glycerides and of cholesterol (risk of pancreatitis if  triglycerides above 9 mmol/litre), flushing; headache;  changes in thyroid function tests; anaemia; myalgia,  raised creatine kinase, arthralgia; conjunctivitis, dry  eyes (may respond to lubricating eye ointment or tear  replacement therapy) — sometimes decreased toler-  ance to contact lenses, eye irritation; dryness of skin  and lips, cheilitis, erythema, alopecia; less commonly  epistaxis, hyperostosis, ankylosing spondylitis,  blurred vision, cataracts, pruritus, and asteototic  eczema; rarely benign intracranial hypertension (dis-  continue if severe headache, nausea, vomiting, papil-  loedema, or visual disturbances occur) and vasculitis;  also reported keratitis and impaired night vision  Dose   • ADULT over 18 years, 30 mg once daily, reduced to  10 mg once daily if not tolerated; patients with dia-  betes, history of hyperlipidaemia, or risk factors for  cardiovascular disease, initially 10 mg once daily,  increased if necessary up to max. 30 mg daily  Note Duration of treatment 12-24 weeks; discontinue if no  response after 12 weeks. Course may be repeated in those  who relapse. See also Pregnancy Prevention, above   Capsules, alitretinoin 10 mg (brown), net price 30-cap  pack = £411.43; 30 mg (red-brown), 30-cap pack =  £411.43. Label: 10, patient information leaflet, 11, 21    Psoriasis is characterised by epidermal thickening and  scaling. It commonly affects extensor surfaces and the  scalp. For mild psoriasis, reassurance and treatment  with an emollient may be all that is necessary.    Occasionally psoriasis is provoked or exacerbated by  drugs such as lithium, chloroquine and hydroxychloro-  quine, beta-blockers, non-steroidal anti-inflammatory  drugs, and ACE inhibitors. Psoriasis may not be seen  until the drug has been taken for weeks or months.    Emollients (section 13.2.1), in addition to their effects  on dryness, scaling and cracking, may have an anti-  proliferative effect in psoriasis. They are particularly  useful in inflammatory psoriasis and in plaque psoriasis  of palms and soles, in which irritant factors can perpe-  tuate the condition. Emollients are useful adjuncts to  other more specific treatment.    More specific topical treatment for chronic stable  plaque psoriasis on extensor surfaces of trunk and  limbs involves the use of vitamin D analogues, coal  tar, dithranol, and the retinoid tazarotene. However,  they can irritate the skin and they are not suitable for the  more inflammatory forms of psoriasis; their use should  be suspended during an inflammatory phase of psor-  iasis. The efficacy and the irritancy of each substance  varies between patients. If a substance irritates signifi-  cantly, it should be stopped or the concentration  reduced; if it is tolerated, its effects should be assessed  after 4 to 6 weeks and treatment continued if it is  effective.    Widespread unstable psoriasis of erythrodermic or gen-  eralised pustular type requires urgent specialist assess-  ment. Initial topical treatment should be limited to using  emollients frequently and generously; emollients should  be prescribed in quantities of 1 kg or more. More loca-  lised acute or subacute inflammatory psoriasis with hot,  spreading or itchy lesions, should be treated topically  with emollients or with a corticosteroid of moderate  potency.   Calcipotriol and tacalcitol are analogues of vitamin D  that affect cell division and differentiation. Calcitriol is  an active form of vitamin D. Vitamin D and its analogues  are used as first-line treatment for plaque psoriasis; they  do not smell or stain and they may be more acceptable  than tar or dithranol products. Of the vitamin D analo-  gues, tacalcitol and calcitriol are less likely to irritate.  Coal tar has anti-inflammatory properties that are use-  ful in chronic plaque psoriasis; it also has antiscaling  properties. Crude coal tar (coal tar, BP) is the most  effective form, typically in a concentration of 1 to 10%  in a soft paraffin base, but few outpatients tolerate the  smell and mess. Cleaner extracts of coal tar included in  proprietary preparations, are more practicable for home  use but they are less effective and improvement takes  longer. Contact of coal tar products with normal skin is  not normally harmful and they can be used for wide-  spread small lesions; however, irritation, contact allergy,  and sterile folliculitis can occur. The milder tar extracts  can be used on the face and flexures. Tar baths and tar  shampoos are also helpful.   Dithranol is effective for chronic plaque psoriasis. Its  major disadvantages are irritation (for which individual  susceptibility varies) and staining of skin and of clothing.  It should be applied to chronic extensor plaques only,  carefully avoiding normal skin. Dithranol is not gener-  ally suitable for widespread small lesions nor should it  be used in the flexures or on the face. Treatment should  be started with a low concentration such as dithranol  0.1%, and the strength increased gradually every few  days up to 3%, according to tolerance. Proprietary  preparations are more suitable for home use; they are  usually washed off after 5 to 60 minutes (‘short con-  tact’). Specialist nurses may apply intensive treatment  with dithranol paste which is covered by stockinette  dressings and usually retained overnight. Dithranol  should be discontinued if even a low concentration  causes acute inflammation; continued use can result  in the psoriasis becoming unstable. When applying dith-  ranol, hands should be protected by gloves or they  should be washed thoroughly afterwards.    Tazarotene, a retinoid, seems to be less effective than  calcipotriol with a greater incidence of irritation.  Although irritation is common, it is minimised by apply-  ing tazarotene sparingly to the plaques and avoiding  normal skin. Tazarotene is clean and odourless.    A topical corticosteroid (section 13.4) is not generally  suitable as the sole treatment of extensive chronic  plaque psoriasis; any early improvement is not usually  maintained and there is a risk of the condition deterior-  ating or of precipitating an unstable form of psoriasis  (e.g. erythrodermic psoriasis or generalised pustular  psoriasis). However, it may be appropriate to treat psor-  iasis in specific sites, such as the face and flexures,  usually with a mild corticosteroid, and psoriasis of the  scalp, palms, and soles with a potent corticosteroid.  Combining the use of a corticosteroid with another  specific topical treatment may be beneficial in chronic  plaque psoriasis; the drugs may be used separately at  different times of the day or used together in a single  formulation. Eczema co-existing with psoriasis may be  treated with a corticosteroid, or coal tar, or both.   Scalp psoriasis is usually scaly, and the scale may be  thick and adherent. This requires softening with an  emollient ointment, cream, or oil and usually combined  with salicylic acid as a keratolytic.   Some preparations prescribed for psoriasis affecting the  scalp combine salicylic acid with coal tar or sulphur.  Preparations containing salicylic acid, sulphur, and coal  tar are available as proprietary products. The product  should be applied generously and an adequate quantity  should be prescribed. It should be left on for at least an  hour, often more conveniently overnight, before wash-  ing it off. If a corticosteroid lotion or gel is required (e.g.  for itch), it can be used in the morning.   Phototherapy Phototherapy is available in specialist  centres under the supervision of a dermatologist. Ultra-  violet B (UVB) radiation is usually effective for chronic  stable psoriasis and for guttate psoriasis. It may be  considered for patients with moderately severe psoriasis  in whom topical treatment has failed, but it may irritate  inflammatory psoriasis.   Photochemotherapy combining long-wave ultraviolet  A radiation with a psoralen (PUVA) is available in  specialist centres under the supervision of a dermatol-  ogist. The psoralen, which enhances the effect of irra-  diation, is administered either by mouth or topically.  PUVA is effective in most forms of psoriasis, including  localised palmoplantar pustular psoriasis. Early  adverse effects include phototoxicity and pruritus. High-  er cumulative doses exaggerate skin ageing, increase  the risk of dysplastic and neoplastic skin lesions, espe-  cially squamous cancer, and pose a theoretical risk of  cataracts.   Phototherapy combined with coal tar, dithranol, tazar-  otene, topical vitamin D or vitamin D analogues, or oral  acitretin, allows reduction of the cumulative dose of  phototherapy required to treat psoriasis.   Systemic treatment Systemic treatment is required  for severe, resistant, unstable or complicated forms of  psoriasis, and it should be initiated only under specialist  supervision. Systemic drugs for psoriasis include acitre-  tin (see below) and drugs that affect the immune  response (such as ciclosporin and methotrexate, section  13.5.3).   Systemic corticosteroids should be used only rarely in  psoriasis because rebound deterioration may occur on  reducing the dose.   Acitretin, a metabolite of etretinate, is a retinoid (vit-  amin A derivative); it is prescribed by specialists. The  main indication for acitretin is psoriasis, but it is also  used in disorders of keratinisation such as severe    Darier’s disease (keratosis follicularis), and some forms  of ichthyosis. Although a minority of cases of psoriasis  respond well to acitretin alone, it is only moderately  effective in many cases and it is combined with other  treatments. A therapeutic effect occurs after 2 to 4  weeks and the maximum benefit after 4 to 6 weeks or  longer. The manufacturers of acitretin do not recom-  mend continuous treatment for longer than 6 months.  However, some patients may benefit from longer treat-  ment, provided that the lowest effective dose is used,  patients are monitored carefully for adverse effects, and  the need for treatment is reviewed regularly.   Apart from teratogenicity, which remains a risk for 3  years after stopping, acitretin is the least toxic systemic  treatment for psoriasis; in women with a potential for  child-bearing, the possibility of pregnancy must be  excluded before treatment and effective contraception  must be used during treatment and for at least 3 years  afterwards (oral progestogen-only contraceptives not  considered effective). Common side-effects derive  from its widespread but reversible effects on epithelia,  such as dry and cracking lips, dry skin and mucosal  surfaces, hair thinning, paronychia, and soft and sticky  palms and soles.   Calcipotriol, calcitriol, and tacalcitol are used for the  management of plaque psoriasis. They should be  avoided by those with calcium metabolism disorders,  and used with caution in generalised pustular or ery-  throdermic exfoliative psoriasis (enhanced risk of hyper-  calcaemia). Local skin reactions (itching, erythema,  burning, paraesthesia, dermatitis) are common. Hands  should be washed thoroughly after application to avoid  inadvertent transfer to other body areas. Aggravation of  psoriasis has also been reported.   Indications see under Dose  Cautions see notes above; avoid use on face; avoid  excessive exposure to sunlight and sunlamps   Breast-feeding no information available  Side-effects see notes above; also photosensitivity,  dry skin; rarely facial or perioral dermatitis, skin  atrophy   • Plaque psoriasis, apply cream or ointment once or  twice daily; max. 100 g weekly (less with scalp solu-  tion, see below); CHILD over 6 years, apply twice daily;  6-12 years max. 50 g weekly; over 12 years max. 75 g  weekly   • Scalp psoriasis, apply scalp solution twice daily; max.  60 mL weekly (less with cream or ointment, see  below); CHILD under 18 years see BNF for Children  Note When preparations used together max. total calcipo-  triol 5 mg in any one week (e.g. scalp solution 60 mL with  cream or ointment 30 g or cream or ointment 60 g with scalp  solution 30 mL)    Calcipotriol (Non-proprietary) (Ml  Ointment, calcipotriol 50 micrograms/g, net price  120 g =£24.04   Note Not licensed for use in children under 18 years  Scalp solution, calcipotriol 50 micrograms /mL, net  price 60 mL = £12.53, 120 mL = £26.07  Dovonex® (LEO) (Ml   Cream, calcipotriol (as hydrate) 50 micrograms/g, net  price 60 g = £11.55, 120 g = £22.66   Scalp solution, calcipotriol (as hydrate) 50micr-  ograms/mL, net price 60 mL = £12.29, 120 mL =  £26.07   For prescribing information and for comment on the limited  role of corticosteroids in psoriasis, see section 13.4.   Ointment, betamethasone (as dipropionate) 0.05%,  calcipotriol (as monohydrate) 50 micrograms/g, net  price 60 g = £32.99, 120 g = £61.27. Label: 28   Excipients none as listed in section 13.1.3  Dose stable plaque psoriasis, apply once daily to max. 30% of  body surface (max. 15 g daily, max. 100 g weekly) for 4 weeks; if  necessary subsequent courses repeated on the advice of a spe-  cialist; CHILD under 18 years see BNF for Children  Gel, betamethasone (as dipropionate) 0.05%, cal-  cipotriol (as monohydrate) 50 micrograms/g, net  price 60 g = £36.50, 2 x 60 g = £67.79. Label: 28   Excipients include butylated hydroxytoluene  Dose scalp psoriasis, ADULT over 18 years, apply 1-4 g to scalp  once daily shampoo off after leaving on scalp overnight or during  day; usual duration of therapy 4 weeks; if necessary, subsequent  courses repeated on the advice of a specialist  Mild to moderate plaque psoriasis, ADULT over 18 years, apply  once daily to max. 30% of body surface (max. 15 g daily, max.  100 g weekly) for 8 weeks; if necessary, subsequent courses  repeated on the advice of a specialist  Note When different preparations containing calcipotriol used  together, max. total calcipotriol 5 mg in any one week   Scalp gel, betamethasone (as dipropionate) 0.05%,  calcipotriol (as monohydrate) 50 micrograms/g, net  price 60 g = £36.50. Label: 28   Excipients include butylated hydroxytoluene  Dose scalp psoriasis, ADULT over 18 years, apply 1-4 g to scalp  once daily, shampoo off after leaving on scalp overnight or during  day; usual duration of therapy 4 weeks; if necessary, subsequent  courses repeated on the advice of a specialist; CHILD under 18  years see BNF for Children   Note When different preparations containing calcipotriol used  together, max. total calcipotriol 5 mg in any one week   Indications mild to moderate plaque psoriasis  Cautions see notes above  Contra-indications see notes above; do not apply  under occlusion   • ADULT and CHILD over 12 years, apply twice daily; not  more than 35% of body surface to be treated daily,  max. 30 g daily   Cautions see notes above; avoid eyes; monitor plasma  calcium if risk of hypercalcaemia; if used in conjunc-  tion with UV treatment, UV radiation should be given  in the morning and tacalcitol applied at bedtime   • ADULT and CHILD over 12 years, apply once daily  preferably at bedtime; max. 10 g ointment or 10 mL  lotion daily   Note When lotion and ointment used together, max. total  tacalcitol 280 micrograms in any one week (e.g. lotion 30 mL  with ointment 40 g)   Ointment, tacalcitol (as monohydrate) 4 micrograms/  g, net price 30 g = £13.40, 60 g = £23.14, 100 g =  £30.86   Indications mild to moderate plaque psoriasis affect-  ing up to 10% of skin area  Cautions wash hands immediately after use, avoid  contact with eyes, face, intertriginous areas, hair-  covered scalp, eczematous or inflamed skin; avoid  excessive exposure to UV light (including sunlight,  solariums, PUVA or UVB treatment); do not apply  emollients or cosmetics within 1 hour of application  Pregnancy avoid; effective contraception required  (oral progestogen-only contraceptives not considered  effective)    Side-effects local irritation (more common with  higher concentration and may require discontinua-  tion), pruritus, burning, erythema, desquamation,  non-specific rash, contact dermatitis, and worsening  of psoriasis; rarely stinging and inflamed, dry or  painful skin  Dose    • Apply once daily in the evening usually for up to 12  weeks; CHILD under 18 years not recommended   Gel, tazarotene 0.05%, net price 30 g = £14.09; 0.1%,  30 g = £14.80   Excipients include benzyl alcohol, butylated hydroxyanisole, butylated  hydroxytoluene, disodium edetate, polysorbate 40   Contra-indications not for use in sore, acute, or  pustular psoriasis or in presence of infection; avoid  eyes, mucosa, genital or rectal areas; broken or  inflamed skin   Side-effects skin irritation and acne-like eruptions,  photosensitivity; stains skin, hair, and fabric   Note For shampoo preparations see section 13.9; for use with  dressings see Appendix 8 (section A8.8.9)   May be difficult to obtain. Patients may find newer proprietary  preparations more acceptable   Ointment, calamine 12.5 g, strong coal tar solution  2.5 g, zinc oxide 12.5 g, hydrous wool fat 25 g, white  soft paraffin 47.5 g   Ointment, coal tar 2g, salicylic acid 2g, emulsifying  wax 1 1.4 g, white soft paraffin 19 g, coconut oil 54 g,  polysorbate ‘80’ 4g, liquid paraffin 7.6 g   Paste, zinc oxide 6%, coal tar 6%, emulsifying wax  5%, starch 38%, yellow soft paraffin 45%   Cream, coal tar solution 10%, in a water-miscible  basis, net price 30 g = £4.77, 100 g = £16.38   Scalp ointment, coal tar solution 12%, salicylic acid  2%, precipitated sulphur 4%, in a coconut oil emoll-  ient basis, net price 40 g (with applicator nozzle) =  £5.98, 100 g = £11.23   Dose scaly scalp disorders including psoriasis, eczema, seborr-  hoeic dermatitis and dandruff, apply to scalp once weekly as  necessary (if severe use daily for first 3-7 days), shampoo off after  1 hour; CHILD 6-12 years, medical supervision required (not  recommended under 6 years)   Lotion, coal tar solution 5% in an emollient basis, net  price 100 mL = £8.11, 250 mL = £16.24   Excipients include hydroxybenzoates (parabens), polysorbate 80  Dose psoriasis, apply to skin or scalp 2-3 times daily; CHILD  under 12 years and ELDERLY, lotion can be diluted with a few drops  of water before applying   Cream, coal tar 6%, lecithin 0.4%, net price 225 mL =  £9.42   Scalp ointment, coal tar solution 12%, salicylic acid  2%, precipitated sulphur 4%, in a coconut oil emoll-  ient basis, net price 40 g = £4.54, 100 g = £8.52   Dose scaly scalp disorders including psoriasis, eczema, seborr-  hoeic dermatitis and dandruff, apply to scalp as necessary (if  severe use daily for first 3-7 days), shampoo off after 1 hour;  CHILD 6-12 years, medical supervision required (not recom-  mended under 6 years)   Bath oil, tar 2.3% in a light liquid paraffin basis, net  price 200 mL = £4.75, 500 mL = £7.95   Dose eczema and psoriasis, use 15-30 mL in a bath or apply  directly to wet skin and rinse after a few minutes; can be used as  soap substitute   Solution, tar 2.3%, net price 200 mL = £4.45, 500 mL  = £7.45   Dose eczema and psoriasis, use 15-30 mL in a bath or dilute  15 mL with 3 litres of water and apply to affected areas or apply  solution directly to wet skin and rinse after a few minutes; can be  used as soap substitute   Bath additive, coal tar solution 2.5%, arachis (peanut)  oil extract of coal tar 7.5%, tar 7.5%, cade oil 7.5%,  liquid paraffin 35%, net price 500 mL = £5.78   Dose psoriasis, eczema, atopic and pruritic dermatoses, use 2-4  capfuls (15-30 mL) in bath and soak for 20 minutes   Dose psoriasis, use 30 mL in a bath and soak for 5 minutes   Cautions avoid use near eyes and sensitive areas of  skin; see also notes above   Side-effects local burning sensation and irritation;  stains skin, hair, and fabrics   • See notes above and under preparations  Note Some of these dithranol preparations also contain coal  tar or salicylic acid — for cautions, contra-indications, and  side-effects see under Tars (above) or under Salicylic Acid   Ointment, dithranol, in yellow soft paraffin; usual  strengths 0.1-2%. Part of basis may be replaced by  hard paraffin if a stiffer preparation is required.   1. (Ml if dithranol content more than 1%, otherwise may be  sold to the public   Paste, dithranol in zinc and salicylic acid (Lassar’s)  paste. Usual strengths 0.1-1% of dithranol. Label: 28   Cream, dithranol 0.1%, net price 50 g = £3.77; 0.25%,  50 g = £4.04; 0.5%, 50 g = £4.66; 1%, 50 g = £5.42; (Ml  2%, 50 g = £6.79. Label: 28   Dose for application to skin or scalp; 0. 1-0.5% cream suitable for   Cream, dithranol 1% in a lipid-stabilised basis, net  price 50 g = £13.48; (Ml 3 %, 50 g = £16.79. Label: 28   Dose for application to skin or scalp, apply 1% cream for up to 30  minutes once daily, if necessary 3% cream can be used under  medical supervision   Note At the end of contact time, use plenty of lukewarm (not hot)  water to rinse off cream; soap may be used after the cream has  been rinsed off; use shampoo before applying cream to scalp and  if necessary after cream has been rinsed off   Ointment, dithranol 0.11%, coal tar 1%, salicylic acid  1.6%, net price 50 g = £9.22, 100 g = £18.44. Label: 28   Dose for application to scalp, initially apply on alternate days for  10-20 minutes; may be increased to daily application for max. 1  hour and then wash off    4With corticosteroids  Alphosyl HC® (GSK Consumer Healthcare) (Ml  Cream, alcoholic coal tar extract 5%, hydrocortisone  0.5%, allantoin 2%, net price 100 g = £3.10. Label: 28.  Potency: mild   Excipients include beeswax, cetyl alcohol, hydroxybenzoates (para-  bens), isopropyl palmitate, wool fat   For coal tar preparations containing salicylic acid, see under  Tars, p. 718; for dithranol preparations containing salicylic acid  see under Dithranol, above   Indications hyperkeratotic skin disorders; acne (sec-  tion 13.6.1); warts and calluses (section 13.7); scalp   Salicylate toxicity Salicylate toxicity may occur particu-  larly if applied on large areas of skin or neonatal skin  Side-effects sensitivity, excessive drying, irritation,  systemic effects after widespread use (see under  Cautions)   Paste, (Lassar’s Paste), zinc oxide 24%, salicylic acid  2%, starch 24%, white soft paraffin 50%, net price 25 g  = 17p   Indications severe extensive psoriasis resistant to  other forms of therapy; palmoplantar pustular psor-  iasis; severe congenital ichthyosis; severe Darier’s  disease (keratosis follicularis)   Cautions exclude pregnancy before starting (test for  pregnancy within 2 weeks before treatment and  monthly thereafter; start treatment on day 2 or 3 of  menstrual cycle) — women (including those with his-  tory of infertility) should avoid pregnancy and use  effective contraception for at least 1 month before,  during, and for at least 3 years after treatment (oral  progestogen-only contraceptives not considered  effective); patients should avoid concomitant tetra-  cycline or methotrexate, high doses of vitamin A  (more than 4000-5000 units daily), and use of  keratolytics, and should not donate blood during or  for at least 1 year after stopping therapy (teratogenic  risk); check liver function at start, then every 2-4  weeks for first 2 months and then every 3 months;  monitor serum-triglyceride and serum-cholesterol  concentrations every 2-4 weeks for first 2 months,  then every 3 months; diabetes (can alter glucose  tolerance — initial frequent blood glucose checks);  radiographic assessment on long-term treatment;  investigate atypical musculoskeletal symptoms; in  children use only in exceptional circumstances (pre-  mature epiphyseal closure reported); avoid excessive  exposure to sunlight and unsupervised use of sun-  lamps; interactions: Appendix 1 (retinoids)  Contra-indications hyperlipidaemia  Hepatic impairment avoid — risk of further impair-  ment   Side-effects dryness of mucous membranes (some-  times erosion), of skin (sometimes scaling, thinning,  erythema especially of face, and pruritus), and of  conjunctiva (sometimes conjunctivitis and decreased  tolerance of contact lenses); sticky skin, dermatitis;  other side-effects reported include palmoplantar  exfoliation, epistaxis, epidermal and nail fragility,  peripheral oedema, vulvovaginal candidiasis, parony-  chia, granulomatous lesions, bullous eruptions,  reversible hair thinning and alopecia, myalgia and    arthralgia, occasional nausea, headache, malaise,  drowsiness, rhinitis, sweating, taste disturbance,  stomatitis, cheilitis, and gingivitis; benign intracranial  hypertension (discontinue if severe headache, vomi-  ting, diarrhoea, abdominal pain, and visual distur-  bance occur; avoid concomitant tetracyclines);  photosensitivity, corneal ulceration, rarely jaundice  and hepatitis (avoid concomitant methotrexate);  raised serum-triglyceride or serum-cholesterol con-  centration; decreased night vision reported; skeletal  hyperostosis and extra-osseous calcification reported  following long-term administration of etretinate (and  premature epiphyseal closure in children, see Cau-  tions above)   • ADULT over 18 years (under expert supervision), initi-  ally 25-30 mg daily (Darier’s disease 10 mg daily) for  2-4 weeks, then adjusted according to response, usual  range 25-50 mg daily; up to 75 mg daily for short  periods in psoriasis and ichthyosis (see p. 716); CHILD  under 18 years see BNF for Children   Neotigason® (Actavis) (Ml  Capsules, acitretin 10 mg (brown/ white), net price  60-cap pack = £23.80; 25 mg (brown/yellow), 60-cap  pack = £55.24. Label: 10, patient information leaflet,  11 , 21   Drugs affecting the immune response are used for ecz-  ema or psoriasis. Systemic drugs acting on the immune  system are used under specialist supervision.  Pimecrolimus by topical application is licensed for mild  to moderate atopic eczema. Tacrolimus is licensed for  topical use in moderate to severe atopic eczema. Both  are drugs whose long-term safety is still being evaluated  and they should not usually be considered first-line  treatments unless there is a specific reason to avoid or  reduce the use of topical corticosteroids. Treatment  with topical pimecrolimus or topical tacrolimus should  be initiated only by prescribers experienced in treating  atopic eczema   Topical pimecrolimus and tacrolimus are options for  atopic eczema not controlled by maximal topical  corticosteroid treatment or if there is a risk of  important corticosteroid side-effects (particularly  skin atrophy).   Topical pimecrolimus is recommended for moderate  atopic eczema on the face and neck of children aged  2-16 years and topical tacrolimus is recommended  for moderate to severe atopic eczema in adults and  children over 2 years. Pimecrolimus and tacrolimus  should be used within their licensed indications.    For the role of topical corticosteroids in eczema, see  section 13.5.1, and for comment on their limited role in  psoriasis, see section 13.4. A short course of a systemic  corticosteroid (section 6.3.2) can be given for eczema  flares that have not improved despite appropriate topi-  cal treatment.    Ciclosporin by mouth can be used for severe psoriasis  and for severe eczema. Azathioprine or mycopheno-  late mofetil (section 8.2.1) are used for severe refrac-  tory eczema [unlicensed indication], Hydroxycarba-  mide (section 8.1.5) is used by mouth for severe  psoriasis [unlicensed indication].   Methotrexate can be used for severe psoriasis, the dose  being adjusted according to severity of the condition  and haematological and biochemical measurements.  Folic acid 5 mg (section 9.1.2) can be given once weekly  [unlicensed indication], on a different day from the  methotrexate, to reduce the possibility of side-effects  associated with methotrexate; alternative regimens of  folic acid may be used in some settings.   Etanercept, adalimumab, and infliximab inhibit the  activity of tumour necrosis factor (TNFa). They are used  for severe plaque psoriasis either refractory to at least 2  standard systemic treatments and photochemotherapy,  or when standard treatments cannot be used because of  intolerance or contra-indications; while either etaner-  cept or adalimumab is considered to be the first choice  in stable disease, adalimumab or infliximab may be  useful when rapid disease control is required. Usteki-  numab (a monoclonal antibody that inhibits interleu-  kins 12 and 23) can be used for severe plaque psoriasis  that has not responded to etanercept, adalimumab, or  infliximab, or when these drugs cannot be used because  of intolerance or contra-indications (see also NICE  guidance below). Adalimumab, etanercept, and inflixi-  mab are also licensed for psoriatic arthritis (section  10.1.3).   Adalimumab is recommended for the treatment of  severe plaque psoriasis which has failed to respond  to standard systemic treatments (including ciclos-  porin and methotrexate) and photochemotherapy, or  when standard treatments cannot be used because  of intolerance or contra-indications. Adalimumab  should be withdrawn if the response is not adequate  after 16 weeks.   Etanercept is recommended for severe plaque psor-  iasis which has failed to respond to standard sys-  temic treatments (including ciclosporin and metho-  trexate) and to photochemotherapy, or when  standard treatments cannot be used because of  intolerance or contra-indications. Etanercept should  be withdrawn if the response is not adequate after 12  weeks.   Following suspension of the marketing authorisation  for efalizumab, NICE has temporarily withdrawn its  guidance on the use of efalizumab for plaque  psoriasis.    1. The Scottish Medicines Consortium issued similar advice  in May 2008.   2. The Scottish Medicines Consortium issued similar advice  (August 2009) on the use of etanercept in adults and  children over 8 years of age   Infliximab is recommended for the treatment of very  severe plaque psoriasis which has failed to respond  to standard systemic treatments (including ciclos-  porin and methotrexate) or to photochemotherapy,  or when standard treatments cannot be used  because of intolerance or contra-indications. Inflix-  imab should be withdrawn if the response is not  adequate after 10 weeks.   Ustekinumab is recommended for the treatment of  severe plaque psoriasis which has failed to respond  to standard systemic treatments (including ciclos-  porin and methotrexate) and to photochemotherapy,  or when standard treatments cannot be used  because of intolerance or contra-indications [but  see notes above], Ustekinumab should be withdrawn  if the response is not adequate after 16 weeks.   For patients weighing over 100 kg, the manufacturer  should provide the 90-mg dose of ustekinumab at  the same price as the 45-mg dose    Indications severe refractory eczema [unlicensed  indication]; inflammatory bowel disease (section  1.5.3); autoimmune conditions and prophylaxis of  transplant rejection (section 8.2.1); rheumatoid arth-  ritis (section 10.1.3)    Contra-indications section 8.2.1; also very low or  deficient thiopurine methyltransferase (TPMT) activ-  ity (homozygous phenotype)   Hepatic impairment section 8.2.1  Renal impairment section 8.2.1  Pregnancy section 8.2.1  Breast-feeding section 8.2.1  Side-effects section 8.2.1  Dose   • Severe refractory eczema [unlicensed indication], by  mouth, normal or high TPMT activity, 1-3 mg/kg  daily; low TPMT activity (heterozygous phenotype),  0.5-1 mg/kg daily   Indications see under Dose; severe acute ulcerative  colitis (section 1.5.3); transplantation and graft-ver-  sus-host disease (section 8.2.2)   Additional cautions in atopic dermatitis and psoriasis  Contra-indicated in abnormal renal function, uncontrolled  hypertension (see also below), infections not under control,  and malignancy (see also below). Dermatological and phy-  sical examination, including blood pressure and renal func-  tion measurements required at least twice before starting.  During treatment, monitor serum creatinine every 2    weeks for first 3 months then every month; reduce dose by  25-50% if serum creatinine increases more than 30% above  baseline (even if within normal range) and discontinue if  reduction not successful within 1 month. Discontinue if  hypertension develops that cannot be controlled by dose  reduction or antihypertensive therapy. Avoid excessive  exposure to sunlight and avoid use of UVB or PUVA. In  atopic dermatitis, also allow herpes simplex infections to  clear before starting (if they occur during treatment withdraw  if severe); Staphylococcus aureus skin infections not abso-  lute contra-indication providing controlled (but avoid  erythromycin unless no other alternative — see also inter-  actions: Appendix 1 (ciclosporin)); investigate lymphade-  nopathy that persists despite improvement in atopic  dermatitis. In psoriasis, also exclude malignancies (including  those of skin and cervix) before starting (biopsy any lesions  not typical of psoriasis) and treat patients with malignant or  pre-malignant conditions of skin only after appropriate  treatment (and if no other option); discontinue if lympho-  proliferative disorder develops  Hepatic impairment section 8.2.2  Renal impairment see Cautions above  Pregnancy see Immunosuppressant therapy, p. 553  Breast-feeding section 8.2.2  Side-effects section 8.2.2  Dose   • Short-term treatment (usually for max. 8 weeks but  can be longer under specialist supervision) of severe  atopic dermatitis where conventional therapy inef-  fective or inappropriate, administered in accordance  with expert advice, by mouth, ADULT and CHILD over 16  years, initially 2.5 mg/kg daily in 2 divided doses, if  good initial response not achieved within 2 weeks,  increase rapidly to max. 5 mg/kg daily; initial dose of  5 mg/kg daily in 2 divided doses if very severe; CHILD  under 16 years see BNF for Children   • Severe psoriasis where conventional therapy ineffec-  tive or inappropriate, administered in accordance with  expert advice, by mouth, ADULT and CHILD over 16  years, initially 2.5 mg/kg daily in 2 divided doses,  increased gradually to max. 5 mg/kg daily if no  improvement within 1 month (discontinue if response  still insufficient after 6 weeks); initial dose of 5 mg/kg  daily justified if rapid control required; CHILD under 16  years see BNF for Children    Indications severe psoriasis unresponsive to conven-  tional therapy (specialist use only); Crohn’s disease  (section 1.5.3); malignant disease (section 8.1.3);  rheumatoid arthritis (section 10.1.3)   • By mouth or by intramuscular or intravenous or  subcutaneous injection, 2.5-10 mg once weekly,  increased according to response in steps of 2.5-5 mg  at intervals of at least 1 week; usual dose 7.5-15 mg    once weekly; max. weekly dose 30 mg; ELDERLY con-  sider dose reduction (extreme caution); CHILD 2-18  years see BNF for Children   Note that the above dose is a weekly dose. To avoid  error with low dose methotrexate, it is recommended  that:   • the patient is carefully advised of the dose and frequency  and the reason for taking methotrexate and any other  prescribed medicine (e.g. folic acid);   • only one strength of methotrexate tablet (usually 2.5 mg) is  prescribed and dispensed;   • the prescription and the dispensing label clearly show the  dose and frequency of methotrexate administration;   • the patient is warned to report immediately the onset of  any feature of blood disorders (e.g. sore throat, bruising,  and mouth ulcers), liver toxicity (e.g. nausea, vomiting,  abdominal discomfort and dark urine), and respiratory  effects (e.g. shortness of breath).   Indications short-term treatment of mild to moderate  atopic eczema (including flares) when topical corti-  costeroids cannot be used; see also notes above   Cautions UV light (avoid excessive exposure to sun-  light and sunlamps), avoid other topical treatments  except emollients at treatment site; alcohol con-  sumption (risk of facial flushing and skin irritation)   Contra-indications contact with eyes and mucous  membranes, application under occlusion, infection at  treatment site; congenital epidermal barrier defects;  generalised erythroderma; immunodeficiency; con-  comitant use with drugs that cause immunosuppres-  sion (may be prescribed in exceptional circumstances  by specialists); application to malignant or potentially  malignant skin lesions   Side-effects burning sensation, pruritus, erythema,  skin infections (including folliculitis and less com-  monly impetigo, herpes simplex and zoster, mollus-  cum contagiosum); rarely papilloma, skin discolora-  tion, local reactions including pain, paraesthesia,  peeling, dryness, oedema, and worsening of eczema;  skin malignancy reported  Dose   • Short-term treatment, apply twice daily until symp-  toms resolve (stop treatment if eczema worsens or no  response after 6 weeks); CHILD under 2 years not  recommended   60 g = £37.41, 100 g = £59.07. Label: 4, 28   Indications short-term treatment of moderate to  severe atopic eczema (including flares) either unre-  sponsive to, or in patients intolerant of conventional  therapy; prevention of flares in patients with moder-  ate to severe atopic eczema and 4 or more flares a  year who have responded to initial treatment with  topical tacrolimus; see also notes above; other indi-  cations section 8.2.2    Cautions infection at treatment site, UV light (avoid  excessive exposure to sunlight and sunlamps); alcohol  consumption (risk of facial flushing and skin irritation)   Contra-indications congenital epidermal barrier  defects; generalised erythroderma; immunodefi-  ciency; concomitant use with drugs that cause  immunosuppression (may be prescribed in excep-  tional circumstances by specialists); application to  malignant or potentially malignant skin lesions; avoid  contact with eyes and mucous membranes; applica-  tion under occlusion   Side-effects application-site reactions including rash,  irritation, pain and paraesthesia; herpes simplex  infection, Kaposi’s varicelliform eruption; application-  site infections; less commonly acne; rosacea and skin  malignancy also reported   • Short-term treatment, ADULT and CHILD over 16 years  initially apply 0.1% ointment thinly twice daily until  lesion clears (consider other treatment if eczema  worsens or no improvement after 2 weeks); reduce to  once daily or switch to 0.03% ointment if condition  allows; CHILD 2-16 years, initially apply 0.03% oint-  ment thinly twice daily for up to 3 weeks (consider  other treatment if eczema worsens or if no improve-  ment after 2 weeks) then reduce to once daily until  lesion clears   • Prevention of flares, ADULT and CHILD over 16 years,  apply 0.1% ointment thinly twice weekly; use short-  term treatment regimen during an acute flare; review  need for preventative therapy after 1 year; CHILD 2-16  years, apply 0.03% ointment thinly twice weekly; use  short-term treatment regimen during an acute flare;  interrupt preventative therapy after 1 year to reassess  condition   Ointment, tacrolimus (as monohydrate) 0.03%, net  price 30 g = £19.44, 60 g =£35.46; 0.1%, 30 g =  £21.60, 60 g = £39.40. Label: 4, 11, 28   Indications see notes above; Crohn’s disease (section  1.5.3); ankylosing spondylitis, polyarticular juvenile  idiopathic arthritis, psoriatic arthritis, rheumatoid  arthritis (section 10.1.3)   Cautions section 10.1.3  Contra-indications section 10.1.3  Pregnancy section 10.1.3  Breast-feeding section 10.1.3  Side-effects section 10.1.3  Dose   • By subcutaneous injection, plaque psoriasis, ADULT  over 18 years, initially 80 mg, then 40 mg on alternate  weeks starting 1 week after initial dose; discontinue  treatment if no response within 16 weeks   Indications see notes above; ankylosing spondylitis,  psoriatic arthritis, polyarticular course juvenile idio-  pathic arthritis, rheumatoid arthritis (section 10.1.3)  Cautions section 10.1.3   Contra-indications section 10.1.3  Hepatic impairment section 10.1.3  Pregnancy section 10.1.3  Breast-feeding section 10.1.3  Side-effects section 10.1.3  Dose   • By subcutaneous injection, plaque psoriasis, 25 mg  twice weekly or 50 mg once weekly; max. treatment  duration 24 weeks; discontinue if no response after 12  weeks; CHILD 8-18 years, 800 micrograms /kg (max.  50 mg) once weekly; max. treatment duration 24  weeks; discontinue if no response after 12 weeks   Indications see notes above; inflammatory bowel  disease (section 1.5.3); ankylosing spondylitis, psor-  iatic arthritis, rheumatoid arthritis (section 10.1.3)  Cautions section 10.1.3; monitor for non-melanoma  skin cancer before and during treatment  Contra-indications section 10.1.3  Pregnancy section 10.1.3  Breast-feeding section 10.1.3  Side-effects section 10.1.3  Dose   • By intravenous infusion, plaque psoriasis, ADULT over  18 years, 5 mg/kg, repeated 2 weeks and 6 weeks  after initial infusion, then every 8 weeks; discontinue if  no response within 14 weeks of initial infusion   Cautions predisposition to infection; history or devel-  opment of malignancy; elderly; interactions: Appen-  dix 1 (ustekinumab)   Tuberculosis Patients should be evaluated for tuberculosis  before treatment. Active tuberculosis should be treated with  standard treatment (section 5.1.9) for at least 2 months  before starting ustekinumab. Patients who have previously  received adequate treatment for tuberculosis can start uste-  kinumab but should be monitored every 3 months for  possible recurrence. In patients without active tuberculosis  but who were previously not treated adequately, chemo-  prophylaxis should ideally be completed before starting  ustekinumab. In patients at high risk of tuberculosis who  cannot be assessed by tuberculin skin test, chemoprophy-  laxis can be given concurrently with ustekinumab. Patients  should be advised to seek medical attention if symptoms  suggestive of tuberculosis (e.g. persistent cough, weight loss,  and fever) develop   Pregnancy avoid; manufacturer advises effective  contraception during treatment and for 15 weeks after  stopping treatment    pain in pharynx and larynx; headache, fatigue, dizzi-  ness, depression; arthralgia; myalgia; nasal conges-  tion; pruritus, injection-site reactions   • By subcutaneous injection, plaque psoriasis, ADULT  over 18 years, body-weight under 100 kg, initially  45 mg, then 45 mg 4 weeks after initial dose, then  45 mg every 12 weeks; body-weight over 100 kg,  initially 45-90 mg, then 45-90 mg 4 weeks after initial  dose, then 45-90 mg every 12 weeks  Note Discontinue if no response within 16 weeks   Stelara® (Janssen-Cilag) ▼ (Ml  Injection, ustekinumab 90mg/mL, net price 0.5-mL  (45-mg) prefilled syringe = £2147.00. Label: 10,  counselling, tuberculosis    Acne Treatment of acne should be commenced early  to prevent scarring. Patients should be counselled that  an improvement may not be seen for at least a couple of  months. The choice of treatment depends on whether  the acne is predominantly inflammatory or comedonal  and its severity.   Mild to moderate acne is generally treated with topical  preparations (section 13.6.1). Systemic treatment (sec-  tion 13.6.2) with oral antibacterials is generally used for  moderate to severe acne or where topical preparations  are not tolerated or are ineffective or where application  to the site is difficult. Another oral preparation used for  acne is the hormone treatment co-cyprindiol (cypro-  terone acetate with ethinylestradiol); it is for women  only.   Severe acne, acne unresponsive to prolonged courses of  oral antibacterials, scarring, or acne associated with  psychological problems calls for early referral to a  consultant dermatologist who may prescribe isotretin-  oin for administration by mouth.   Rosacea Rosacea is not comedonal (but may exist with  acne which may be comedonal). The pustules and  papules of rosacea respond to topical metronidazole  (section 13.10.1.2) or to topical azelaic acid (section  13.6.1). Alternatively, oral administration of oxytetra-  cycline or tetracycline 500 mg twice daily (section  5.1.3), or of erythromycin 500 mg twice daily (section  5.1.5), can be used; courses usually last 6-12 weeks and  are repeated intermittently. Doxycycline (section 5.1.3)  100 mg once daily can be used [unlicensed indication] if  oxytetracycline or tetracycline is inappropriate (e.g. in  renal impairment). A modified-release preparation of  doxycycline is licensed in low doses of 40 mg once  daily for the treatment of facial rosacea (section 5.1.3).  Isotretinoin is occasionally given in refractory cases  [unlicensed indication]. Camouflages (section 13.8.2)  may be required for the redness.    In mild to moderate acne, comedones and inflamed  lesions respond well to benzoyl peroxide (see below)    or to a topical retinoid (see p. 725). Alternatively, topical  application of an antibacterial such as erythromycin or  clindamycin may be effective for inflammatory acne. If  topical preparations prove inadequate, oral preparations  maybe needed (section 13.6.2).   Benzoyl peroxide is effective in mild to moderate acne.  Both comedones and inflamed lesions respond well to  benzoyl peroxide. The lower concentrations seem to be  as effective as higher concentrations in reducing inflam-  mation. It is usual to start with a lower strength and to  increase the concentration of benzoyl peroxide gradu-  ally. Adverse effects include local skin irritation, parti-  cularly when therapy is initiated, but the scaling and  redness often subside with treatment continued at a  reduced frequency of application. If the acne does not  respond after 2 months then use of a topical anti-  bacterial should be considered.   Azelaic acid has antimicrobial and anticomedonal  properties. It may be an alternative to benzoyl peroxide  or to a topical retinoid for treating mild to moderate  comedonal acne, particularly of the face. Some patients  prefer azelaic acid because it is less likely to cause local  irritation than benzoyl peroxide.   Cautions avoid contact with eyes, mouth, and mucous  membranes; may bleach fabrics and hair; avoid  excessive exposure to sunlight  Side-effects skin irritation (reduce frequency or sus-  pend use until irritation subsides and re-introduce at  reduced frequency)   • Apply 1-2 times daily preferably after washing with  soap and water, start treatment with lower-strength  preparations  Note May bleach clothing   Cream, benzoyl peroxide 4% in an aqueous basis, net  price 40 g = £3.30   Aquagel (= aqueous gel), benzoyl peroxide 2.5%, net  price 40 g = £1.76; 5%, 40 g = £1.92; 10%, 40 g = £2.13   Cream, benzoyl peroxide 5% in a non-greasy basis,  net price 40 g = £1.89   Gel, benzoyl peroxide 5% in an aqueous alcoholic  basis, net price 40 g = £1.51; 10%, 40 g = £1.69   Wash, benzoyl peroxide 10% in a detergent basis, net  price 150 mL = £4.00   Gel, benzoyl peroxide 5%, clindamycin 1% (as phos-  phate) in an aqueous basis, net price 25 g = £9.95, 50 g  = £19.90   Cream, benzoyl peroxide 5%, potassium hydroxy-  quinoline sulphate 0.5%, in an astringent vanishing-  cream basis, net price 50 g = £2.21   Cream, benzoyl peroxide 10%, potassium hydroxy-  quinoline sulphate 0.5%, in an astringent vanishing-  cream basis, net price 25 g = £1.30, 50 g = £2.49   Side-effects local irritation (reduce frequency or dis-  continue temporarily); less commonly skin discolora-  tion; very rarely photosensitisation   Finacea® (Bayer Schering) (Ml  Gel, azelaic acid 15%, net price 30 g = £7.48   Excipients include disodium edetate, polysorbate 80, propylene glycol  Dose facial acne vulgaris, ADULT and CHILD over 12 years, apply  twice daily; discontinue if no improvement after 1 month  Papulopustular rosacea, ADULT over 18 years, apply twice daily   Skinoren® (Bayer Schering) (Ml  Cream, azelaic acid 20%, net price 30 g = £3.74   Dose acne vulgaris, apply twice daily (sensitive skin, once daily  for first week). Extended treatment may be required but manu-  facturer advises period of treatment should not exceed 6 months   For many patients with mild to moderate inflammatory  acne, topical antibacterials may be no more effective  than topical benzoyl peroxide or tretinoin. Topical anti-  bacterials are probably best reserved for patients who  wish to avoid oral antibacterials or who cannot tolerate  them. Topical preparations of erythromycin and  clindamycin are effective for inflammatory acne. Topi-  cal antibacterials can produce mild irritation of the skin,  and on rare occasions cause sensitisation.   Antibacterial resistance of Propionibacterium acnes is  increasing; there is cross-resistance between erythro-  mycin and clindamycin. To avoid development of resis-  tance;   • when possible use non-antibiotic antimicrobials  (such as benzoyl peroxide or azelaic acid);   • if a particular antibacterial is effective, use it for  repeat courses if needed (short intervening courses  of benzoyl peroxide or azelaic acid may eliminate  any resistant propionibacteria);   • do not continue treatment for longer than necessary  (however, treatment with a topical preparation  should be continued for at least 6 months).   Cautions some manufacturers advise preparations  containing alcohol are not suitable for use with  benzoyl peroxide   Dalacin T® (Pharmacia) (MI  Topical solution, clindamycin 1% (as phosphate), in  an aqueous alcoholic basis, net price (both with  applicator) 30 mL = £4.34, 50 mL = £7.23   Lotion, clindamycin 1% (as phosphate) in an aqueous  basis, net price 30 mL = £5.08, 50 mL = £8.47   Topical solution, powder for reconstitution, erythro-  mycin 40 mg, zinc acetate 12mg/mL when reconsti-  tuted with solvent containing ethanol, net price per  pack of powder and solvent to provide 30 mL = £7.71,  90 mL = £16.68    Topical tretinoin, its isomer isotretinoin, and adapa-  lene (a retinoid-like drug), are useful for treating come-  dones and inflammatory lesions in mild to moderate  acne. Patients should be warned that some redness and  skin peeling can occur initially but settles with time.  Several months of treatment may be needed to achieve  an optimal response and the treatment should be con-  tinued until no new lesions develop.   Isotretinoin is given by mouth in severe acne; see  section 13.6.2 for warnings relating to use by mouth.    Cautions Topical retinoids should be avoided in severe  acne involving large areas. Contact with eyes, nostrils,  mouth and mucous membranes, eczematous, broken or  sunburned skin should be avoided. These drugs should  be used with caution in sensitive areas such as the neck,  and accumulation in angles of the nose should be  avoided. Exposure to UV light (including sunlight, solar-  iums) should be avoided; if sun exposure is unavoidable,  an appropriate sunscreen or protective clothing should  be used. Use of retinoids with abrasive cleaners, come-  dogenic or astringent cosmetics should be avoided.  Allow peeling (resulting from other irritant treatments)  to subside before using a topical retinoid; alternating a  preparation that causes peeling with a topical retinoid  may give rise to contact dermatitis (reduce frequency of  retinoid application).    Pregnancy Topical retinoids are contra-indicated in  pregnancy; women of child-bearing age must use effec-  tive contraception (oral progestogen-only contra-  ceptives not considered effective).   Side-effects Local reactions include burning, erythe-  ma, stinging, pruritus, dry or peeling skin (discontinue if  severe). Increased sensitivity to UVB light or sunlight  occurs. Temporary changes of skin pigmentation with  tretinoin have been reported. Eye irritation and oedema,  and blistering or crusting of skin have been reported  rarely.   Indications mild to moderate acne  Cautions see notes above  Pregnancy see notes above  Breast-feeding amount of drug in breast milk prob-  ably too small to be harmful; ensure infant does not  come in contact with treated areas  Side-effects see notes above  Dose   • ADULT and CHILD over 12 years, apply thinly once daily  before retiring to bed; reduce frequency or suspend  treatment if irritation occurs   Cautions see notes above  Contra-indications personal or familial history of  non-melanoma skin cancer; rosacea; perioral  dermatitis   Pregnancy see notes above  Breast-feeding amount of drug in milk after topical  application probably too small to be harmful; ensure  infant does not come in contact with treated areas  Side-effects see notes above  Dose   Retin-A® Qanssen-Cilag) (Ml  Gel, tretinoin 0.01%, net price 60 g = £5.28; 0.025%,  60 g = £5.28. Label: 11   Excipients include butylated hydroxytoluene  Dose acne vulgaris, apply thinly 1-2 times daily   4With antibacterial  Aknemycin® Plus (Almirall) (Ml  Solution, tretinoin 0.025%, erythromycin 4% in an  alcoholic basis, net price 25 mL = £7.05. Label: 11   Excipients include disodium edetate, polysorbate 80, propylene glycol  Dose ADULT and CHILD over 12 years, acne vulgaris, apply thinly  once daily in the evening; reduce frequency or suspend treatment  if irritation occurs  Note May bleach clothing and hair   Cautions ( topical application only) see notes above;  also personal or familial history of non-melanoma  skin cancer   Salicylic acid is available in various preparations for  sale direct to the public for the treatment of mild acne.  Other products are more suitable for acne; salicylic acid  is used mainly for its keratolytic effect.   Preparations containing abrasive agents are not con-  sidered beneficial in acne.   Indications acne vulgaris (but see notes above)  Cautions avoid contact with eyes; discontinue use  temporarily if skin becomes irritated  Contra-indications superficial venules, telangiectasia   Paste No. 1, aluminium oxide 38.09% in fine parti-  cles, in a soap-detergent basis, net price 75 g = £2.21   Indications see under preparation  Cautions avoid contact with eyes and mucous mem-  branes (including nose and mouth); reduce frequency  of application if excessive dryness, irritation or peel-  ing   Indications acne; psoriasis (section 13.5.2); warts and  calluses (section 13.7); fungal nail infections (section  13.10.2)   Cautions avoid contact with mouth, eyes, mucous  membranes; systemic effects after excessive use  Salicylate toxicity Salicylate toxicity can occur particularly  if applied on large areas of skin or on neonatal skin  Side-effects local irritation   Topical solution, salicylic acid 2% in a detergent and  emollient basis, net price 177 mL = £3.39.   Excipients include benzyl alcohol  Dose use up to 3 times daily  Note May be difficult to obtain   Systemic antibacterial treatment is useful for inflamm-  atory acne if topical treatment is not adequately effec-  tive or if it is inappropriate. Anticomedonal treatment  (e.g. with topical benzoyl peroxide) may also be  required.   Either oxytetracycline or tetracycline (section 5.1.3) is  usually given for acne in a dose of 500 mg twice daily. If  there is no improvement after the first 3 months another  oral antibacterial should be used. Maximum improve-  ment usually occurs after 4 to 6 months but in more  severe cases treatment may need to be continued for 2  years or longer.   Doxycycline and lymecycline (section 5.1.3) are alter-  natives to tetracycline. Doxycycline can be used in a  dose of 100 mg daily. Lymecycline is given in a dose of  408 mg daily.   Although minocycline is as effective as other tetracy-  clines for acne, it is associated with a greater risk of  lupus erythematosus-like syndrome. Minocycline some-  times causes irreversible pigmentation; it is given in a  dose of 100 mg once daily or 50 mg twice daily.   Erythromycin (section 5.1.5) in a dose of 500 mg twice  daily is an alternative for the management of acne but  propionibacteria strains resistant to erythromycin are  becoming widespread and this may explain poor  response.   Trimethoprim (section 5.1.8) in a dose of 300 mg twice  daily may be used for acne resistant to other antibac-  terials [unlicensed indication]. Prolonged treatment with  trimethoprim may depress haematopoiesis; it should  generally be initiated by specialists.   Concomitant use of different topical and systemic anti-  bacterials is undesirable owing to the increased like-  lihood of the development of bacterial resistance.   Co-cyprindiol (cyproterone acetate with ethinylestra-  diol) contains an anti-androgen. It is no more effective  than an oral broad-spectrum antibacterial but is useful  in women who also wish to receive oral contraception.   Improvement of acne with co-cyprindiol probably  occurs because of decreased sebum secretion which is  under androgen control. Some women with moderately  severe hirsutism may also benefit because hair growth is  also androgen-dependent. Contra-indications of co-  cyprindiol include pregnancy and a predisposition to  thrombosis.    Venous thromboembolism occurs more frequently  in women taking co-cyprindiol than in those taking a  low-dose combined oral contraceptive. Co-cyprin-  diol is licensed for use in women with severe acne  that has not responded to oral antibacterials and for  moderately severe hirsutism; it should not be used  solely for contraception. It is contra-indicated in  those with a personal or close family history of  venous thromboembolism. Women with severe  acne or hirsutism may have an inherently increased  risk of cardiovascular disease.   A mixture of cyproterone acetate and ethinylestradiol in the  mass proportions 2000 parts to 35 parts, respectively    Contra-indications see under Combined Hormonal  Contraceptives, section 7.3.1 and notes above  Hepatic impairment see under Combined Hormonal  Contraceptives, section 7.3.1  Pregnancy avoid — risk of feminisation of male fetus  with cyproterone   Breast-feeding manufacturer advises avoid; possibi-  lity of anti-androgen effects in neonate with cypro-  terone   • 1 tablet daily for 21 days starting on day 1 of men-  strual cycle and repeated after a 7-day interval,  usually for several months; withdraw 3-4 months after  acne or hirsutism completely resolved (repeat courses  may be given if recurrence); long-term treatment may  be necessary for severe symptoms   Tablets, co-cyprindiol 2000/35 (cyproterone acetate  2 mg, ethinylestradiol 35 micrograms), net price 63-  tab pack = £4.70    Dianette® (Bayer Schering) (Ml  Tablets, beige, s/c, co-cyprindiol 2000/35 (cypro-  terone acetate 2 mg, ethinylestradiol 35 micrograms),  net price 63-tab pack = £7.71   The retinoid isotretinoin reduces sebum secretion. It is  used for the systemic treatment of nodulo-cystic and  conglobate acne, severe acne, scarring, acne which has  not responded to an adequate course of a systemic  antibacterial, or acne which is associated with psycho-  logical problems. It is also useful in women who develop  acne in the third or fourth decades of life, since late  onset acne is frequently unresponsive to antibacterials.  Isotretinoin is a toxic drug that should be prescribed  only by, or under the supervision of, a consultant  dermatologist. It is given for at least 16 weeks; repeat  courses are not normally required.   Side-effects of isotretinoin include severe dryness of the  skin and mucous membranes, nose bleeds, and joint  pains. The drug is teratogenic and must not be given to  women of child-bearing age unless they practise effec-  tive contraception (oral progestogen-only contra-  ceptives not considered effective) and then only after  detailed assessment and explanation by the physician.  Women must also be registered with a pregnancy pre-  vention programme (see under Cautions below).  Although a causal link between isotretinoin use and  psychiatric changes (including suicidal ideation) has  not been established, the possibility should be consid-  ered before initiating treatment; if psychiatric changes  occur during treatment, isotretinoin should be stopped,  the prescriber informed, and specialist psychiatric  advice should be sought.   Cautions see notes above; also avoid blood donation  during treatment and for at least 1 month after treat-  ment; history of depression; monitor all patients for  depression; measure hepatic function and serum  lipids before treatment, 1 month after starting and  then every 3 months (reduce dose or discontinue if  transaminase or serum lipids persistently raised);  discontinue if uncontrolled hypertriglyceridaemia or  pancreatitis; diabetes; dry eye syndrome (associated  with risk of keratitis); avoid keratolytics; interactions:  Appendix 1 (retinoids)   Pregnancy prevention In women of child-bearing poten-  tial, exclude pregnancy up to 3 days before treatment (start  treatment on day 2 or 3 of menstrual cycle), every month  during treatment (unless there are compelling reasons to  indicate that there is no risk of pregnancy), and 5 weeks after  stopping treatment — perform pregnancy test in the first 3  days of the menstrual cycle. Women must practise effective  contraception for at least 1 month before starting treatment,  during treatment, and for at least 1 month after stopping  treatment. Women should be advised to use at least 1  method of contraception, but ideally they should use 2  methods of contraception. Oral progestogen-only contra-  ceptives are not considered effective. Barrier methods  should not be used alone, but can be used in conjunction  with other contraceptive methods. Each prescription for  isotretinoin should be limited to a supply of up to 30 days’  treatment and dispensed within 7 days of the date stated on  the prescription. Women should be advised to discontinue  treatment and to seek prompt medical attention if they  become pregnant during treatment or within 1 month of  stopping treatment.   Counselling Warn patient to avoid wax epilation (risk of  epidermal stripping), dermabrasion, and laser skin treat-  ments (risk of scarring) during treatment and for at least 6  months after stopping; patient should avoid exposure to UV  light (including sunlight) and use sunscreen and emollient  (including lip balm) preparations from the start of treatment.   Renal impairment in severe impairment, reduce  initial dose (e.g. 10 mg daily) and increase gradually  up to 1 mg/kg daily as tolerated   Side-effects dryness of skin (with dermatitis, scaling,  thinning, erythema, pruritus), epidermal fragility  (trauma may cause blistering), dryness of lips (some-  times cheilitis), dryness of eyes (with blepharitis and  conjunctivitis), dryness of pharyngeal mucosa (with  hoarseness), dryness of nasal mucosa (with epistaxis),  headache, myalgia and arthralgia, raised plasma-tri-  glyceride concentration (risk of pancreatitis if tri-  glycerides above 9 mmol/litre), raised serum-choles-  terol concentration (with reduced high-density  lipoprotein concentration), raised blood-glucose con-  centration, raised serum-transaminase concentration,  haematuria and proteinuria, thrombocytopenia,  thrombocytosis, neutropenia and anaemia; rarely  mood changes (depression, aggressive behaviour,  anxiety, and very rarely psychosis and suicidal idea-  tion) — expert referral required, skin reactions  (including reports of Stevens-Johnson syndrome and  toxic epidermal necrolysis), alopecia; very rarely  nausea, hepatitis, inflammatory bowel disease, gastro-  intestinal haemorrhage, haemorrhagic diarrhoea  (discontinue treatment), benign intracranial hyper-  tension (avoid concomitant tetracyclines), con-  vulsions, malaise, drowsiness, dizziness, diabetes  mellitus, lymphadenopathy, hyperuricaemia, glomer-  ulonephritis, tendinitis, arthritis, raised serum-creatine  kinase concentration, bone changes (including  reduced bone density, early epiphyseal closure, and  skeletal hyperostosis) and calcification of tendons and  ligaments following long-term administration, visual  disturbances (papilloedema, corneal opacities, catar-  acts, decreased night vision, photophobia, blurred  vision, colour blindness) — expert referral required  and consider withdrawal, decreased tolerance to  contact lenses, keratitis, impaired hearing, Gram-  positive infections of skin and mucous membranes,  exacerbation of acne, acne fulminans, allergic vascu-  litis and granulomatous lesions, paronychia, hirsutism,  nail dystrophy, skin hyperpigmentation, photosensit-  ivity, increased sweating   • ADULT and CHILD over 12 years, 500 micrograms/kg  daily increased if necessary to 1 mg/kg (in 1-2  divided doses) for 16-24 weeks (repeat treatment  course after a period of at least 8 weeks if failure or  relapse after first course); max. cumulative dose  150 mg/kg per course   Isotretinoin (Non-proprietary) (Ml  Capsules, isotretinoin 5 mg, net price 56-cap pack =  £14.99; 20 mg, 56-cap pack = £39.99. Label: 10,  patient information leaflet, 11, 21   Roaccutane® (Roche) (Ml  Capsules, isotretinoin 10 mg (brown-red), net price  30-cap pack = £14.54; 20 mg (brown-red/white), 30-  cap pack = £20.02. Label: 10, patient information  card, 11, 21   Warts (verrucas) are caused by a human papillomavirus,  which most frequently affects the hands, feet (plantar  warts), and the anogenital region (see below); treatment  usually relies on local tissue destruction. Warts may  regress on their own and treatment is required only if  the warts are painful, unsightly, persistent, or cause  distress.   Preparations of salicylic acid, formaldehyde, gluter-  aldehyde or silver nitrate are available for purchase by  the public; they are suitable for the removal of warts on  hands and feet. Salicylic acid is a useful keratolytic  which may be considered first; it is also suitable for the  removal of corns and calluses. Preparations of salicylic  acid in a collodion basis are available but some patients  may develop an allergy to colophony in the formulation.  An ointment combining salicylic acid with podo-  phyllum resin ( Posalfilin ®) is available for treating  plantar warts; severe systemic toxicity including gastro-  intestinal, renal haematological, and CNS effects may  occur with excessive application of preparations con-  taining podophyllum. Cryotherapy causes pain, swel-  ling, and blistering and may be no more effective than  topical salicylic acid in the treatment of warts.   Indications see under preparations; psoriasis (section  13.5.2); acne (section 13.6.1); fungal nail infections  (section 13.10.2)   Cautions significant peripheral neuropathy, patients  with diabetes at risk of neuropathic ulcers; protect  surrounding skin and avoid broken skin; not suitable  for application to face, anogenital region, or large  areas   • See under preparations; advise patient to apply care-  fully to wart and to protect surrounding skin (e.g. with  soft paraffin or specially designed plaster); rub wart  surface gently with file or pumice stone once weekly;  treatment may need to be continued for up to 3 months  Cuplex® (Crawford)   Gel, salicylic acid 11%, lactic acid 4%, in a collodion  basis, net price 5 g = £2.23. Label: 15  Dose for plantar and mosaic warts, corns, and calluses, apply  twice daily   Dose for warts, particularly plantar warts, verrucas, corns, and  calluses, apply daily   Gel, salicylic acid 12%, lactic acid 4% in a collodion  basis, net price 8 g (with applicator) = £2.98. Label: 15  Dose for warts, verrucas, corns, and calluses, apply daily   Ointment, podophyllum resin 20%, salicylic acid 25%,  net price 10 g = £3.37   Note Owing to the salicylic acid content, not suitable for ano-  genital warts; owing to the podophyllum content, also contra-  indicated in pregnancy and breast-feeding   Indications see under preparations  Cautions see under Salicylic Acid  Side-effects see under Salicylic Acid  Veracur® (Typharm)   Gel, formaldehyde 0.75% in a water-miscible gel  basis, net price 15 g = £2.41.   Indications warts, particularly plantar warts  Cautions protect surrounding skin; not for application  to face, mucosa, or anogenital areas  Side-effects rashes, skin irritation (discontinue if  severe); stains skin brown  Dose   • Apply twice daily (see also under Salicylic acid)  Glutarol® (Dermal)   Cautions protect surrounding skin and avoid broken  skin; not suitable for application to face, ano-genital  region, or large areas   • Common warts and verrucas, apply moistened caus-  tic pencil tip for 1-2 minutes; repeat after 24 hours up  to max. 3 applications for warts or max. 6 applications  for verrucas   Note Instructions in proprietary packs generally incorporate  advice to remove dead skin before use by gentle filing and to  cover with adhesive dressing after application   • Umbilical granulomas, apply moistened caustic pencil  tip (usually containing silver nitrate 40%) for 1-2  minutes while protecting surrounding skin with soft  paraffin   Caustic pencil, tip containing silver nitrate 40%,  potassium nitrate 60%, net price = 93p   Caustic pencil, tip containing silver nitrate 95%,  potassium nitrate 5%, net price, treatment pack  (including emery file, 6 adhesive dressings and pro-  tector pads) = £1.94.   The treatment of anogenital warts (condylomata acu-  minata) should be accompanied by screening for other  sexually transmitted infections. Podophyllotoxin (the  major active ingredient of podophyllum) may be used  for soft, non-keratinised external anogenital warts.  Patients with a limited number of external warts or  keratinised lesions may be better treated with cryo-  therapy or other forms of physical ablation.   Imiquimod cream is licensed for the treatment of  external anogenital warts; it may be used for both  keratinised and non-keratinised lesions. It is also  licensed for the treatment of superficial basal cell carci-  noma and actinic keratosis (section 13.8.1).   Inosine pranobex (section 5.3.2. 1) is licensed for adjunc-  tive treatment of genital warts but it has been super-  seded by more effective drugs.   Indications see under Dose  Cautions avoid normal or broken skin, and open  wounds; not suitable for internal genital warts; uncir-  cumcised males (risk of phimosis or stricture of fore-  skin); autoimmune disease; immunosuppressed  patients   Pregnancy no evidence of teratogenicity or toxicity in  animal studies; manufacturer advises caution  Breast-feeding no information available  Side-effects local reactions (including itching, burn-  ing sensation, erythema, erosion, oedema, excoria-  tion, and scabbing); headache; influenza-like symp-  toms; myalgia; less commonly local ulceration and  alopecia; rarely Stevens-Johnson syndrome and  cutaneous lupus erythematosus-like effect; very rarely  dysuria in women; permanent hypopigmentation or  hyperpigmentation reported  Dose   • Warts (external genital and perianal), apply thinly 3  times a week at night until lesions resolve (max. 16  weeks)   1 cm beyond it) on 5 days each week for 6 weeks;  assess response 12 weeks after completing treatment   • Actinic keratosis, apply to lesion 3 times a week for 4  weeks; assess response after a 4 week treatment-free  interval; repeat 4-week course if lesions persist; max.   • CHILD under 18 years see BNF for Children  Important Should be rubbed in and allowed to stay on the  treated area for 6-10 hours for warts or for 8 hours for basal cell  carcinoma and actinic keratosis, then washed off with mild  soap and water (uncircumcised males treating warts under  foreskin should wash the area daily). The cream should be  washed off before sexual contact   Cream, imiquimod 5%, net price 12-sachet pack =  £48.34. Label: 10, patient information leaflet   Indications see under preparations  Cautions avoid normal skin and open wounds; keep  away from face; very irritant to eyes  Pregnancy avoid  Breast-feeding avoid  Side-effects local irritation  Condyline® (Nycomed) (Ml  Solution, podophyllotoxin 0.5% in alcoholic basis, net  price 3.5 mL (with applicators) = £14.49. Label: 15  Dose condylomata acuminata affecting the penis or the female  external genitalia, apply twice daily for 3 consecutive days;  treatment may be repeated at weekly intervals if necessary for a  total of five 3-day treatment courses; direct medical supervision  for lesions in the female and for lesions greater than 4 cm 2 in the  male; max. 50 single applications (‘loops') per session (consult  product literature); CHILD 2-18 years see BNF for Children   Excipients include butylated hydroxyanisole, cetyl alcohol, hydroxy-  benzoates (parabens), sorbic acid, stearyl alcohol  Dose condylomata acuminata affecting the penis or the female  external genitalia, apply twice daily for 3 consecutive days;  treatment may be repeated at weekly intervals if necessary for a  total of four 3-day treatment courses; direct medical supervision  for lesions greater than 4 cm 2 ; CHILD 2-18 years see BNF for  Children   Dose condylomata acuminata affecting the penis or the female  external genitalia, apply twice daily for 3 consecutive days;  treatment may be repeated at weekly intervals if necessary for a  total of four 3-day treatment courses; direct medical supervision  for lesions greater than 4 cm 2 ; max. 50 single applications (‘loops')  per session (consult product literature); CHILD 2-18 years see BNF  for Children    Solar ultraviolet irradiation can be harmful to the skin. It  is responsible for disorders such as polymorphic light  eruption, solar urticaria, and it provokes the various  cutaneous porphyrias. It also provokes (or at least  aggravates) skin lesions of lupus erythematosus and  may aggravate rosacea and some other dermatoses.  Certain drugs, such as demeclocycline, phenothiazines,  or amiodarone, can cause photosensitivity. All these  conditions (as well as sunburn) may occur after rela-  tively short periods of exposure to the sun. Solar ultra-  violet irradiation may provoke attacks of recurrent  herpes labialis (but it is not known whether the effect  of sunlight exposure is local or systemic).    The effects of exposure over longer periods include  ageing changes and more importantly the initiation of  skin cancer.    Solar ultraviolet radiation is approximately 200-400 nm  in wavelength. The medium wavelengths (290-320 nm,  known as UVB) cause sunburn. The long wavelengths  (320-400 nm, known as UVA) are responsible for many    photosensitivity reactions and photodermatoses. Both  UVA and UVB contribute to long-term photodamage  and to the changes responsible for skin cancer and  ageing.   Sunscreen preparations contain substances that protect  the skin against UVA and UVB radiation, but they are no  substitute for covering the skin and avoiding sunlight.  The sun protection factor (SPF, usually indicated in the  preparation title) provides guidance on the degree of  protection offered against UVB; it indicates the multi-  ples of protection provided against burning, compared  with unprotected skin; for example, an SPF of 8 should  enable a person to remain 8 times longer in the sun  without burning. However, in practice, users do not  apply sufficient sunscreen product and the protection  is lower than that found in experimental studies.   Some manufacturers use a star rating system to indicate  the protection against UVA relative to protection against  UVB for sunscreen products. However, the usefulness of  the star rating system remains controversial. The EU  Commission (September 2006) has recommended that  the UVA protection factor for a sunscreen should be at  least one-third of the sun protection factor (SPF); pro-  ducts that achieve this requirement will be labelled with  a UVA logo alongside the SPF classification. Prepara-  tions that also contain reflective substances, such as  titanium dioxide, provide the most effective protection  against UVA.    For optimum photoprotection, sunscreen prepara-  tions should be applied thickly and frequently  (approximately 2 hourly). In photodermatoses,  they should be used from spring to autumn. As  maximum protection from sunlight is desirable, pre-  parations with the highest SPF should be prescribed.    The European Commission Cosmetic Products Regulation  (EC) 1223/2009 requires the use of INCI (International  Nomenclature of Cosmetic Ingredients) for cosmetics and  sunscreens. This table includes the rINN and the INCI  synonym for the active ingredients of sunscreen pre-  parations in the BNF    Borderline substances The preparations marked  ACBS’ are regarded as drugs when prescribed for skin  protection against ultraviolet radiation in abnormal  cutaneous photosensitivity resulting from genetic dis-  orders or photodermatoses, including vitiligo and those    resulting from radiotherapy; chronic or recurrent herpes  simplex labialis. Preparations with SPF less than 30  should not normally be prescribed. See also Appendix 7.  Delph® (Fenton)   Lotion, (UVA and UVB protection; UVB-SPF 30), octinoxate  4.8%, oxybenzone 1.5%, titanium dioxide 2%, net price  200 mL = £3.57. ACBS   Lotion (UVA and UVB protection; UVB-SPF 50+), octinoxate  6%, enzacamene 4%, avobenzone 2%, oxybenzone 2%,  ensulizole 2%, titanium dioxide 3%, net price 50-mL bottle  with roll-on applicator = £4.11, 125 mL = £6.86, 500 mL =  £15.54. ACBS   Excipients include butylated hydroxytoluene, cetyl alcohol, fragrance,  hydroxybenzoates (parabens), propylene glycol  Note For INCI synonyms, see table above   Cream (UVA and UVB protection; UVB-SPF 30), avoben-  zone 5%, bisoctrizole 1.5%, octinoxate 7.5%, octrocrilene  4%, titanium dioxide 5.2%, net price 125 mL = £7.45. ACBS  Excipients include disodium edetate, hydroxybenzoates (parabens),  propylene glycol   Note For INCI synonyms, see table above  Cream (UVA and UVB protection; UVB-SPF 50), amiloxate  2%, avobenzone 5%, bisoctrizole 6%, octinoxate 10%,  octrocrilene 4%, titanium dioxide 4.8%, net price 125 mL =  £8.45. ACBS   Excipients include disodium edetate, polysorbate 60, propylene glycol  Note For INCI synonyms, see table above  Lipscreen (UVA and UVB protection; UVB-SPF 50), avo-  benzone 5%, bemotrizinol 3%, octinoxate 10%, octocrilene  4%, titanium dioxide 3%, net price 5 g = £2.99. ACBS  Excipients include butylated hydroxytoluene, hydroxybenzoates (para-  bens)    Patients should be advised to use a high-SPF sunscreen  and to minimise exposure of the skin to direct sunlight  or sun lamps.    Topical treatments are used for non-hypertrophic acti-  nic keratosis. An emollient may be sufficient for mild  lesions. Diclofenac gel is suitable for the treatment of  superficial lesions in mild disease. Fluorouracil cream is  effective against most types of non-hypertrophic actinic  keratosis. Imiquimod (section 13.7) is used for lesions  on the face and scalp when cryotherapy or other topical  treatments cannot be used. Fluorouracil and imiquimod  produce a more marked inflammatory reaction than  diclofenac but lesions resolve faster. Photodynamic  therapy in combination with methyl-5-aminolevulinate  cream (Metvix®, available from Galderma) is used in  specialist centres for treating superficial and confluent,  non-hypertrophic actinic keratosis when other treat-  ments are inadequate or unsuitable; it is particularly  suitable for multiple lesions, for periorbital lesions, or for  lesions located at sites of poor healing.   Imiquimod or topical fluorouracil is used for treating  superficial basal cell carcinomas. Photodynamic ther-  apy in combination with methyl-5-aminolevulinate  cream is used in specialist centres for treating super-  ficial, nodular basal cell carcinomas when other treat-  ments are unsuitable.   Side-effects as for topical NSAIDs, see section 10.3.2;  also paraesthesia; application of large amounts may  result in systemic effects, see section 10.1   • Apply thinly twice daily for 60-90 days; max. 8 g daily  Solaraze® (Almirall) (Ml   Gel, diclofenac sodium 3% in a sodium hyaluronate  basis, net price 50 g = £38.30, 100 g = £76.60   Indications superficial malignant and pre-malignant  skin lesions; other malignant disease (section 8.1.3)  Cautions avoid contact with mucous membranes;   • Apply thinly to the affected area once or twice daily;  max. area of skin treated at one time, 500 cm 2 (e.g.  23 cm x 23 cm); usual duration of initial therapy, 3-4  weeks   Note Alternative regimens may be in use in some settings  Efudix® (Meda) ®   Excipients include hydroxybenzoates (parabens), polysorbate 60, pro-  pylene glycol, stearyl alcohol    Disfigurement of the skin can be very distressing to  patients and may have a marked psychological effect. In  skilled hands, or with experience, camouflage cosmetics  can be very effective in concealing scars and birth-  marks. The depigmented patches in vitiligo are also  very disfiguring and camouflage creams are of great  cosmetic value.   Borderline substances The preparations marked  ACBS’ are regarded as drugs when prescribed for post-  operative scars and other deformities and as an adjunc-  tive therapy in the relief of emotional disturbances due  to disfiguring skin disease, such as vitiligo. See also  Appendix 7.   Excipients include beeswax, hydroxybenzoates (parabens), fragrance  Finishing powder, net price 25 g = £11.32. ACBS  Excipients include beeswax, hydroxybenzoates (parabens), fragrance   Excipients include beeswax, butylated hydroxytoluene, fragrance, pro-  pylene glycol, stearyl alcohol, wool fat  Fixing powder, (7 shades), net price 60 g = £8.45. ACBS  Excipients include fragrance   Masking cream, (9 shades), net price 15 mL = £5.68. ACBS  Excipients include butylated hydroxyanisole, hydroxybenzoates (para-  bens), wool fat, propylene glycol    Finishing powder, net price 20 g = £5.68. ACBS  Excipients include butylated hydroxytoluene, hydroxybenzoates (para-  bens)   Cover cream, (40 shades), net price 19 g = £20.63, 44 g =  £30.68, 70 g = £38.74. ACBS   Excipients include hydroxybenzoates (parabens), wool fat derivative  Finishing powder, translucent, net price 35 g = £22.62. ACBS  Excipients include butylated hydroxyanisole, hydroxybenzoates (para-  bens)   Dandruff is considered to be a mild form of seborrhoeic  dermatitis (see also section 13.5.1). Shampoos contain-  ing antimicrobial agents such as pyrithione zinc (which  are widely available) and selenium sulphide may have  beneficial effects. Shampoos containing tar extracts  may be useful and they are also used in psoriasis.  Ketoconazole shampoo should be considered for  more persistent or severe dandruff or for seborrhoeic  dermatitis of the scalp.   Shampoos containing coal tar and salicylic acid may  also be useful. A cream or an ointment containing coal  tar and salicylic acid is very helpful in psoriasis that  affects the scalp (section 13.5.2). Patients who do not  respond to these treatments may need to be referred to  exclude the possibility of other skin conditions.   Cradle cap in infants may be treated with coconut oil or  olive oil applications followed by shampooing.   See below for male-pattern baldness and also section  13.5 (psoriasis and eczema), section 13.10.4 (lice), and  section 13.10.2 (ringworm).   Dose treatment of seborrhoeic dermatitis and dandruff apply  twice weekly for 2-4 weeks (prophylaxis apply once every 1-2  weeks); treatment of pityriasis versicolor apply once daily for max.  5 days (prophylaxis apply once daily for up to 3 days before sun  exposure); leave preparation on for 3-5 minutes before rinsing  1 . Can be sold to the public for the prevention and treatment of  dandruff and seborrhoeic dermatitis of the scalp as a  shampoo formulation containing ketoconazole max. 2%, in a  pack containing max. 120 mL and labelled to show a max.  frequency of application of once every 3 days   Alphosyl 2 in 1® (GSK Consumer Healthcare)  Shampoo, alcoholic coal tar extract 5%, net price  125 mL = £1.81, 250mL = £3.43   Shampoo, coal tar 1%, coconut oil 1%, salicylic acid  0.5%, net price 250 mL = £4.69    13.9 Shampoos and other preparations for scalp and hair conditions 733   Shampoo, cetrimide 10%, undecenoic acid 1%, phe-  nylethyl alcohol 7.5%, net price 150mL = £3.40,   Dose seborrhoeic scalp conditions associated with dandruff and  scaling, apply as necessary   Shampoo, salicylic acid 3%, sulphur 5%, net price  120 mL = £3.80   Dose scaly scalp disorders including psoriasis, seborrhoeic  dermatitis, and dandruff, apply at least twice weekly  Note May be difficult to obtain   Excipients none as listed in section 13.1.3  Dose scaly scalp disorders including psoriasis, seborrhoeic  dermatitis, and dandruff, apply at least twice weekly  Note May be difficult to obtain   Scalp lotion (= shampoo), coal tar 2.5%, lecithin  0.3%, net price 250 mL = £4.74   Shampoo, selenium sulphide 2.5%, net price 50 mL =  £1.44, 100 mL = £1.96, 150 mL = £2.75   Cautions avoid using 48 hours before or after applying hair  colouring, straightening or waving preparations  Dose seborrhoeic dermatitis and dandruff, apply twice weekly  for 2 weeks then once weekly for 2 weeks and then as necessary;  CHILD under 5 years not recommended; pityriasis versicolor,  section 13.10.2 [unlicensed indication]   Shampoo, coal tar extract 2%, net price 125 mL =  £3.18, 250 mL = £4.78   Excipients include fragrance, hydroxybenzoates (parabens), imidurea  Dose scalp psoriasis, seborrhoeic dermatitis, dandruff, apply 2-3  times weekly   Liquid, arachis (peanut) oil extract of coal tar 0.3%,  cade oil 0.3%, coal tar solution 0.1%, oleyl alcohol 1%,  tar 0.3%, net price 250 mL = £2.23   Hirsutism may result from hormonal disorders or as a  side-effect of drugs such as minoxidil, corticosteroids,   Weight loss can reduce hirsutism in obese women.  Women should be advised about local methods of hair  removal, and in the mildest cases this may be all that is  required.   Eflornithine, an antiprotozoal drug, inhibits the enzyme  ornithine decarboxylase in hair follicles. Topical eflor-  nithine can be used as an adjunct to laser therapy for  facial hirsutism in women. Eflornithine should be dis-  continued in the absence of improvement after treat-  ment for 4 months.   Co-cyprindiol (section 13.6.2) may be effective for  moderately severe hirsutism. Metformin (section  6.1. 2. 2) is an alternative in women with polycystic  ovary syndrome [unlicensed indication]. Systemic treat-  ment is required for 6-12 months before benefit is seen.   Side-effects acne, application site reactions including  burning and stinging sensation, rash; less commonly  abnormal hair texture and growth   Note Preparation must be rubbed in thoroughly; cosmetics  may be applied over treated area 5 minutes after eflor-  nithine; do not wash treated area for 4 hours after application   Cream, eflornithine (as hydrochloride) 11.5%, net  price 60 g = £52.08   Note The Scottish Medicines Consortium has advised (Sep-  tember 2005) that eflornithine for facial hirsutism be  restricted for use in women in whom alternative drug treat-  ment cannot be used   Finasteride is licensed for the treatment of androge-  netic alopecia in men. Continuous use for 3-6 months is  required before benefit is seen, and effects are reversed  6-12 months after treatment is discontinued.    Topical application of minoxidil may stimulate limited  hair growth in a small proportion of adults but only for  as long as it is used.   Tablets, f/c, beige, finasteride 1 mg, net price 28-tab  pack = £26.99, 84-tab pack = £81.55   Cautions section 2.5.1 (but only about 1-2%  absorbed); avoid contact with eyes, mouth and  mucous membranes, broken, infected, shaved, or  inflamed skin; avoid inhalation of spray mist; avoid  occlusive dressings and topical drugs which enhance  absorption   Side-effects section 2.5.1; also less commonly local  irritation, changes in hair colour or texture (discon-  tinue if increased hair loss persists for more than 2  weeks)   • Apply 1 mL twice daily to dry hair and scalp (dis-  continue if no improvement after 1 year)   Excipients include propylene glycol  Cautions flammable; wash hands after application  Regaine® for Men Extra Strength topical solution,  minoxidil 5% in an aqueous alcoholic basis, net price  60-mL bottle with applicators = £17.00, 3 x 60-mL  bottles = £34.03   Cellulitis, a rapidly spreading deeply seated inflamma-  tion of the skin and subcutaneous tissue, requires sys-  temic antibacterial treatment (see Table 1, section 5.1).  Lower leg infections or infections spreading around  wounds are almost always cellulitis. Erysipelas, a super-  ficial infection with clearly defined edges (and often  affecting the face), is also treated with a systemic anti-  bacterial (see Table 1, section 5.1).   In the community, acute impetigo on small areas of the  skin may be treated by short-term topical application of  fusidic acid; mupirocin should be used only to treat    meticillin-resistant Staphylococcus aureus. If the im-  petigo is extensive or longstanding, an oral antibacterial  such as flucloxacillin (or clarithromycin in penicillin-  allergy) (Table 1, section 5.1) should be used. Mild  antiseptics (section 13.11) can be used to soften crusts.   Although many antibacterial drugs are available in topi-  cal preparations, some are potentially hazardous and  frequently their use is not necessary if adequate hygie-  nic measures can be taken. Moreover, not all skin  conditions that are oozing, crusted, or characterised  by pustules are actually infected. Topical antibacterials  should be avoided on leg ulcers unless used in short  courses for defined infections; treatment of bacterial  colonisation is generally inappropriate.   To minimise the development of resistant organisms it is  advisable to limit the choice of antibacterials applied  topically to those not used systemically. Unfortunately  some of these, for example neomycin, may cause sensi-  tisation, and there is cross-sensitivity with other amino-  glycoside antibiotics, such as gentamicin. If large areas  of skin are being treated, ototoxicity may also be a  hazard with aminoglycoside antibiotics (and also with  polymyxins), particularly in children, in the elderly, and  in those with renal impairment. Resistant organisms are  more common in hospitals, and whenever possible  swabs should be taken for bacteriological examination  before beginning treatment.   Mupirocin is not related to any other antibacterial in  use; it is effective for skin infections, particularly those  due to Gram-positive organisms but it is not indicated  for pseudomonal infection. Although Staphylococcus  aureus strains with low-level resistance to mupirocin  are emerging, it is generally useful in infections resistant  to other antibacterials. To avoid the development of  resistance, mupirocin or fusidic acid should not be  used for longer than 10 days and local microbiology  advice should be sought before using it in hospital. In  the presence of mupirocin-resistant MRSA infection, a  topical antiseptic such as povidone-iodine, chlorhexi-  dine, or alcohol can be used; their use should be dis-  cussed with the local microbiologist.   Retapamulin can be used for impetigo and other super-  ficial bacterial skin infections caused by Staphylococcus  aureus and Streptococcus pyogenes that are resistant to  first-line topical antibacterials. However, it is not effec-  tive against MRSA. The Scottish Medicines Consortium  (p. 4) has advised (March 2008) that retapamulin  ( Altargo ®) is not recommended for use within NHS  Scotland for the treatment of superficial skin infections.   Renal impairment manufacturer advises caution  when Bactroban® ointment used in moderate or  severe impairment because it contains macrogols  (polyethylene glycol)    Breast-feeding no information available  Side-effects local reactions including urticaria, pru-  ritus, burning sensation, rash   • ADULT and CHILD over 1 year, apply up to 3 times daily  for up to 10 days; CHILD under 1 year see BNF for  Children   Cream, mupirocin (as mupirocin calcium) 2%, net  price 15 g = £4.38   Indications bacterial skin infections  Cautions large areas, see below  Large areas If large areas of skin are being treated ototoxi-  city may be a hazard, particularly in children, in the elderly,  and in those with renal impairment  Contra-indications neonates  Renal impairment see Cautions above  Side-effects sensitisation (see also notes above)   Cream, neomycin sulphate 0.5%, cetomacrogol  emulsifying ointment 30%, chlorocresol 0.1%,  disodium edetate 0.01%, in freshly boiled and cooled  purified water, net price 15 g = £2.17   Indications bacterial skin infections  Cautions large areas, see below  Large areas If large areas of skin are being treated nephro-  toxicity and neurotoxicity may be a hazard, particularly in  children, in the elderly, and in those with renal impairment  Renal impairment see Cautions above  Side-effects sensitisation (see also notes above)   Ointment, polymyxin B sulphate 10 000 units, baci-  tracin zinc 500 units/g, net price 4 g = £3.26, 20 g =  £4.62    Indications prophylaxis and treatment of infection in  bum wounds; as an adjunct to short-term treatment of  infection in leg ulcers and pressure sores; as an  adjunct to prophylaxis of infection in skin graft donor  sites and extensive abrasions; for conservative man-  agement of finger-tip injuries  Cautions G6PD deficiency; may inactivate enzymatic  debriding agents — concomitant use may be inap-  propriate; for large amounts see also interactions:  Appendix 1 (sulfonamides)   Large areas Plasma-sulfadiazine concentrations may  approach therapeutic levels with side-effects and interac-  tions as for sulfonamides (see section 5.1.8) if large areas of  skin are treated. Owing to the association of sulfonamides  with severe blood and skin disorders, treatment should be  stopped immediately if blood disorders or rashes develop —  but leucopenia developing 2-3 days after starting treatment  of bums patients is reported usually to be self-limiting and  silver sulfadiazine need not usually be discontinued provided  blood counts are monitored carefully to ensure return to  normality within a few days. Argyria may also occur if large  areas of skin are treated (or if application is prolonged).  Contra-indications sensitivity to sulfonamides; not  recommended for neonates  Hepatic impairment manufacturer advises caution if  significant impairment; see also Large Areas, above  Renal impairment manufacturer advises caution if  significant impairment; see also Large Areas, above  Pregnancy risk of neonatal haemolysis and  methaemoglobinaemia in third trimester  Breast-feeding small risk of kemicterus in jaundiced  infants and of haemolysis in G6PD-deficient infants  Side-effects allergic reactions including burning,  itching and rashes; argyria reported following pro-  longed use; leucopenia reported (monitor blood  levels)    Flamazine® (S&N Hlth.) (Ml  Cream, silver sulfadiazine 1%, net price 20 g = £2.91,  50 g = £3.85, 250 g = £10.32, 500g = £18.27   Excipients include cetyl alcohol, polysorbates, propylene glycol  Dose burns, apply daily or more frequently if very exudative; leg  ulcers or pressure sores, apply daily or on alternate days (not  recommended if ulcer very exudative); finger-tip injuries, apply  every 2-3 days; consult product literature for details  Note Apply with sterile applicator   Side-effects local reactions including irritation,  erythema, pain, contact dermatitis, and pruritus   • ADULT over 18 years, apply thinly twice daily for 5 days;  max. area of skin treated 100 cm 2 or lesion length  10 cm; CHILD 9 months- 18 years, apply thinly twice  daily for 5 days; max. area of skin treated 2% of body  surface area    Sodium fusidate is a narrow-spectrum antibacterial  used for staphylococcal infections. For the role of sod-  ium fusidate in the treatment of impetigo see p. 734.  Metronidazole is used topically for rosacea and to  reduce the odour associated with anaerobic infections;  oral metronidazole (section 5.1.11) is used to treat  wounds infected with anaerobic bacteria.   Angular cheilitis An ointment containing sodium  fusidate is used in the fissures of angular cheilitis  when associated with staphylococcal infection. For  further information on angular cheilitis, see section  12.3.2.   Indications staphylococcal skin infections; penicillin-  resistant staphylococcal infections (section 5.1.7);  staphylococcal eye infections (section 11.3.1)  Cautions see notes above; avoid contact with eyes  Side-effects rarely hypersensitivity reactions  Dose   Cream, fusidic acid 2%, net price 15 g = £1.92, 30 g =  £3.64   Ointment, sodium fusidate 2%, net price 15 g = £2.23,  30 g = £3.79   Indications see preparations; rosacea (see also section  13.6); Helicobacter pylori eradication (section 1.3);  anaerobic infections (section 5.1.11 and section 7.2.2);  protozoal infections (section 5.4.2)   Excipients include disodium edetate, hydroxybenzoates (parabens)  Dose acute inflammatory exacerbation of rosacea, apply thinly  twice daily for 8 weeks   Gel, metronidazole 0.75%, net price 15 g = £4.47, 30 g  = £7.89   Excipients include hydroxybenzoates (parabens), propylene glycol  Dose malodorous fungating tumours and malodorous gravita-  tional and decubitus ulcers, apply to clean wound 1-2 times daily  and cover with non-adherent dressing   Metrogel® (Galderma) (Ml  Gel, metronidazole 0.75%, net price 40 g = £6.86   Excipients include hydroxybenzoates (parabens), propylene glycol  Dose acute inflammatory exacerbation of rosacea, apply thinly  twice daily for 8-9 weeks   Malodorous fungating tumours, apply to clean wound 1-2 times  daily and cover with non-adherent dressing   Dose acute exacerbation of rosacea, apply thinly twice daily for  up to 8 weeks   Excipients none as listed in section 13.1.3  Dose malodorous fungating tumours and malodorous gravita-  tional and decubitus ulcers, apply to clean wound 1-2 times daily  and cover (flat wounds, apply liberally; cavities, smear on paraffin  gauze and pack loosely)   Dose inflammatory papules, pustules and erythema of rosacea,  apply twice daily for 3-4 months   Excipients include benzyl alcohol, disodium edetate, propylene glycol  Dose acute inflammatory exacerbation of rosacea, apply thinly  twice daily for 8-9 weeks   Most localised fungal infections are treated with topical  preparations. To prevent relapse, local antifungal treat-  ment should be continued for 1-2 weeks after the  disappearance of all signs of infection. Systemic therapy  (section 5.2) is necessary for nail or scalp infection or if  the skin infection is widespread, disseminated, or  intractable. Skin scrapings should be examined if sys-  temic therapy is being considered or where there is  doubt about the diagnosis.   Dermatophytoses Ringworm infection can affect the  scalp (tinea capitis), body (tinea corporis), groin (tinea  cruris), hand (tinea manuum), foot (tinea pedis, athlete’s  foot), or nail (tinea unguium). Scalp infection requires  systemic treatment (section 5.2); additional application  of a topical antifungal, during the early stages of treat-  ment, may reduce the risk of transmission. A topical  antifungal can also be used to treat asymptomatic  carriers of scalp ringworm. Most other local ringworm  infections can be treated adequately with topical anti-  fungal preparations (including shampoos, section 13.9).  The imidazole antifungals clotrimazole, econazole,  ketoconazole, and miconazole are all effective. Ter-  binafine cream is also effective but it is more expensive.  Other topical antifungals include griseofulvin and the  undecenoates. Compound benzoic acid ointment  (Whitfield’s ointment) has been used for ringworm infec-  tions but it is cosmetically less acceptable than proprie-  tary preparations. Topical preparations for athlete’s foot  containing tolnaftate are on sale to the public.  Antifungal dusting powders are of little therapeutic  value in the treatment of fungal skin infections and  may cause skin irritation; they may have some role in  preventing re-infection.   Antifungal treatment may not be necessary in asympto-  matic patients with tinea infection of the nails. If treat-  ment is necessary, a systemic antifungal (section 5.2) is  more effective than topical therapy. However, topical  application of amorolfine or tioconazole may be useful  for treating early onychomycosis when involvement is  limited to mild distal disease in up to 2 nails, or for  superficial white onychomycosis, or where there are  contra-indications to systemic therapy.   Dose inflammatory papules and pustules of rosacea, apply twice  daily for 6 weeks (longer if necessary)    Pityriasis versicolor Pityriasis (tinea) versicolor can  be treated with ketoconazole shampoo (section 13.9).  Alternatively, selenium sulphide shampoo [unlicensed  indication] (section 13.9) can be used as a lotion (dilut-  ing with water can reduce irritation) and left on the  affected area for 10 minutes before rinsing off; it should  be applied once daily for 7 days, and the course  repeated if necessary.    Topical imidazole antifungals clotrimazole, econazole,  ketoconazole, and miconazole, and topical terbinafine  are alternatives, but large quantities may be required.   If topical therapy fails, or if the infection is widespread,  pityriasis versicolor is treated systemically with a tri-  azole antifungal (section 5.2). Relapse is common, espe-  cially in the immunocompromised.   Candidiasis Candidal skin infections can be treated  with a topical imidazole antifungal, such as clotrim-  azole, econazole, ketoconazole, or miconazole; topi-  cal terbinafine is an alternative. Topical application of  nystatin is also effective for candidiasis but it is ineffec-  tive against dermatophytosis. Refractory candidiasis  requires systemic treatment (section 5.2) generally  with a triazole such as fluconazole; systemic treatment  with terbinafine is not appropriate for refractory candi-  diasis.   Angular cheilitis Miconazole cream is used in the  fissures of angular cheilitis when associated with Can-  dida. For further information on angular cheilitis, see  p. 695.   Compound topical preparations Combination of an  imidazole and a mild corticosteroid (such as hydrocorti-  sone 1%) (section 13.4) may be of value in the treatment  of eczematous intertrigo and, in the first few days only,  of a severely inflamed patch of ringworm. Combination  of a mild corticosteroid with either an imidazole or  nystatin may be of use in the treatment of intertrigo  associated with Candida.   Indications fungal skin infections; vaginal candidiasis  (section 7.2.2); otitis externa (section 12.1.1)  Cautions see notes above   Cream, clotrimazole 1%, net price 20 g = £2.14, 50 g =  £3.50   Solution, clotrimazole 1% in macrogol 400 (poly-  ethylene glycol 400), net price 20 mL = £2.43. For  hairy areas   Spray, clotrimazole 1%, in 30% isopropyl alcohol, net  price 40-mL atomiser = £4.99. Label: 15. For large or  hairy areas    Side-effects Occasional local irritation and hyper-  sensitivity reactions include mild burning sensation,  erythema, and itching. Treatment should be discontin-  ued if these are severe.   • Apply to infected nails 1-2 times weekly after filing  and cleansing; allow to dry (approx. 3 minutes); treat  finger nails for 6 months, toe nails for 9-12 months  (review at intervals of 3 months); avoid nail varnish or  artificial nails during treatment   Nail lacquer, amorolfine (as hydrochloride) 5%, net  price 5-mL pack (with nail files, spatulas, and cleans-  ing swabs) = £18.17. Label; 10, patient information  leaflet   Note Amorolfine nail lacquer can be sold to the public if supplied  for the treatment of mild cases of distal and lateral subungual  onychomycoses caused by dermatophytes, yeasts and moulds;  subject to treatment of max. 2 nails, max. strength of nail lacquer  amorolfine 5% and a pack size of 3 mL   • Skin infections apply twice daily; nail infections, apply  once daily under occlusive dressing   • Apply 400 micrograms (1 spray) to an area approx.  13 cm 2 once daily, increased to 1.2 mg (3 sprays,  allowing each spray to dry between applications)  once daily if necessary; max. treatment duration 4  weeks   Spray, griseofulvin 400 micrograms /metered spray,  net price 20-mL (400-dose) spray = £4.00. Label: 15   Indications fungal skin infections; systemic or resis-  tant fungal infections (section 5.2.2); vulval candi-  diasis (section 7.2.2)   Cautions see notes above; do not use within 2 weeks  of a topical corticosteroid for seborrhoeic  dermatitis — risk of skin sensitisation  Side-effects see notes above   • Tinea pedis, apply twice daily; other fungal infections,  apply 1-2 times daily   Note A 15-g tube is available for sale to the public for the  treatment of tinea pedis, tinea cruris, and candidal intertrigo   Indications fungal skin infections; oral and intestinal  fungal infections (section 12.3.2); vaginal candidiasis  (section 7.2.2)   • Apply twice daily continuing for 10 days after lesions  have healed; nail infections, apply 1-2 times daily   Cream, miconazole nitrate 2%, net price 20 g = £2.05,  45 g = £1.97   Indications fungal nail infections, particularly tinea;  hyperkeratotic skin disorders (section 13.5.2); acne  vulgaris (section 13.6.1); warts and calluses (section  13.7)   • ADULT and CHILD over 5 years, apply twice daily and  after washing   Paint, salicylic acid 1.46% (total combined), tannic  acid 4.89% and boric acid 3.12% (as borotannic  complex), in a vehicle containing alcohol and ethyl  acetate, net price 25 mL (with brush) = £2.81   Breast-feeding manufacturer advises avoid — present  in milk, but less than 5% of the dose is absorbed after  topical application of terbinafine; avoid application to  mother’s chest   • Apply thinly 1-2 times daily for up to 1 week in tinea  pedis, 1-2 weeks in tinea corporis and tinea cruris, 2  weeks in cutaneous candidiasis and pityriasis versi-  color; review after 2 weeks; CHILD see BNF for Chil-  dren   terbinafine (Non-proprietary) (M  Cream, terbinafine hydrochloride 1%, net price 15 g =  £5.10, 30 g = £2.69   1. Preparations of terbinafine hydrochloride (max. 1%) can be  sold to the public for external use for the treatment of tinea  pedis as a cutaneous solution in a pack containing max. 15 g,  or for the treatment of tinea pedis and cruris as a cream in a  pack containing max. 15 g, or for the treatment of tinea  pedis, cruris, and corporis as a spray in a pack containing  max. 30 mL spray or as a gel in a pack containing max. 30 g  gel   Lamisil® (Novartis Consumer Health) (Ml  Cream, terbinafine hydrochloride 1%, net price 15 g =  £4.86, 30 g = £8.76   Indications fungal nail infections  Cautions see notes above  Pregnancy manufacturer advises avoid  Side-effects see notes above; also local oedema, dry  skin, nail discoloration, periungual inflammation, nail  pain, rash, exfoliation   Excipients include butylated hydroxyanisole  Note A 15-g tube CM1 is on sale to the public  Powder!^ miconazole nitrate 2%, net price 20 g =  £2.27   Indications skin infections due to Candida spp.; oral  fungal infections (section 12.3.2)   Excipients include benzyl alcohol, cetostearyl alcohol, polysorbate 60  Dose apply 2-3 times daily continuing for 7 days after lesions  have healed.   • Apply to nails and surrounding skin twice daily usually  for up to 6 months (may be extended to 12 months)   Cream, zinc undecenoate 20%, undecenoic acid 5%,  net price 25 g = £1.64   Dose treatment of athlete’s foot, apply twice daily continuing for  7 days after lesions have healed  Prevention of athlete’s foot, apply once daily  Spray application, undecenoic acid 3.9%, dichloro-  phen 0.4% (pressurised aerosol pack), net price  100 mL = £2.46   Dose treatment of athlete’s foot, apply twice daily continuing for  7 days after lesions have healed  Prevention of athlete’s foot, apply once daily   Aciclovir cream is licensed for the treatment of initial  and recurrent labial and genital herpes simplex infec-  tions', treatment should begin as early as possible. Sys-  temic treatment is necessary for buccal or vaginal infec-  tions and for herpes zoster (shingles) (for details of  systemic use see section 5.3.2. 1).   Herpes labialis Aciclovir cream can be used for the  treatment of initial and recurrent labial herpes simplex  infections (cold sores). It is best applied at the earliest  possible stage, usually when prodromal changes of  sensation are felt in the lip and before vesicles appear.   Penciclovir cream is also licensed for the treatment of  herpes labialis; it needs to be applied more frequently  than aciclovir cream. These creams should not be used  in the mouth.   Systemic treatment is necessary if cold sores recur  frequently or for infections in the mouth (see p. 392).   Indications see notes above; herpes simplex and  varicella-zoster infections (section 5.3.2. 1); eye  infections (section 11.3.3)    Pregnancy not known to be harmful — manufacturers  advise use only when potential benefit outweighs risk;  limited absorption from topical aciclovir preparations  Side-effects transient stinging or burning; occasion-  ally erythema, itching or drying of the skin  Dose   • Apply to lesions every 4 hours (5 times daily) for 5-10  days, starting at first sign of attack   1 Aciclovir (Non-proprietary) (Ml  Cream, aciclovir 5%, net price 2g = £1.10, 10 g =  £1.81   Brands include Zuvogen ® ( excipients also include cetyl alcohol,  propylene glycol)   Dental prescribing on NHS Aciclovir Cream may be prescribed  1 . A 2-g tube and a pump pack are on sale to the public for the  treatment of cold sores   Cream, aciclovir 5%, net price 2g = £4.63, 10 g =  £13.96   Excipients include cetostearyl alcohol, propylene glycol  Dose herpes labialis, apply to lesions every 2 hours during  waking hours for 4 days, starting at first sign of attack; CHILD  under 12 years, not recommended   Indications herpes simplex and herpes zoster infec-  tion but of little value   Cautions avoid contact with the eyes, mucous mem-  branes, and textiles; interactions: Appendix 1  (dimethyl sulfoxide)   Side-effects stinging on application, changes in taste;  overuse may cause maceration   Application, idoxuridine 5% in dimethyl sulfoxide, net  price 5mL (with applicator) = £6.33  Dose apply to lesions 4 times daily for 4 days, starting at first sign  of attack; CHILD under 12 years, not recommended   These amounts are usually suitable for an adult for  single application.   Permethrin is used for the treatment of scabies ( Sar -  coptes scabiei); malathion can be used if permethrin is  inappropriate.   Benzyl benzoate is an irritant and should be avoided in  children; it is less effective than malathion and per-  methrin.   Ivermectin (available on a named patient basis from  ‘special-order’ manufacturers or specialist importing  companies, see p. 988) in a single dose of 200 micr-  ograms/kg by mouth has been used, in combination  with topical drugs, for the treatment of hyperkeratotic  (crusted or ‘Norwegian’) scabies that does not respond  to topical treatment alone.    Application Although acaricides have traditionally  been applied after a hot bath, this is not necessary  and there is even evidence that a hot bath may increase  absorption into the blood, removing them from their site  of action on the skin.   All members of the affected household should be trea-  ted simultaneously. Treatment should be applied to the  whole body including the scalp, neck, face, and ears.  Particular attention should be paid to the webs of the  fingers and toes and lotion brushed under the ends of  nails. It is now recommended that malathion and per-  methrin should be applied twice, one week apart; in the  case of benzyl benzoate up to 3 applications on con-  secutive days may be needed. It is important to warn  users to reapply treatment to the hands if they are  washed. Patients with hyperkeratotic scabies may  require 2 or 3 applications of acaricide on consecutive  days to ensure that enough penetrates the skin crusts to  kill all the mites.    Itching The itch and eczema of scabies persists for  some weeks after the infestation has been eliminated  and treatment for pruritus and eczema (section 13.5.1)  may be required. Application of crotamiton can be used  to control itching after treatment with more effective  acaricides. A topical corticosteroid may help to reduce  itch and inflammation after scabies has been treated  successfully; however, persistent symptoms suggest that  scabies eradication was not successful. Oral administra-  tion of a sedating antihistamine (section 3.4.1) at night  may also be useful.   Dimeticone is effective against head lice ( Pediculus  humanus capitis) and acts on the surface of the organ-  ism. Malathion, an organophosphorus insecticide, is an  alternative, but resistance has been reported. Benzyl  benzoate is licensed for the treatment of head lice but  it is less effective than other drugs.   Head lice infestation (pediculosis) should be treated  using lotion or liquid formulations only if live lice are  present. Shampoos are diluted too much in use to be  effective. A contact time of 8-12 hours or overnight  treatment is recommended for lotions and liquids; a 2-  hour treatment is not sufficient to kill eggs.   In general, a course of treatment for head lice should be  2 applications of product 7 days apart to kill lice emer-  ging from any eggs that survive the first application. All  affected household members should be treated simulta-  neously.   Wet combing methods Head lice can be mechani-  cally removed by combing wet hair meticulously with a  plastic detection comb (probably for at least 30 minutes  each time) over the whole scalp at 4-day intervals for a  minimum of 2 weeks, and continued until no lice are  found on 3 consecutive sessions; hair conditioner or  vegetable oil can be used to facilitate the process.  Combing devices and topical solutions to aid the  removal of head lice are available; some of these pro-  ducts are prescribable on the NHS, including Bug Buster  kit, Full Marks solution, Lyclear SprayAway, Nitcomb-  M2, Nitcomb-Sl, Nitlotion, and Nitty Gritty Nilfree.   Permethrin and malathion are used to eliminate crab  lice ( Pthirus pubis). An aqueous preparation should be  applied, allowed to dry naturally and washed off after 12  hours; a second treatment is needed after 7 days to kill  lice emerging from surviving eggs. All surfaces of the  body should be treated, including the scalp, neck, and  face (paying particular attention to the eyebrows and  other facial hair). A different insecticide should be used  if a course of treatment fails.   Benzyl benzoate is effective for scabies but is not a  first-choice for scabies (see notes above).   Cautions children (not recommended, see also under  Dose, below), avoid contact with eyes and mucous  membranes; do not use on broken or secondarily  infected skin   Side-effects skin irritation, burning sensation espe-  cially on genitalia and excoriations, occasionally  rashes   • Apply over the whole body; repeat without bathing on  the following day and wash off 24 hours later; a third  application may be required in some cases  Note Not recommended for children — dilution to reduce  irritant effect also reduces efficacy. Some manufacturers  recommend application to the body but to exclude the head  and neck. However, application should be extended to the  scalp, neck, face, and ears    • Scabies, apply 0.5% preparation over whole body, and  wash off after 24 hours; if hands are washed with soap  within 24 hours, they should be retreated; see also  notes above; repeat application after 7 days  Note For scabies, manufacturer recommends application to  the body but not necessarily to the head and neck However,  application should be extended to the scalp, neck, face, and  ears   Liquid, malathion 0.5% in an aqueous basis, net price  50 mL = £2.37, 200 mL = £5.93   Dimeticone coats head lice and interferes with water  balance in lice by preventing the excretion of water; it is  less active against eggs and treatment should be  repeated after 7 days.   Cautions avoid contact with eyes; children under 6  months, medical supervision required   • Rub into dry hair and scalp, allow to dry naturally,  shampoo after minimum 8 hours (or overnight);  repeat application after 7 days   Note Patients should be told to keep hair away from fire and   Malathion is recommended for scabies, head lice and  crab lice (for details see notes above).   The risk of systemic effects associated with 1-2 applica-  tions of malathion is considered to be very low; how-  ever, applications of malathion liquid repeated at inter-  vals of less than 1 week or application for more than 3  consecutive weeks should be avoided since the like-  lihood of eradication of lice is not increased.   Indications see notes above and under preparations  Cautions avoid contact with eyes; do not use on  broken or secondarily infected skin; children under 6  months, medical supervision required  Side-effects skin irritation and hypersensitivity reac-  tions; chemical burns also reported  Dose   • Head lice, rub 0.5% preparation into dry hair and  scalp, allow to dry naturally, remove by washing after  12 hours (see also notes above); repeat application  after 7 days   • Crab lice, apply 0.5% aqueous preparation over whole  body, allow to dry naturally, wash off after 12 hours or  overnight; repeat application after 7 days   Permethrin is effective for scabies and crab lice (for  details see notes above). Permethrin is active against  head lice but the formulation and licensed methods of  application of the current products make them unsuita-  ble for the treatment of head lice.    Indications see notes above and under Dose  Cautions avoid contact with eyes; do not use on  broken or secondarily infected skin; children under 6  months, medical supervision required for cream rinse  (head lice); children aged 2 months-2 years, medical  supervision required for dermal cream (scabies)  Side-effects pruritus, erythema, and stinging; rarely  rashes and oedema    • Scabies, apply 5% preparation over whole body and  wash off after 8-12 hours; CHILD (see also Cautions,  above) apply over whole body including face, neck,  scalp and ears; if hands washed with soap within 8  hours of application, they should be treated again with  cream (see notes above); repeat application after 7  days   Note Manufacturer recommends application to the body but  to exclude head and neck. However, application should be  extended to the scalp, neck face, and ears  Larger patients may require up to two 30-g packs for  adequate treatment   • Crab lice, ADULT over 18 years, apply 5% cream over  whole body, allow to dry naturally and wash off after  12 hours or after leaving on overnight; repeat appli-  cation after 7 days   Cream rinse, permethrin 1% in basis containing iso-  propyl alcohol 20%, net price 59 mL = £2.38, 2 x 59-  mL pack = £4.32   Some of the preparations listed are used in minor bums,  and abrasions. They are applied as necessary but should  not be used on large wounds or for prolonged periods  because of the possibility of hypersensitivity. The effer-  vescent effect of hydrogen peroxide (section 13.11.6) is  used to clean minor cuts and abrasions. Preparations  containing camphor and sulphonamides should be  avoided. Preparations such as magnesium sulphate  paste are also listed but are now rarely used to treat  carbuncles and boils as these are best treated with  antibiotics (section 5. 1.1.2).   Cream, cetrimide 0.5% in a suitable water-miscible  basis such as cetostearyl alcohol 5%, liquid paraffin  50% in freshly boiled and cooled purified water, net  price 50 g = £1.11   Cream, proflavine hemisulphate 0.1%, yellow bees-  wax 2.5%, chlorocresol 0.1%, liquid paraffin 67.3%,  freshly boiled and cooled purified water 25%, wool fat  5%, net price 100 mL = £1.59   Paste, dried magnesium sulphate 45 g, glycerol 55 g,  phenol 500 mg, net price 25 g = 75p, 50 g = 87p  Note Should be stirred before use  Dose apply under dressing   Flexible collodion may be used to seal minor cuts and  wounds that have partially healed.   Collodion, castor oil 2.5%, colophony 2.5% in a coll-  odion basis, prepared by dissolving pyroxylin (10%) in  a mixture of 3 volumes of ether and 1 volume of  alcohol (90%), net price 10 mL = 38p. Label: 15  Contra-indications allergy to colophony in elastic adhesive  plasters and tape   Tissue adhesives are used for closure of minor skin  wounds and for additional suture support. They should  be applied by an appropriately trained healthcare pro-  fessional. Skin tissue adhesives may cause skin sensiti-  sation.   Tissue adhesive, sterile, ethyl-2-cyanoacrylate 954.5 mg/g,  polymethylmethacrylate, net price 4 x 3-g vials = £149.50  (with dispensing pipettes and pallete)   Tissue adhesive, sterile, enbucrilate, net price 5 x 200-mg  unit (blue) = £32.00, 10 x 200-mg unit (blue) = £67.20, 5 x  500-mg unit (clear or blue) = £34.65, 10 x 500-mg unit (blue)  = £69.30   Soap or detergent is used with water to cleanse intact  skin; emollient preparations such as aqueous cream or  emulsifying ointment (section 13.2.1) that do not irritate  the skin are best used in place of soap or detergent for  cleansing dry skin.   An antiseptic is used for skin that is infected or that is  susceptible to recurrent infection. Detergent prepara-  tions containing chlorhexidine or povidone-iodine,  which should be thoroughly rinsed off, are used. Emol-  lients may also contain antiseptics (section 13.2.1).   Antiseptics such as chlorhexidine or povidone-iodine  are used on intact skin before surgical procedures; their  antiseptic effect is enhanced by an alcoholic solvent.  Antiseptic solutions containing cetrimide can be used if  a detergent effect is also required.   For irrigating ulcers or wounds, lukewarm sterile sodium  chloride 0.9% solution is used, but tap water is often  appropriate.   Potassium permanganate solution 1 in 10 000, a mild  antiseptic with astringent properties, can be used for  exudative eczematous areas; treatment should be  stopped when the skin becomes dry. It can stain skin  and nails especially with prolonged use.   Indications skin preparation before injection  Cautions flammable; avoid broken skin; patients have  suffered severe bums when diathermy has been pre-  ceded by application of alcoholic skin disinfectants   Solution, 19 volumes of ethanol and 1 volume  approved wood naphtha, net price ‘66 OP’ (containing  95% by volume alcohol) 100 mL = 40p; 74 OP’  (containing 99% by volume alcohol) 100 mL = 39p.  Label: 15   Spirit, methyl salicylate 0.5 mL, diethyl phthalate 2%,  castor oil 2.5%, in industrial methylated spirit, net  price 100 mL = 20p. Label: 15   Indications see notes above; nebuliser diluent (section  3.1.5); sodium depletion (section 9.2. 1.2); electrolyte  imbalance (section 9.2.2. 1); eye (section 11.8.1); oral  hygiene (section 12.3.4)   Solution (sterile), sodium chloride 0.9%, net price 25  x 20-mL unit = £5.50, 200-mL can = £2.65, 1 litre =  97p   Solution (sterile), sodium chloride 0.9%, net price 25  x 20-mL sachet = £5.50   Solution (sterile), sodium chloride 0.9%, net price 30  x 45-mL unit = £13.20; 30 x 100-mL unit = £19.50   Solution (sterile), sodium chloride 0.9%, net price 25  x 25-mL sachet = £6.14; 10 x 100-mL sachet = £7.47   Solution in aerosol can (sterile), sodium chloride  0.9%, net price 100-mL can = £1.94, 240-mL can =  £2.95   Solution (sterile), sodium chloride 0.9%, net price 25  x 20-mL sachet = £7.57   Indications see under preparations; bladder irrigation  and catheter patency solutions (see section 7.4.4)  Cautions avoid contact with eyes, brain, meninges and  middle ear; not for use in body cavities; alcoholic  solutions not suitable before diathermy  Side-effects occasional sensitivity   2000 Solution (sterile), pink, chlorhexidine acetate  0.05%, net price 500 mL = 72p, 1000 mL = 77p  For cleansing and disinfecting wounds and bums   Skin wash (= solution), red, chlorhexidine gluconate  1%, net price 150 mL = £2.48  For use as skin wash in acne   Cutaneous solution, sterile, chlorhexidine gluconate  2% in isopropyl alcohol 70%, net price (single appli-  cator) 0.67 mL = 30p, 1.5 mL = 55p, 3 mL = 85p,   10.5 mL = £2.92, 26 mL = £6.50; (single applicator,  with tint) 3mL = 90p, 10.5 mL = £3.07, 26mL = £6.83  For skin disinfection before invasive procedures; CHILD under 2  months, not recommended  Note Flammable   Cleansing solution, red, chlorhexidine gluconate 4%,  perfumed, in a surfactant solution, net price 250 mL =  £4.25, 500 mL = £5.25, 5 litres = £24.00   Use instead of soap for pre-operative hand and skin preparation  and for general hand and skin disinfection   Solution, chlorhexidine gluconate 0.5%, in isopropyl  alcohol 70%, net price 500 mL = £5.25  To be used undiluted for hand and skin disinfection   Cream, chlorhexidine gluconate solution 5% (= 1%  chlorhexidine gluconate), in a pourable water-misci-  ble basis, net price 250 mL = £4.44  For use in obstetrics and gynaecology as an antiseptic and  lubricant (for application to skin around vulva and perineum and  to hands of midwife or doctor)   Solution, chlorhexidine gluconate solution 2.5% ( =  chlorhexidine gluconate 0.5%), in an alcoholic solu-  tion, net price 600 mL (clear) = £2.72; 600 mL (pink) =  £2.72, 200-mL spray = £1.77, 500-mL spray = £3.01;  600 mL (blue) = £2.26  For pre-operative skin disinfection  Note Flammable    Surgical scrub, chlorhexidine gluconate 4% in a sur-  factant solution, net price 250 mL = £2.44, 500 mL =  £2.58   For pre-operative hand and skin preparation and for general hand  disinfection   Solution (sterile), pink, chlorhexidine gluconate  0.05%, net price 25 x 25-mL sachet = £5.40; 10 x  100-mL sachet = £6.67   For cleansing and disinfecting wounds and burns and swabbing in  obstetrics   Solution (sterile), yellow, chlorhexidine gluconate  0.015%, cetrimide 0.15%, net price 25 x 25-mL  sachet = £5.20; 10 x 100-mL sachet = £6.68  To be used undiluted for general skin disinfection and wound  cleansing   Solution (sterile), yellow, chlorhexidine acetate  0.015%, cetrimide 0.15%, net price 500 mL = 72p,   To be used undiluted in skin disinfection such as wound cleansing  and obstetrics   Large open wounds The application of povidone-iodine to  large wounds or severe bums may produce systemic adverse  effects such as metabolic acidosis, hypematraemia and  impairment of renal function.   Contra-indications preterm neonate gestational age  under 32 weeks; avoid regular use in patients with  thyroid disorders or those receiving lithium therapy  Renal impairment avoid regular application to  inflamed or broken mucosa  Pregnancy sufficient iodine may be absorbed to affect  the fetal thyroid in the second and third trimester  Breast-feeding avoid   Dry powder spray, povidone-iodine 2.5% in a pres-  surised aerosol unit, net price 150-g unit = £2.63  For skin disinfection, particularly minor wounds and infections;  CHILD under 2 years not recommended  Note Not for use in serous cavities   Powder spray, povidone-iodine 1.14% in a pres-  surised aerosol unit, net price 50-mL unit = £2.39  For minor wounds   To be applied undiluted in pre-operative skin disinfection  Antiseptic solution, povidone-iodine 10% in  aqueous solution, net price 500 mL = £3.46  To be applied undiluted in pre-operative skin disinfection and  general antisepsis   To be used as a pre-operative scrub for hand and skin disinfection   Triclosan has been used for disinfection of the hands  and wounds, and for disinfection of the skin before  surgery.   Solution 6% (20 vols), net price 200 mL = 45p  Solution 3% (10 vols), net price 200 mL = 44p  For skin disinfection, particularly cleansing and deodorising  wounds and ulcers   Note The BP directs that when hydrogen peroxide is prescribed,  hydrogen peroxide solution 6% (20 vols) should be dispensed.  Important Strong solutions of hydrogen peroxide which contain  27% (90 vols) and 30% (100 vols) are only for the preparation of  weaker solutions   Cream, hydrogen peroxide 1%, net price 10 g = £4.82,  25 g = £8.07, 40 g = £11.62   Dose superficial bacterial skin infection, apply 2-3 times daily for  up to 3 weeks   Dose to be diluted 1 in 10 to provide a 0.01% (1 in 10 000)  solution   Solution tablets, for preparation of topical solution,  potassium permanganate 400 mg, net price 30-tab  pack = £9.85   Note 1 tablet dissolved in 4 litres of water provides a 0.01% (1 in  10 000) solution   Alginate, hydrogel and hydrocolloid dressings (Appen-  dix 8) are effective at wound debridement. Sterile larvae  (maggots) ( LarvE ®, Zoobiotic) are also used for  managing sloughing wounds and are prescribable on  the NHS.   Desloughing solutions and creams are of little clinical  value. Substances applied to an open area are easily  absorbed and perilesional skin is easily sensitised; grav-  itational dermatitis may be complicated by superim-    posed contact sensitivity to substances such as neo-  mycin or lanolin.   For further information on wound management pro-  ducts see Appendix 8, p. 935.   A topical preparation of becaplermin (recombinant  human platelet-derived growth factor) is licensed as  an adjunct treatment of full-thickness, neuropathic, dia-  betic ulcers. It enhances the formation of granulation  tissue, thereby promoting wound healing.   Side-effects pain; infections including cellulitis and  osteomyelitis; local reactions including erythema;  rarely bullous eruption, oedema, and hypertrophic  granulation   • Full-thickness, neuropathic, diabetic ulcers (no larger  than 5 cm 2 ), apply thin layer daily and cover with  gauze dressing moistened with physiological saline;  max. duration of treatment 20 weeks (reassess if no  healing after first 10 weeks); CHILD under 18 years see  BNF for Children   Regranex® Qanssen-Cilag) (Ml  Gel, becaplermin (recombinant human platelet-  derived growth factor) 0.01%, net price 15 g = £240.92    Aluminium chloride is a potent antiperspirant used in  the treatment of hyperhidrosis. Aluminium salts are also  incorporated in preparations used for minor fungal skin  infections associated with hyperhidrosis.   In more severe cases specialists use glycopyrronium  bromide as a 0.05% solution in the iontophoretic treat-  ment of hyperhidrosis of plantar and palmar areas.  Botox® contains botulinum toxin type A complex  and is licensed for use intradermally for severe hyper-  hidrosis of the axillae unresponsive to topical anti-  perspirant or other antihidrotic treatment (section  4.9.3).   Indications see under Dose below  Cautions avoid contact with eyes or mucous mem-  branes; avoid use on broken or irritated skin; do not  shave axillae or use depilatories within 12 hours of  application; avoid contact with clothing  Side-effects skin irritation  Dose   • Hyperhidrosis affecting axillae, hands or feet, apply  liquid formulation at night to dry skin, wash off the  following morning, initially daily then reduce fre-   • Hyperhidrosis, bromidrosis, intertrigo, and prevention  of tinea pedis and related conditions, apply powder to  dry skin   Application, aluminium chloride hexahydrate 20% in  an alcoholic basis, net price 75-mL bottle with roll-on  applicator = £3.01. Label: 15   Excipients none as listed in section 13.1.3  1 . A 30-mL pack is on sale to the public   Dusting powder, aldioxa 0.22%, chloroxylenol 0.5%,  net price 50 g = £2.61   • Consult product literature; only 1 site to be treated at  a time, max. 2 sites treated in any 24 hours, treatment  not to be repeated within 7 days    These preparations are used to improve circulation in  conditions such as bruising, superficial thrombophleb-  itis, chilblains and varicose veins but are of little value.  Chilblains are best managed by avoidance of exposure  to cold; neither systemic nor topical vasodilator therapy  is established as being effective. Sclerotherapy of  varicose veins is described in section 2.13.   Cream, heparinoid 0.3% in a vanishing-cream basis,  net price 50 g = £3.99   Dose apply up to 4 times daily in superficial soft-tissue injuries    Active immunity can be acquired by natural disease or  by vaccination. Vaccines stimulate production of anti-  bodies and other components of the immune mechan-  ism; they consist of either:   1 . a live attenuated form of a virus (e.g. measles, mumps and  rubella vaccine) or bacteria (e.g. BCG vaccine), or   2. inactivated preparations of the virus (e.g. influenza  vaccine) or bacteria, or   3. detoxified exotoxins produced by a micro-organism (e.g.  tetanus vaccine), or   4. extracts of a micro-organism, which may be derived from  the organism (e.g. pneumococcal vaccine) or produced by  recombinant DNA technology (e.g. hepatitis B vaccine).    Live attenuated vaccines usually produce a durable  immunity, but not always as long-lasting as that result-  ing from natural infection.   Inactivated vaccines may require a primary series of  injections of vaccine to produce an adequate antibody  response, and in most cases booster (reinforcing) injec-  tions are required; the duration of immunity varies from  months to many years. Some inactivated vaccines are  adsorbed onto an adjuvant (such as aluminium hydro-  xide) to enhance the antibody response.    Advice in this chapter reflects that in the handbook  Immunisation against Infectious Disease (2006),  which in turn reflects the guidance of the Joint  Committee on Vaccination and Immunisation  (JCVI).    Cautions Most individuals can safely receive the  majority of vaccines. Vaccination may be postponed if    the individual is suffering from an acute illness; however,  it is not necessary to postpone immunisation in patients  with minor illnesses without fever or systemic upset.  See also Predisposition to Neurological Problems,  below. For individuals with bleeding disorders, see  Route of administration, below. If alcohol or disinfectant  is used for cleansing the skin it should be allowed to  evaporate before vaccination to prevent possible inacti-  vation of live vaccines.   When 2 or more vaccines are required (and are not  available as a combined preparation), they should be  given simultaneously at different sites, preferably in a  different limb; if more than one injection is to be given in  the same limb, they should be administered at least  2.5 cm apart (but see also BCG Vaccines, p. 750).  When 2 live vaccines cannot be given at the same  time, they should be separated by an interval of at  least 4 weeks. For interactions see Appendix 1 (vac-  cines).   Contra-indications Vaccines are contra-indicated in  those who have a confirmed anaphylactic reaction to a  preceding dose of a vaccine containing the same anti-  gens or vaccine component (such as antibacterials in  viral vaccines). The presence of the following excipients  in vaccines and immunological products has been noted  under the relevant entries:    Hypersensitivity to egg with evidence of previous ana-  phylactic reaction, contra-indicates influenza vaccine  (prepared in hens’ eggs), tick-borne encephalitis  vaccine, and yellow fever vaccine. See also Cautions  under MMR vaccine.   Impaired immune response Immune response to vac-  cines may be reduced in immunosuppressed patients  and there is also a risk of generalised infection with live  vaccines. Severely immunosuppressed patients should  not be given live vaccines (including those with severe  primary immunodeficiency). Specialist advice should be  sought for those being treated with high doses of corti-  costeroids (dose equivalents of prednisolone: adults, at    least 40 mg daily for more than 1 week; children, 2 mg/  kg daily for at least 1 week or 1 mg/kg daily for 1  month), or other immunosuppressive drugs 1 , and  those being treated for malignant conditions with  chemotherapy or generalised radiotherapy 1,2 . For spe-  cial reference to HIV infection, see below  The Royal College of Paediatrics and Child Health has  produced a statement, Immunisation of the Immuno-  compromised Child (2002) (available at  www.rcpch.ac.uk).    Pregnancy Live vaccines should not be administered  routinely to pregnant women because of the theoretical  risk of fetal infection but where there is a significant risk  of exposure to disease (e.g. to yellow fever), the need for  vaccination usually outweighs any possible risk to the  fetus. Termination of pregnancy following inadvertent  immunisation is not recommended. There is no evi-  dence of risk from vaccinating pregnant women with  inactivated viral or bacterial vaccines or toxoids. For use  of specific vaccines during pregnancy, see under indivi-  dual vaccines.    Breast-feeding Although there is a theoretical risk of  live vaccine being present in breast milk, vaccination is  not contra-indicated for women who are breast-feeding  when there is significant risk of exposure to disease.  There is no evidence of risk from vaccinating women  who are breast-feeding, with inactivated viral or bacter-  ial vaccines or toxoids. For use of specific vaccines  during breast-feeding, see under individual vaccines.    Side-effects Injection of a vaccine may be followed by  local reactions such as pain, inflammation, redness, and  lymphangitis. An induration or sterile abscess may  develop at the injection site. Gastro-intestinal distur-  bances, fever, headache, irritability, loss of appetite,  fatigue, myalgia, and malaise are among the most com-  monly reported side-effects. Other side-effects include  influenza-like symptoms, dizziness, paraesthesia, asthe-  nia, drowsiness, arthralgia, rash, and lymphadenopathy.  Hypersensitivity reactions, such as bronchospasm,  angioedema, urticaria, and anaphylaxis, are very rare  but can be fatal (see section 3.4.3 for management of  allergic emergencies).   Oral vaccines such as cholera, live poliomyelitis, rota-  virus, and live typhoid can also cause gastro-intestinal  disturbances such as nausea, vomiting, abdominal pain  and cramps, and diarrhoea.   See also Predisposition to neurological problems, below.  Some vaccines (e.g. poliomyelitis) produce very few  reactions, while others (e.g. measles, mumps and ru-  bella) may cause a very mild form of the disease.  Occasionally more serious adverse reactions can  occur — these should always be reported to the CHM  (see Adverse Reactions to Drugs, p. 12).    1. Live vaccines should be postponed until at least 3 months  after stopping high-dose systemic corticosteroids and at  least 6 months after stopping other immunosuppressive  drugs or generalised radiotherapy (at least 12 months after  discontinuing immunosuppressants following bone-mar-  row transplantation).   2. Use of normal immunoglobulin should be considered after  exposure to measles (see p. 769) and varicella-zoster  immunoglobulin considered after exposure to chickenpox  or herpes zoster (see p. 772).    Post-immunisation pyrexia in infants  The parent should be advised that if pyrexia devel-  ops after childhood immunisation, and the infant  seems distressed, a dose of paracetamol can be  given and, if necessary, a second dose can be  given 6 hours later; ibuprofen may be used if para-  cetamol is unsuitable. The parent should be warned  to seek medical advice if the pyrexia persists.   For post-immunisation pyrexia in an infant aged 2-3  months, the dose of paracetamol is 60 mg; the dose  of ibuprofen is 50 mg (on a doctor’s advice). An oral  syringe can be obtained from any pharmacy to give  the small volume required.   Predisposition to neurological problems  When there is a personal or family history of febrile  convulsions, there is an increased risk of these  occurring during fever from any cause including  immunisation, but this is not a contra-indication to  immunisation. In children who have had a seizure  associated with fever without neurological deteriora-  tion, immunisation is recommended, advice on the  management of fever (see Post-immunisation  pyrexia in infants, above) should be given before  immunisation. When a child has had a convulsion  not associated with fever, and the neurological con-  dition is not deteriorating, immunisation is recom-  mended.   Children with stable neurological disorders (e.g.  spina bifida, congenital brain abnormality, and peri-  natal hypoxic-ischaemic encephalopathy) should be  immunised according to the recommended sche-  dule.   When there is a still evolving neurological problem,  including poorly controlled epilepsy, immunisation  should be deferred and the child referred to a spe-  cialist. Immunisation is recommended if a cause for  the neurological disorder is identified. If a cause is  not identified, immunisation should be deferred until  the condition is stable.    Further information on adverse effects associated with  specific vaccines can be found under individual vac-  cines.    Vaccines and HIV infection HIV-positive individuals  with or without symptoms can receive the following live  vaccines:   and the following inactivated vaccines:  anthrax, cholera (oral), diphtheria, haemophilus influenzae  type b, hepatitis A, hepatitis B, human papilloma virus,  influenza, meningococcal, pertussis, pneumococcal, polio-  myelitis, rabies, tetanus, tick-bome encephalitis, typhoid  (injection).   BCG, typhoid (oral), yellow fever 3 4  Note The above advice differs from that for other immuno-  compromised patients; Immunisation Guidelines for HIV-  infected Adults issued by British HIV Association (BHIVA) are  available at www.bhiva.org and, Immunisation of HIV-infected  Children issued by Children ’s HIV Association (CHIVA) are  available at www.chiva.org.uk    3. The Royal College of Paediatrics and Child Health  recommends that MMR is not given to a child with HIV  infection whilst severely immunosuppressed.   4. If yellow fever risk is unavoidable, specialist advice should  be sought.   Vaccines for the childhood immunisation schedule should be obtained from local health organisations or direct from  Movianto — not to be prescribed on FP10 (HS21 in Northern Ireland; GP10 in Scotland; WP10 in Wales).   Babies born preterm should receive all routine immunisations based on their actual date of birth. The risk of  apnoea following vaccination is increased in preterm babies, particularly in those born at or before 28 weeks  postmenstrual age. If babies at risk of apnoea are in hospital at the time of their first immunisation, they should  be monitored for 48 hours after immunisation. If a baby develops apnoea, bradycardia, or desaturation after the  first immunisation, the second immunisation should also be given in hospital with similar monitoring.  Seroconversion may be unreliable in babies bom earlier than 28 weeks’ gestation or in babies treated with  corticosteroids for chronic lung disease; consideration should be given to testing for antibodies against  Haemophilus influenzae (type b), meningococcal C, and hepatitis B after primary immunisation.   • Diphtheria, Tetanus, Pertussis (Acellular, Component), Poliomyelitis (Inactivated), and  Haemophilus Type b Conjugate Vaccine (Adsorbed)   • Diphtheria, Tetanus, Pertussis (Acellular, Component), Poliomyelitis (Inactivated), and  Haemophilus Type b Conjugate Vaccine (Adsorbed)   • Diphtheria, Tetanus, Pertussis (Acellular, Component), Poliomyelitis (Inactivated), and  Haemophilus Type b Conjugate Vaccine (Adsorbed)   • Haemophilus Type b Conjugate Vaccine and Meningococcal Group C Conjugate Vaccine   • Adsorbed Diphtheria [low dose], Tetanus, Pertussis (Acellular, Component) and Polio-  myelitis (Inactivated) Vaccine   Adsorbed Diphtheria, Tetanus, Pertussis (Acellular, Component) and Poliomyelitis (Inac-  tivated) Vaccine   Note: Preferably allow interval of at least 3 years after completing primary course   3 doses; second dose 1-2 months, and third dose 6 months after first dose 1   Women of child-bearing age who have not received 2 doses of a rubella-containing vaccine  or who do not have a positive antibody test for rubella should be offered rubella  immunisation (using the MMR vaccine)— exclude pregnancy before immunisation, but see  also section 14.4, Measles, Mumps and Rubella Vaccine   Booster dose at least 1 year after primary course and again 5-10 years later   1. The two human papilloma virus vaccines are not interchangeable and one vaccine product should be used for the entire  course; however for individuals with previous incomplete vaccination with Gardasil ® who are eligible for HPV vaccination  under the national programme, Cervarix ® can be used to complete the vaccination course if necessary; the individual must be  informed that Cervarix® does not protect against genital warts.    Vaccines and asplenia The following vaccines are  recommended for asplenic patients or those with sple-  nic dysfunction:   haemophilus influenzae type b; influenza; meningococcal A,  C, W135, and Y conjugate; pneumococcal.   Route of administration Vaccines should not be  given intravenously. Most vaccines are given by the  intramuscular route; some vaccines are given by others  routes — the intradermal route for BCG vaccine, deep  subcutaneous route for Japanese encephalitis, and vari-  cella vaccine, and the oral route for cholera, live polio-  myelitis, rotavirus, and live typhoid vaccines. The intra-  muscular route should not be used in patients with  bleeding disorders such as haemophilia or thrombocy-  topenia. Vaccines usually given by the intramuscular  route should be given by deep subcutaneous injection  instead.   Note The Department of Health has advised against the use of  jet guns for vaccination owing to the risk of transmitting blood-  borne infections, such as HIV.   For information on high-risk groups, see section 14.4  under individual vaccines   BCG Vaccines  Hepatitis A Vaccine  Hepatitis B Vaccine  Influenza Vaccine  Pneumococcal Vaccines  Tetanus Vaccines    Immunity with immediate protection against certain  infective organisms can be obtained by injecting pre-  parations made from the plasma of immune individuals  with adequate levels of antibody to the disease for which  protection is sought (see under Immunoglobulins, sec-  tion 14.5). The duration of this passive immunity varies  according to the dose and the type of immunoglobulin.  Passive immunity may last only a few weeks; when  necessary, passive immunisation can be repeated.   Antibodies of human origin are usually termed immu-  noglobulins. The term antiserum is applied to material  prepared in animals. Because of serum sickness and  other allergic-type reactions that may follow injections  of antisera, this therapy has been replaced wherever  possible by the use of immunoglobulins. Reactions are  theoretically possible after injection of human immuno-  globulins but reports of such reactions are very rare.    Care must be taken to store all vaccines and other  immunological products under the conditions recom-  mended in the product literature, otherwise the prepara-  tion may become ineffective. Refrigerated storage is  usually necessary; many vaccines and immunoglobulins  need to be stored at 2-8°C and not allowed to freeze.  Vaccines and immunoglobulins should be protected  from light. Reconstituted vaccines and opened multi-    dose vials must be used within the period recommended  in the product literature. Unused vaccines should be  disposed of by incineration at a registered disposal  contractor.   Particular attention must be paid to instructions on the  use of diluents. Vaccines which are liquid suspensions or  are reconstituted before use should be adequately  mixed to ensure uniformity of the material to be  injected.   Availability Anthrax and yellow fever vaccines, botul-  ism antitoxin, diphtheria antitoxin, and snake and spider  venom antitoxins are available from local designated  holding centres.   Enquiries for vaccines not available commercially can  also be made to:   In Scotland information about availability of vaccines  can be obtained from a Specialist in Pharmaceutical  Public Health. In Wales enquiries for vaccines not avail-  able commercially should be directed to:   Welsh Medicines Information Centre  University Hospital of Wales  Cardiff, CF14 4XW  Tel: (029) 2074 2979  and in Northern Ireland:   Anthrax vaccine is made from antigens from B. anthra-  cis. Anthrax immunisation is indicated for individuals  who handle infected animals, for those exposed to  imported infected animal products, and for laboratory  staff who work with Bacillus anthracis. A 4-dose regi-  men is used for primary immunisation; booster doses  should be given annually to workers at continued risk of  exposure to anthrax.   In the event of possible contact with B. anthracis , post-  exposure immunisation may be indicated, in addition to  antimicrobial prophylaxis (section 5.1.12). Advice on the  use of anthrax vaccine for post-exposure prophylaxis  must be obtained from the Centre for Infections, Health  Protection Agency (tel. 020 8200 4400).   Contra-indications see section 14.1  Pregnancy see p. 747  Breast-feeding see p. 747  Side-effects see section 14.1   • By intramuscular injection in deltoid region, initial  course 3 doses of 0.5 mL at intervals of 3 weeks  followed by a fourth dose after an interval of 6  months; booster, 0.5 mL every 12 months   Injection, suspension of anthrax antigens (not less  than 0.125mL/0.5mL dose), sterile filtrate, adsorbed  on to aluminium potassium sulphate   Available from the Health Protection Agency’s Centre for Emer-  gency Preparedness and Response (Porton Down)   BCG (Bacillus Calmette-Guerin) is a live attenuated  strain derived from Mycobacterium bovis which stimu-  lates the development of hypersensitivity to M. tuber-  culosis. BCG vaccine should be given intradermally by  operators skilled in the technique (see below).   The expected reaction to successful BCG vaccination is  induration at the site of injection followed by a local  lesion which starts as a papule 2 or more weeks after  vaccination; the lesion may ulcerate then subside over  several weeks or months, leaving a small, flat scar. A dry  dressing may be used if the ulcer discharges, but air  should not be excluded.   Apart from children under 6 years, any person being  considered for BCG immunisation must first be given a  skin test for hypersensitivity to tuberculoprotein (see  under Diagnostic Agents, below). A skin test is not  necessary for a child under 6 years provided that the  child has not stayed for longer than 3 months in a  country with an incidence of tuberculosis greater than  40 per 100 000, the child has not had contact with a  person with tuberculosis, and there is no family history  of tuberculosis within the last 5 years.    • new immigrants aged 16-35 years from Sub-Sahar-  an Africa or a country with an incidence 1 of tuber-  culosis greater than 500 per 100 000   • contacts aged under 36 years of those with active  respiratory tuberculosis (for healthcare or labora-  tory workers who have had contact with clinical  materials or patients with tuberculosis, age limit  does not apply);   • healthcare workers and laboratory staff (irrespec-  tive of age) who are likely to have contact with  patients, clinical materials, or derived isolates; other  individuals under 35 years 2 at occupational risk  including veterinary and other staff who handle  animal species susceptible to tuberculosis, and  staff working directly with prisoners, in care  homes for the elderly, or in hostels or facilities for  the homeless or refugees;   • individuals under 16 years intending to live with  local people for more than 3 months in a country  with an incidence 1 of tuberculosis greater than 40  per 100 000 (section 14.6).   BCG vaccine can be given simultaneously with another  live vaccine (see also section 14.1), but if they are not  given at the same time an interval of 4 weeks should  normally be allowed. When BCG is given to infants,  there is no need to delay routine primary immunisa-  tions. No further vaccination should be given in the arm  used for BCG vaccination for at least 3 months because  of the risk of regional lymphadenitis.   Bladder instillations of BCG are licensed for the man-  agement of bladder carcinoma (section 8.2.4).   For advice on chemoprophylaxis against tuberculosis,  see section 5.1.9; for the treatment of infection following  vaccination, seek expert advice.   Contra-indications see section 14.1; also neonate in  household contact with known or suspected case of  active tuberculosis; generalised septic skin conditions  (for patients with eczema, lesion-free site should be  used)   Side-effects see section 14.1 and notes above; also at  the injection site, subcutaneous abscess, prolonged  ulceration; rarely disseminated complications such as  osteitis or osteomyelitis   • By intradermal injection ADULT and CHILD over 1 year,  0.1 mL; NEONATE and CHILD under 1 year, 0.05 mL  Intradermal injection technique Skin is stretched  between thumb and forefinger and needle (size 25G or  26G) inserted (bevel upwards) for about 3 mm into superficial  layers of dermis (almost parallel with surface). Needle should  be short with short bevel (can usually be seen through  epidermis during insertion). Tense raised blanched bleb   2. There is inadequate evidence of protection by BCG  vaccine in adults aged over 35 years; however, vaccination  is recommended for healthcare workers irrespective of age  because of the increased risk to them or their patients   • all neonates and infants (0-12 months) born in areas  where the incidence 1 of tuberculosis is greater than  40 per 100 000;   • neonates, infants, and children under 16 years with  a parent or grandparent born in a country with an  incidence 1 of tuberculosis greater than 40 per  100 000;   • new immigrants aged under 16 years who were  bom in, or lived for more than 3 months in a  country with an incidence 1 of tuberculosis greater  than 40 per 100 000;   1. List of countries or primary care trusts where the incidence  of tuberculosis is greater than 40 cases per 100 000 is  available at www.hpa.org.uk    showing tips of hair follicles is sign of correct injection; 7 mm  bleb = 0.1 mL injection, 3 mm bleb = 0.05 mL injection; if  considerable resistance not felt, needle too deep and should  be removed and reinserted before giving more vaccine.   To be injected at insertion of deltoid muscle onto humerus  (keloid formation more likely with sites higher on arm); tip of  shoulder should be avoided.   Injection (powder for suspension), freeze-dried  preparation of live bacteria of a strain derived from  the bacillus of Calmette and Guerin.   Available from health organisations or direct from Movianto (SSI  brand, multidose vial with diluent)   A preparation containing the specific antitoxic glo-  bulins that have the power of neutralising the toxins  formed by types A, B, and E of Clostridium botulinum.  Note The BP title Botulinum Antitoxin is not used because the  preparation currently in use may have a different specification.  Dose prophylaxis, consult product literature  Available from local designated centres, for details see TOXBASE  (requires registration) www.toxbase.org. For supplies outside  working hours apply to other designated centres or to the duty  doctor at the Health Protection Agency (Tel (020) 8200 6868). For  major incidents, obtain supplies from the local blood bank   The Mantoux test is recommended for tuberculin skin  testing, but no licensed preparation is currently avail-  able. Guidance for healthcare professionals is available  at www.dh.gov.uk/immunisation.   In the Mantoux test, the diagnostic dose is administered  by intradermal injection of Tuberculin Purified Protein  Derivative (PPD).   The Heaf test (involving the use of multiple-puncture  apparatus) is no longer available.   Note Response to tuberculin may be suppressed by live viral  vaccines, viral infection, sarcoidosis, corticosteroid therapy, or  immunosuppression due to disease or treatment. Tuberculin  testing should not be carried out within 4 weeks of receiving a  live viral vaccine.   Two interferon gamma release assay (IGRA) tests are  also available as an aid in the diagnosis of tuberculosis  infection: QuanitFERON® TB Gold and T-SPOT®.TB.  Both tests measure T-cell mediated immune response to  synthetic antigens. For further information on the use of  interferon gamma release assay tests for tuberculosis,  see www.hpa.org.uk.   Injection, heat-treated products of growth and lysis of  appropriate Mycobacterium spp. 20 units/mL  (2 units/0. 1-mL dose) (for routine use), 1.5-mL vial;  100 units/mL (10 units/0. 1-mL dose), 1.5-mL vial  Dose by intradermal injection, for Mantoux test, 2 units (0.1 mL  of 20 units/mL strength) for routine Mantoux test; if first test is  negative and a further test is considered appropriate 10 units  (0.1 mL of 100 units/mL strength)   Note The strength of tuberculin PPD in this product may be  different to the strengths of products used previously for the  Mantoux test; care is required to select the correct strength   A polyvalent botulism antitoxin is available for the post-  exposure prophylaxis of botulism and for the treatment  of persons thought to be suffering from botulism. It  specifically neutralises the toxins produced by Clostri-  dium botulinum types A, B, and E. It is not effective  against infantile botulism as the toxin (type A) is seldom,  if ever, found in the blood in this type of infection.   Hypersensitivity reactions are a problem. It is essential  to read the contra-indications, warnings, and details of  sensitivity tests on the package insert. Prior to treatment  checks should be made regarding previous administra-  tion of any antitoxin and history of any allergic condi-  tion, e.g. asthma, hay fever, etc. All patients should be   Cholera vaccine (oral) contains inactivated Inaba  (including El-Tor biotype) and Ogawa strains of Vibrio  cholerae, serotype 01 together with recombinant B-  subunit of the cholera toxin produced in Inaba strains  of V. cholerae, serotype 01.   Oral cholera vaccine is licensed for travellers to ende-  mic or epidemic areas on the basis of current recom-  mendations (see also section 14.6). Immunisation  should be completed at least 1 week before potential  exposure. However, there is no requirement for cholera  vaccination for international travel.   Immunisation with cholera vaccine does not provide  complete protection and all travellers to a country  where cholera exists should be warned that scrupulous  attention to food, water, and personal hygiene is essen-  tial.   Injectable cholera vaccine provides unreliable protec-  tion and is no longer available in the UK.   Side-effects see section 14.1; also rarely respiratory  symptoms such as rhinitis and cough; very rarely sore  throat, insomnia    • ADULT and CHILD over 6 years 2 doses separated by an  interval of 1-6 weeks; CHILD 2-6 years 3 doses each  separated by an interval of 1-6 weeks   Note If more than 6 weeks have elapsed between doses, the  primary course should be restarted   • A single booster dose can be given 2 years after  primary course for adults and children over 6 years,  and 6 months after primary course for children 2-6  years. If more than 2 years have elapsed since the last  vaccination, the primary course should be repeated  Counselling Dissolve effervescent sodium bicarbonate  granules in a glassful of water (approximately 150mL). For  adults and children over 6 years, add vaccine suspension to  make one dose. For child 2-6 years, discard half (approxi-  mately 75 mL) of the solution, then add vaccine suspension  to make one dose. Drink within 2 hours. Food, drink, and  other oral medicines should be avoided for 1 hour before and  after vaccination   Oral suspension, for dilution with solution of effer-  vescent sodium bicarbonate granules, heat- and  formaldehyde-inactivated Inaba (including El-Tor  biotype) and Ogawa strains of Vibrio cholerae bac-  teria and recombinant cholera toxin B-subunit pro-  duced in V. cholerae, net price 2-dose pack = £23.42.  Counselling, administration   Diphtheria vaccines are prepared from the toxin of  Cory neb acterium diphtheriae and adsorption on alu-  minium hydroxide or aluminium phosphate improves  antigenicity. The vaccine stimulates the production of  the protective antitoxin. The quantity of diphtheria  toxoid in a preparation determines whether the vaccine  is defined as ‘high dose’ or ‘low dose’. Vaccines contain-  ing the higher dose of diphtheria toxoid are used for  primary immunisation of children under 10 years of age.  Vaccines containing the lower dose of diphtheria toxoid  are used for primary immunisation in adults and chil-  dren over 10 years. Single-antigen diphtheria vaccine is  not available and adsorbed diphtheria vaccine is given  as a combination product containing other vaccines.   For primary immunisation of children aged between 2  months and 10 years vaccination is recommended  usually in the form of 3 doses (separated by 1 -month  intervals) of diphtheria, tetanus, pertussis (acellular,  component), poliomyelitis (inactivated) and haemo-  philus type b conjugate vaccine (adsorbed) (see  Immunisation schedule, section 14.1). In unimmunised  individuals aged over 10 years the primary course  comprises of 3 doses of adsorbed diphtheria [low  dose], tetanus and poliomyelitis (inactivated)  vaccine.   A booster dose should be given 3 years after the primary  course (this interval can be reduced to a minimum of 1  year if the primary course was delayed). Children under  10 years should receive either adsorbed diphtheria,  tetanus, pertussis (acellular, component) and polio-  myelitis (inactivated) vaccine or adsorbed diphtheria  [low dose], tetanus, pertussis (acellular, component)  and poliomyelitis (inactivated) vaccine. Individuals  aged over 10 years should receive adsorbed diphtheria  [low dose], tetanus, and poliomyelitis (inactivated)  vaccine.    A second booster dose, of adsorbed diphtheria [low  dose], tetanus and poliomyelitis (inactivated) vaccine,  should be given 10 years after the previous booster dose  (this interval can be reduced to a minimum of 5 years if  previous doses were delayed).    of diphtheria-containing vaccine given at appropriate  intervals); further doses should be given at 10-year  intervals if risk persists. Individuals at risk who are not  fully immunised should complete the primary course; a  booster dose should be given after 5 years and then at  10-year intervals. Adsorbed diphtheria [low dose],  tetanus and poliomyelitis (inactivated) vaccine is  used for this purpose; immunity should be checked by  antibody testing at least 3 months after completion of  immunisation.   Advice on the management of cases, carriers, contacts  and outbreaks must be sought from health protection  units. The immunisation history of infected individuals  and their contacts should be determined; those who  have been incompletely immunised should complete  their immunisation and fully immunised individuals  should receive a reinforcing dose. For advice on anti-  bacterial treatment to prevent a secondary case of  diphtheria in a non-immune individual, see Table 2,  section 5.1.   Side-effects see section 14.1; also restlessness, sleep  disturbances, and unusual crying in infants   Important Not recommended for persons aged 10 years or  over (see Diphtheria-containing Vaccines for Children over 10  years and Adults, p. 753)   Diphtheria, Tetanus, Pertussis (Acellular, Compo-  nent), Poliomyelitis (Inactivated) and Haemo-  philus Type b Conjugate Vaccine (Adsorbed) (Ml   Injection, suspension of diphtheria toxoid, tetanus  toxoid, acellular pertussis, inactivated poliomyelitis  and Haemophilus influenzae type b (conjugated to  tetanus protein), net price 0.5-mL vial = £19.94   Excipients may include neomycin, polymyxin B and streptomycin  Dose by intramuscular injection, CHILD 2 months-10 years,  primary immunisation, 3 doses each of 0.5 mL separated by  intervals of 1 month; see also notes on booster doses, above  Brands include Pediacel !•; available as part of childhood  immunisation schedule, from health organisations or Movianto    Travel Those intending to travel to areas with a risk of  diphtheria infection should be fully immunised accord-  ing to the UK schedule (see also section 14.6). If more  than 10 years have lapsed since completion of the UK  schedule, a dose of adsorbed diphtheria [low dose],  tetanus and poliomyelitis (inactivated) vaccine  should be administered.   Contacts Staff in contact with diphtheria patients or  with potentially pathogenic clinical specimens or work-  ing directly with C. diphtheriae or C. ulcerans should  receive a booster dose if fully immunised (with 5 doses    Adsorbed Diphtheria, Tetanus, Pertussis (Acellu-  lar, Component) and Poliomyelitis (Inactivated)  Vaccine [Ml   Injection, suspension of diphtheria toxoid, tetanus  toxoid, acellular pertussis and inactivated poliomyel-  itis vaccine components adsorbed on a mineral car-  rier, net price 0.5-mL prefilled syringe = £17.56   Excipients may include neomycin and polymyxin B  Dose by intramuscular injection, CHILD 3-10 years, first booster  dose 3 years after primary immunisation, 0.5 mL; see also notes  on booster doses, above   Brands include Infanrix-IPV ® ; available as part of childhood  immunisation schedule, from health organisations or Movianto    Adsorbed Diphtheria [low dose]. Tetanus, Per-  tussis (Acellular, Component) and Poliomyelitis  (Inactivated) Vaccine (M]   Injection, suspension of diphtheria toxoid [low dose],  tetanus toxoid, acellular pertussis and inactivated  poliomyelitis vaccine components adsorbed on a  mineral carrier, net price 0.5-mL prefilled syringe =  £11.98   Excipients may include neomycin, polymyxin B and streptomycin  Dose by intramuscular injection, CHILD 3-10 years, first booster  dose 3 years after primary immunisation, 0.5 mL; see also notes  on booster doses, above   A low dose of diphtheria toxoid is sufficient to recall  immunity in individuals previously immunised against  diphtheria but whose immunity may have diminished  with time; it is insufficient to cause serious reactions  in an individual who is already immune. Preparations  containing low dose diphtheria should be used for  adults and children over 10 years, for both primary  immunisation and booster doses.   Injection, suspension of diphtheria toxoid [low dose],  tetanus toxoid and inactivated poliomyelitis vaccine  components adsorbed on a mineral carrier, net price  0.5-mL prefilled syringe = £6.35   Excipients may include neomycin, polymyxin B and streptomycin  Dose by intramuscular injection, ADULT and CHILD over 10 years,  primary immunisation, 3 doses each of 0.5 mL separated by  intervals of 1 month; second booster dose, 0.5 mL given 10 years  after first booster dose (may also be used as first booster dose in  those over 10 years who have received only 3 previous doses of a  diphtheria-containing vaccine); see also notes on booster doses  and contacts, above   Diphtheria antitoxin is used for passive immuni-  sation in suspected cases of diphtheria only (without  waiting for bacteriological confirmation); tests for  hypersensitivity should be first carried out. It is  derived from horse serum, and reactions are common  after administration; resuscitation facilities should be  available immediately.   It is no longer used for prophylaxis because of the risk  of hypersensitivity; unimmunised contacts should be  promptly investigated and given antibacterial prophy-  laxis (section 5.1, table 2) and vaccine (see Contacts  above).   Treatment, consult product literature  Available from Centre for Infections (Tel (020) 8200 6868) or in  Northern Ireland from Public Health Laboratory, Belfast City  Hospital (Tel (028) 9032 9241)    tion with diphtheria, tetanus, pertussis (acellular,  component) and poliomyelitis (inactivated) vaccine, as  a component of the primary course of childhood  immunisation (see Immunisation schedule, section  14.1) (see under Diphtheria-containing Vaccines). For  infants under 1 year, the course consists of 3 doses of a  vaccine containing haemophilus influenzae type b com-  ponent with an interval of 1 month between doses. A  booster dose of haemophilus influenzae type b vaccine  (combined with meningococcal group C conjugate  vaccine) should be given at 12-13 months of age.   Children 1-10 years who have not been immunised  against Haemophilus influenzae type b need to receive  only 1 dose of Haemophilus influenzae type b vaccine  (combined with meningococcal group C conjuate  vaccine). However, if a primary course of immunisation  has not been completed, these children should be given  3 doses of diphtheria, tetanus, pertussis (acellular, com-  ponent), poliomyelitis (inactivated) and haemophilus  type b conjugate vaccine (adsorbed). The risk of infec-  tion falls sharply in older children and the vaccine is not  normally required for children over 10 years.   Haemophilus influenzae type b vaccine may be given to  those over 10 years who are considered to be at  increased risk of invasive H. influenzae type b disease  (such as those with sickle-cell disease or complement  deficiency, or those receiving treatment for malig-  nancy).   For use of Rifampicin in the prevention of secondary  cases of Haemophilus influenzae type b disease, see  Table 2, section 5.1.    Asplenia or splenic dysfunction Haemophilus  influenzae type b vaccine is recommended for patients  with asplenia or splenic dysfunction. Immunised adults  and children over 1 year, who develop splenic dysfunc-  tion, should be given 1 additional dose of haemophilus  influenzae type b vaccine (combined with meningo-  coccal group C conjugate vaccine). For elective splenec-  tomy, the vaccine should ideally be given at least 2  weeks before surgery. Adults and children over 1 year,  who are not immunised against haemophilus influenzae  type b, should be given 2 doses of haemophilus influ-  enzae type b vaccine (combined with meningococcal  group C conjugate vaccine) with an interval of 2 months  between doses. However, children under 10 years, who  are not immunised against diphtheria, tetanus, pertussis,  poliomyelitis, and haemophilus influenzae type b should  be given 3 doses (with an interval of 1 month between  doses) of combined diphtheria, tetanus, pertussis (acel-  lular component), poliomyelitis (inactivated) and  haemophilus type b conjugate vaccine.   Complement deficiency Individuals who have been  fully immunised with haemophilus influenzae type b  vaccine, and who subsequently become complement  deficient, may require further doses of haemophilus  influenzae type b vaccine if they have insufficient anti-  body levels.   Haemophilus influenzae type b (Hib) vaccine is made  from capsular polysaccharide; it is conjugated with a  protein such as tetanus toxoid to increase immunogeni-  city, especially in young children. Haemophilus influ-  enzae type b vaccine immunisation is given in combina-    A vaccine for close contacts (of confirmed cases of  hepatitis A) who have chronic liver disease or HIV  infection, or who are immunosuppressed or over 50  years of age.   Injection, powder for reconstitution, capsular poly-  saccharide of Haemophilus influenzae type b and  capsular polysaccharide of Neisseria meningitidis  group C (both conjugated to tetanus protein), net  price single-dose vial (with syringe containing 0.5 mL  diluent) = £39.87   Dose by intramuscular injection, CHILD 1-10 years, 0.5 mL  ADULT and CHILD over 1 year, with asplenia or splenic dysfunction  (see notes above), 0.5 mL   Hepatitis A vaccine is prepared from formaldehyde-  inactivated hepatitis A virus grown in human diploid  cells.   • staff and residents of homes for those with severe  learning difficulties;   • patients with haemophilia or other conditions trea-  ted with plasma-derived clotting factors;   • individuals who are at risk due to their sexual  behaviour;   • patients with chronic liver disease including chronic  hepatitis B or chronic hepatitis C;    • prevention of secondary cases in close contacts of  confirmed cases of hepatitis A, within 14 days of  exposure to the primary case (within 8 weeks of  exposure to the primary case where there is more  than 1 contact in the household).    A booster dose is usually given 6-12 months after the  initial dose. A second booster dose can be given 20  years after the previous booster dose to those who  continue to be at risk. Specialist advice should be sought  on re-immunisation of immunocompromised indivi-  duals.    For rapid protection against hepatitis A after exposure  or during an outbreak, in adults a single dose of a  monovalent vaccine is recommended; for children  under 16 years, a single dose of the combined vaccine  Ambirix® can also be used.    Intramuscular normal immunoglobulin (section  14.5.1) is recommended for use in addition to Hepatitis   Contra-indications see section 14.1  Pregnancy see p. 747  Breast-feeding see p. 747   ^Single component  Avaxim® (Sanofi Pasteur) (S  Injection, suspension of formaldehyde-inactivated  hepatitis A virus (GBM grown in human diploid cells)  320 antigen units/mL adsorbed onto aluminium  hydroxide, net price 0.5-mL prefilled syringe = £18.10   Dose by intramuscular injection (see note below), ADULT and  CHILD over 16 years, 0.5 mL as a single dose; booster dose 0.5 mL  6-12 months after initial dose   Note Booster dose may be delayed by up to 3 years if not given  after recommended interval following primary dose with  Avaxim ® . The deltoid region is the preferred site of injection. The  subcutaneous route may be used for patients with bleeding  disorders; not to be injected into the buttock (vaccine efficacy  reduced)   Injection, suspension of formaldehyde-inactivated  hepatitis A virus (RG-SB grown in human diploid cells)  at least 48 units/mL, net price 0.5-mL prefilled  syringe = £23.81   Dose by intramuscular injection (see note below), ADULT and  CHILD over 1 year, 0.5 mL as a single dose; booster dose 0.5 mL 6-  12 months after initial dose (1-6 months if splenectomised)   Note Booster dose may be delayed by up to 4 years in adults if not  given after recommended interval following primary dose. The  deltoid region is the preferred site of injection. The subcutaneous  route may be used for patients with bleeding disorders  Important Epaxal ® contains influenza virus haemagglutinin  grown in the allantoic cavity of chick embryos, therefore contra-  indicated in those hypersensitive to eggs or chicken protein.   Havrix Monodose® (GSK) (Ml  Injection, suspension of formaldehyde-inactivated  hepatitis A virus (HM 175 grown in human diploid  cells) 1440 ELISA units/mL adsorbed onto aluminium  hydroxide, net price 1-mL prefilled syringe = £22.14,  0.5-mL (720 ELISA units) prefilled syringe (. Havrix  Junior Monodose®) = £16.77   Dose by intramuscular injection (see note below), ADULT and  CHILD over 16 years, 1 mL as a single dose; booster dose, 1 mL 6-  12 months after initial dose; CHILD 1-15 years 0.5 mL; booster  dose, 0.5 mL 6-12 months after initial dose  Note Booster dose may be delayed by up to 3 years if not given  after recommended interval following primary dose with Havrix  Monodose® . The deltoid region is the preferred site of injection.  The subcutaneous route may be used for patients with bleeding  disorders   Vaqta® Paediatric (Sanofi Pasteur) (Ml  Injection, suspension of formaldehyde-inactivated  hepatitis A virus (grown in human diploid cells)   Dose by intramuscular injection (see note below) CHILD 1-17  years, 0.5 mL as a single dose; booster dose 0.5 mL 6-18 months  after initial dose; under 1 year, not recommended  Note The deltoid region is the preferred site of injection. The  subcutaneous route may be used for patients with bleeding dis-  orders (but immune response may be reduced)   Injection, suspension of inactivated hepatitis A virus  (grown in human diploid cells) 720 ELISA units/mL  adsorbed onto aluminium hydroxide, and recombi-  nant (DNA) hepatitis B surface antigen (grown in yeast  cells) 20 micrograms/mL adsorbed onto aluminium  phosphate, net price 1-mL prefilled syringe = £31.18   Dose CHILD 1-15 years, by intramuscular injection (see note  below); primary course, 2 doses of 1 mL, the second 6-12 months  after initial dose   Note Primary course should be completed with Ambirix? (single  component vaccines given at appropriate intervals may be used  for booster dose); the deltoid region is the preferred site of  injection in older children; anterolateral thigh is the preferred site  in infants; not to be injected into the buttock (vaccine efficacy  reduced); subcutaneous route used for patients with bleeding  disorders (but immune response may be reduced)   Important Ambirix ® is not recommended for post-exposure  prophylaxis following percutaneous (needle-stick), ocular, or  mucous membrane exposure to hepatitis B virus   Injection, inactivated hepatitis A virus (grown in  human diploid cells) 720 ELISA units/mL adsorbed  onto aluminium hydroxide and recombinant (DNA)  hepatitis B surface antigen (grown in yeast cells)   20 micrograms/mL adsorbed onto aluminium phos-  phate, net price 1-mL prefilled syringe ( Twinrix ®  Adult ) = £27.76, 0.5-mL prefilled syringe (Twinrix®  Paediatric) = £20.79   Dose by intramuscular injection (see note below); ADULT and  CHILD over 16 years, primary course of 3 doses of 1 mL ( Twinrix ®  Adult), the second 1 month and the third 6 months after the first  dose; CHILD 1-15 years, 3 doses of 0.5 mL ( Twinrix ® Paediatric)  Accelerated schedule (e.g. for travellers departing within 1  month), ADULT, second dose 7 days after first dose, third dose after  further 14 days and a fourth dose 12 months after the first dose  Note Primary course should be completed with Twinrix :® (single  component vaccines given at appropriate intervals may be used  for booster dose); the deltoid region is the preferred site of  injection in adults and older children; anterolateral thigh is  preferred site in infants; not to be injected into the buttock  (vaccine efficacy reduced); subcutaneous route used for patients  with bleeding disorders (but immune response may be reduced).  Important Twinrix ® not recommended for post-exposure  prophylaxis following percutaneous (needle-stick), ocular or  mucous membrane exposure to hepatitis B virus.   Injection, suspension of inactivated hepatitis A virus  (grown in human diploid cells) 1440 ELISA units/mL  adsorbed onto aluminium hydroxide, combined with  typhoid vaccine containing 25 micrograms/mL viru-  lence polysaccharide antigen of Salmonella typhi, net  price 1-mL prefilled syringe = £32.08   Dose by intramuscular injection (see note below), ADULT and  CHILD over 15 years, 1 mL as a single dose; booster doses, see  under single component hepatitis A vaccine (above) and under  polysaccharide typhoid vaccine, p. 767  Note The deltoid region is the preferred site of injection. The  subcutaneous route may be used for patients with bleeding dis-  orders; not to be injected into the buttock (vaccine efficacy  reduced)    ViATIM® (Sanofi Pasteur) [Ml  Injection, suspension of inactivated hepatitis A virus  (grown in human diploid cells) 160 antigen units/mL  adsorbed onto aluminium hydroxide, combined with  typhoid vaccine containing 25 micrograms/mL viru-  lence polysaccharide antigen of Salmonella typhi, net  price 1-mL prefilled syringe = £29.80   Dose by intramuscular injection (see note below), ADULT and  CHILD over 16 years, 1 mL as a single dose; booster doses, see  under single component hepatitis A vaccine (above) and under  polysaccharide typhoid vaccine, p. 767  Note The deltoid region is the preferred site of injection. The  subcutaneous route may be used for patients with bleeding dis-  orders; not to be injected into the buttock (vaccine efficacy  reduced)    Hepatitis B vaccine contains inactivated hepatitis B  virus surface antigen (HBsAg) adsorbed onto aluminium  hydroxide adjuvant. It is made biosynthetically using  recombinant DNA technology. The vaccine is used in  individuals at high risk of contracting hepatitis B.    • parenteral drug misusers, their sexual partners, and  household contacts; other drug misusers who are  likely to ‘progress’ to injecting;   • close family contacts of a case or individual with  chronic hepatitis B infection;   • babies whose mothers have had acute hepatitis B  during pregnancy or are positive for hepatitis B  surface antigen (regardless of e-antigen markers);  hepatitis B vaccination is started immediately on  delivery and hepatitis B immunoglobulin (see  p. 771) given at the same time (but preferably at a  different site). Babies whose mothers are positive  for hepatitis B surface antigen and for e-antigen  antibody should receive the vaccine only (but  babies weighing 1.5 kg or less should also receive  the immunoglobulin regardless of the mother’s e-  antigen antibody status);    • individuals with haemophilia, those receiving reg-  ular blood transfusions or blood products, and  carers responsible for the administration of such  products;   • patients with chronic renal failure including those  on haemodialysis. Haemodialysis patients should be  monitored for antibodies annually and re-immu-  nised if necessary. Home carers (of dialysis patients)  should be vaccinated;    • healthcare personnel (including trainees) who have  direct contact with blood or blood-stained body  fluids or with patients’ tissues;    • staff and patients of day-care or residential accom-  modation for those with severe learning difficulties;    • those travelling to areas of high or intermediate  prevalence who are at increased risk or who plan  to remain there for lengthy periods (see p. 774);    • families adopting children from countries with a  high or intermediate prevalence of hepatitis B;   Different immunisation schedules for hepatitis B  vaccine are recommended for specific circumstances  (see under individual preparations). Generally, three or  four doses are required for primary immunisation; an  ‘accelerated schedule’ is recommended for pre-expo-  sure prophylaxis in high-risk groups where rapid protec-  tion is required, and for post-exposure prophylaxis (see  below).   Immunisation may take up to 6 months to confer  adequate protection; the duration of immunity is not  known precisely, but a single booster 5 years after the  primary course may be sufficient to maintain immunity  for those who continue to be at risk.   Immunisation does not eliminate the need for common-  sense precautions for avoiding the risk of infection from  known carriers by the routes of infection which have  been clearly established, consult Guidance for Clinical  Health Care Workers: Protection against Infection with  Blood-borne Viruses (available at www.dh.gov.uk). Acci-  dental inoculation of hepatitis B virus-infected blood  into a wound, incision, needle-prick, or abrasion may  lead to infection, whereas it is unlikely that indirect  exposure to a carrier will do so.   Following significant exposure to hepatitis B, an accel-  erated schedule, with the second dose given 1 month,  and the third dose 2 months after the first dose, is  recommended. For those at continued risk, a fourth  dose should be given 12 months after the first dose.  More detailed guidance is given in the handbook  Immunisation against Infectious Disease see p. 746.   Specific hepatitis B immunoglobulin (‘HBIG’) is avail-  able for use with the vaccine in those accidentally  inoculated and in neonates at special risk of infection  (section 14.5.2).   A combined hepatitis A and hepatitis B vaccine is also  available.   Contra-indications see section 14.1  Pregnancy see p. 747  Breast-feeding see p. 747  Side-effects see section 14.1   Injection, suspension of hepatitis B surface antigen  (prepared from yeast cells by recombinant DNA  technique) 20 micrograms/mL adsorbed onto alu-  minium hydroxide, net price 0.5-mL (paediatric) pre-  filled syringe = £9.67, 1-mL vial = £12.34, 1-mL  prefilled syringe = £12.99   Dose by intramuscular injection (see note below), ADULT and  CHILD over 16 years, 3 doses of 20 micrograms, the second 1  month and the third 6 months after the first dose; NEONATE  (except if bom to hepatitis B surface antigen positive mother, see  below) and CHILD 1 month-16 years, 3 doses of 10 micrograms  Accelerated schedule (all ages), second dose 1 month after first  dose, third dose 2 months after first dose and fourth dose 12  months after first dose; exceptionally (e.g. for travellers departing    within 1 month), ADULT over 18 years, second dose 7 days after  first dose, third dose 21 days after first dose, and fourth dose 12  months after first dose   Alternative schedule for CHILD 11-15 years, 2 doses of 20 micr-  ograms, the second dose 6 months after the first dose (this  schedule not suitable if high risk of infection between doses or if  compliance with second dose uncertain)   NEONATE born to hepatitis B surface antigen-positive mother (see  also notes above), 4 doses of 10 micrograms, first dose at birth  with hepatitis B immunoglobulin injection (separate site) the  second 1 month, the third 2 months and the fourth 12 months after  the first dose   Renal insufficiency (including haemodialysis patients), by intra-  muscular injection (see note below), ADULT and CHILD over 16  years, 4 doses of 40 micrograms, the second 1 month, the third 2  months and the fourth 6 months after the first dose; immunisation  schedule and booster doses may need to be adjusted in those with  low antibody concentration; NEONATE (except if born to hepatitis  B surface antigen positive mother, see above) and CHILD 1 month-  16 years 3 doses of 10 micrograms, second dose 1 month and third  dose 6 months after first dose or accelerated schedule, 4 doses of  10 micrograms, second dose 1 month, third dose 2 months and  fourth dose 12 months after first dose; immunisation schedule and  booster doses may need to be adjusted in those with low antibody  concentration   Note Deltoid muscle is preferred site of injection in adults and  older children; anterolateral thigh is preferred site in neonates,  infants and young children; not to be injected into the buttock  (vaccine efficacy reduced)   Injection, suspension of hepatitis B surface antigen  (prepared from yeast cells by recombinant DNA  technique) 40 micrograms/mL adsorbed onto alu-  minium phosphate, net price 0.5-mL prefilled syringe  = £38.10   Dose ADULT and CHILD over 15 years with renal insufficiency  (including pre-haemodialysis and haemodialysis patients), by  intramuscular injection (see note below) 4 doses of 20 micr-  ograms, the second 1 month, the third 2 months and the fourth 6  months after the first dose; immunisation schedule and booster  doses may need to be adjusted in those with low antibody  concentration   Note Deltoid muscle is preferred site of injection; not to be  injected into the buttock (vaccine efficacy reduced)   HBvaxPRO® (Sanofi Pasteur) (MD  Injection, suspension of hepatitis B surface antigen  (prepared from yeast cells by recombinant DNA  technique) 10 micrograms/mL adsorbed onto alu-  minium hydroxyphosphate sulphate, net price 0.5-mL  (5-microgram) prefilled syringe = £8.95, 1-mL (10-  microgram) prefilled syringe = £12.20; 40 micr-  ograms/mL, 1-mL (40-microgram) vial = £27.60  Dose by intramuscular injection (see note below), ADULT and  CHILD over 16 years, 3 doses of 10 micrograms, the second 1  month and the third 6 months after the first dose; CHILD under 16  years, 3 doses of 5 micrograms   Accelerated schedule (all ages), second dose 1 month after first  dose, third dose 2 months after first dose with fourth dose at 12  months   Booster doses may be required in immunocompromised patients  with low antibody concentration   NEONATE bom to hepatitis B surface antigen-positive mother (see  also notes above), 5 micrograms, first dose at birth with hepatitis B  immunoglobulin injection (separate site), the second 1 month, the  third 2 months and the fourth 12 months after the first dose  Chronic haemodialysis patients, by intramuscular injection (see  note below) 3 doses of 40 micrograms, the second 1 month and  the third 6 months after the first dose; booster doses may be  required in those with low antibody concentration  Note Deltoid muscle is preferred site of injection in adults and  older children; anterolateral thigh is preferred site in neonates and  infants; not to be injected into the buttock (vaccine efficacy  reduced)   Human papilloma virus vaccine is available as a  bivalent vaccine ( Cervarix ®) or a quadrivalent vaccine  ( Gardasil ®). Cervarix® is licensed for use in females for  the prevention of cervical cancer and other pre-  cancerous lesions caused by human papilloma virus  types 16 and 18. Gardasil® is licensed for use in females  for the prevention of cervical cancer, genital warts and  pre-cancerous lesions caused by human papilloma virus  types 6, 11, 16, and 18. The two vaccines are not  interchangeable and one vaccine product should be  used for an entire course. However, the Department of  Health (November 2008) states that for individuals with  previous incomplete vaccination with Gardasil®, who  are eligible for HPV vaccination under the national  programme, Cervarix® can be used to complete the  vaccination course if necessary; the individual must be  informed that Cervarix® does not protect against  genital warts.   Human papilloma virus vaccine will be most effective if  given before sexual activity starts. The first dose is given  to females aged 12 to 13 years, the second and third  doses are given 1-2 and 6 months after the first dose  (see Immunisation schedule, section 14.1); all 3 doses  should be given within a 12-month period. If the course  is interrupted, it should be resumed but not repeated,  allowing the appropriate interval between the remaining  doses. Where there are significant challenges in sche-  duling vaccinations, or a high likelihood that the third  dose will not be given, the third dose of Cervarix® can  be given 3 months after the second dose. Under the  national programme in England, females remain eligible  to receive the vaccine up to the age of 18 years if they  did not receive the vaccine when scheduled. Where  appropriate, immunisation with human papilloma virus  vaccine should be offered to females coming into the  UK as they may not have been offered protection in  their country of origin. The duration of protection has  not been established, but current studies suggest that  protection is maintained for at least 6 years after  completion of the primary course.   As the vaccines do not protect against all strains of  human papilloma virus, routine cervical screening  should continue.   Contra-indications see section 14.1  Pregnancy not known to be harmful, but vaccination  should be postponed until completion of pregnancy  Breast-feeding see p. 747  Side-effects see section 14.1  Dose   • See notes above and under preparations  Note To avoid confusion, prescribers should specify the  brand to be dispensed   Injection, suspension of virus-like particles of human  papillomavirus type 16 (40 micrograms/mL), type 18  (40 micrograms/mL) capsid protein (prepared by    recombinant DNA technique using a Baculovirus  expression system) in monophosphoryl lipid A adju-  vant adsorbed onto aluminium hydroxide, net price  0.5-mL prefilled syringe = £80.50  Dose prevention of premalignant genital lesions and cervical  cancer, by intramuscular injection into deltoid region, ADULT and  CHILD 10-25 years, 3 doses of 0.5 mL, the second 1 month and the  third 6 months after the first dose   Alternative schedule for ADULT and CHILD 10-25 years, 3 doses of  0.5 mL, the second 1-2.5 months, and the third 5-12 months after  the first dose   Injection, suspension of virus-like particles of human  papilloma virus type 6 (40 micrograms/mL), type 1 1  (80 micrograms/mL), type 16 (80 micrograms/mL),  type 18 (40 micrograms/mL) capsid protein (prepared  from yeast cells by recombinant DNA technique)  adsorbed onto aluminium hydroxyphosphate sul-  phate, net price 0.5-mL prefilled syringe = £86.50  Dose prevention of premalignant genital lesions, cervical cancer  and genital warts, by intramuscular injection preferably into  deltoid region or higher anterolateral thigh, ADULT and CHILD 9-26  years, 3 doses of 0.5 mL, the second 2 months and the third 6  months after the first dose   Alternative schedule for ADULT and CHILD 9-26 years, 3 doses of  0.5 mL, the second at least 1 month, and the third at least 4  months after the first dose; schedule should be completed within  12 months   While most viruses are antigenically stable, the influ-  enza viruses A and B (especially A) are constantly  altering their antigenic structure as indicated by  changes in the haemagglutinins (H) and neuraminidases  (N) on the surface of the viruses. It is essential that  influenza vaccines in use contain the H and N compo-  nents of the prevalent strain or strains as recommended  each year by the World Health Organization.    vaccines will not control epidemics — immunisation is  recommended only for persons at high risk. Annual  immunisation is strongly recommended for individuals  aged over 6 months with the following conditions:   • chronic respiratory disease (includes asthma treated  with continuous or repeated use of inhaled or systemic  corticosteroids or asthma with previous exacerbations  requiring hospital admission);    • immunosuppression because of disease (including  asplenia or splenic dysfunction) or treatment (including  chemotherapy and prolonged corticosteroid treatment);    Seasonal influenza vaccine is also recommended for all  pregnant women, for all persons aged over 65 years, for  residents of nursing or residential homes for the elderly  and other long-stay facilities, and for carers of persons  whose welfare may be at risk if the carer falls ill. Influ-  enza immunisation should also be considered for house-  hold contacts of immunocompromised individuals.    As part of winter planning, NHS employers should offer  vaccination to healthcare workers who are directly  involved in patient care. Employers of social care work-  ers should consider similar action.   For people who work in close contact with poultry on a  regular basis, influenza immunisation is recommended  as a precautionary public health measure. Seasonal  human influenza vaccine does not protect against  avian influenza, but it reduces the risk of poultry work-  ers contracting both human and avian influenza simul-  taneously, and therefore also reduces the risk of a new  influenza virus emerging.   A single dose of Pandemrix® can be used instead of the  seasonal influenza vaccine if supplies of seasonal  influenza vaccine are exhausted and cannot be  replenished rapidly.   Pandemrix® and Celvapan® are monovalent vaccines  licensed against the influenza A(HlNl)v (swine flu)  strain.   Pandemrix® is recommended for children aged 6  months-5 years who have not received the monovalent  vaccine previously and who are in the risk groups  prioritised for seasonal influenza vaccine. Pandemrix®  is also recommended for all immunocompromised  patients over 6 months of age who have not received  the monovalent vaccine previously. Seasonal influenza  vaccine should continue to be offered as normal.  Pandemrix® can be given at the same time as the first  dose of seasonal influenza vaccine; however,  Pandemrix® should be given 4 weeks before the  seasonal influenza vaccine to immunocompromised  patients who only require one dose of seasonal influ-  enza vaccine.   Further information on pandemic influenza, avian influ-  enza and swine influenza may be found at  www.dh.gov.uk/pandemicflu and at www.hpa.org.uk.   Indications annual immunisation against seasonal  influenza; immunisation against influenza during a  pandemic   Contra-indications see section 14.1; avoid Enzira® or  preparations marketed by Pfizer, Wyeth or CSL  Biotherapies in child under 5 years — increased risk of  febrile convulsions   • Seasonal influenza, by intramuscular injection, ADULT  and CHILD over 13 years, 0.5 mL as a single dose; CHILD  6 months-3 years, 0.25-0.5 mL; 3-13 years 0.5 mL; for  children 6 months to 13 years who have not received  seasonal influenza vaccine previously, repeat after 4-  6 weeks   Injection, suspension of formaldehyde-inactivated  influenza virus (split virion grown in fertilised hens’  egg’s), net price 0.25-mL prefilled syringe = £6.29; 0.5-  mL prefilled syringe = £6.29   Contra-indications avoid preparations marketed by Pfizer,  Wyeth, or CSL Biotherapies in child under 5 years — increased risk  of febrile convulsions   Excipients may include neomycin and polymyxin B, and traces of  thiomersal   Agrippal® (Novartis Vaccines) (Mi  Injection, suspension of formaldehyde-inactivated  influenza virus (surface antigen, grown in fertilised  hens’ eggs), net price 0.5-mL prefilled syringe = £5.85   Begrivac® (Novartis Vaccines) (Ml  Injection, suspension of formaldehyde-inactivated  influenza virus (split virion, grown in fertilised hens’  eggs), net price 0.5-mL prefilled syringe = £5.85   Fluvirin® (Novartis Vaccines) ImD  Injection, suspension of formaldehyde-inactivated  influenza virus (surface antigen, grown in fertilised  hens’ eggs), net price 0.5-mL prefilled syringe = £5.55   Excipients include neomycin, polymyxin B, and traces of thiomersal  Note Not licensed for use in children under 4 years   Influvac Sub-unit® (Abbott) (M  Injection, suspension of formaldehyde-inactivated  influenza virus (surface antigen, grown in fertilised  hens’ eggs), net price 0.5-mL prefilled syringe = £5.22    ^Seasonal influenza vaccine for intradermal use  Intanza® (Sanofi Pasteur) ▼ (5°!   Injection, suspension of formaldehyde-inactivated  influenza virus (split virion, grown in fertilised hens’  eggs), net price, prefilled syringe, 9 micrograms  (0.1 mL) = £9.05; prefilled syringe, 15 micrograms  (0.1 mL) =£9.05   Dose by intradermal injection into deltoid region, ADULT 18-60  years, 9 micrograms as a single dose; ADULT over 60 years,   Injection, suspension of formaldehyde-inactivated  influenza A(HlNl)v virus (whole virion, grown in vero  cells), 15 micrograms /mL, 5-mL multidose vial con-  tains 10 doses of 0.5 mL   Dose prevention of influenza A(HlNl)v, by intramuscular  injection, ADULT and CHILD over 6 months, 2 doses each of 0.5 mL  separated by an interval of at least 3 weeks  Note Celvapan ® is not interchangeable with Pandemrix r®   Pandemrix® (GSK) ▼ fMI  Injection, suspension of inactivated influenza  A(HlNl)v virus (split virion, grown in fertilised hens’  eggs) 7.5 micrograms/mL when mixed with emulsion  of adjuvant, 5 mL of mixed multidose vial contains 10  doses of 0.5 mL   Excipients include gentamicin and thiomersal  Dose prevention of influenza A(HlNl)v, by intramuscular  injection, ADULT and CHILD over 10 years, 0.5 mL as a single dose;  CHILD 6 months -10 years, a single dose of 0.25 mL  Note Pandemrix r® is not interchangeable with Celvapan ®   Japanese encephalitis vaccine is indicated for travellers  to areas in Asia and the Far East where infection is  endemic and for laboratory staff at risk of exposure to  the virus. The primary immunisation course of 2 doses  should be completed at least one week before potential  exposure to Japanese encephalitis virus.   Up-to-date information on the risk of Japanese  encephalitis in specific countries can be obtained from  the National Travel Health Network and Centre  (www.nathnac.org)   Contra-indications see section 14.1; hypersensitivity  reaction after first dose — do not give the second dose  Pregnancy although manufacturer advises avoid  because of limited information, miscarriage has been  associated with Japanese encephalitis virus infection  acquired during the first 2 trimesters of pregnancy  Breast-feeding see p. 747  Side-effects see section 14.1; also less commonly  migraine, vertigo, pharyngolaryngeal pain   Uxiaro® (Novartis Vaccines) T (Ml [Ml  Injection, suspension, inactivated Japanese  encephalitis virus (produced in Vero cells), adsorbed  onto aluminium hydroxide, net price 0.5-mL (6 micr-  ograms) prefilled syringe = £48.00  Dose by intramuscular injection in deltoid region, ADULT over 18  years 2 doses of 0.5 mL separated by interval of 28 days; booster  dose 1-2 years after completing primary course, but for those at  continued risk the booster dose should be given 1 year after  completing the primary course   Note Ixiaro ® doses differ from the other previously available  unlicensed Japanese encephalitis vaccines   Measles vaccine has been replaced by a combined live  measles, mumps and rubella vaccine (MMR vaccine).   MMR vaccine may be used in the control of outbreaks of  measles (see under MMR Vaccine).    A combined live measles, mumps, and rubella  vaccine (MMR vaccine) aims to eliminate measles,  mumps, and rubella (and congenital rubella syndrome).  Every child should receive two doses of MMR vaccine  by entry to primary school, unless there is a valid  contra-indication (see section 14.1). MMR vaccine  should be given irrespective of previous measles,  mumps, or rubella infection or vaccination.    The first dose of MMR vaccine is given to children aged  12-13 months. A second dose is given before starting  school at 3-5 years of age (see Immunisation Schedule,  section 14.1   When protection against measles is required urgently  (e.g. during a measles outbreak), the second dose of  MMR vaccine can be given 1 month after the first dose;  if the second dose is given before 18 months of age, then  children should still receive the routine dose before  starting school at 3-5 years of age.   Children presenting for pre-school booster who have  not received the first dose of MMR vaccine should be  given a dose of MMR vaccine followed 3 months later by  a second dose. At school-leaving age or at entry into  further education, MMR immunisation should be  offered to individuals of both sexes who have not  received 2 doses during childhood. In a young adult  who has received only a single dose of MMR in child-  hood, a second dose is recommended to achieve full  protection. If 2 doses of MMR vaccine are required, the  second dose should be given one month after initial  dose.    1. Japanese encephalitis vaccine not prescribable on the  NHS; health authorities may investigate circumstances  under which vaccine prescribed    MMR vaccine should be used to protect against rubella  in seronegative women of child-bearing age (see  Immunisation Schedule, section 14.1); unimmunised  healthcare workers who might put pregnant women  and other vulnerable groups at risk of rubella or measles  should be vaccinated. MMR vaccine may also be offered  to previously unimmunised and seronegative post-par-  tum women — vaccination a few days after delivery is  important because about 60% of congenital abnormal-  ities from rubella infection occur in babies of women  who have borne more than one child. Immigrants arriv-  ing after the age of school immunisation are particularly  likely to require immunisation.   Contacts MMR vaccine may also be used in the  control of outbreaks of measles and should be offered  to susceptible children aged over 6 months who are  contacts of a case, within 3 days of exposure to infec-  tion; these children should still receive routine MMR  vaccinations at the recommended ages. Children aged  under 9 months for whom avoidance of measles infec-  tion is particularly important (such as those with history  of recent severe illness) can be given normal immuno-  globulin (section 14.5.1) after exposure to measles;  routine MMR immunisation should then be given after  at least 3 months at the appropriate age.   MMR vaccine is not suitable for prophylaxis following  exposure to mumps or rubella since the antibody  response to the mumps and rubella components is too  slow for effective prophylaxis.   Children and adults with impaired immune response  should not receive live vaccines (for advice on HIV see  section 14.1). If they have been exposed to measles  infection they should be given normal immunoglobulin  (section 14.5.1).   Travel Unimmunised travellers, including children over  6 months, to areas where measles is endemic or epi-  demic should receive MMR vaccine. Children immu-  nised before 12 months of age should still receive two  doses of MMR at the recommended ages. If one dose of  MMR has already been given to a child, then the second  dose should be brought forward to at least one month  after the first, to ensure complete protection. If the child  is under 18 months of age and the second dose is given  within 3 months of the first, then the routine dose before  starting school at 3-5 years should still be given.   Side-effects See section 14.1; also malaise, fever, or a  rash can occur after the first dose of MMR vaccine, most  commonly about a week after vaccination and lasting  about 2 to 3 days. Leaflets are available for parents on  advice for reducing fever (including the use of paraceta-  mol). Febrile seizures occur rarely 6 to 11 days after  MMR vaccination; the incidence of febrile seizures is  lower than that following measles infection. Parotid  swelling occurs occasionally, usually in the third week,  and rarely, arthropathy 2 to 3 weeks after immunisation.  Adverse reactions are considerably less frequent after  the second dose of MMR vaccine than after the first  dose.   Hypersensitivity to egg — there is increasing evidence  that MMR vaccine can be given safely even when the  child has had an anaphylactic reaction to food contain-  ing egg (dislike of egg or refusal to eat eggs is not a  contra-indication). For children with a confirmed ana-  phylactic reaction to egg-containing food, MMR vaccine  should be administered in a hospital setting.    Idiopathic thrombocytopenic purpura has occurred  rarely following MMR vaccination, usually within 6  weeks of the first dose. The risk of idiopathic thrombo-  cytopenic purpura after MMR vaccine is much less than  the risk after infection with wild measles or rubella virus.  Children who develop idiopathic thrombocytopenic  purpura within 6 weeks of the first dose of MMR should  undergo serological testing before the second dose is  due; if the results suggest incomplete immunity against  measles, mumps or rubella then a second dose of MMR  is recommended. The Specialist and Reference Micro-  biology Division, Health Protection Agency offers free  serological testing for children who develop idiopathic  thrombocytopenic purpura within 6 weeks of the first  dose of MMR.   Post-vaccination aseptic meningitis was reported (rarely  and with complete recovery) following vaccination with  MMR vaccine containing Urabe mumps vaccine, which  has now been discontinued; no cases have been con-  firmed in association with the currently used Jeryl Lynn  mumps vaccine. Children with post-vaccination symp-  toms are not infectious.   Reviews undertaken on behalf of the CSM, the  Medical Research Council, and the Cochrane Colla-  boration, have not found any evidence of a link  between MMR vaccination and bowel disease or  autism. The Chief Medical Officers have advised  that the MMR vaccine is the safest and best way to  protect children against measles, mumps, and ru-  bella. Information (including fact sheets and a list of  references) may be obtained from:  www.dh.gov.uk/immunisation   Cautions see section 14.1; also, after immunoglobulin  administration or blood transfusion, leave an interval  of at least 3 months before MMR immunisation as  antibody response to measles component may be  reduced — see also p. 772; interactions: Appendix 1  (vaccines)   Hypersensitivity to egg There is increasing evidence that  MMR vaccine can be given safely even when the child has  had an anaphylactic reaction to food containing egg (dislike  of egg or refusal to eat egg is not a contra-indication). For  children with a confirmed anaphylactic reaction to egg-  containing food, MMR vaccine may be administered in a  hospital setting   Pregnancy avoid pregnancy for at least 1 month after  vaccination; see also, p. 747   Side-effects see section 14.1 and notes above; also  less commonly sleep disturbances, unusual crying in  infants; also reported peripheral and optic neuritis   • By intramuscular or deep subcutaneous injection,  ADULT and CHILD over 9 months (but see also notes  above), primary immunisation, 2 doses each of  0.5 mL, see Immunisation Schedule, section 14.1,  p. 748; see also notes above for use in outbreaks, for  contacts of cases, and for travel    ^Combined vaccines  MMRvaxPro® (Sanofi Pasteur) ▼ (Ml  Injection, powder for reconstitution, live attenuated,  measles virus (Enders’ Edmonston strain) and mumps  virus (Jeryl Lynn strain) prepared in chick embryo  cells, and rubella virus (Wistar RA 27/3 strain); single-  dose vial (with syringe containing solvent)   Injection, powder for reconstitution, live attenuated,  measles virus (Schwarz strain) and mumps virus (RIT  4385 strain) prepared in chick embryo cells, and ru-  bella virus (Wistar RA 27/3 strain); net price single-  dose vial (with syringe containing solvent) = £6.37   Almost all childhood meningococcal disease in the UK  is caused by Neisseria meningitidis serogroups B and C.  Meningococcal group C conjugate vaccine protects  only against infection by serogroup C. The risk of  meningococcal disease declines with age — immuni-  sation is not generally recommended after the age of  25 years.   Tetravalent meningococcal vaccines that cover sero-  types A, C, W135, and Y are available. Although the  duration of protection has not been established, the  meningococcal A, C, W135, and Y conjugate vaccine  is likely to provide longer-lasting protection than the  unconjugated meningococal polysaccharide vaccine.  The antibody response to serotype C in unconjugated  meningococcal polysaccharide vaccines in young chil-  dren may be suboptimal.   Childhood immunisation Meningococcal group C  conjugate vaccine provides long-term protection  against infection by serogroup C of Neisseria meningi-  tidis. Immunisation consists of 2 doses given at 3  months and 4 months of age; a booster should be  given at 12-13 months of age, usually combined with  haemophilus influenzae type b vaccine (see Immuni-  sation Schedule, section 14.1, p. 748).   It is recommended that meningococcal group C con-  jugate vaccine be given to anyone aged under 25 years  who has not been vaccinated previously with this  vaccine; those over 1 year receive a single dose.   A single dose of meningococcal group C conjugate  vaccine is also recommended for unimmunised indivi-  duals attending university, irrespective of age.   Patients under 25 years of age with confirmed serogroup  C disease, who have previously been immunised with  meningococcal group C vaccine, should be offered  meningococcal group C conjugate vaccine before dis-  charge from hospital.   Asplenia or splenic dysfunction Children under 1  year should be vaccinated according to the Immuni-  sation Schedule (section 14.1), but should receive 2  doses of meningococcal A, C, W135, and Y conjugate  vaccine at 3 months and 4 months of age instead of the  meningococcal group C conjugate vaccine; these chil-  dren should also receive one dose of meningococcal    group C conjugate vaccine (combined with haemophilus  influenzae type b vaccine) at 12 months of age, followed  2 months later by one dose of meningococcal A, C,  W135, and Y conjugate vaccine. Unimmunised adults  and children over 1 year should be given 1 dose of  meningococcal group C conjugate vaccine (preferably  combined with haemophilus influenzae type b vaccine)  followed 2 months later by one dose of meningococcal  A, C, W135, and Y conjugate vaccine. Immunised adults  and children who develop splenic dysfunction should be  given 1 additional dose of meningococcal group C  conjugate vaccine (preferably combined with haemo-  philus influenzae type b vaccine) followed 2 months  later by a single dose of meningococcal A, C, W135, and  Y conjugate vaccine.    Complement deficiency Unimmunised adults and  children over 1 year of age with complement deficiency  should be given 1 dose of meningococcal group C  conjugate vaccine (preferably combined with haemo-  philus influenzae type b vaccine) followed 2 months  later by 1 dose of meningococcal A, C, W135 and Y  conjugate vaccine. Immunised adults and children, who  subsequently become complement deficient, should be  given 1 dose of meningococcal A, C, W135 and Y  conjugate vaccine at least 2 months after the last dose  of meningococcal group C conjugate vaccine.    Travel Individuals travelling to countries of risk (see  below) should be immunised with meningococcal A, C,  W135, and Y conjugate vaccine, even if they have  previously received meningitis C conjugate vaccine. If  an individual has recently received meningococcal  group C conjugate vaccine, an interval of at least 4  weeks should be allowed before administration of the  tetravalent (A, C, W135, and Y) vaccine.   Vaccination is particularly important for those living or  working with local people or visiting an area of risk  during outbreaks.    Immunisation recommendations and requirements for  visa entry for individual countries should be checked  before travelling, particularly to countries in Sub-Sahar-  an Africa, Asia, and the Indian sub-continent where  epidemics of meningococcal outbreaks and infection  are reported. Country-by-country information is avail-  able from the National Travel Health Network and  Centre (www.nathnac.org).   Proof of vaccination with the tetravalent (A, C, W135,  and Y) meningococcal vaccine is required for those  travelling to Saudi Arabia during the Hajj and Umrah  pilgrimages (where outbreaks of the W1 3 5 strain have  occurred).    Contacts For advice on the immunisation of labora-  tory workers and close contacts of cases of meningo-  coccal disease in the UK and on the role of the vaccine  in the control of local outbreaks, consult Guidance for  Public Health Management of Meningococcal Disease  in the UK at www.hpa.org.uk. See Table 2, section 5.1  for antibacterial prophylaxis for prevention of second-  ary cases of meningococcal meningitis.   The need for immunisation of laboratory staff who work  directly with Neisseria meningitidis should be consid-  ered.   Side-effects see section 14.1; also rarely symptoms of  meningitis reported (but no evidence that the vaccine  causes meningococcal C meningitis)   ACWY Vax® (GSK) ▼ m  Injection, powder for reconstitution, capsular poly-  saccharide antigens of Neisseria meningitidis groups  A, C, W135, and Y, net price single-dose vial (with  syringe containing diluent) = £16.73  Dose by deep subcutaneous injection, ADULT and CHILD over 5  years 0.5 mL as a single dose; booster dose for those at continued  risk, 0.5 mL 5 years after initial dose   Injection, suspension of capsular polysaccharide  antigen of Neisseria meningitidis group C (conjugated  to Corynebacterium diphtheriae protein), adsorbed  onto aluminium phosphate, net price 0.5-mL prefilled  syringe = £7.50   Dose by intramuscular injection, ADULT and CHILD over 1 year  0.5 mL as a single dose; for routine immunisation in CHILD 2  months-1 year, 0.5 mL, see notes above and Immunisation  schedule, section 14. 1    Menjugate Kit® (Sanofi Pasteur) (Ml  Injection, powder for reconstitution, capsular poly-  saccharide antigen of Neisseria meningitidis group C  (conjugated to Corynebacterium diphtheriae protein),  adsorbed onto aluminium hydroxide, single-dose vial  with diluent   Dose by intramuscular injection, ADULT and CHILD over 1 year  0.5 mL as a single dose; for routine immunisation in CHILD 2  months-1 year, 0.5 mL, see notes above and Immunisation  schedule, section 14.1   Injection, suspension of polysaccharide antigen of  Neisseria meningitidis group C (conjugated to tetanus  toxoid protein), adsorbed onto aluminium hydroxide,  0.5-mL prefilled syringe   Dose by intramuscular injection, ADULT and CHILD over 1 year  0.5 mL as a single dose; for routine immunisation in CHILD 2  months-1 year, 0.5 mL, see notes above and Immunisation  schedule, section 14.1   Pertussis vaccine is given as a combination prepara-  tion containing other vaccines (see Diphtheria contain-  ing Vaccines). Acellular vaccines are derived from  highly purified components of Bordetella pertussis. Pri-  mary immunisation against pertussis (whooping cough)  requires 3 doses of an acellular pertussis-containing  vaccine (see Immunisation schedule, section 14.1),  given at intervals of 1 month from the age of 2 months.   A booster dose of an acellular pertussis-containing  vaccine should be given 3 years after the primary  course.   All children up to the age of 10 years should receive  primary immunisation with diphtheria, tetanus, per-  tussis (acellular, component), poliomyelitis (inactivated)  and haemophilus type b conjugate vaccine (adsorbed).   Children aged 1-10 years who have not received a  pertussis-containing vaccine as part of their primary  immunisation should be offered 1 dose of a suitable  pertussis-containing vaccine; after an interval of at least  1 year, a booster dose of a suitable pertussis-containing  vaccine should be given. Immunisation against pertussis  is not currently recommended in individuals over 10  years of age.    ^Meningococcal Group C conjugate vaccine with  Haemophilus Influenzae type B vaccine  See Haemophilus Influenzae type B vaccine   Menveo® (Novartis Vaccines) T [Ml  Injection, powder for reconstitution, capsular oligo-  saccharide antigens of Neisseria meningitidis groups  A, C, W135, and Y (conjugated to Corynebacterium  diphtheriae protein), net price single-dose vial (with  syringe containing diluent) = £40.01  Dose by intramuscular injection preferably into deltoid region,  ADULT and CHILD 0.5 mL as a single dose; CHILD under 1 year with  asplenia or splenic dysfunction (see p. 761), 0.5 mL  Note Advice in BNF may differ from that in product literature   Side-effects See also section 14.1. The incidence of  local and systemic effects is generally lower with vac-  cines containing acellular pertussis components than  with the whole-cell pertussis vaccine used previously.  However, compared with primary vaccination, booster  doses with vaccines containing acellular pertussis are  reported to increase the risk of injection-site reactions  (some of which affect the entire limb); local reactions do  not contra-indicate further doses (see below).    The vaccine should not be withheld from children with a  history to a preceding dose of:   Pneumococcal vaccines protect against infection with  Streptococcus pneumoniae (pneumococcus); the vac-  cines contain polysaccharide from capsular pneumo-  cocci. Pneumococcal polysaccharide vaccine con-  tains purified polysaccharide from 23 capsular types of  pneumococci, whereas pneumococcal polysaccharide  conjugate vaccine (adsorbed) contains polysaccharide  from either 10 capsular types ( Synflorix ®) or 13  capsular types ( Prevenar 13®) and the polysaccharide  is conjugated to protein.   The 13-valent conjugate vaccine [Prevenar 13®) is used  in the childhood immunisation schedule. The recom-  mended schedule consists of 3 doses, the first at 2  months of age, the second at 4 months, and the third at  12-13 months (see Immunisation Schedule, section  14.1).   Pneumococcal vaccination is recommended for indivi-  duals at increased risk of pneumococcal infection as  follows:   • asplenia or splenic dysfunction (including homozy-  gous sickle cell disease and coeliac disease which  could lead to splenic dysfunction);   • chronic respiratory disease (includes asthma trea-  ted with continuous or frequent use of a systemic  corticosteroid);   • immune deficiency because of disease (e.g. HIV  infection) or treatment (including prolonged sys-  temic corticosteroid treatment);   • child under 5 years with a history of invasive  pneumococcal disease.   Where possible, the vaccine should be given at least 2  weeks before splenectomy, cochlear implant surgery,  and chemotherapy; patients should be given advice  about increased risk of pneumococcal infection. Pro-  phylactic antibacterial therapy against pneumococcal  infection (Table 2, section 5.1) should not be stopped  after immunisation. A patient card and information  leaflet for patients with asplenia are available from the  Department of Health or in Scotland from the Scottish   Choice of vaccine Children under 2 years at increased  risk of pneumococcal infection (see list above) should  receive the 13-valent pneumococcal polysaccharide  conjugate vaccine (adsorbed) at the recommended  ages, followed by a single dose of the 23-valent pneumo-  coccal polysaccharide vaccine after their second birth-  day (see below). Children at increased risk of pneumo-  coccal infection presenting late for vaccination should  receive 2 doses (separated by at least 1 month) of the  13-valent pneumococcal polysaccharide conjugate  vaccine (adsorbed) before the age of 12 months, and a  third dose at 12-13 months. Children over 12 months  and under 5 years (who have not been vaccinated or not  completed the primary course) should receive a single  dose of the 13-valent pneumococcal polysaccharide  conjugate vaccine (adsorbed) (2 doses separated by an  interval of 2 months in the immunocompromised or  those with asplenia or splenic dysfunction). All children  under 5 years at increased risk of pneumococcal infec-  tion should receive a single dose of the 23-valent  pneumococcal polysaccharide vaccine after their sec-  ond birthday and at least 2 months after the final dose of  the 13-valent pneumococcal polysaccharide conjugate  vaccine (adsorbed).   Children over 5 years and adults who are at increased  risk of pneumococcal disease should receive a single  dose of the 23-valent unconjugated pneumococcal poly-  saccharide vaccine.   Revaccination In individuals with higher concentra-  tions of antibodies to pneumococcal polysaccharides,  revaccination with the 23-valent pneumococcal poly-  saccharide vaccine more commonly produces adverse  reactions. Revaccination is therefore not recommended,  except every 5 years in individuals in whom the anti-  body concentration is likely to decline rapidly (e.g.  asplenia, splenic dysfunction and nephrotic syndrome).  If there is doubt, the need for revaccination should be  discussed with a haematologist, immunologist, or  microbiologist.   Contra-indications see section 14.1  Pregnancy see p. 747  Breast-feeding see p. 747  Side-effects see section 14.1; also Revaccination,  above  Dose   ^ Pneumococcal polysaccharide vaccine  Pneumovax® II (Sanofi Pasteur) (Ml  Injection, polysaccharide from each of 23 capsular  types of pneumococcus, net price 0.5-mL vial = £8.32  Dose by intramuscular or subcutaneous injection, ADULT and  CHILD over 2 years, 0.5 mL; revaccination, see notes above   Prevenar 13® (Wyeth) ▼ (Ml  Injection, polysaccharide from each of 13 capsular  types of pneumococcus (conjugated to carrier pro-  tein) adsorbed onto aluminium phosphate, net price  0.5-mL prefilled syringe = £49.10  Dose by intramuscular injection, CHILD 2 months-5 years,   0.5 mL (see notes above and Immunisation schedule, section 14.1)  Note Deltoid muscle is preferred site of injection in young  children; anterolateral thigh is preferred site in infants.   The dose in the BNF may differ from that in product literature.  Available as part of childhood immunisation schedule from  Movianto   Note Deltoid muscle is preferred site of injection in young  children; anterolateral thigh is preferred site in infants   Two types of poliomyelitis vaccine (containing strains of  poliovirus types 1, 2, and 3) are available, inactivated  poliomyelitis vaccine (for injection) and live (oral) polio-  myelitis vaccine. Inactivated poliomyelitis vaccine,  only available in combined preparation (see under Diph-  theria Vaccines), is recommended for routine immuni-  sation.   A course of primary immunisation consists of 3 doses of  a combined preparation containing inactivated polio-  myelitis vaccine, starting at 2 months of age with inter-  vals of 1 month between doses (see Immunisation  schedule, section 14.1). A course of 3 doses should  also be given to all unimmunised adults; no adult should  remain unimmunised against poliomyelitis.    adsorbed diphtheria [low dose], tetanus and polio-  myelitis (inactivated) vaccine. Information about  countries with a high incidence of poliomyelitis can be  obtained from www.travax.nhs.uk or from the National  Travel Health Network and Centre (www.nathnac.org).   Indications immunisation against poliomyelitis  Cautions see section 14.1; also for live vaccine,  interactions: Appendix 1 (vaccines)  Contra-indications see notes above and section 14.1   A suspension of suitable live attenuated strains of  poliomyelitis virus, types 1, 2, and 3. Available in  single-dose and 10-dose containers   Excipients include neomycin and polymyxin B  Dose control of outbreaks, 3 drops; may be given on a lump of  sugar; not to be given with foods which contain preservatives  Note Live poliomyelitis vaccine loses potency once the container  has been opened — any vaccine remaining at the end of an  immunisation session should be discarded; whenever possible  sessions should be arranged to avoid undue wastage.   Two booster doses of a preparation containing inacti-  vated poliomyelitis vaccine are recommended, the first  before school entry and the second before leaving  school (see Immunisation schedule, section 14.1).  Further booster doses are only necessary for adults at  special risk, such as travellers to endemic areas, or  laboratory staff likely to be exposed to the viruses, or  healthcare workers in possible contact with cases; boos-  ter doses should be given to such individuals every 10  years.    Preparations containing inactivated poliomyelitis  vaccine can be used to complete an immunisation  course initiated with the live (oral) poliomyelitis vaccine.  Live (oral) poliomyelitis vaccine is available only for  use during outbreaks. The live (oral) vaccine poses a  very rare risk of vaccine-associated paralytic polio  because the attenuated strain of the virus can revert  to a virulent form. For this reason the live (oral) vaccine  must not be used for immunosuppressed individuals or  their household contacts. The use of inactivated polio-  myelitis vaccine removes the risk of vaccine-associated  paralytic polio altogether.    Travel Unimmunised travellers to areas with a high  incidence of poliomyelitis should receive a full 3 -dose  course of a preparation containing inactivated polio-  myelitis vaccine. Those who have not been vaccinated  in the last 10 years should receive a booster dose of    Rabies vaccine contains inactivated rabies virus culti-  vated in either human diploid cells or purified chick  embryo cells; vaccines are used for pre- and post-  exposure prophylaxis.   Pre-exposure prophylaxis Immunisation should be  offered to those at high risk of exposure to rabies —  laboratory staff who handle the rabies virus, those  working in quarantine stations, animal handlers, veter-  inary surgeons and field workers who are likely to be  bitten by infected wild animals, certain port officials,  and bat handlers. Transmission of rabies by humans has  not been recorded but it is advised that those caring for  patients with the disease should be vaccinated.   Immunisation against rabies is also recommended  where there is limited access to prompt medical care  for those living in areas where rabies is enzootic, for  those travelling to such areas for longer than 1 month,  and for those on shorter visits who may be exposed to  unusual risk.   Immunisation against rabies is indicated during  pregnancy if there is substantial risk of exposure to  rabies and rapid access to post-exposure prophylaxis  is likely to be limited.   Up-to-date country-by-country information on the inci-  dence of rabies can be obtained from the National  Travel Health Network and Centre (www.nathnac.org)   Immunisation against rabies requires 3 doses of rabies  vaccine, with further booster doses for those who  remain at continued risk . To ensure continued protec-  tion in persons at high risk (e.g. laboratory workers), the  concentration of antirabies antibodies in plasma is used  to determine the intervals between doses.    on days 0, 7, and 21 or 28; for those at continued risk  give a single reinforcing dose 1 year after the primary  course is completed and booster doses every 3-5  years; for those at intermittent risk give booster doses  every 2-5 years   • Post-exposure prophylaxis, by intramuscular injection  in deltoid region or anterolateral thigh in infants, 1 mL  (see notes above)    Post-exposure management Following potential  exposure to rabies, the wound or site of exposure (e.g.  mucous membrane) should be cleansed under running  water and washed for several minutes with soapy water  as soon as possible after exposure. Disinfectant and a  simple dressing can be applied, but suturing should be  delayed because it may increase the risk of introducing  rabies virus into the nerves.   Post-exposure prophylaxis against rabies depends on  the level of risk in the country, the nature of exposure,  and the individual’s immunity. In each case, expert risk  assessment and advice on appropriate management  should be obtained from the Health Protection Agency  Virus Reference Department, Colindale, London (tel.  (020) 8200 4400) or the Centre for Infections (tel.  (020) 8200 6868), in Scotland from Health Protection  Scotland (tel. (0141) 300 1100), in Northern Ireland from  the Public Health Laboratory, Belfast City Hospital (tel.  (028) 9032 9241).   There are no specific contra-indications to the use of  rabies vaccine for post-exposure prophylaxis and its use  should be considered whenever a patient has been  attacked by an animal in a country where rabies is  enzootic, even if there is no direct evidence of rabies  in the attacking animal. Because of the potential con-  sequences of untreated rabies exposure and because  rabies vaccination has not been associated with fetal  abnormalities, pregnancy is not considered a contra-  indication to post-exposure prophylaxis.   For post-exposure prophylaxis of fully immunised indi-  viduals (who have previously received pre-exposure or  post-exposure prophylaxis with cell-derived rabies  vaccine), 2 doses of cell-derived vaccine, given on day  0 and day 3, are likely to be sufficient. Rabies immuno-  globulin is not necessary in such cases.   Post-exposure treatment for unimmunised individuals  (or those whose prophylaxis is possibly incomplete)  comprises 5 doses of rabies vaccine given over 1  month (on days 0, 3, 7, 14, and 30); also, depending  on the level of risk (determined by factors such as the  nature of the bite and the country where it was sus-  tained), rabies immunoglobulin (section 14.5.2) is given  on day 0. The immunisation course can be discontinued  if it is proved that the individual was not at risk.   Rabipur® (Novartis Vaccines) (Ml  Injection, powder for reconstitution, freeze-dried  inactivated Flury LEP rabies virus strain cultivated in  chick embryo cells, net price single-dose vial = £28.80   Rotavirus vaccine a live, oral vaccine is licensed for  immunisation of infants over 6 weeks of age for protec-  tion against gastro-enteritis caused by rotavirus infec-  tion. The vaccine is not included in the childhood  immunisation schedule.   The rotavirus vaccine virus is excreted in the stool and  may be transmitted to close contacts; the vaccine  should be used with caution in those with immunosup-  pressed close contacts. Carers of a recently vaccinated  baby should be advised of the need to wash their hands  after changing the baby’s nappies.   Cautions see section 14.1; also diarrhoea or vomiting  (postpone vaccination); immunosuppressed close  contacts (see notes above); interactions: Appendix 1  (vaccines)    Contra-indications see section 14.1; also predisposi-  tion to, or history of, intussusception  Side-effects see section 14.1   • By mouth, CHILD over 6 weeks, 2 doses of 1.5 mL,  separated by an interval of at least 4 weeks; course  should be completed before 24 weeks of age (prefer-  ably before 16 weeks)   • Pre-exposure prophylaxis, by intramuscular injection  in deltoid region or anterolateral thigh in infants, 1 mL   Oral suspension, live attenuated rotavirus (RIX4414  strain), net price 1.5 mL prefilled oral syringe = £41.38   A combined measles, mumps and rubella vaccine (MMR  vaccine) aims to eliminate rubella (German measles)  and congenital rubella syndrome. MMR vaccine is used  for childhood vaccination as well as for vaccinating  adults (including women of child-bearing age) who do   ^Single antigen vaccine  No longer available in the UK; the combined live  measles, mumps and rubella vaccine is a suitable  alternative   Limited supplies of smallpox vaccine are held at the  Specialist and Reference Microbiology Division, Health  Protection Agency (Tel. (020) 8200 4400) for the exclu-  sive use of workers in laboratories where pox viruses  (such as vaccinia) are handled.   If a wider use of the vaccine is being considered, Guide-  lines for smallpox response and management in the  post-eradication era should be consulted at  www.dh.gov.uk   Tetanus vaccine contains a cell-free purified toxin of  Clostridium tetani adsorbed on aluminium hydroxide or  aluminium phosphate to improve antigenicity.   Primary immunisation for children under 10 years con-  sists of 3 doses of a combined preparation containing  adsorbed tetanus vaccine (see Diphtheria-containing  Vaccines), with an interval of 1 month between doses.  Following routine childhood vaccination, 2 booster  doses of a preparation containing adsorbed tetanus  vaccine are recommended, the first before school  entry and the second before leaving school (see  Immunisation schedule, section 14.1).   The recommended schedule of tetanus vaccination not  only gives protection against tetanus in childhood but  also gives the basic immunity for subsequent booster  doses. In most circumstances, a total of 5 doses of  tetanus vaccine is considered sufficient for long term  protection.   For primary immunisation of adults and children over  10 years previously unimmunised against tetanus, 3  doses of adsorbed diphtheria [low dose], tetanus  and poliomyelitis (inactivated) vaccine are given  with an interval of 1 month between doses (see Diph-  theria-containing Vaccines).    All laboratory staff should be offered a primary course if  unimmunised.   Wounds Wounds are considered to be tetanus-prone if  they are sustained more than 6 hours before surgical  treatment or at any interval after injury and are punc-  ture-type (particularly if contaminated with soil or man-  ure) or show much devitalised tissue or are septic or are  compound fractures or contain foreign bodies. All  wounds should receive thorough cleansing.   • For clean wounds : fully immunised individuals  (those who have received a total of 5 doses of a  tetanus-containing vaccine at appropriate intervals)  and those whose primary immunisation is complete  (with boosters up to date), do not require tetanus  vaccine; individuals whose primary immunisation is  incomplete or whose boosters are not up to date  require a reinforcing dose of a tetanus-containing  vaccine (followed by further doses as required to  complete the schedule); non-immunised individuals  (or those whose immunisation status is not known  or who have been fully immunised but are now  immunocompromised) should be given a dose of  the appropriate tetanus-containing vaccine imme-  diately (followed by completion of the full course of  the vaccine if records confirm the need).   • For tetanus-prone wounds', management is as for  clean wounds with the addition of a dose of tetanus  immunoglobulin (section 14.5.2) given at a different  site; in fully immunised individuals and those whose  primary immunisation is complete (with boosters  up to date) the immunoglobulin is needed only if the  risk of infection is especially high (e.g. contamina-  tion with manure). Antibacterial prophylaxis (with  benzylpenicillin, co-amoxiclav, or metronidazole)  may also be required for tetanus-prone wounds.   Tick-borne encephalitis vaccine contains inactivated  tick-bome encephalitis virus cultivated in chick embryo  cells. It is recommended for immunisation of those  working in, or visiting, high-risk areas (see International  Travel, section 14.6). Those working, walking or camp-  ing in warm forested areas of Central and Eastern  Europe, Scandinavia, Northern and Eastern China, and  some parts of Japan, particularly from April to Novem-  ber when ticks are most prevalent, are at greatest risk of  tick-bome encephalitis. For full protection, 3 doses of  the vaccine are required; booster doses are required  every 3-5 years for those still at risk. Ideally, immuni-  sation should be completed at least one month before  travel.    Cautions See also section 14.1. When an individual  presents for a booster dose but has been vaccinated  following a tetanus-prone wound, the vaccine prepara-  tion administered at the time of injury should be deter-  mined. If this is not possible, the booster should still be  given to ensure adequate protection against all antigens  in the booster vaccine.   Very rarely, tetanus has developed after abdominal  surgery; patients awaiting elective surgery should be  asked about tetanus immunisation and immunised if  necessary.   Parenteral drug abuse is also associated with tetanus;  those abusing drugs by injection should be vaccinated if  unimmunised — booster doses should be given if there is  any doubt about their immunisation status.    edly) exposed to Salmonella typhi, but occasional tra-  vellers require further courses at intervals of 1 year.   • Initial immunisation, by intramuscular injection in  deltoid region or anterolateral thigh in infants, ADULT  and CHILD over 16 years, 3 doses each of 0.5 mL,  second dose after 1-3 months and third dose after  further 5-12 months; CHILD 1-16 years 3 doses of  0.25 mL, second dose after 1-3 months and third dose  after further 5-12 months; ELDERLY over 60 years and  immunocompromised (including those receiving  immunosuppressants), antibody concentration may  be measured 4 weeks after second dose and dose  repeated if protective levels not achieved   Note To achieve more rapid protection, second dose maybe  given 14 days after first dose   • Booster doses, give first dose within 3 years after  initial course completed, then every 3-5 years   Injection, suspension, formaldehyde-inactivated  Neudorfl tick-borne encephalitis virus strain (culti-  vated in chick embryo cells) adsorbed onto hydrated  aluminium hydroxide, net price 0.25-mL prefilled  syringe ( TicoVac Junior ®) = £28.00, 0.5-mL prefilled  syringe = £32.00   Typhoid vaccine is available as Vi capsular polysaccha-  ride (from Salmonella typhi) vaccine for injection and as   • travellers to areas where typhoid is endemic, espe-  cially if staying with or visiting local people   • travellers to endemic areas where frequent or pro-  longed exposure to poor sanitation and poor food  hygiene is likely   • laboratory personnel who, in the course of their  work, may be exposed to Salmonella typhi    Interactions Oral typhoid vaccine is inactivated by  concomitant administration of antibacterials or anti-  malarials:   • Antibacterials should be avoided for 3 days before  and after oral typhoid vaccination;   • Mefloquine should be avoided for at least 12 hours  before or after oral typhoid; vaccination with oral  typhoid should preferably be completed at least 3  days before the first dose of mefloquine;   • For other antimalarials vaccination with oral typh-  oid vaccine should be completed at least 3 days  before the first dose of the antimalarial (except  proguanil hydrochloride with atovaquone, which  may be given concomitantly).   Injection, Vi capsular polysaccharide typhoid  vaccine, 50 micrograms /mL virulence polysaccharide  antigen of Salmonella typhi, net price 0.5-mL prefilled  syringe = £9.93   Dose by intramuscular injection, 0.5 mL at least 2 weeks before  potential exposure to typhoid infection; CHILD under 2 years (see  notes above)    Typhim Vi® (Sanofi Pasteur) MI  Injection, Vi capsular polysaccharide typhoid  vaccine, 50 micrograms /mL virulence polysaccharide  antigen of formaldehyde-inactivated Salmonella  typhi, net price 0.5-mL prefilled syringe = £9.00  Dose by intramuscular injection, 0.5 mL, at least 2 weeks before  potential exposure to typhoid infection CHILD under 2 years (see  notes above)    Typhoid vaccination is not a substitute for scrupulous  personal hygiene (see p. 774).   Capsular polysaccharide typhoid vaccine is usually  given by intramuscular injection. Children under 2  years may respond suboptimally to the vaccine, but  children aged between 1-2 years should be immunised  if the risk of typhoid fever is considered high (immuni-  sation is not recommended for infants under 12  months). Booster doses are needed every 3 years on  continued exposure.   Oral typhoid vaccine is a live attenuated vaccine  contained in an enteric-coated capsule. One capsule  taken on alternate days for a total of 3 doses, provides  protection 7-10 days after the last dose. Protection may  persist for up to 3 years in those constantly (or repeat-   Capsules, e/c, live attenuated Salmonella typhi  (Ty21a), net price 3-cap pack = £14.77. Label: 23, 25,  counselling, administration   Dose ADULT and CHILD over 6 years, 1 capsule on days 1, 3, and 5  Counselling Swallow as soon as possible after placing in mouth  with a cold or lukewarm drink; it is important to store capsules in a  refrigerator   Varicella-zoster vaccine (live) is licensed for immuni-  sation against varicella in seronegative individuals. It is  not recommended for routine use in children but can be    given to seronegative healthy children over 1 year who  come into close contact with individuals at high risk of  severe varicella infections. The Department of Health  recommends varicella-zoster vaccine for seronegative  healthcare workers who come into direct contact with  patients. Those with a history of chickenpox or shingles  can be considered immune, but healthcare workers with  a negative or uncertain history should be tested.   Rarely, the varicella-zoster vaccine virus has been  transmitted from the vaccinated individual to close  contacts. Therefore, contact with the following should  be avoided if a vaccine-related cutaneous rash develops  within 4-6 weeks of the first or second dose:   • individuals at high risk of severe varicella, including  those with immunodeficiency or those receiving  immunosuppressive therapy.   Healthcare workers who develop a generalised papular  or vesicular rash on vaccination should avoid contact  with patients until the lesions have crusted. Those who  develop a localised rash after vaccination should cover  the lesions and be allowed to continue working unless in  contact with patients at high risk of severe varicella.  Varicella-zoster immunoglobulin is used to protect  susceptible individuals at increased risk of varicella  infection, see p. 772.   Cautions see section 14.1; also post-vaccination close-  contact with susceptible individuals (see notes above);  interactions: Appendix 1 (vaccines)   Injection, powder for reconstitution, live attenuated  varicella-zoster virus (Oka strain) propagated in  human diploid cells, net price 0.5-mL vial (with dilu-  ent) =£27.31   Dose by subcutaneous injection preferably into deltoid region,  ADULT and CHILD over 1 year (see notes above), 2 doses of 0.5 mL  separated by an interval of at least 6 weeks (minimum 4 weeks)   Varivax® (Sanofi Pasteur) ▼ (Ml  Injection powder for reconstitution, live attenuated  varicella-zoster virus (Oka/ Merck strain) propagated  in human diploid cells, net price 0.5-mL vial (with  diluent) = £30.28   Excipients include gelatin and neomycin  Dose by intramuscular or subcutaneous injection into deltoid  region (or higher anterolateral thigh in children), ADULT and CHILD  over 13 years (see notes above), 2 doses of 0.5 mL separated by 4-  8 weeks; CHILD 1-13 years (see notes above) 2 doses of 0.5 mL  separated by an interval of at least 4 weeks (two doses separated  by 12 weeks in children with asymptomatic HIV infection)   Live yellow fever vaccine is indicated for those travel-  ling or living in areas where infection is endemic (see  p. 774) and for laboratory staff who handle the virus or  who handle clinical material from suspected cases.  Infants under 6 months of age should not be vaccinated  because there is a small risk of encephalitis; infants aged  6-9 months should be vaccinated only if the risk of  yellow fever is high and unavoidable (seek expert  advice). The immunity which probably lasts for life is  officially accepted for 10 years starting from 10 days  after primary immunisation and for a further 10 years  immediately after revaccination.   Very rare, vaccine-associated adverse effects have been  reported, such as viscerotropic disease (yellow fever  vaccine-associated viscerotropic disease, YEL-AVD), a  syndrome which may include metabolic acidosis,  muscle and liver cytolysis, and multi-organ failure. Neu-  rological disorders (yellow fever vaccine-associated  neurotropic disease, YEL-AND) such as encephalitis  have also been reported. These very rare adverse effects  usually have occurred after the first dose of yellow fever  vaccine in those with no previous immunity.   Pregnancy Live yellow fever vaccine should not be  given during pregnancy, but if a significant risk of  exposure cannot be avoided then vaccination should  be delayed to the third trimester if possible (but the need  for immunisation usually outweighs risk to the fetus).   Breast-feeding Vaccination should be considered in  breast-feeding women when there is a real risk to the  mother from yellow fever disease.   Cautions see section 14.1; also individuals over 60  years — greater risk of vaccine-associated adverse  effects, see notes above; interactions: Appendix 1  (vaccines)   Contra-indications see section 14.1 and notes above;  also children under 6 months; history of thymus  dysfunction   Side-effects see section 14.1; also reported neuro-  tropic disease and viscerotropic disease (see notes  above)   • By deep subcutaneous injection, ADULT and CHILD over  9 months, 0.5 mL (see also notes above)   Injection, powder for reconstitution, live, attenuated  17D-204 strain of yellow fever virus, cultivated in  chick embryos; single dose vial with syringe contain-  ing 0.5 mL diluent   Two types of human immunoglobulin preparation are  available, normal immunoglobulin and disease-speci-  fic immunoglobulins.   Human immunoglobulin is a sterile preparation of con-  centrated antibodies (immune globulins) recovered  from pooled human plasma or serum obtained from  outside the UK, tested and found non-reactive for hepat-  itis B surface antigen and for antibodies against hepatitis  C virus and human immunodeficiency virus (types 1 and  2). A global shortage of human immunoglobulin and the  rapidly increasing range of clinical indications for treat-  ment with immunoglobulins has resulted in the need for  a Demand Management programme in the UK (for  further information consult www.ivig.nhs.uk and Clinical  Guidelines for Immunoglobulin Use, www.dh.gov.uk.  Immunoglobulins of animal origin (antisera were fre-  quently associated with hypersensitivity reactions and  are no longer used.   Further information on the use of immunoglobulins is  included in the Health Protection Agency’s Immuno-  globulin Handbook www.hpa.org.uk, and in the Depart-  ment of Health’s publication, Immunisation against  Infectious Disease, www.dh.gov.uk.   Availability Normal immunoglobulin for intramus-  cular administration is available from some regional  Health Protection Agencies and microbiology labora-  tories for protection of contacts and the control of  outbreaks of hepatitis A, measles and rubella, only.  For other indications, subcutaneous or intravenous nor-  mal immunoglobulin should be purchased from the  manufacturer.   Disease-specific immunoglobulins (section 14.5.2)  are available from some regional Health Protection  Agencies and microbiology laboratories, with the excep-  tion of tetanus immunoglobulin which is available  from BPL, hospital pharmacies, or blood transfusion  departments. Rabies immunoglobulin is available  from the Specialist and Reference Microbiology Divi-  sion, Health Protection Agency. Hepatitis B immuno-  globulin required by transplant centres should be  obtained commercially.   In Scotland all immunoglobulins are available from the  Scottish National Blood Transfusion Service (SNBTS)   months after an injection of normal immunoglobulin  (this does not apply to yellow fever vaccine since  normal immunoglobulin does not contain antibody to  this virus).   Uses Normal immunoglobulin (containing 1 0%— 1 8%)  is administered by intramuscular injection for the pro-  tection of susceptible contacts against hepatitis A virus  (infectious hepatitis), measles and, to a lesser extent,  rubella. Injection of immunoglobulin produces immedi-  ate protection lasting several weeks.   Normal immunoglobulin (containing 3%— 12% protein)  for intravenous administration is used as replacement  therapy for patients with congenital agammaglobulin-  aemia and hypogammaglobulinaemia, and for the short-  term treatment of idiopathic thrombocytopenic purpura  and Kawasaki syndrome; it is also used for the prophy-  laxis of infection following bone-marrow transplantation  and in children with symptomatic HIV infection who  have recurrent bacterial infections. Normal immuno-  globulin for replacement therapy may also be given  intramuscularly or subcutaneously, but intravenous for-  mulations are normally preferred. Intravenous immuno-  globulin is also used in the treatment of Guillain-Barre  syndrome as an alternative to plasma exchange.   For guidance on the use of intravenous normal immu-  noglobulins and alternative therapies for certain condi-  tions, consult Clinical Guidelines for Immunoglobulin  Use (www.dh.gov.uk).    Hepatitis A Hepatitis A vaccine is preferred for  individuals at risk of infection (see p. 754) including  those visiting areas where the disease is highly endemic  (all countries excluding Northern and Western Europe,  North America, Japan, Australia, and New Zealand). In  unimmunised individuals, transmission of hepatitis A is  reduced by good hygiene. Intramuscular normal  immunoglobulin is no longer recommended for routine  prophylaxis in travellers, but it may be indicated for  immunocompromised patients if their antibody  response to the vaccine is unlikely to be adequate.    Intramuscular normal immunoglobulin is recommended  for prevention of infection in close contacts (of con-  firmed cases of hepatitis A) who have chronic liver  disease or HIV infection, or who are immunosuppressed  or over 50 years of age; normal immunoglobulin should  be given as soon as possible, preferably within 14 days  of exposure to the primary case. However, normal  immunoglobulin can still be given to contacts at risk  of severe disease up to 28 days after exposure to the  primary case. Hepatitis A vaccine can be given at the  same time, but it should be given at a separate injection  site.   Human normal immunoglobulin (‘HNIG’) is prepared  from pools of at least 1000 donations of human plasma;  it contains immunoglobulin G (IgG) and antibodies to  hepatitis A, measles, mumps, rubella, varicella, and  other viruses that are currently prevalent in the general  population.   Normal immunoglobulin may interfere with the  immune response to live virus vaccines which should  therefore only be given at least 3 weeks before or 3    Measles Intravenous or subcutaneous normal  immunoglobulin may be given to prevent or attenuate  an attack of measles in individuals who do not have  adequate immunity. Children and adults with compro-  mised immunity who have come into contact with  measles should receive intravenous or subcutaneous  normal immunoglobulin as soon as possible after expo-  sure. It is most effective if given within 72 hours but can  be effective if given within 6 days.   Subcutaneous or intramuscular normal immunoglobulin  should also be considered for the following individuals if  they have been in contact with a confirmed case of   Further advice should be sought from the Centre for  Infections, Health Protection Agency (tel. (020) 8200  6868 ).   Individuals with normal immunity who are not in the  above categories and who have not been fully immu-  nised against measles, can be given MMR vaccine  (section 14.4) for prophylaxis following exposure to  measles.   Rubella Intramuscular immunoglobulin after exposure  to rubella does not prevent infection in non-immune  contacts and is not recommended for protection of  pregnant women exposed to rubella. It may, however,  reduce the likelihood of a clinical attack which may  possibly reduce the risk to the fetus. Risk of intrauterine  transmission is greatest in the first 11 weeks of  pregnancy, between 16 and 20 weeks there is minimal  risk of deafness only, after 20 weeks there is no  increased risk. Intramuscular normal immunoglobulin  should be used only if termination of pregnancy would  be unacceptable to the pregnant woman — it should be  given as soon as possible after exposure. Serological  follow-up of recipients is essential to determine if the  woman has become infected despite receiving immuno-  globulin.   Intravenous use thrombophilic disorders, or risk factors for  arterial or venous thromboembolic events; obesity; ensure  adequate hydration, renal insufficiency  Contra-indications patients with selective IgA defi-  ciency who have known antibody against IgA  Renal impairment monitor for acute renal failure;  consider discontinuation if renal function deteriorates.  Intravenous preparations with added sucrose have  been associated with cases of renal dysfunction and  acute renal failure   Side-effects nausea, diarrhoea, chills, fever, head-  ache, dizziness, arthralgia, myalgia, muscle spasms,  low back pain; rarely hypotension, anaphylaxis,  cutaneous skin reactions, aseptic meningitis, acute  renal failure; also reported with intravenous use,  injection site reactions, abdominal pain and disten-  sion, blood pressure fluctuations, haemolytic anae-  mia, thromboembolic events including myocardial  infarction, stroke, pulmonary embolism, and deep  vein thrombosis   Note Adverse reactions are more likely to occur in patients  receiving normal immunoglobulin for the first time, or fol-  lowing a prolonged period between treatments, or when a  different brand of normal immunoglobulin is administered.   Note Antibody titres can vary widely between normal  immunoglobulin preparations from different manufacturers —  formulations are not interchangeable; patients should be  maintained on the same formulation throughout long-term  treatment to avoid adverse effects   Dose by deep intramuscular injection, to control outbreaks of  hepatitis A (see notes above), 500 mg; CHILD under 10 years  250 mg   Rubella in pregnancy, prevention of clinical attack, 750 mg  Available from the Centre for Infections and other regional Health  Protection Agency offices (for contacts and control of outbreaks  only, see above)   Normal immunoglobulin (protein 16%) injection, net  price 5-mL vial = £32.56, 10-mL vial = £65.12  Dose by subcutaneous injection, ADULT and CHILD over 12 years  antibody deficiency syndromes, consult product literature  Note May be administered by intramuscular injection (if subcu-  taneous route not possible) but not for patients with thrombocy-  topenia or other bleeding disorders   Normal immunoglobulin (protein 14%-18%) injection,  net price 250-mg vial = £11.20, 750-mg vial = £28.50,  1.5-g vial = £57.00   By intramuscular injection, Hepatitis A prophylaxis in outbreaks  (see notes above), ADULT and CHILD over 10 years, 750 mg, CHILD  under 10 years, 500 mg   Rubella, in pregnancy prevention of clinical attack (see also notes  above), 750 mg   Note Subgam ® is not licensed for prophylactic use, but due to  difficulty in obtaining suitable immunoglobulin products, the Health  Protection Agency recommends intramuscular use for prophylaxis  against Hepatitis A or rubella   Vivaglobin® (CSL Behring) (Ml  Normal immunoglobulin (protein 16%) injection, net  price 3-mL vial = £17.76, 10-mL vial = £59.20, 20-mL  vial = £118.40   Flebogammadif® (Grifols) ▼ (Ml  Intravenous infusion, human normal immunoglobu-  lin (protein 5%), net price 0.5 g (10 mL) = £30.00, 2.5 g  (50 mL) = £150.00, 5 g (100 mL) = £300.00, 10 g  (200 mL) = £600.00, 20 g (400 mL) = £1200.00  Note Contains sorbitol 50mg/mL; contra-indicated in patients  with hereditary fructose intolerance   Gammagard S/D® (Baxter) (Ml  Intravenous infusion, (providing protein 5% or 10%),  net price 0.5 g (with diluent) = £20.05, 2.5 g (with  diluent) = £100.25, 5 g (with diluent) = £200.50, 10 g  (with diluent) = £401.00   Gammaplex® (BPL) ▼ (Ml  Intravenous infusion, human normal immunoglobu-  lin (protein 5%), net price 2.5 g (50 mL) = £85.00, 5 g  (100 mL) = £170.00, 10 g (200 mL) = £340.00  Note Contains sorbitol 50mg/mL; contra-indicated in patients  with hereditary fructose intolerance   Intravenous infusion, human normal immunoglobu-  lin (protein 5%), net price 1 g (20 mL) = £45.00, 2.5 g  (50 mL) = £112.50, 5 g (100 mL) = £225.00, lOg  (200 mL) = £450.00,   Intravenous infusion, human normal immunoglobu-  lin (protein 10%), net price 1 g (10 mL) = £49.00, 2.5 g  (25 mL) = £122.50, 5 g (50 mL) = £245.00, 10 g  (100 mL) = £490.00, 20 g (200 mL) = £980.00,   Note Use Glucose 5% intravenous infusion, if dilution prior  to administration is required   Privigen® (CSL Behring) T (Ml  Intravenous infusion, human normal immunoglobu-  lin (protein 10%), net price 2.5 g (25 mL) = £135.00,   5 g (50 mL) = £270.00, 10 g (100 mL) = £540.00, 20 g  (200 mL) = £1080.00   Intravenous infusion, human normal immunoglobu-  lin (protein 5%), net price 2.5 g (50 mL) = £95.00, 5g  (100 mL) = £190.00, 10 g (200 mL) = £380.00  Note Contains sucrose (see Renal impairment, above)   Specific immunoglobulins are prepared by pooling the  plasma of selected human donors with high levels of the  specific antibody required. For further information, see  Immunoglobulin Handbook (www.hpa.org.uk).   There are no specific immunoglobulins for hepatitis A,  measles, or rubella — normal immunoglobulin, section  14.5.1 is used in certain circumstances. There is no  specific immunoglobulin for mumps; neither normal  immunoglobulin nor MMR vaccine is effective as post-  exposure prophylaxis.   Disease-specific hepatitis B immunoglobulin (‘HBIG’)  is available for use in association with hepatitis B  vaccine for the prevention of infection in laboratory  and other personnel who have been accidentally inocu-  lated with hepatitis B virus, and in infants bom to  mothers who have become infected with this virus in  pregnancy or who are high-risk carriers (see Hepatitis B  Vaccine, p. 755). Hepatitis B immunoglobulin will not  inhibit the antibody response when given at the same  time as hepatitis B vaccine but should be given in  different sites.   An intravenous and subcutaneous preparation of hepat-  itis B-specific immunoglobulin is licensed for the pre-  vention of hepatitis B recurrence in HBV-DNA negative  patients who have undergone liver transplantation for  liver failure caused by the virus.   Injection, hepatitis B-specific immunoglobulin,  lOOunits/mL. Vials containing 200 units or 500 units,  available from selected Health Protection Agency and  NHS laboratories (except for Transplant Centres, see  p. 769), also available from BPL  Dose by intramuscular injection (as soon as possible after  exposure; ideally within 12-48 hours, but no later than 7 days after  exposure), ADULT and CHILD over 10 years 500 units; CHILD under  5 years 200 units, 5-9 years 300 units; NEONATE 200 units  Prevention of transmitted infection at birth, NEONATE 200 units as  soon as possible after birth; for full details consult Immunisation  against Infectious Disease (www.dh.gov.uk)   Note Hepatitis B immunoglobulin for intravenous use is  available from BPL on a named-patient basis   Hepatect®CP (Biotest UK) (Ml  Intravenous infusion, hepatitis B-specific immuno-  globulin 50units/mL, net price 500 units (10 mL) =  £300.00, 2000 units (40 mL) = £1100.00  Dose by intravenous infusion, after exposure to hepatitis B virus-  contaminated material — consult product literature  Prevention of transmitted infection at birth — consult product  literature   Prevention of hepatitis B in haemodialysed patients, prophylaxis  against re-infection of transplanted liver — consult product litera-  ture   500 units/mL, net price 5 x 1-mL prefilled syringes =  £1500.00   Dose prevention of hepatitis B re-infection more than 6 months  after liver transplantation in stable HBV-DNA negative patients  starting 2-3 weeks after last dose of intravenous hepatitis B  immunoglobulin, by subcutaneous injection, ADULT body-weight  under 75 kg 500 units once weekly, increased if necessary up to  1000 units once weekly; body-weight over 75 kg 1000 units once  weekly    Following exposure of an unimmunised individual to an  animal in or from a country where the risk of rabies is  high the site of the bite should be washed with soapy  water and specific rabies immunoglobulin of human  origin administered. All of the dose should be injected  around the site of the wound; if this is difficult or the  wound has completely healed it can be given in the  anterolateral thigh (remote from the site used for vaccin-  ation).   Rabies vaccine should also be given intramuscularly at a  different site (for details see Rabies vaccine p. 764)    Indications prophylaxis against hepatitis B infection  Cautions IgA deficiency; interference with live virus  vaccines see under Normal Immunoglobulin, p. 769.  Side-effects injection site reactions; less frequently,  buccal ulceration, glossitis, abdominal pain, chest  pain, dyspnoea, anaphylaxis, tremor, dizziness, head-  ache, arthralgia; for side-effects associated with  intravenous immunoglobulin, see section 14.5.1  Dose   Cautions IgA deficiency; interference with live virus  vaccines — see p. 769 under Normal Immunoglobulin  Side-effects injection site swelling and pain; very  rarely anaphylaxis; buccal ulceration, glossitis, chest  tightness, dyspnoea, tremor, dizziness, arthralgia, and  facial oedema also reported  Dose   Dose 20 units/kg by infiltration in and around the cleansed  wound; if wound not visible or healed or if infiltration of whole  volume not possible, give remainder by intramuscular injection  into anterolateral thigh (remote from vaccination site)   Note The potency of individual batches of rabies immunoglobulin  from the manufacturer may vary; potency may also be described  differently by different manufacturers. It is therefore critical to  know the potency of the batch to be used and the weight of the  patient in order to calculate the specific volume required to  provide the necessary dose   Available from Specialist and Reference Microbiology Division,  Health Protection Agency (see section 14.5 under availability)  (also from BPL)   For the management of tetanus-prone wounds, tetanus  immunoglobulin should be used in addition to wound  cleansing and, where appropriate, antibacterial prophy-  laxis and a tetanus-containing vaccine (see Diphtheria-  containing Vaccines, section 14.4). Tetanus immuno-  globulin, together with metronidazole (section 5.1.11)  and wound cleansing, should also be used for the treat-  ment of established cases of tetanus.   • Post-exposure prophylaxis, by intramuscular injection  250 units, increased to 500 units if more than 24 hours  have elapsed or there is risk of heavy contamination  or following burns   • Treatment of tetanus infection, by intramuscular  injection 150 units/kg (multiple sites)    Varicella-zoster immunoglobulin (VZIG) is recom-  mended for individuals who are at increased risk of  severe varicella and who have no antibodies to vari-  cella-zoster virus and who have significant exposure to  chickenpox or herpes zoster. Those at increased risk  include:   • neonates whose mothers develop chickenpox in the  period 7 days before to 7 days after delivery;   • susceptible neonates exposed in the first 7 days of  life;   • susceptible women exposed at any stage of  pregnancy (but when supplies of VZIG are short,  may only be issued to those exposed in the first 20  weeks’ gestation or to those near term) providing  VZIG is given within 10 days of contact;    • immunocompromised individuals including those  who have received corticosteroids in the previous  3 months at the following dose equivalents of pred-  nisolone; children 2 mg/kg daily for at least 1 week  or 1 mg/kg daily for 1 month; adults about 40 mg  daily for more than 1 week.   • By intramuscular injection, prophylaxis (as soon as  possible — not later than 10 days after exposure),  ADULT and CHILD over 14 years, lg; NEONATE, INFANT  and CHILD up to 5 years 250 mg, 5-10 years 500 mg,  10-14 years 750 mg; give second dose if further  exposure occurs more than 3 weeks after first dose  Note No evidence that effective in treatment of severe  disease. Normal immunoglobulin for intravenous use (sec-  tion 14.5.1) may be used in those unable to receive intra-  muscular injections   Anti-D (Rh 0 ) immunoglobulin is prepared from plasma  taken from rhesus-negative donors who have been  immunised against the anti-D-antigen. Anti-D (Rh 0 )  immunoglobulin is used to prevent a rhesus-negative  mother from forming antibodies to fetal rhesus-positive  cells which may pass into the maternal circulation. The  objective is to protect any subsequent child from the  hazard of haemolytic disease of the newborn.   Anti-D immunoglobulin should be administered to the  mother following any sensitising episode (e.g. abortion,  miscarriage and birth); it should be injected within 72  hours of the episode but even if a longer period has  elapsed it may still give protection and should be  administered. Anti-D (Rh 0 ) immunoglobulin is also  given when significant feto-matemal haemorrhage  occurs in rhesus-negative women during delivery. The  dose of anti-D immunoglobulin is determined according  to the level of exposure to rhesus-positive blood.   For routine antenatal prophylaxis NICE recommends  that two doses of either 500 units or 1000-1650 units of  anti-D immunoglobulin should be given, the first at 28  weeks’ gestation and the second at 34 weeks; alterna-  tively a single dose of 1500 units given between 28 and  30 weeks gestation can be used (see also NICE guidance  below).   Use of routine antenatal anti-D prophylaxis should be  given irrespective of previous anti-D prophylaxis for a    sensitising event early in the same pregnancy. Similarly,  postpartum anti-D prophylaxis should be given irre-  spective of previous routine antenatal anti-D prophy-  laxis or antenatal anti-D prophylaxis for a sensitising  event in the same pregnancy.   Routine antenatal anti-D prophylaxis should be  offered to all non-sensitised pregnant women who  are rhesus negative.   MMR vaccine may be given in the postpartum  period with anti-D (Rh 0 ) immunoglobulin injection  provided that separate syringes are used and the  products are administered into different limbs. If  blood is transfused, the antibody response to the  vaccine may be inhibited — measure rubella anti-  bodies after 6-8 weeks and revaccinate if necessary.    Anti-D (Rh 0 ) immunoglobulin is also given to women of  child-bearing potential after the inadvertent transfusion  of rhesus-incompatible blood components and is used  for the treatment of idiopathic thrombocytopenia  purpura.   Cautions immunoglobulin A deficiency; possible  interference with live virus vaccines, see under p. 769,  but see notes above about administration with MMR  vaccine   Contra-indications treatment of idiopathic thrombo-  cytopenia purpura in rhesus negative or splenecto-  mised patients   Side-effects nausea, vomiting, diarrhoea, abdominal  pain; hypotension, hypertension, headache, fever,  malaise, asthenia, drowsiness, dizziness, back pain,  arthralgia, myalgia; pruritus, rash, sweating, injection  site pain; rarely tachycardia, anaphylaxis, dyspnoea,  hypotension, and urticaria; (for side-effects associated  with intravenous immunoglobulins, see section 14.5.1  Dose   Injection, anti-D (Rh 0 ) immunoglobulin, net price  250-unit vial = £19.00, 500-unit vial = £27.00, 1500-  unit vial = £58.00, 2500-unit vial = £94.40  Dose by deep intramuscular injection, to rhesus-negative  woman for prevention of Rh 0 (D) sensitisation:   Following birth of rhesus-positive infant, 500 units immediately or  within 72 hours; for transplacental bleed of over 4 mL fetal red  cells, extra 100-125 units per mL fetal red cells  Following any potentially sensitising episode (e.g. stillbirth, abor-  tion, amniocentesis) up to 20 weeks’ gestation 250 units per  episode (after 20 weeks, 500 units) immediately or within 72 hours  Antenatal prophylaxis, 500 units given at weeks 28 and 34 of  pregnancy; if infant rhesus-positive, a further dose is still needed  immediately or within 72 hours of delivery  Following Rh 0 (D) incompatible blood transfusion, 100-125 units  per mL transfused rhesus-positive red cells   Note Subcutaneous route used for patients with bleeding disorders  Available from Blood Centres and from BPL ( D-Gam ®)    Partobulin SDF® (Baxter) (Ml  Injection, anti-D (Rh 0 ) immunoglobulin 1250 units/  mL (250micrograms/mL), net price 1-mL prefilled  syringe = £35.00   Dose by intramuscular injection, to rhesus-negative woman for  prevention of Rh 0 (D) sensitisation:   Following birth of rhesus-positive infant, 1000-1650 units imme-  diately or within 72 hours; for large transplacental blood loss, 50-  125 units per mL of fetal red cells    Rhophylac® (CSL Behring) (Ml  Injection, anti-D (Rh 0 ) immunoglobulin 750units/mL  (150micrograms/mL), net price 2-mL (1500-unit)  prefilled syringe = £46.50.   Dose by intramuscular or intravenous injection, to rhesus-  negative woman for prevention of Rh 0 (D) sensitisation:   Following birth of rhesus-positive infant, 1000-1500 units imme-  diately or within 72 hours; for large transplacental bleed, extra  100 units per mL fetal red cells (preferably by intravenous injec-  tion)   Following any potentially sensitising episode (e.g. abortion,  amniocentesis, chorionic villous sampling) up to 12 weeks’  gestation 1000 units per episode (after 12 weeks, higher doses  may be required) immediately or within 72 hours  Antenatal prophylaxis, 1500 units given between weeks 28-30 of  pregnancy; if infant rhesus-positive, a further dose is still needed  immediately or within 72 hours of delivery  Following Rh 0 (D) incompatible blood transfusion, by intravenous  injection, 50 units per mL transfused rhesus-positive blood (or  100 units per mL of erythrocyte concentrate)   No special immunisation is required for travellers to the  United States, Europe, Australia, or New Zealand,  although all travellers should have immunity to tetanus  and poliomyelitis (and childhood immunisations should  be up to date); see also Tick-borne Encephalitis, p. 766.  Certain special precautions are required in non-Eur-  opean areas surrounding the Mediterranean, in Africa,  the Middle East, Asia, and South America.   Travellers to areas that have a high incidence of polio-  myelitis or tuberculosis should be immunised with the  appropriate vaccine; in the case of poliomyelitis pre-  viously immunised adults may be given a booster dose  of a preparation containing inactivated poliomyelitis  vaccine (see p. 764). BCG immunisation (see p. 750) is  recommended for travellers aged under 16 years 1 pro-    1. There is inadequate evidence of protection by BCG  vaccine in adults aged over 35 years; however, vaccination  is recommended for healthcare workers irrespective of age  because of the increased risk to them or their patients    posing to stay for longer than 3 months (or in close  contact with the local population) in countries with an  incidence of tuberculosis greater than 40 per 100 000 1 ; it  should preferably be given 3 months or more before  departure.   Monovalent influenza A(HlNl)v vaccine (see p. 758)  can be offered to travellers visiting countries in the  southern hemisphere during their influenza season.   Yellow fever immunisation (see p. 768) is recom-  mended for travel to the endemic zones of Africa and  South America. Many countries require an International  Certificate of Vaccination from individuals arriving  from, or who have been travelling through, endemic  areas; other countries require a certificate from all  entering travellers (consult the Department of Health  handbook, Health Information for Overseas Travel,  www. dh . gov.uk) .    Immunisation against meningococcal meningitis is  recommended for a number of areas of the world (for  details, see p. 761).   Protection against hepatitis A is recommended for  travellers to high-risk areas outside Northern and Wes-  tern Europe, North America, Japan, Australia and New  Zealand. Hepatitis A vaccine (see p. 754) is preferred  and it is likely to be effective even if given shortly before  departure; normal immunoglobulin is no longer given  routinely but may be indicated in the immunocompro-  mised (see p. 769). Special care must also be taken with  food hygiene (see below).   Hepatitis B vaccine (see p. 755) is recommended for  those travelling to areas of high or intermediate pre-  valence who intend to seek employment as healthcare  workers or who plan to remain there for lengthy periods  and who may therefore be at increased risk of acquiring  infection as the result of medical or dental procedures  carried out in those countries. Short-term tourists or  business travellers are not generally at increased risk of  infection but may put themselves at risk by their sexual  behaviour when abroad.   Prophylactic immunisation against rabies (see p. 764) is  recommended for travellers to enzootic areas on long  journeys or to areas out of reach of immediate medical  attention.   Travellers who have not had a tetanus booster in the  last 10 years and are visiting areas where medical  attention may not be accessible should receive a boos-  ter dose of adsorbed diphtheria [low dose], tetanus and  poliomyelitis (inactivated) vaccine (see p. 752), even if  they have received 5 doses of a tetanus-containing  vaccine previously.   Typhoid vaccine (see p. 767) is indicated for travellers  to countries where typhoid is endemic, but the vaccine  is no substitute for personal precautions (see below).  There is no requirement for cholera vaccination as a  condition for entry into any country, but oral cholera  vaccine (see p. 751) should be considered for back-  packers and those travelling to situations where the  risk is greatest (e.g. refugee camps). Regardless of  vaccination, travellers to areas where cholera is ende-    1. List of countries where the incidence of tuberculosis is  greater than 40 cases per 100 000 is available at  www.hpa.org.uk   2. Japanese encephalitis vaccine not prescribable on the  NHS; health authorities may investigate circumstances  under which vaccine prescribed   Advice on diphtheria (see p. 752), on Japanese  encephalitis 2 (see p. 759) and on tick-borne encephal-  itis (see p. 766) is included in Health Information for  Overseas Travel, see below.   Food hygiene In areas where sanitation is poor, good  food hygiene is important to help prevent hepatitis A,  typhoid, cholera, and other diarrhoeal diseases (includ-  ing travellers’ diarrhoea). Food should be freshly pre-  pared and hot, and uncooked vegetables (including  green salads) should be avoided; only fruits which can  be peeled should be eaten. Only suitable bottled water,  or tap water that has been boiled or treated with  sterilising tablets, should be used for drinking.   Information on health advice for travellers  Health professionals and travellers can find the latest  information on immunisation requirements and pre-  cautions for avoiding disease while travelling from:   The handbook, Health Information for Overseas  Travel (2010), which draws together essential infor-  mation for healthcare professionals regarding health  advice for travellers, can also be obtained here.    Immunisation requirements change from time to time,  and information on the current requirements for any  particular country may be obtained from the embassy or  legation of the appropriate country or from:   Welsh Medicines Information Centre  University Hospital of Wales  Cardiff, CF14 4XW   Tel: (029) 2074 2979 (8.30 a.m.-5.p.m. weekdays for  health professionals in Wales only)    The drugs in section 15.1 should be used by experi-  enced personnel only and when resuscitation equip-  ment is available.    Several different types of drug are given together during  general anaesthesia. Anaesthesia is induced with either  a volatile drug given by inhalation (section 15.1.2) or  with an intravenously administered drug (section  15.1.1); anaesthesia is maintained with an intravenous  or inhalational anaesthetic. Analgesics (section 15.1.4),  usually short-acting opioids, are also used. The use of  neuromuscular blocking drugs (section 15.1.5) necessi-  tates intermittent positive-pressure ventilation. Follow-  ing surgery, anticholinesterases (section 15.1.6) can be  given to reverse the effects of neuromuscular blocking  drugs; specific antagonists (section 15.1.7) can be used  to reverse central and respiratory depression caused by  some drugs used in surgery. A local topical anaesthetic  (section 15.2) can be used to reduce pain at the injection  site.    Individual requirements vary considerably and the  recommended doses are only a guide. Smaller doses  are indicated in ill, shocked, or debilitated patients and  in significant hepatic impairment, while robust indivi-  duals may require larger doses. The required dose of  induction agent may be less if the patient has been  premedicated with a sedative agent or if an opioid  analgesic has been used.   Surgery and long-term medication The risk of  losing disease control on stopping long-term medication  before surgery is often greater than the risk posed by  continuing it during surgery. It is vital that the anaes-  thetist knows about all drugs that a patient is (or has  been) taking.   Patients with adrenal atrophy resulting from long-term  corticosteroid use (section 6.3.2) may suffer a precipi-  tous fall in blood pressure unless corticosteroid cover is  provided during anaesthesia and in the immediate post-  operative period. Anaesthetists must therefore know  whether a patient is, or has been, receiving corticoster-  oids (including high-dose inhaled corticosteroids).    Other drugs that should normally not be stopped before  surgery include antiepileptics, antiparkinsonian drugs,  antipsychotics, anxiolytics, bronchodilators, cardiovas-  cular drugs (but see potassium-sparing diuretics, angio-  tensin-converting enzyme inhibitors, and angiotensin-II  receptor antagonists below), glaucoma drugs, immuno-  suppressants, drugs of dependence, and thyroid or anti-  thyroid drugs. Expert advice is required for patients  receiving antivirals for HIV infection. For general advice  on surgery in diabetic patients see section 6.1.1, p. 421.   Patients taking antiplatelet medication or an oral anti-  coagulant present an increased risk for surgery. In these  circumstances, the anaesthetist and surgeon should  assess the relative risks and decide jointly whether the  antiplatelet or the anticoagulant drug should be stopped  or replaced with unfractionated or low molecular weight  heparin therapy.   Drugs that should be stopped before surgery include  combined oral contraceptives (see Surgery, section 7.3.1  for details); for advice on hormone replacement therapy,  see section 6.4.1. 1. If antidepressants need to be  stopped, they should be withdrawn gradually to avoid  withdrawal symptoms. MAOIs can have important inter-  actions with some drugs used during surgery, such as  pethidine (for interactions of MAOIs, see Appendix 1,  MAOIs). Tricyclic antidepressants need not be stopped,  but there may be an increased risk of arrhythmias and  hypotension (and dangerous interactions with vasopres-  sor drugs); therefore, the anaesthetist should be  informed if they are not stopped. Lithium should be  stopped 24 hours before major surgery but the normal  dose can be continued for minor surgery (with careful  monitoring of fluids and electrolytes). Potassium-spar-  ing diuretics may need to be withheld on the morning of  surgery because hyperkalaemia may develop if renal  perfusion is impaired or if there is tissue damage. Angio-  tensin-converting enzyme (ACE) inhibitors and angio-  tensin-II receptor antagonists can be associated with  severe hypotension after induction of anaesthesia; these  drugs may need to be discontinued 24 hours before  surgery.   Anaesthesia and driving Patients given sedatives  and analgesics during minor outpatient procedures  should be very carefully warned about the risk of driving  afterwards. For intravenous benzodiazepines and for a  short general anaesthetic the risk extends to at least 24  hours after administration. Responsible persons should  be available to take patients home. The dangers of  taking alcohol should also be emphasised.    Prophylaxis of acid aspiration Regurgitation and  aspiration of gastric contents (Mendelson’s syndrome)  can be an important complication of general anaes-  thesia, particularly in obstetrics and during emergency  surgery, and requires prophylaxis against acid aspira-  tion. Prophylaxis is also needed in those with gastro-  oesophageal reflux disease and in circumstances where  gastric emptying may be delayed.   An H 2 -receptor antagonist (section 1.3.1) or a proton  pump inhibitor (section 1.3.5), such as omeprazole, can  be used before surgery to increase the pH and reduce  the volume of gastric fluid. They do not affect the pH of  fluid already in the stomach and this limits their value in  emergency procedures; oral H 2 -receptor antagonists  can be given 1-2 hours before the procedure, but ome-  prazole must be given at least 12 hours earlier. Antacids  are frequently used to neutralise the acidity of the fluid    already in the stomach; ‘clear’ (non-particulate) antacids  such as sodium citrate are preferred. Sodium citrate  300 mmol/litre (88.2mg/mL) oral solution is licensed  for use before general anaesthesia for caesarean section  (available from Viridian).   Each gas cylinder bears a label with the name of the gas  contained in the cylinder. The name or chemical symbol  of the gas appears on the shoulder of the cylinder and is  also clearly and indelibly stamped on the cylinder valve.  The colours on the valve end of the cylinder extend  down to the shoulder; in the case of mixed gases the  colours for the individual gases are applied in four  segments, two for each colour.   Gas cylinders should be stored in a cool well-ventilated  room, free from flammable materials.   No lubricant of any description should be used on  the cylinder valves.   For details see A Conscious Decision: A review of  the use of general anaesthesia and conscious seda-  tion in primary dental care, report by a group  chaired by the Chief Medical Officer and Chief  Dental Officer, July 2000 and associated documents.  Further details can also be found in Conscious Seda-  tion in the Provision of Dental Care', report of an  Expert Group on Sedation for Dentistry (commis-  sioned by the Department of Health), 2003. Both  documents are available at www.dh.gov.uk.  Guidance is also included in Standards for Dental  Professionals, London, General Dental Council, May  2005 (and as amended subsequently), and Con-  scious Sedation in Dentistry: Dental Clinical Gui-  dance, Scottish Dental Clinical Effectiveness Pro-  gramme, May 2006.   The drugs in this section should be used by experi-  enced personnel only and when resuscitation equip-  ment is available.    Intravenous anaesthetics may be used either to induce  anaesthesia or for maintenance of anaesthesia through-  out surgery. Intravenous anaesthetics nearly all produce  their effect in one arm-brain circulation time and can  cause apnoea and hypotension, and so adequate resus-  citative facilities must be available. They are contra-  indicated if the anaesthetist is not confident of being  able to maintain the airway (e.g. in the presence of a  tumour in the pharynx or larynx). Extreme care is  required in surgery of the mouth, pharynx, or larynx  and in patients with acute circulatory failure (shock) or  fixed cardiac output.    To facilitate tracheal intubation, induction is usually  followed by a neuromuscular blocking drug (section  15.1.5) or a short-acting opioid (section 15.1.4.3).   The doses of all intravenous anaesthetic drugs should  be titrated to effect (except when using ‘rapid sequence  induction’). The doses and rates of administration  should be reduced in the elderly, and particularly in  those with hypovolaemia or cardiovascular disease;  lower doses may also be required in premedicated  patients.   Total intravenous anaesthesia This is a technique  in which major surgery is carried out with all drugs  given intravenously. Respiration can be spontaneous, or  controlled with oxygen-enriched air. Neuromuscular  blocking drugs can be used to provide relaxation and  prevent reflex muscle movements. The main problem to  be overcome is the assessment of depth of anaesthesia.  Target Controlled Infusion (TCI) systems can be used to  titrate intravenous anaesthetic infusions to predicted  plasma-drug concentrations in ventilated adult patients.   Propofol, the most widely used intravenous anaesthetic,  can be used for induction or maintenance of anaesthesia  in adults and children, but it is not commonly used in  neonates.   Propofol is associated with rapid recovery and less  hangover effect than other intravenous anaesthetics. It  causes pain on intravenous injection, which can be  reduced by intravenous lidocaine. Significant extra-  neous muscle movements can occur. Rarely, con-  vulsions, anaphylaxis, and delayed recovery from anaes-  thesia can occur after propofol administration; the onset  of convulsions can be delayed. Propofol is associated  with bradycardia, occasionally profound; intravenous  administration of an antimuscarinic drug is used to  treat this.   Propofol can be used for sedation during diagnostic  procedures. In adults, it can be used for sedation in  intensive care, but it is contra-indicated in children  under 16 years receiving intensive care because of the  risk of propofol infusion syndrome (potentially fatal  effects, including metabolic acidosis, cardiac failure,  rhabdomyolysis, hyperlipidaemia, and hepatomegaly).   Thiopental sodium is a barbiturate that is used for  induction of anaesthesia, but has no analgesic proper-  ties. Induction is generally smooth and rapid, but dose-  related cardiovascular and respiratory depression can  occur. Awakening from a moderate dose of thiopental is  rapid because the drug redistributes into other tissues,  particularly fat. However, metabolism is slow and seda-  tive effects can persist for 24 hours. Repeated doses  have a cumulative effect and recovery is much slower.   Etomidate is an intravenous agent associated with rapid  recovery without a hangover effect. Etomidate causes  less hypotension than thiopental and propofol during  induction. It produces a high incidence of extraneous  muscle movements, which can be minimised by an  opioid analgesic or a short-acting benzodiazepine  given just before induction. Pain on injection can be    reduced by injecting into a larger vein or by giving an  opioid analgesic just before induction. Etomidate sup-  presses adrenocortical function, particularly during con-  tinuous administration, and it should not be used for  maintenance of anaesthesia.   Ketamine is used rarely. Ketamine causes less hypo-  tension than thiopental and propofol during induction. It  is used mainly for paediatric anaesthesia, particularly  when repeated administration is required (such as for  serial bums dressings); recovery is relatively slow and  there is a high incidence of extraneous muscle move-  ments. The main disadvantage of ketamine is the high  incidence of hallucinations, nightmares, and other tran-  sient psychotic effects; these can be reduced by a  benzodiazepine such as diazepam or midazolam.   Breast-feeding breast-feeding can be resumed as  soon as mother has recovered sufficiently from  anaesthesia   Side-effects see notes above; also nausea, vomiting;  hypotension; apnoea, hyperventilation, stridor; rash;  less commonly hypersalivation, arrhythmia, hyper-  tension, hiccups, cough, phlebitis; AV block, cardiac  arrest, respiratory depression, seizures, shivering, and  Stevens- Johnson syndrome also reported   Etomidate-Lipuro® (Braun) (Ml  Injection (emulsion), etomidate 2mg/mL, net price  10-mL amp = £1.53   Dose ADULT and CHILD over 6 months, by slow intravenous  injection, 150-300 micrograms/kg; CHILD under 10 years may  need up to 400 micrograms/kg, ELDERLY 150-200 micrograms/kg    Hypnomidate® Qanssen-Cilag) (Ml  Injection, etomidate 2mg/mL, net price 10-mL amp  = £1.38   300 micrograms/kg (max. total dose 60 mg); ELDERLY ISO-  ZOO micrograms/kg (max. total dose 60 mg)   Cautions see under Intravenous Anaesthetics and  notes above; dehydration; hypertension; respiratory  tract infection; increased cerebrospinal fluid pressure;  predisposition to seizures, hallucinations, or night-  mares; psychotic disorders; head injury or intracranial  mass lesions; thyroid dysfunction; raised intra-ocular  pressure; interactions: Appendix 1 (anaesthetics,  general)    severe cardiac disease, stroke; raised intracranial  pressure; head trauma; acute porphyria (section 9.8.2)  Hepatic impairment consider dose reduction  Pregnancy may depress neonatal respiration if used  during delivery   Side-effects see notes above; also nausea, vomiting;  tachycardia, hypertension, arrhythmias, hypotension,  bradycardia; hypersalivation, laryngospasm; anxiety,  insomnia; diplopia, nystagmus, raised intra-ocular  pressure; rash; apnoea and respiratory depression  also reported  Dose   • By intramuscular injection, short procedures, initially  6.5-13 mg/kg, adjusted according to response   Diagnostic manoeuvres and procedures not involving  intense pain, initially 4 mg/kg   • By intravenous injection over at least 60 seconds,  short procedures, initially 1-4.5 mg/kg, adjusted  according to response (2 mg/kg usually produces 5-  10 minutes of surgical anaesthesia)   1 mg/mL, longer procedures, induction, total dose of  0.5-2 mg/kg; maintenance, 10-45 micrograms/kg/  minute, rate adjusted according to response   Injection, ketamine (as hydrochloride) 10 mg/mL, net  price 20-mL vial = £5.06; 50 mg/mL, 10-mL vial =  £8.77; 100 mg/mL, 10-mL vial = £16.10  Note For intravenous injection, dilute 100 mg/mL strength  to a concentration of not more than 50 mg/mL with Glucose  5% or Sodium Chloride 0.9% or Water for Injections   Cautions see under Intravenous Anaesthetics and  notes above; cardiac impairment; respiratory impair-  ment; elderly; hypovolaemia; epilepsy; hypotension;  raised intracranial pressure; monitor blood-lipid con-  centration if risk of fat overload or if sedation longer  than 3 days; interactions: Appendix 1 (anaesthetics,  general)   Contra-indications see notes above  Hepatic impairment use with caution  Renal impairment use with caution  Pregnancy may depress neonatal respiration if used  during delivery; max. dose for maintenance of  anaesthesia 6 mg/kg/hour  Breast-feeding breast-feeding can be resumed as  soon as mother has recovered sufficiently from  anaesthesia    Side-effects see notes above; also hypotension,  tachycardia, flushing; transient apnoea, hyperventila-  tion, coughing, and hiccup during induction; head-  ache; less commonly thrombosis, phlebitis; rarely  arrhythmia, headache, vertigo, shivering, euphoria;  very rarely pancreatitis, pulmonary oedema, sexual  disinhibition, and discoloration of urine; serious and  sometimes fatal side-effects reported with prolonged  infusion of doses exceeding 5 mg/kg/hour, including  metabolic acidosis, rhabdomyolysis, hyperkalaemia,  and cardiac failure, dystonia and dyskinesia also  reported   • Induction of anaesthesia using 0.5% or 1% injection,  by intravenous injection or infusion, ADULT under 55  years and CHILD over 12 years, 1.5-2. 5 mg/kg at a rate  of 20-40 mg every 10 seconds until response; ADULT  over 55 years or debilitated, 1-1.5 mg/kg at a rate of  20 mg every 10 seconds until response; CHILD 1  month-12 years, administer slowly until response  (usual dose in child over 8 years 2.5 mg/kg, may need  more in younger child e.g. 2.5-4 mg/kg)   • Induction of anaesthesia using 2% injection, by  intravenous infusion, ADULT under 55 years and CHILD  over 12 years, 1.5-2. 5 mg/kg at a rate of 20-40 mg  every 10 seconds; ADULT over 55 years or debilitated,  1-1.5 mg/kg at a rate of 20 mg every 10 seconds until  response; CHILD 3-12 years, administer slowly until  response (usual dose in child over 8 years 2.5 mg/kg,  may need more in younger child e.g. 2.5-4 mg/kg)   • Maintenance of anaesthesia using 1% injection, by  intravenous infusion, 4-12 mg/kg/hour (3-6 mg/kg/  hour in ELDERLY or debilitated) or by intravenous  injection, 25-50 mg repeated according to response;  CHILD 1 month-12 years, by intravenous infusion, 9-  15 mg/kg/hour   • Maintenance of anaesthesia using 2% injection, by  intravenous infusion, 4-12 mg/kg/hour (3-6 mg/kg/  hour in ELDERLY or debilitated); CHILD 3-12 years, by  intravenous infusion, 9-15 mg/kg/hour   • Sedation of ventilated patients in intensive care using  1% or 2% injection, by intravenous infusion, ADULT  and CHILD over 16 years, 0.3-4 mg/kg/hour   • Induction of sedation for surgical and diagnostic  procedures using 0.5% or 1% injection, ADULT and  CHILD over 12 years, initially by intravenous injection  over 1-5 minutes, 0.5-1 mg/kg, dose and rate of  administration adjusted according to desired level of  sedation and response; CHILD 1 month-12 years, 1-  2 mg/kg, dose and rate of administration adjusted  according to desired level of sedation and response   • Induction of sedation for surgical and diagnostic  procedures using 2% injection, ADULT and CHILD over  12 years, initially by intravenous infusion over 1-5  minutes, 0.5-1 mg/kg, dose and rate of administration  adjusted according to desired level of sedation and  response   • Maintenance of sedation for surgical and diagnostic  procedures using 0.5% injection, by intravenous  infusion, ADULT and CHILD over 12 years, 1. 5-4.5 mg/  kg/hour, dose and rate of administration adjusted  according to desired level of sedation and response  (additionally, if rapid increase in sedation required, by  intravenous injection, 10-20 mg); patients over 55  years or debilitated may require lower dose and rate  of administration   • Maintenance of sedation for surgical and diagnostic  procedures using 1% injection, by intravenous infu-  sion, ADULT and CHILD over 12 years, 1. 5-4.5 mg/kg/  hour, dose and rate of administration adjusted  according to desired level of sedation and response  (additionally, if rapid increase in sedation required, by  intravenous injection, 10-20 mg); patients over 55  years or debilitated may require lower dose and rate  of administration; CHILD 1 month-12 years, 1.5-9 mg/  kg/hour, dose and rate of administration adjusted  according to desired level of sedation and response  (additionally, if rapid increase in response required, by  intravenous injection, max. 1 mg/kg)    • Maintenance of sedation for surgical and diagnostic  procedures using 2% injection, by intravenous infu-  sion, ADULT and CHILD over 12 years, 1. 5-4.5 mg/kg/  hour, dose and rate of administration adjusted  according to desired level of sedation and response  (additionally, if rapid increase in sedation required, by  intravenous injection using 0.5% or 1% injection, 10-  20 mg); patients over 55 years or debilitated may  require lower dose and rate of administration; CHILD  3-12 years, 1.5-9 mg/kg/hour, dose and rate of  administration adjusted according to desired level of  sedation and response    500 mg); CHILD 1 month-18 years, initially up to 4 mg/  kg, then 1 mg/kg repeated as necessary (max. total  dose 7 mg/kg)   • Raised intracranial pressure, by slow intravenous  injection, 1.5-3 mg/kg, repeated as required   • Status epilepticus (only if other measures fail, see  section 4.8.2), by slow intravenous injection as a 2.5%  (25 mg/mL) solution, ADULT over 18 years, 75-125 mg  as a single dose; CHILD 1 month-18 years, initially up  to 4 mg/kg by slow intravenous injection, then up to  8 mg/kg/hour by continuous intravenous infusion,  adjusted according to response    Propofol (Non-proprietary) (Ml  0.5% injection (emulsion), propofol 5 mg/mL, net  price 20-mL amp = £3.46  Brands include Propofol-Lipuro ®   1% injection (emulsion), propofol 10 mg/mL, net  price 20-mL amp =£4.18, 50-mL bottle =£10.10, 100-  mL bottle = £19.40   Diprivan® (AstraZeneca) (Ml  1% injection (emulsion), propofol 10 mg/mL, net  price 20-mL amp = £1.07, 50-mL prefilled syringe (for  use with Diprifusor® TCI system) = £4.72  2% injection (emulsion), propofol 20 mg/mL, net  price 50-mL prefilled syringe (for use with  Diprifusor® TCI system) = £5.27  Note Diprifusor® TCI (‘target controlled infusion’) system is  licensed only for induction and maintenance of general anaes-  thesia in adults   Indications induction of general anaesthesia; anaes-  thesia of short duration; reduction of raised intracra-  nial pressure if ventilation controlled; status epilepti-  cus (see also section 4.8.2)   Cautions see notes above; cardiovascular disease;  reconstituted solution is highly alkaline — extravasa-  tion causes tissue necrosis and severe pain; avoid  intra-arterial injection; interactions: Appendix 1  (anaesthetics, general)   Contra-indications see notes above; acute porphyria  (section 9.8.2); myotonic dystrophy  Hepatic impairment use with caution — reduce dose  Renal impairment caution in severe impairment  Pregnancy may depress neonatal respiration if used  during delivery; dose should not exceed 250 mg  Breast-feeding breast-feeding can be resumed as  soon as mother has recovered sufficiently from  anaesthesia   Side-effects hypotension, arrhythmias, myocardial  depression, laryngeal spasm, cough, headache,  sneezing, hypersensitivity reactions, rash   • Induction of general anaesthesia, by slow intravenous  injection usually as a 2.5% (25 mg/mL) solution,  ADULT over 18 years, fit and premedicated, initially  100-150 mg (reduced in elderly or debilitated) over  10-15 seconds (longer in elderly or debilitated), fol-  lowed by further quantity if necessary according to  response after 30-60 seconds; or up to 4 mg/kg (max.   The drugs in this section should be used by experi-  enced personnel only and when resuscitation equip-  ment is available.    Inhalational anaesthetics include gases and volatile  liquids. Gaseous anaesthetics require suitable equip-  ment for storage and administration. They may be  supplied via hospital pipelines or from metal cylinders  (section 15.1). Volatile liquid anaesthetics are adminis-  tered using calibrated vaporisers, using air, oxygen, or  nitrous oxide-oxygen mixtures as the carrier gas. To  prevent hypoxia, the inspired gas mixture should con-  tain a minimum of 25% oxygen at all times. Higher  concentrations of oxygen (greater than 30%) are usually  required during inhalational anaesthesia when nitrous  oxide is being administered, see Nitrous Oxide, p. 781.    Volatile liquid anaesthetics can be used for induction  and maintenance of anaesthesia, and following induc-  tion with an intravenous anaesthetic (section 15.1.1).    Volatile liquid anaesthetics can trigger malignant hyper-  thermia (section 15.1.8) and are contra-indicated in  those susceptible to malignant hyperthermia. They  can increase cerebrospinal pressure and should be  used with caution in those with raised intracranial  pressure. They can also cause hepatotoxicity in those  sensitised to halogenated anaesthetics; halothane has  been associated with severe hepatotoxicity (important:  see below). In children with neuromuscular disease,  inhalational anaesthetics are very rarely associated  with hyperkalaemia, resulting in cardiac arrhythmias  and death. Cardiorespiratory depression, hypotension,  and arrhythmias are common side-effects of volatile  liquid anaesthetics.   Isoflurane is a volatile liquid anaesthetic. Heart rhythm  is generally stable during isoflurane anaesthesia, but  heart-rate can rise, particularly in younger patients.  Systemic arterial pressure and cardiac output can fall,  owing to a decrease in systemic vascular resistance.  Muscle relaxation occurs and the effects of muscle    relaxant drugs are potentiated. Isoflurane can irritate  mucous membranes, causing cough, breath-holding,  and laryngospasm. Isoflurane is the preferred inhala-  tional anaesthetic for use in obstetrics.   Desflurane is a rapid acting volatile liquid anaesthetic;  it is reported to have about one-fifth the potency of  isoflurane. Emergence and recovery from anaesthesia  are particularly rapid because of its low solubility. Des-  flurane is not recommended for induction of anaes-  thesia as it is irritant to the upper respiratory tract;  cough, breath-holding, apnoea, laryngospasm, and  increased secretions can occur.    Sevoflurane is a rapid acting volatile liquid anaesthetic  and is more potent than desflurane. Emergence and  recovery are particularly rapid, but slower than desflur-  ane. Sevoflurane is non-irritant and is therefore often  used for inhalational induction of anaesthesia; it has  little effect on heart rhythm compared with other vola-  tile liquid anaesthetics. Sevoflurane can interact with  carbon dioxide absorbents to form compound A, a  potentially nephrotoxic vinyl ether. However, in spite  of extensive use, no cases of sevoflurane-induced per-  manent renal injury have been reported and the carbon  dioxide absorbents used in the UK produce very low  concentrations of compound A, even in low-flow anaes-  thetic systems.    Halothane is a volatile liquid anaesthetic that has lar-  gely been superseded by newer agents, but is occasion-  ally used for inhalation induction of anaesthesia with  careful monitoring for cardiorespiratory depression and  arrhythmias. It is potent, induction is smooth, and the  vapour is non-irritant and seldom induces coughing or  breath-holding.   Halothane hepatotoxicity  Severe hepatotoxicity can follow halothane anaes-  thesia. It occurs more frequently after repeated  exposure to halothane and has a high mortality.  The risk of severe hepatotoxicity appears to be  increased by repeated exposures within a short  time interval, but even after a long interval (some-  times of several years), susceptible patients have  been reported to develop jaundice. Since there is  no reliable way of identifying patients at risk, the  following precautions are recommended before the  use of halothane:   • a careful anaesthetic history should be taken to  determine previous exposure and previous reac-  tions to halothane;   • repeated exposure to halothane within a period  of at least 3 months should be avoided unless  there are overriding clinical circumstances;   • a history of unexplained jaundice or pyrexia in a  patient following exposure to halothane is an  absolute contra-indication to its future use in  that patient.   Indications see notes above  Cautions see notes above; interactions: Appendix 1  (anaesthetics, general)    Breast-feeding breast-feeding can be resumed as  soon as mother has recovered sufficiently from  anaesthesia   • Induction of anaesthesia (but not recommended), by  inhalation through specifically calibrated vaporiser,  ADULT 4-11%   • Maintenance of anaesthesia, by inhalation through  specifically calibrated vaporiser, ADULT 2-6% in  nitrous oxide; 2. 5-8.5% in oxygen or oxygen-enriched  air; CHILD see BNF for Children   Cautions see notes above (important: see Halothane  Hepatotoxicity, above); avoid for dental procedures in  those under 18 years unless treated in hospital (high  risk of arrhythmia); avoid in acute porphyria (section  9.8.2); interactions: Appendix 1 (anaesthetics, gen-  eral)   Breast-feeding breast-feeding can be resumed as  soon as mother has recovered sufficiently from  anaesthesia   • Induction of anaesthesia, using specifically calibrated  vaporiser, in oxygen or nitrous oxide-oxygen, ADULT  and CHILD over 1 month, initially 0.5% then increased  gradually according to response to 2-4%   • Maintenance of anaesthesia, using specifically cali-  brated vaporiser, in oxygen, oxygen-air, or nitrous  oxide-oxygen, ADULT and CHILD over 1 month, 0.5-2%   Breast-feeding breast-feeding can be resumed as  soon as mother has recovered sufficiently from  anaesthesia   • Induction of anaesthesia, using specifically calibrated  vaporiser, in oxygen or nitrous oxide-oxygen,  increased gradually from 0.5% to 3%   • Maintenance of anaesthesia, using specifically cali-  brated vaporiser, 1-2.5% in nitrous oxide-oxygen; an  additional 0.5-1% may be required when given with  oxygen alone; caesarean section, 0.5-0.75% in nitrous  oxide-oxygen   Breast-feeding breast-feeding can be resumed as  soon as mother has recovered sufficiently from  anaesthesia   Side-effects see notes above; also urinary retention,  leucopenia, agitation in children; dystonia and sei-  zures also reported   • Induction of anaesthesia, using a specifically cali-  brated vaporiser, in oxygen or nitrous oxide-oxygen,  adjusted according to response, ADULT and CHILD over  1 month initially 0.5-1% then increased gradually up  to 8%   • Maintenance of anaesthesia, using a specifically cali-  brated vaporiser, in oxygen or nitrous oxide-oxygen,  adjusted according to response, ADULT and CHILD over  1 month 0.5-3%   Nitrous oxide is used for maintenance of anaesthesia  and, in sub-anaesthetic concentrations, for analgesia.  For anaesthesia, nitrous oxide is commonly used in a  concentration of 50 to 66% in oxygen as part of a  balanced technique in association with other inhala-  tional or intravenous agents. Nitrous oxide is unsatis-  factory as a sole anaesthetic owing to lack of potency,  but is useful as part of a combination of drugs since it  allows a significant reduction in dosage.   For analgesia (without loss of consciousness), a mixture  of nitrous oxide and oxygen containing 50% of each gas  ( Entonox ®, Equanox ®) is used. Self-administration  using a demand valve is popular in obstetric practice,  for changing painful dressings, as an aid to postoper-  ative physiotherapy, and in emergency ambulances.  Nitrous oxide may have a deleterious effect if used in  patients with an air-containing closed space since  nitrous oxide diffuses into such a space with a resulting  increase in pressure. This effect may be dangerous in  the presence of a pneumothorax, which may enlarge to  compromise respiration, or in the presence of intracra-  nial air after head injury.   Hypoxia can occur immediately following the adminis-  tration of nitrous oxide; additional oxygen should always  be given for several minutes after stopping the flow of  nitrous oxide.   Exposure of patients to nitrous oxide for prolonged  periods, either by continuous or by intermittent admin-  istration, may result in megaloblastic anaemia owing to  interference with the action of vitamin B 12 ; neurological  toxic effects can occur without preceding overt haema-  tological changes. For the same reason, exposure of  theatre staff to nitrous oxide should be minimised.  Depression of white cell formation may also occur.   Assessment of plasma-vitamin B 12 concentration should  be considered in those at risk of deficiency, including the  elderly, those who have a poor or vegetarian diet, and  those with a history of anaemia. Nitrous oxide should  not be given continuously for longer than 24 hours or  more frequently than every 4 days without close super-  vision and haematological monitoring.   Breast-feeding breast-feeding can be resumed as  soon as mother has recovered sufficiently from  anaesthesia   • Maintenance of anaesthesia in conjunction with other  anaesthetic agents (using suitable anaesthetic appa-  ratus), 50-66% in oxygen   • Analgesia, up to 50% in oxygen, according to the  patient’s needs   The drugs in this section should be used by experi-  enced personnel only.    Antimuscarinic drugs are used (less commonly nowa-  days) as premedicants to dry bronchial and salivary  secretions which are increased by intubation, upper  airway surgery, or some inhalational anaesthetics.  They are also used before or with neostigmine (section  15.1.6) to prevent bradycardia, excessive salivation, and  other muscarinic actions of neostigmine. They also  prevent bradycardia and hypotension associated with  drugs such as halothane, propofol, and suxamethonium.   Atropine sulphate is now rarely used for premedication  but still has an emergency role in the treatment of  vagotonic side-effects. For its role in acute arrhythmias  after myocardial infarction, see section 2.3.1.   Hyoscine hydrobromide reduces secretions and also  provides a degree of amnesia, sedation and anti-emesis.  Unlike atropine it may produce bradycardia rather than  tachycardia. In some patients, especially the elderly,  hyoscine may cause the central anticholinergic  syndrome (excitement, ataxia, hallucinations,  behavioural abnormalities, and drowsiness).    Glycopyrronium bromide reduces salivary secretions.  When given intravenously it produces less tachycardia  than atropine. It is widely used with neostigmine for  reversal of non-depolarising neuromuscular blocking  drugs (section 15.1.5).   Indications premedication; intra-operative brady-  cardia; with anticholinesterases for reversal of non-  depolarising neuromuscular block; antidote to orga-  nophosphorous poisoning (see Emergency Treatment  of Poisoning p. 41); symptomatic relief of gastro-  intestinal disorders characterised by smooth muscle  spasm (section 1.2); bradycardia (section 2.3.1);  cardiopulmonary resuscitation (section 2.7.3); cyclo-  plegia, anterior uveitis (section 11.5)   Duration of action Since atropine has a shorter duration of  action than neostigmine, late unopposed bradycardia may  result; close monitoring of the patient is necessary  Contra-indications section 1.2  Pregnancy not known to be harmful; use with caution  Breast-feeding small amount present in milk — use  with caution   By subcutaneous or intramuscular injection, 300-  600 micrograms 30-60 minutes before induction of  anaesthesia; CHILD under 12 years see BNF for Chil-  dren   • Control of muscarinic side-effects of neostigmine in  reversal of competitive neuromuscular block, by  intravenous injection, 0.6-1. 2 mg; CHILD under 12  years, 20 micrograms/kg (max. 1.2 mg)   • Control of muscarinic side-effects of edrophonium in  reversal of competitive neuromuscular block [unli-  censed indication], by intravenous injection,    1 Atropine (Non-proprietary) Ml  Injection, atropine sulphate 600 micrograms/mL, net  price 1-mL amp = 62p  Note Other strengths also available  Injection, prefilled disposable syringe, atropine sul-  phate 100 micrograms/mL, net price 5mL = £4.58,  10 mL =£5.39, 30 mL = £8.95  Injection, prefilled disposable syringe, atropine sul-  phate 200 micrograms/mL, net price 5mL = £5.91;  300 micrograms/mL, 10 mL = £5.91; 600 micr-  ograms/mL, 1 mL = £5.91   1 Minijet® Atropine (UCB Pharma) (Ml  Injection, atropine sulphate 100 micrograms/mL, net  price 5 mL = £5.04, 10 mL = £5.93, 30 mL = £9.85  1. Ml restriction does not apply where administration is for  saving life in emergency   Indications drying secretions (see Prescribing in Pal-  liative Care, p. 21); premedication; intra-operative  bradycardia; with neostigmine for reversal of non-  depolarising neuromuscular block; hyperhidrosis  (section 13.12)   • Premedication, by intramuscular or intravenous  injection, 200-400 micrograms or 4-5 micrograms/kg  (max. 400 micrograms); CHILD 1 month-12 years, 4-  8 micrograms/kg (max. 200 micrograms)    • Intra-operative bradycardia, by intravenous injection,  200-400 micrograms or 4-5 micrograms/kg (max.  400 micrograms), repeated if necessary; CHILD 1  month-18 years, 4-8 micrograms /kg (max. 200 micr-  ograms), repeated if necessary   • Control of muscarinic side-effects of neostigmine in  reversal of non-depolarising neuromuscular block, by  intravenous injection, 200 micrograms per 1 mg of  neostigmine, or 10-15 micrograms /kg; CHILD 1  month-12 years, 10 micrograms /kg (max. 500 micr-  ograms)   Glycopyrronium bromide (Non-proprietary) (Ml  Injection, glycopyrronium bromide 200 micrograms/  mL, net price 1-mL amp = 54p, 3-mL amp = 91p   Pregnancy use only if potential benefit outweighs risk;  injection may depress neonatal respiration   • Premedication, by subcutaneous or intramuscular  injection, 200-600 micrograms 30-60 minutes before  induction of anaesthesia; CHILD 1 5 micrograms/kg   Hyoscine (Non-proprietary) Ml  Injection, hyoscine hydrobromide 400 micrograms/  mL, net price 1-mL amp = £2.80; 600 micrograms/  mL, 1-mL amp = £2.94   The drugs in this section should be used by experi-  enced personnel only.    Premedication These drugs are given to allay fear and  anxiety in the pre-operative period (including the night  before an operation), to relieve pain and discomfort  when present, and to augment the action of subsequent    anaesthetic agents. A number of the drugs used also  provide some degree of pre-operative amnesia. The  choice will vary with the individual patient, the nature  of the operative procedure, the anaesthetic to be used,  and other prevailing circumstances such as outpatients,  obstetrics, and recovery facilities. The choice also varies  between elective and emergency operations.   Premedication in children Oral administration is  preferred where possible; the rectal route should only  be used in exceptional circumstances. For further  details, consult BNF for Children.   Application of a local anaesthetic (section 15.2) to the  injection site can help to prevent pain.   Dental procedures Anxiolytics diminish tension,  anxiety and panic, and may benefit anxious patients.  However, their use is no substitute for sympathy and  reassurance.   Diazepam and temazepam are effective anxiolytics for  dental treatment in adults, but they are less suitable for  children. Diazepam has a longer duration of action than  temazepam. When given at night diazepam is asso-  ciated with more residual effects the following day;  patients should be very carefully warned not to drive  (important: for general advice on anaesthesia and driv-  ing see p. 776). For further information on hypnotics  and anxiolytics, see section 4.1. For further information  on hypnotics used for dental procedures, see section  4.1.1.   Benzodiazepines possess useful properties for premedi-  cation including relief of anxiety, sedation, and amnesia;  short-acting benzodiazepines taken by mouth are the  most common premedicants. They have no analgesic  effect so an opioid analgesic may sometimes be  required for pain.   Benzodiazepines can alleviate anxiety at doses that do  not necessarily cause excessive sedation and they are of  particular value during short procedures or during  operations under local anaesthesia (including dentistry).  Amnesia reduces the likelihood of any unpleasant mem-  ories of the procedure (although benzodiazepines, par-  ticularly when used for more profound sedation, can  sometimes induce sexual fantasies). Benzodiazepines  are also used in intensive care units for sedation, parti-  cularly in those receiving assisted ventilation.   Benzodiazepines may occasionally cause marked resp-  iratory depression and facilities for its treatment are  essential; flumazenil (section 15.1.7) is used to antag-  onise the effects of benzodiazepines. They are best  avoided in myasthenia gravis, especially peri-opera-  tively.   Diazepam is used to produce mild sedation with amne-  sia. It is a long-acting drug with active metabolites and a  second period of drowsiness can occur several hours    after its administration. Peri-operative use of diazepam  in children is not generally recommended; its effect and  timing of response are unreliable and paradoxical  effects may occur.   Diazepam is relatively insoluble in water and prepara-  tions formulated in organic solvents are painful on  intravenous injection and give rise to a high incidence  of venous thrombosis (which may not be noticed for  several days after the injection). Intramuscular injection  of diazepam is painful and absorption is erratic. An  emulsion formulated for intravenous injection is less  irritant and reduces the risk of venous thrombosis; it is  not suitable for intramuscular injection. Diazepam is  also available as a rectal solution but this preparation  is not used for premedication or sedation.   Temazepam is given by mouth and has a shorter  duration of action and a more rapid onset than diaze-  pam given by mouth. It has been used as a premedicant  in inpatient and day-case surgery; anxiolytic and seda-  tive effects last about 90 minutes although there may be  residual drowsiness.   Lorazepam produces more prolonged sedation than  temazepam and it has marked amnesic effects. It is  used as a premedicant the night before major surgery;  a further, smaller dose may be required the following  morning if any delay in starting surgery is anticipated.  Alternatively the first dose may be given early in the  morning on the day of operation.   Midazolam is a water-soluble benzodiazepine that is  often used in preference to intravenous diazepam;  recovery is faster than from diazepam, but may be  significantly longer in the elderly, in patients with a  low cardiac output, or after repeated dosing. Midazolam  is associated with profound sedation when high doses  are given intravenously or when it is used with certain  other drugs.    Overdosage with midazolam  There have been reports of overdosage when high  strength midazolam has been used for conscious  sedation. The use of high-strength midazolam  (5mg/mL in 2mL and 10 mL ampoules, or 2 mg/  mL in 5 mL ampoules) should be restricted to gen-  eral anaesthesia, intensive care, palliative care, or  other situations where the risk has been assessed. It  is advised that flumazenil (section 15.1.7) is available  when midazolam is used, to reverse the effects if   Indications premedication; conscious sedation for  procedures, and in conjunction with local anaesthesia;  short-term use in anxiety or insomnia, adjunct in  acute alcohol withdrawal (section 4.1.2); status epi-  lepticus (section 4.8.2); muscle spasms (section  10 . 2 . 2 )   Cautions see notes above, section 4.1.2, and section  4.8.2; interactions: Appendix 1 (anxiolytics and hyp-  notics)   • By mouth, 5-10 mg 1-2 hours before procedure (up to  max. 20 mg for dental procedures carried out in  hospital); ELDERLY (or debilitated), half adult dose   • By intravenous injection into a large vein (emulsion  preparation preferred), sedative cover for minor sur-  gical and medical procedures, ADULT over 18 years,  10-20 mg over 2-4 minutes, immediately before pro-  cedure; premedication 100-200 micrograms /kg;  CHILD under 18 years see BNF for Children   Indications conscious sedation for procedures; pre-  medication; short-term use in anxiety or insomnia  (section 4.1.2); status epilepticus (section 4.8.2)   Cautions see notes above and section 4.1.2; interac-  tions: Appendix 1 (anxiolytics and hypnotics)   • By mouth, 2-3 mg the night before operation; 2-4 mg  1-2 hours before operation   • By slow intravenous injection, preferably diluted with  an equal volume of sodium chloride intravenous  infusion 0.9% or water for injections, 50 micrograms/  kg 30-45 minutes before operation   Indications conscious sedation for procedures; seda-  tion in intensive care; sedation in anaesthesia; pre-  medication; induction of anaesthesia; status epilepti-  cus (section 4.8.2)   Cautions see notes above; cardiac disease; respiratory  disease; myasthenia gravis; neonates; children (parti-  cularly if cardiovascular impairment); risk of airways  obstruction and hypoventilation in children under 6  months (monitor respiratory rate and oxygen satura-  tion); history of drug or alcohol abuse; reduce dose in  elderly and debilitated; risk of severe hypotension in  hypovolaemia, vasoconstriction, hypothermia; avoid  prolonged use (and abrupt withdrawal thereafter);  concentration of midazolam in children under 1 5 kg  not to exceed 1 mg/mL; interactions: Appendix 1  (anxiolytics and hypnotics)   Contra-indications marked neuromuscular respir-  atory weakness including unstable myasthenia gravis;  severe respiratory depression; acute pulmonary  insufficiency   Pregnancy avoid regular use (risk of neonatal with-  drawal symptoms); use only if clear indication such as  seizure control (high doses during late pregnancy or  labour may cause neonatal hypothermia, hypotonia,  and respiratory depression)   Breast-feeding present in milk — avoid breast-feeding  for 24 hours after administration   Side-effects see notes above; gastro-intestinal distur-  bances, increased appetite, jaundice; hypotension,  cardiac arrest, heart rate changes, anaphylaxis,  thrombosis; laryngospasm, bronchospasm, respir-  atory depression and respiratory arrest (particularly  with high doses or on rapid injection); drowsiness,  confusion, ataxia, amnesia, headache, euphoria, hal-  lucinations, convulsions (more common in neonates),  dizziness, vertigo, involuntary movements, paradox-  ical excitement and aggression (especially in children  and elderly), dysarthria; urinary retention, incont-  inence, changes in libido; blood disorders; muscle  weakness; visual disturbances; salivation changes;  skin reactions; injection-site reactions  Dose   • Conscious sedation for procedures, by slow intra-  venous injection (approx. 2 mg/minute) 5-10 minutes  before procedure, initially 2-2.5 mg (ELDERLY 0.5-   1 mg), increased if necessary in steps of 1 mg (ELDERLY  0.5-1 mg); usual total dose 3.5-5 mg (max. 7.5 mg),  ELDERLY max. 3.5 mg; CHILD 1 month-18 years see  BNF for Children   • Sedative in combined anaesthesia, by intravenous  injection, 30-100 micrograms/kg repeated as  required or by continuous intravenous infusion, 30-  100 micrograms/kg/hour (ELDERLY lower doses  needed); CHILD not recommended   • Premedication, by deep intramuscular injection,  ADULT over 18 years, 70-100 micrograms /kg (ELDERLY  or debilitated 25-50 micrograms/kg) 20-60 minutes  before induction   By intravenous injection, ADULT over 18 years, 1-2 mg  5-30 minutes before procedure, repeated as required  (ELDERLY or debilitated 0.5 mg, repeat dose slowly as  required)   • Induction (but rarely used), by slow intravenous  injection, 150-200 micrograms/kg (ELDERLY or debili-  tated 50-1 50 micrograms/kg) given in divided doses  (max. 5 mg) at intervals of 2 minutes; max. total dose  600 micrograms/kg; CHILD 7-18 years initially   150 micrograms/kg (max. 7.5 mg) given in steps of  50 micrograms/kg (max. 2.5 mg) over 2-5 minutes;  wait for 2-5 minutes then give additional doses of  50 micrograms/kg (max. 2.5 mg) every 2 minutes if  necessary; max. total dose 500 micrograms/kg (not  exceeding 25 mg)    • Sedation of patients receiving intensive care, by slow  intravenous injection, initially 30-300 micrograms/kg  given in steps of 1-2.5 mg every 2 minutes, then by  slow intravenous injection or by continuous intra-  venous infusion, 30-200 micrograms/kg/hour;  reduce dose (or reduce or omit initial dose) in hypo-  volaemia, vasoconstriction, or hypothermia; lower  doses may be adequate if opioid analgesic also used;  CHILD under 12 years see BNF for Children   Injection, midazolam (as hydrochloride) lmg/mL,  net price 2-mL amp = 50p, 5-mL amp = 60p, 50-mL  vial = £7.87; 2 mg/mL, 5-mL amp = 65p; 5 mg/mL, 2-  mL amp = 58p, 10-mL amp = £2.50   Injection, midazolam (as hydrochloride) 2 mg/mL,  net price 5-mL amp = 85p; 5 mg/mL, 2-mL amp =  72p   Cautions see notes above and Diazepam, section  4.1.2; interactions: Appendix 1 (anxiolytics and hyp-  notics)   Renal impairment see Benzodiazepines, section 4.1.1  Pregnancy see Benzodiazepines, section 4.1.1  Breast-feeding see Benzodiazepines, section 4.1.1  Side-effects see notes above and Diazepam, section   30 mg in exceptional circumstances) 1-2 hours before  procedure; ELDERLY 10 mg (up to 20 mg in exceptional  circumstances); CHILD 1 mg/kg (max. 30 mg)   Note Temazepam doses in BNF may differ from those in  product literature    Since non-steroidal anti-inflammatory drugs (NSAIDs)  do not depress respiration, do not impair gastrointes-  tinal motility, and do not cause dependence, they may  be useful alternatives or adjuncts to opioids for the relief  of postoperative pain. NSAIDs may be inadequate for  the relief of severe pain.    Acemetacin, diclofenac, flurbiprofen, ibuprofen,  ketoprofen, (section 10.1.1), paracetamol (section  4.7.1), parecoxib, and ketorolac are licensed for post-  operative use. Diclofenac, ketoprofen, ketorolac, and  paracetamol can be given by injection as well as by  mouth. Diclofenac can be given by intravenous infusion  for the treatment or prevention of postoperative pain.  Intramuscular injections of diclofenac and ketoprofen  are rarely used; they are given deep into the gluteal  muscle to minimise pain and tissue damage. Ketorolac is    less irritant on intramuscular injection but pain has been  reported; it can also be given by intravenous injection.  Parecoxib (a selective inhibitor of cyclo-oxygenase-2)  can be given by intramuscular or intravenous injection  (but see also NSAIDs and Cardiovascular Events, sec-  tion 10.1.1). The Scottish Medicines Consortium (p. 4)  has advised (January 2003) that parecoxib is not recom-  mended for use within NHS Scotland.   Suppositories of diclofenac and ketoprofen may be  effective alternatives to the parenteral use of these  drugs.    Indications short-term management of moderate to  severe acute postoperative pain only  Cautions section 10.1.1; avoid in acute porphyria  (section 9.8.2); interactions: Appendix 1 (NSAIDs)  Contra-indications section 10.1.1; also complete or  partial syndrome of nasal polyps; haemorrhagic dia-  theses (including coagulation disorders) and following  operations with high risk of haemorrhage or incom-  plete haemostasis; confirmed or suspected cerebro-  vascular bleeding; hypovolaemia or dehydration  Hepatic impairment section 10.1.1  Renal impairment max. 60 mg daily by intramuscular  or intravenous injection; avoid if serum creatinine  greater than 160micromol/litre; see also section  10 . 1.1   Pregnancy section 10.1.1  Breast-feeding amount too small to be harmful  Side-effects section 10.1.1; also gastro-intestinal dis-  turbances, taste disturbances, dry mouth; flushing,  bradycardia, palpitation, chest pain, hypertension,  pallor; dyspnoea, asthma; malaise, euphoria, psycho-  sis, paraesthesia, convulsions, abnormal dreams,  hyperkinesia, confusion, hallucinations; urinary fre-  quency, thirst, sweating; hyponatraemia, hyperkal-  aemia, myalgia; visual disturbances (including optic  neuritis); purpura, pain at injection site  Dose    • ADULT and CHILD over 16 years, by mouth, 10 mg every  4-6 hours (ELDERLY every 6-8 hours) as required; max.  40 mg daily; max. duration of treatment 7 days   • ADULT and CHILD over 16 years, by intramuscular  injection or by intravenous injection over at least 15  seconds, initially 10 mg, then 10-30 mg every 4-6  hours as required (up to every 2 hours during initial  postoperative period); max. 90 mg daily (ELDERLY and  patients weighing less than 50 kg max. 60 mg daily);  max. duration of treatment 2 days; CHILD 6 months-16  years see BNF for Children   Note When converting from parenteral to oral administra-  tion, total combined dose on the day of converting should  not exceed 90 mg (60 mg in the elderly and patients weighing  less than 50 kg) of which the oral component should not  exceed 40 mg   Ketorolac (Non-proprietary) (Ml  Injection, ketorolac trometamol 30 mg/mL, net price  1-mL amp = £1.10   Tablets, ivory, f/c, ketorolac trometamol 10 mg, net  price 20-tab pack = £5.45. Label: 17, 21  Injection, ketorolac trometamol 10 mg/mL, net price  1-mL amp = 89p; 30 mg/mL, 1-mL amp = £1.08   Contra-indications section 10.1.1; also history of  allergic drug reactions including sulphonamide  hypersensitivity; inflammatory bowel disease   Hepatic impairment halve dose in moderate impair-  ment (max. 40 mg daily); see also section 10.1.1   Side-effects section 10.1.1; also flatulence, hypo-  tension, hypoaesthesia, alveolar osteitis, postoper-  ative anaemia, hypokalaemia, sweating; less com-  monly bradycardia, cardiovascular events, pulmonary  embolism, anorexia, malaise, hyperglycaemia,  increased blood urea nitrogen, arthralgia, ecchymosis;  rarely tachycardia   • By deep intramuscular injection or by intravenous  injection, initially 40 mg, then 20-40 mg every 6-12  hours when required for up to 3 days; max. 80 mg  daily; ELDERLY weighing less than 50 kg, initially 20 mg,  then max. 40 mg daily; CHILD under 18 years, not  recommended   Injection, powder for reconstitution, parecoxib (as  sodium salt), net price 40-mg vial = £4.96, 40-mg vial  (with solvent) = £5.67   Opioid analgesics are now rarely used as premedicants;  they are more likely to be administered at induction.  Pre-operative use of opioid analgesics is generally lim-  ited to those patients who require control of existing  pain. The main side-effects of opioid analgesics are  respiratory depression, cardiovascular depression,  nausea, and vomiting; for general notes on opioid anal-  gesics and their use in postoperative pain, see section  4.7.2.    jaw; this can be managed by the use of neuromuscular  blocking drugs.   In contrast to other opioids which are metabolised in the  liver, remifentanil undergoes rapid metabolism by non-  specific blood and tissue esterases; its short duration of  action allows prolonged administration at high dosage,  without accumulation, and with little risk of residual  postoperative respiratory depression. Remifentanil  should not be given by intravenous injection intra-  operatively, but it is well suited to continuous infusion;  a supplementary analgesic is given before stopping the  infusion of remifentanil.   Indications analgesia especially during short opera-  tive procedure and outpatient surgery; enhancement  of anaesthesia; analgesia and suppression of respir-  atory activity in patients receiving intensive care, with  assisted ventilation, for up to 4 days   Side-effects section 4.7.2 and notes above; also  hypertension, myoclonic movements; less commonly  arrhythmias, hiccup, laryngospasm; rarely epistaxis;  also reported cardiac arrest, cough, convulsions, and  pyrexia  Dose   ^To avoid excessive dosage in obese patients, dose may  need to be calculated on the basis of ideal body-weight   • By intravenous injection, spontaneous respiration,  ADULT, initially up to 500 micrograms over 30 seconds;  supplemental, 250 micrograms   With assisted ventilation, ADULT over 18 years, initially  30-50 micrograms /kg; supplemental, 15 micr-  ograms/kg; CHILD 1 month-18 years, initially 10-  20 micrograms /kg; supplemental doses up to  10 micrograms /kg   • By intravenous infusion, with assisted ventilation,  ADULT and CHILD, initially 50-100 micrograms/kg over  10 minutes or as a bolus, followed by maintenance of  0.5-1 micrograms /kg/minute   Analgesia and suppression of respiratory activity  during intensive care, with assisted ventilation, by  intravenous infusion, initially 2 mg/hour subse-  quently adjusted according to response (usual range  0.5-10 mg/hour); more rapid initial control may be  obtained with an intravenous dose of 5 mg given in  divided portions over 10 minutes (slowing if hypo-  tension or bradycardia occur); additional doses of 0.5-  1 mg may be given by intravenous injection during  short painful procedures   Alfentanil (Non-proprietary) (S El  Injection, alfentanil (as hydrochloride) 500micr-  ograms/mL, net price 2-mL amp = 70p, 10-mL amp =  £3.20   Intra-operative analgesia Opioid analgesics given in  small doses before or with induction reduce the dose  requirement of some drugs used during anaesthesia.   Alfentanil, fentanyl, and remifentanil are particularly  useful because they act within 1-2 minutes and have  short durations of action. The initial doses of alfentanil  or fentanyl are followed either by successive intra-  venous injections or by an intravenous infusion; pro-  longed infusions increase the duration of effect.  Repeated intra-operative doses of alfentanil or fentanyl  should be given with care since the resulting respiratory  depression can persist postoperatively and occasionally  it may become apparent for the first time postopera-  tively when monitoring of the patient might be less  intensive. Alfentanil, fentanyl, and remifentanil can  cause muscle rigidity, particularly of the chest wall or   Injection, alfentanil (as hydrochloride) 500micr-  ograms/mL, net price 2-mL amp = 64p; 10-mL amp =  £2.90   Indications analgesia during operation, enhancement  of anaesthesia; respiratory depressant in assisted  respiration; analgesia in other situations (section  4.7.2)   Cautions see Fentanyl, section 4.7.2 and notes above  Contra-indications see notes in section 4.7.2  Hepatic impairment see notes in section 4.7.2  Renal impairment see notes in section 4.7.2  Pregnancy see notes in section 4.7.2  Breast-feeding see Fentanyl, section 4.7.2  Side-effects see Fentanyl, section 4.7.2 and notes  above; also myoclonic movements; less commonly  laryngospasm; rarely asystole and insomnia  Dose   To avoid excessive dosage in obese patients, dose may  need to be calculated on the basis of ideal body-weight   • By slow intravenous injection, with spontaneous  respiration, ADULT and CHILD over 12 years, initially 50-  100 micrograms (max. 200 micrograms on specialist  advice), then 25-50 micrograms as required; CHILD 1  month- 12 years see BNF for Children   With assisted ventilation, ADULT and CHILD over 12  years, initially 0.3-3. 5 mg, then 100-200 micrograms  as required; CHILD 1 month-12 years see BNF for  Children   • By intravenous infusion, with spontaneous respira-  tion, ADULT, 3-4.8 micrograms /kg/hour adjusted  according to response   With assisted ventilation, ADULT, initially 10 micr-  ograms/kg over 10 minutes then 6 micrograms/kg/  hour adjusted according to response; may require up  to 180 micrograms/kg/hour during cardiac surgery;  CHILD 1 month-18 years see BNF for Children   Injection, fentanyl (as citrate) 50 micrograms/mL, net  price 2-mL amp = 3 Op, 10-mL amp = 64p   Sublimaze® Oanssen-Cilag) LtEI  Injection, fentanyl (as citrate) 50 micrograms/mL, net  price 10-mL amp = £1.31   Indications supplementation of general anaesthesia  during induction and analgesia during maintenance of  anaesthesia (consult product literature for use in  patients undergoing cardiac surgery); analgesia and  sedation in ventilated, intensive care patients  Cautions section 4.7.2 (but no dose adjustment  necessary in renal impairment) and notes above    Contra-indications section 4.7.2 and notes above; left  ventricular dysfunction; analgesia in conscious  patients   ( To avoid excessive dosage in obese patients, dose  should be calculated on the basis of ideal body-weight    • Induction of anaesthesia, ADULT and CHILD over 12  years, by intravenous infusion, 0.5-1 micrograms/  kg/minute, with or without an initial dose by intra-  venous injection of 0.25-1 microgram/kg over at  least 30 seconds    Note If patient to be intubated more than 8 minutes after  start of intravenous infusion, initial intravenous injection  dose is not necessary   • Maintenance of anaesthesia in ventilated patients,  ADULT and CHILD over 12 years, by intravenous infu-  sion, 0.05-2 micrograms/kg/minute (with or without  an initial dose by intravenous injection of 0.25-   1 micrograms/kg over at least 30 seconds) according  to anaesthetic technique and adjusted according to  response; in light anaesthesia supplemental doses by  intravenous injection every 2-5 minutes; CHILD 1-12  years, 0.05-1.3 micrograms/kg/minute (with or  without an initial dose by intravenous injection of 0.1-  1 microgram/kg over at least 30 seconds) according  to anaesthetic technique and adjusted according to  response   • Maintenance of anaesthesia with spontaneous  respiration, ADULT and CHILD over 12 years, by intra-  venous infusion, initially 40 nanograms/kg/minute  adjusted according to response, usual range 25-  100 nanograms/kg/minute    • Analgesia and sedation in ventilated, intensive-care  patients for max. 3 days, by intravenous infusion,  ADULT over 18 years, initially 100-150 nanograms/kg/  minute adjusted according to response in steps of  25 nanograms/kg/minute (allow at least 5 minutes  between dose adjustments); usual range 6-740 nan-  ograms/kg/minute; if an infusion rate of 200 nan-  ograms/kg/minute does not produce adequate  sedation add another sedative (consult product lit-  erature for details)   • Additional analgesia during stimulating or painful  procedures in ventilated, intensive-care patients, by  intravenous infusion, ADULT over 18 years, maintain  infusion rate of at least 100 nanograms/kg/minute for  at least 5 minutes before procedure and adjust every  2-5 minutes according to requirements, usual range  250-750 nanograms/kg/minute   Injection, powder for reconstitution, remifentanil (as  hydrochloride), net price 1-mg vial = £5.12; 2-mg vial  = £10.23; 5-mg vial = £25.58   The drugs in this section should be used by experi-  enced personnel only.    Neuromuscular blocking drugs used in anaesthesia are  also known as muscle relaxants. By specific blockade  of the neuromuscular junction they enable light anaes-  thesia to be used with adequate relaxation of the mus-  cles of the abdomen and diaphragm. They also relax the  vocal cords and allow the passage of a tracheal tube.  Their action differs from the muscle relaxants used in  musculoskeletal disorders (section 10.2.2) that act on  the spinal cord or brain.   Patients who have received a neuromuscular blocking  drug should always have their respiration assisted or  controlled until the drug has been inactivated or antag-  onised (section 15.1.6). They should also receive suffi-  cient concomitant inhalational or intravenous anaes-  thetic or sedative drugs to prevent awareness.    Non-depolarising neuromuscular blocking drugs (also  known as competitive muscle relaxants) compete with  acetylcholine for receptor sites at the neuromuscular  junction and their action can be reversed with anti-  cholinesterases such as neostigmine (section 15.1.6).  Non-depolarising neuromuscular blocking drugs can  be divided into the aminosteroid group, comprising  pancuronium, rocuronium, and vecuronium, and the  benzylisoquinolinium group, comprising atracurium,  cisatracurium, and mivacurium.   Non-depolarising neuromuscular blocking drugs have a  slower onset of action than suxamethonium. These  drugs can be classified by their duration of action as  short-acting (15-30 minutes), intermediate-acting (30-  40 minutes), and long-acting (60-120 minutes),  although duration of action is dose-dependent. Drugs  with a shorter or intermediate duration of action, such  as atracurium and vecuronium, are more widely used  than those with a longer duration of action, such as  pancuronium.   Non-depolarising neuromuscular blocking drugs have  no sedative or analgesic effects and are not considered  to trigger malignant hyperthermia.    For patients receiving intensive care and who require  tracheal intubation and mechanical ventilation, a non-  depolarising neuromuscular blocking drug is chosen  according to its onset of effect, duration of action, and  side-effects. Rocuronium, with a rapid onset of effect,  may facilitate intubation. Atracurium or cisatracurium  may be suitable for long-term neuromuscular blockade  since their duration of action is not dependent on  elimination by the liver or the kidneys.    Cautions Allergic cross-reactivity between neuro-  muscular blocking drugs has been reported; caution is  advised in cases of hypersensitivity to these drugs. Their  activity is prolonged in patients with myasthenia gravis  and in hypothermia, and lower doses are required. Non-  depolarising neuromuscular blocking drugs should be    used with great care in those with other neuromuscular  disorders and those with fluid and electrolyte distur-  bances, as response is unpredictable. Resistance can  develop in patients with bums, who may require  increased doses; low plasma cholinesterase activity in  these patients requires dose titration for mivacurium.  The rate of administration of neuromuscular blocking  drugs should be reduced in patients with cardiovascular  disease. Interactions: Appendix 1 (muscle relaxants).   Pregnancy Non-depolarising neuromuscular blocking  drugs are highly ionised at physiological pH and are  therefore unlikely to cross the placenta in significant  amounts.   Breast-feeding Because they are ionised at physio-  logical pH, non-depolarising neuromuscular blocking  drugs are unlikely to be present in milk in significant  amounts. Breast-feeding may be resumed once the  mother has recovered from neuromuscular block.   Side-effects Benzylisoquinolinium non-depolarising  neuromuscular blocking drugs (except cisatracurium)  are associated with histamine release, which can  cause skin flushing, hypotension, tachycardia, broncho-  spasm, and very rarely anaphylactoid reactions. Most  aminosteroid neuromuscular blocking drugs produce  minimal histamine release. Drugs with vagolytic activity  can counteract any bradycardia that occurs during  surgery. Acute myopathy has also been reported after  prolonged use in intensive care.   Atracurium, a mixture of 10 isomers, is a benzylisoqui-  nolinium neuromuscular blocking drug with an inter-  mediate duration of action. It undergoes non-enzymatic  metabolism which is independent of liver and kidney  function, thus allowing its use in patients with hepatic or  renal impairment. Cardiovascular effects are associated  with significant histamine release.   Cisatracurium is a single isomer of atracurium. It is  more potent and has a slightly longer duration of action  than atracurium and provides greater cardiovascular  stability because cisatracurium lacks histamine-releas-  ing effects.   Mivacurium, a benzylisoquinolinium neuromuscular  blocking drug, has a short duration of action. It is  metabolised by plasma cholinesterase and muscle  paralysis is prolonged in individuals deficient in this  enzyme. It is not associated with vagolytic activity or  ganglionic blockade although histamine release can  occur, particularly with rapid injection.   Pancuronium, an aminosteroid neuromuscular block-  ing drug, has a long duration of action and is often used  in patients receiving long-term mechanical ventilation  in intensive care units. It lacks a histamine-releasing  effect, but vagolytic and sympathomimetic effects can  cause tachycardia and hypertension.   Rocuronium exerts an effect within 2 minutes and has  the most rapid onset of any of the non-depolarising  neuromuscular blocking drugs. It is an aminosteroid  neuromuscular blocking drug with an intermediate  duration of action. It is reported to have minimal cardi-  ovascular effects; high doses produce mild vagolytic  activity.   Vecuronium, an aminosteroid neuromuscular blocking  drug, has an intermediate duration of action. It does not  generally produce histamine release and lacks cardio-  vascular effects.   To avoid excessive dosage in obese patients, dose  should be calculated on the basis of ideal body-weight    • Intubation and surgery, ADULT and CHILD over 1 month,  by intravenous injection, initially 300-600 micr-  ograms/kg, then 100-200 micrograms/kg as required  or initially by intravenous injection, 200-600 micr-  ograms/kg followed by intravenous infusion, 300-  600 micrograms/kg/hour   • Intensive care, ADULT and CHILD over 1 month, by  intravenous injection, initially 300-600 micrograms/  kg (optional) then by intravenous infusion 270-  1770 micrograms /kg/hour (usual dose 650-   Atracurium (Non-proprietary) [Ml  Injection, atracurium besilate lOmg/mL, net price  2.5-mL amp = £1.85; 5-mL amp = £3.37; 25-mL vial =  £14.45   Injection, atracurium besilate lOmg/mL, net price  2.5-mL amp = £1.66; 5-mL amp = £3.00; 25-mL vial =  £12.91   'To avoid excessive dosage in obese patients, dose  should be calculated on the basis of ideal body-weight    • By intravenous injection, 70-250 micrograms /kg;  maintenance 100 micrograms/kg every 15 minutes;  CHILD 2-6 months initially 150 micrograms/kg, 7  months-12 years initially 200 micrograms/kg; main-  tenance (CHILD 2 months-12 years) 100 micrograms/  kg every 6-9 minutes   Note Doses up to 150 micrograms/kg may be given over 5-  15 seconds, higher doses should be given over 30 seconds. In  patients with asthma, cardiovascular disease or those who  are sensitive to falls in arterial blood pressure give over 60  seconds   • By intravenous infusion after initial bolus intravenous  dose, maintenance of block, 8-10 micrograms/kg/  minute, adjusted if necessary every 3 minutes by   1 microgram/kg/minute to usual dose of 6-7 micr-  ograms/kg/minute; CHILD 2 months-12 years, usual  dose 11-14 micrograms/kg/minute   To avoid excessive dosage in obese patients, dose  should be calculated on the basis of ideal body-weight    • Intubation and surgery, by intravenous injection,  ADULT and CHILD over 1 month, initially 150 micr-  ograms/kg; maintenance, by intravenous injection,  ADULT and CHILD over 12 years, 30 micrograms/kg  approx, every 20 minutes; CHILD 2-12 years, 20 micr-  ograms/kg approx, every 10 minutes; or mainte-  nance, by intravenous infusion, ADULT and CHILD over  2 years, initially 180 micrograms/kg/hour, then after  stabilisation, 60-120 micrograms /kg/hour   Note Lower doses can be used for children over 2 years  when not for intubation   • Intensive care, ADULT initially 150 micrograms/kg  (optional) by intravenous injection, then by intra-  venous infusion 180 micrograms/kg/hour adjusted  according to response (usual range 30-600 micr-  ograms/kg/hour)   Injection, cisatracurium (as besilate) 2mg/mL, net  price 10-mL amp = £7.55   Forte injection, cisatracurium (as besilate) 5mg/mL,  net price 30-mL vial = £31.09   Injection, mivacurium (as chloride) 2mg/mL, net  price 5-mL amp = £2.79; 10-mL amp = £4.51    Indications neuromuscular blockade (long duration)  for surgery or during intensive care  Cautions see notes above  Hepatic impairment possibly slower onset, higher  dose requirement, and prolonged recovery time  Renal impairment use with caution; prolonged dura-  tion of block   Pregnancy see notes above  Breast-feeding see notes above  Side-effects see notes above    To avoid excessive dosage in obese patients, dose  should be calculated on the basis of ideal body-weight    • Intubation, by intravenous injection, ADULT and CHILD  over 1 month, initially 100 micrograms/kg then   • Intensive care, by intravenous injection, initially  100 micrograms/kg (optional) then 60 micrograms/  kg every 60-90 minutes   Pancuronium (Non-proprietary) (Ml  Injection, pancuronium bromide 2mg/mL, net price  2-mL amp = £1.20   Indications neuromuscular blockade (intermediate  duration) for surgery or during intensive care  Cautions see notes above   To avoid excessive dosage in obese patients, dose  should be calculated on the basis of ideal body-weight    • Intubation, ADULT and CHILD over 1 month, by intra-  venous injection, initially 600 micrograms /kg; main-  tenance by intravenous injection, 150 micrograms/kg  (ELDERLY 75-100 micrograms/kg) or maintenance by  intravenous infusion, 300-600 micrograms/kg/hour  (ELDERLY up to 400 micrograms /kg/hour) adjusted  according to response   • Intensive care, by intravenous injection, ADULT initially  600 micrograms/kg (optional); maintenance by intra-  venous infusion, 300-600 micrograms/kg/hour for  first hour, then adjusted according to response   Rocuronium (Non-proprietary) (Ml  Injection, rocuronium bromide lOmg/mL, net price  5-mL vial = £3.00, 10-mL vial = £6.00   Injection, rocuronium bromide lOmg/mL, net price  5-mL vial = £2.90, 10-mL vial = £5.79   To avoid excessive dosage in obese patients, dose  should be calculated on the basis of ideal body-weight    • ADULT and CHILD over 1 month, by intravenous injec-  tion, 80-100 micrograms/kg; then maintenance, by  intravenous injection either 20-30 micrograms /kg,  adjusted according to response (max. 100 micr-  ograms/kg in caesarian section), or by intravenous  infusion, 0.8-1. 4 micrograms/kg/minute, adjusted  according to response; NEONATE see BNF for Children   Norcuron® (Organon) (Ml  Injection, powder for reconstitution, vecuronium  bromide, net price 10-mg vial = £3.38 (with water for  injections)   Suxamethonium has the most rapid onset of action of  any of the neuromuscular blocking drugs and is ideal if  fast onset and brief duration of action are required, e.g.  with tracheal intubation.   Suxamethonium acts by mimicking acetylcholine at the  neuromuscular junction but hydrolysis is much slower  than for acetylcholine; depolarisation is therefore pro-  longed, resulting in neuromuscular blockade. Unlike the  non-depolarising neuromuscular blocking drugs, its  action cannot be reversed and recovery is spontaneous;  anticholinesterases such as neostigmine potentiate the  neuromuscular block.   Suxamethonium should be given after anaesthetic  induction because paralysis is usually preceded by pain-  ful muscle fasciculations. While tachycardia occurs with  single use, bradycardia may occur with repeated doses  in adults and with the first dose in children. Premedi-  cation with atropine reduces bradycardia as well as the  excessive salivation associated with suxamethonium  use.   Prolonged paralysis may occur in dual block, which  occurs with high or repeated doses of suxamethonium  and is caused by the development of a non-depolarising  block following the initial depolarising block; edrophon-  ium (section 15.1.6) may be used to confirm the diag-  nosis of dual block. Individuals with myasthenia gravis  are resistant to suxamethonium but can develop dual  block resulting in delayed recovery. Prolonged paralysis  may also occur in those with low or atypical plasma  cholinesterase. Assisted ventilation should be continued  until muscle function is restored.   Indications neuromuscular blockade (short duration)  Cautions see notes above; hypersensitivity to other  neuromuscular blocking drugs; patients with cardiac,  respiratory, or neuromuscular disease; raised intra-  ocular pressure (avoid in penetrating eye injury);  severe sepsis (risk of hyperkalaemia); interactions:  Appendix 1 (muscle relaxants)   Contra-indications family history of malignant  hyperthermia, hyperkalaemia; major trauma, severe  bums, neurological disease involving acute wasting of  major muscle, prolonged immobilisation — risk of  hyperkalaemia, personal or family history of conge-  nital myotonic disease, Duchenne muscular dystro-  phy, low plasma-cholinesterase activity (including  severe liver disease, see Hepatic Impairment)  Hepatic impairment prolonged apnoea may occur in  severe liver disease because of reduced hepatic  synthesis of pseudocholinesterase  Pregnancy mildly prolonged maternal neuromuscular  blockade may occur   Breast-feeding unlikely to be present in breast milk in  significant amounts (ionised at physiological pH);  breast-feeding may be resumed once the mother  recovered from neuromuscular block  Side-effects see notes above; also increased gastric  pressure; hyperkalaemia; postoperative muscle pain,  myoglobinuria, myoglobinaemia; increased intra-  ocular pressure; flushing, rash; rarely arrhythmias,  cardiac arrest; bronchospasm, apnoea, prolonged    respiratory depression; limited jaw mobility; very  rarely anaphylactic reactions, malignant hyper-  thermia; also reported hypertension, hypotension,  rhabdomyolysis   • By intravenous injection, ADULT, 1-1.5 mg/kg; CHILD  under 1 year, 2 mg/kg; CHILD 1-18 years, 1 mg/kg   • By intramuscular injection (onset in 2-3 minutes),  CHILD 1 month-1 year, up to 4-5 mg/kg; CHILD 1-12  years, up to 4 mg/kg; max. 150 mg   Note Doses of suxamethonium in BNF may differ from those in   Suxamethonium Chloride (Non-proprietary) (Ml  Injection, suxamethonium chloride 50mg/mL, net  price 2-mL amp = 58p, 2-mL prefilled syringe = £8.45   The drugs in this section should be used by experi-  enced personnel only.   Anticholinesterases reverse the effects of the non-depo-  larising (competitive) neuromuscular blocking drugs  such as pancuronium but they prolong the action of  the depolarising neuromuscular blocking drug suxa-  methonium.   Edrophonium has a transient action and may be used in  the diagnosis of suspected dual block due to suxa-  methonium. Atropine (section 15.1.3) is given before  or with edrophonium to prevent muscarinic effects  when given for reversal of non-depolarising neuro-  muscular blockade.   Neostigmine has a longer duration of action than edro-  phonium and is used specifically for reversal of non-  depolarising (competitive) blockade. It acts within one  minute of intravenous injection and its effects last for 20  to 30 minutes; a second dose may then be necessary.  Glycopyrronium or alternatively atropine (section  15.1.3), given before or with neostigmine, prevent  bradycardia, excessive salivation, and other muscarinic  effects of neostigmine.   • Brief reversal of non-depolarising neuromuscular  blockade, by intravenous injection over several min-  utes, 500-700 micrograms/kg (after or with atropine)   Edrophonium (Non-proprietary) LmD  Injection, edrophonium chloride 10 mg/mL, net price  1-mL amp = £19.50   • Reversal of non-depolarising neuromuscular block-  ade, by intravenous injection over 1 minute, ADULT  over 18 years, 2.5 mg repeated if necessary (max.   Glycopyrronium-Neostigmine (Non-proprietary) (Ml  Injection, neostigmine metilsulfate 2.5 mg, glyco-  pyrronium bromide 500 micrograms/mL, net price 1-  mL amp = 91p   Dose reversal of non-depolarising neuromuscular blockade, by  intravenous injection over 10-30 seconds, 1-2 mL or 0.02 mL/kg,  dose may be repeated if required (total max. 2mL); CHILD  0.02 mL/kg (or 0.2 mL/kg of a 1 in 10 dilution using water for  injections or sodium chloride injection 0.9%), dose may be  repeated if required (total max. 2 mL)    Sugammadex is a modified gamma cyclodextrin used  for reversal of neuromuscular blockade induced by  rocuronium or vecuronium (section 15.1.5).    Indications reversal of neuromuscular blockade  induced by rocuronium or vecuronium  Cautions recurrence of neuromuscular blockade —  monitor respiratory function until fully recovered;  recovery may be delayed in cardiovascular disease  and elderly; pre-existing coagulation disorders or use  of anticoagulants (unrelated to surgery); wait 24 hours  before re-administering rocuronium or vecuronium;  interactions: Appendix 1 (sugammadex)   Renal impairment avoid if eGFR less than 30 mL/  minute/ 1.73 m z   Side-effects taste disturbances; less commonly aller-  gic reactions; bronchospasm also reported   • Routine reversal of neuromuscular blockade induced  by rocuronium or vecuronium, by intravenous injec-  tion, ADULT over 18 years, 2-4 mg/kg (consult product  literature); a further dose of 4 mg/kg may be required  if recurrence of neuromuscular blockade occurs   • Routine reversal of neuromuscular blockade induced  by rocuronium, by intravenous injection, CHILD 2-18  years, 2 mg/kg (consult product literature)   • Immediate reversal of neuromuscular blockade  induced by rocuronium, by intravenous injection,  ADULT over 18 years, 16 mg/kg (consult product lit-  erature)   Bridion® (Schering-Plough) T (Ml  Injection, sugammadex (as sodium salt) lOOmg/mL,  net price 2-mL amp = £59.64, 5-mL amp = £149.10    Pregnancy may cross placenta in small amounts —  avoid unless potential benefit outweighs risk  Breast-feeding avoid breast-feeding for 24 hours  Side-effects nausea, vomiting, and flushing; if  wakening too rapid, agitation, anxiety, and fear; tran-  sient increase in blood pressure and heart-rate in  intensive care patients; very rarely convulsions (par-  ticularly in those with epilepsy), hypersensitivity  reactions including anaphylaxis  Dose   • By intravenous injection, 200 micrograms over 15  seconds, then 100 micrograms at 60-second intervals  if required; usual dose range, 300-600 micrograms;  max. total dose 1 mg (2 mg in intensive care); question  aetiology if no response to repeated doses   • By intravenous infusion, if drowsiness recurs after  injection, 100-400 micrograms/hour, adjusted  according to level of arousal   The drugs in this section should be used by experi-  enced personnel only.    Respiratory depression is a major concern with opioid  analgesics and it may be treated by artificial ventilation  or be reversed by naloxone. Naloxone will immediately  reverse opioid-induced respiratory depression but the  dose may have to be repeated because of the short  duration of action of naloxone; however, naloxone will  also antagonise the analgesic effect.   Flumazenil is a benzodiazepine antagonist for the  reversal of the central sedative effects of benzodiaz-  epines after anaesthetic and similar procedures. Flum-  azenil has a shorter half-life and duration of action than  diazepam or midazolam so patients may become rese-  dated.   Doxapram (section 3.5.1) is a central and respiratory  stimulant but is of limited value in anaesthesia.   Indications reversal of sedative effects of benzodiaz-  epines in anaesthetic, intensive care, and diagnostic  procedures; overdosage with benzodiazepines (see  Emergency Treatment of Poisoning)   Cautions short-acting (repeat doses may be neces-  sary — benzodiazepine effects may persist for at least  24 hours); benzodiazepine dependence (may precipi-  tate withdrawal symptoms); prolonged benzodiaze-  pine therapy for epilepsy (risk of convulsions); history  of panic disorders (risk of recurrence); ensure neuro-  muscular blockade cleared before giving; avoid rapid  injection in high-risk or anxious patients and following  major surgery; head injury (rapid reversal of benzo-  diazepine sedation may cause convulsions); elderly;  children    Contra-indications life-threatening condition (e.g.  raised intracranial pressure, status epilepticus) con-  trolled by benzodiazepines  Hepatic impairment carefully titrate dose   Indications see under Dose  Cautions cardiovascular disease or those receiving  cardiotoxic drugs (serious adverse cardiovascular  effects reported); physical dependence on opioids  (precipitates withdrawal); pain (see also under Titra-  tion of Dose, below); has short duration of action  (repeated doses or infusion may be necessary to  reverse effects of opioids with longer duration of  action)   Titration of dose In postoperative use, the dose should be  titrated for each patient in order to obtain sufficient respir-  atory response; however, naloxone antagonises analgesia  Pregnancy use only if potential benefit outweighs risk  Breast-feeding not orally bioavailable  Side-effects nausea, vomiting; hypotension, hyper-  tension, ventricular tachycardia and fibrillation, car-  diac arrest; hyperventilation, dyspnoea, pulmonary  oedema; headache, dizziness; less commonly diarr-  hoea, dry mouth, agitation, excitement, paraesthesia,  tremor, sweating; very rarely seizures, erythema  multiforme, and hypersensitivity reactions including  anaphylaxis  Dose   • Reversal of respiratory depression caused by medic-  inal use of opioids, ADULT and CHILD over 12 years, by  intravenous injection, 100-200 micrograms (1.5-   3 micrograms/kg); if response inadequate, give sub-  sequent dose of 100 micrograms every 2 minutes;  alternatively, subsequent doses can be given by  intramuscular injection every 1-2 hours; CHILD 1  month- 12 years see BNF for Children   • Reversal of respiratory and CNS depression resulting  from opioid administration to mother during labour,  NEONATE, by intramuscular injection, 200 micrograms  (60 micrograms /kg) as a single dose at birth; alter-  natively by subcutaneous or intravenous injection,  10 micrograms /kg, repeated every 2-3 minutes   Note Naloxone doses in BNF may differ from those in product  literature   The drugs in this section should be used by experi-  enced personnel only    Malignant hyperthermia is a rare but potentially lethal  complication of anaesthesia. It is characterised by a  rapid rise in temperature, increased muscle rigidity,  tachycardia, and acidosis. The most common triggers  of malignant hyperthermia are the volatile anaesthetics.  Suxamethonium has also been implicated, but malig-  nant hyperthermia is more likely if it is given following a  volatile anaesthetic. Volatile anaesthetics and suxa-  methonium should be avoided during anaesthesia in  patients at high risk of malignant hyperthermia.  Dantrolene is used in the treatment of malignant hyper-  thermia. It acts on skeletal muscle cells by interfering  with calcium efflux, thereby stopping the contractile  process.   interactions: Appendix 1 (muscle relaxants)  Pregnancy use only if potential benefit outweighs risk  Breast-feeding present in milk — use only if potential  benefit outweighs risk   Side-effects hepatotoxicity, pulmonary oedema, diz-  ziness, weakness, and injection-site reactions includ-  ing erythema, rash, swelling, and thrombophlebitis   • By rapid intravenous injection, ADULT, initially 2-  3 mg/kg, then 1 mg/kg repeated as required to a  cumulative max. of 10 mg/kg; CHILD 1 month-18  years see BNF for Children   The drugs in section 15.2 should be used by experi-  enced personnel only and should not be adminis-  tered parenterally unless adequate resuscitation  equipment is available.    The use of local anaesthetics by injection or by applica-  tion to mucous membranes to produce local analgesia is  discussed in this section.    See also section 1.7 (anus), section 11.7 (eye), section  12.3 (oropharynx), and section 13.3 (skin).    Use of local anaesthetics Local anaesthetic drugs  act by causing a reversible block to conduction along  nerve fibres. They vary widely in their potency, toxicity,  duration of action, stability, solubility in water, and  ability to penetrate mucous membranes. These factors  determine their application, e.g. topical (surface), infil-  tration, peripheral nerve block, intravenous regional  anaesthesia (Bier’s block), plexus, epidural (extradural),  or spinal (intrathecal or subarachnoid) block. Local  anaesthetics may also be used for postoperative pain  relief, thereby reducing the need for analgesics such as  opioids.    Administration The dose of local anaesthetic  depends on the injection site and the procedure used.  In determining the safe dosage, it is important to take  account of the rate of absorption and excretion, and of  the potency. The patient’s age, weight, physique, and  clinical condition, and the vascularity of the administra-  tion site and the duration of administration, must also be  considered.   Uptake of local anaesthetics into the systemic circula-  tion determines their duration of action and produces  toxicity.   Great care must be taken to avoid accidental intravas-  cular injection; local anaesthetic injections should be  given slowly in order to detect inadvertent intravascular  administration. When prolonged analgesia is required, a  long-acting local anaesthetic is preferred to minimise  the likelihood of cumulative systemic toxicity. Local  anaesthesia around the oral cavity may impair swallow-  ing and therefore increases the risk of aspiration.  Following most regional anaesthetic procedures, max-  imum arterial plasma concentration of anaesthetic  develops within about 10 to 25 minutes, so careful  surveillance for toxic effects (see Toxicity and Side-  effects, below) is necessary during the first 30 minutes  after injection.   Epidural anaesthesia is commonly used during surgery,  often combined with general anaesthesia, because of its  protective effect against the stress response of surgery.  It is often used when good postoperative pain relief is  essential (e.g. major thoracic or intra-abdominal sur-  gery).    Use of vasoconstrictors Local anaesthetics cause  dilation of blood vessels. The addition of a vasocon-  strictor such as adrenaline (epinephrine) to the local  anaesthetic preparation diminishes local blood flow,  slowing the rate of absorption and thereby prolonging  the anaesthetic effect. Great care should be taken to  avoid inadvertent intravenous administration of a pre-  paration containing adrenaline, and it is not advisable to  give adrenaline with a local anaesthetic injection in  digits or appendages because of the risk of ischaemic  necrosis.   Adrenaline must be used in a low concentration when  administered with a local anaesthetic (but see also  Dental Anaesthesia, below). The total dose of adrenaline  should not exceed 500 micrograms and it is essential  not to exceed a concentration of 1 in 200 000 (5 micr-  ograms/mL) if more than 50 mL of the mixture is to be  injected. Care must also be taken to calculate a safe  maximum dose of local anaesthetic when using combi-  nation products. For prescribing information on adrena-    line, see section 2.7.3. For drug interactions of adrena-  line, see Appendix 1 (sympathomimetics).   In patients with severe hypertension or unstable cardiac  rhythm, the use of adrenaline with a local anaesthetic  may be hazardous. For these patients an anaesthetic  without adrenaline should be used.   Dental anaesthesia Lidocaine is widely used in  dental procedures; it is most often used in combination  with adrenaline (epinephrine). Lidocaine 2% combined  with adrenaline 1 in 80 000 (12.5 micrograms /mL) is a  safe and effective preparation; there is no justification  for using higher concentrations of adrenaline. See also  Use of Vasoconstrictors, above.   The local anaesthetics articaine and mepivacaine are  also used in dentistry; they are available in cartridges  suitable for dental use. Mepivacaine is available with or  without adrenaline and articaine is available with adr-  enaline.   In patients with severe hypertension or unstable cardiac  rhythm, mepivacaine without adrenaline may be used.  Alternatively, prilocaine with or without felypressin can  be used but there is no evidence that it is any safer.  Felypressin can cause coronary vasoconstriction when  used at high doses; limit dose in patients with coronary  artery disease.   Cautions of local anaesthetics Local anaesthetics  should be administered with caution in children, elderly  or debilitated patients (consider dose reduction), or in  patients with impaired cardiac conduction, cardiovas-  cular disease, hypovolaemia, shock, impaired respir-  atory function, epilepsy, or myasthenia gravis. See also  Administration and Use of Vasoconstrictors, above.   Contra-indications of local anaesthetics Local  anaesthetics should not be injected into inflamed or  infected tissues nor should they be applied to damaged  skin. In such circumstances, increased absorption into  the blood increases the possibility of systemic side-  effects, and the local anaesthetic effect may also be  reduced by altered local pH. See also Use of Vaso-  constrictors, above.   Local anaesthetic preparations containing preservatives  should not be used for caudal, epidural, or spinal block,  or for intravenous regional anaesthesia (Bier’s block).   Local anaesthetics can cause ototoxicity and should not  be applied to the middle ear. They are also contra-  indicated in patients with complete heart block.   Toxicity and side-effects A single application of a  topical lidocaine preparation does not generally cause  systemic side-effects. Toxic effects after administration  of local anaesthetics are a result of excessively high  plasma concentrations; severe toxicity usually results  from inadvertent intravascular injection or too rapid  injection.   The systemic toxicity of local anaesthetics mainly  involves the central nervous and cardiovascular sys-  tems. CNS effects include a feeling of inebriation and  lightheadedness followed by sedation, numbness of the  tongue and perioral region, restlessness, paraesthesia  (including sensations of hot and cold), dizziness, blurred  vision, nausea and vomiting, muscle twitching, tremors,  and convulsions. Transient excitation may also occur,  followed by depression with drowsiness, respiratory  failure, unconsciousness, and coma. Effects on the car-   diovascular system include myocardial depression and  peripheral vasodilatation resulting in hypotension and  bradycardia; arrhythmias and cardiac arrest can occur.  Hypersensitivity reactions occur mainly with the ester-  type local anaesthetics such as tetracaine; reactions are  less frequent with the amide types such as articaine,  bupivacaine, levobupivacaine, lidocaine, mepivacaine,  prilocaine, and ropivacaine. Cross-sensitivity reactions  may be avoided by using the alternative chemical type.   Articaine is an amide-type local anaesthetic used for  dental anaesthesia (see Dental Anaesthesia, above). It is  available in a preparation that also contains adrenaline  (see Use of Vasoconstrictors, p. 793).   Indications infiltration anaesthesia in dentistry  Cautions see Cautions of Local Anaesthetics, above  and Adrenaline, section 2.7.3  Contra-indications see Contra-indications of Local  Anaesthetics, above and Adrenaline, section 2.7.3  Hepatic impairment use with caution; increased risk  of side-effects in severe impairment  Renal impairment see Adrenaline, section 2.7.3  Pregnancy use only if potential benefit outweighs  risk — no information available  Breast-feeding avoid breast-feeding for 48 hours after  administration   Side-effects see Toxicity and Side-effects, above and  Adrenaline, section 2.7.3; also methaemoglobinaemia  (see Prilocaine (p. 797) for treatment)   Injection, articaine hydrochloride 40mg/mL, adr-  enaline 1 in 200 000 (5 micrograms/mL), net price  2.2-mL cartridge = 41p   Injection, articaine hydrochloride 40mg/mL, adr-  enaline 1 in 100 000 (10 micrograms/mL), net price  2.2-mL cartridge = 41p   Bupivacaine has a longer duration of action than other  local anaesthetics. It has a slow onset of action, taking  up to 30 minutes for full effect. It is often used in lumbar  epidural blockade and is particularly suitable for con-  tinuous epidural analgesia in labour, or for postoperative  pain relief. It is the principal drug used for spinal anaes-  thesia. Hyperbaric solutions containing glucose may be  used for spinal block.   Indications see under Dose  Cautions see Cautions of Local Anaesthetics, above;  myocardial depression may be more severe and more    resistant to treatment; cardiovascular disease; hyper-  tension; hypotension; cerebral atheroma; interac-  tions: Appendix 1 (bupivacaine)   Hepatic impairment caution in severe impairment  Renal impairment caution in severe impairment  Pregnancy large doses during delivery can cause  neonatal respiratory depression, hypotonia, and  bradycardia after paracervical or epidural block; use  lower doses for intrathecal use during late pregnancy  Breast-feeding amount too small to be harmful  Side-effects see Toxicity and Side-effects, p. 794  Dose   ( To avoid excessive dosage in obese patients, dose may  need to be calculated on the basis of ideal body-weight   • Local infiltration, max. 60 mL, using a 2.5mg/mL  (0.25%) solution   • Peripheral nerve block, max. 60 mL (150 mg), using a  2.5mg/mL (0.25%) solution; max. 30 mL, using a   Surgery, lumbar, 10-20 mL (50-100 mg), using a  5 mg/mL (0.5%) solution  Surgery, caudal, 15-30 mL (75-150 mg), using a  5 mg/mL (0.5%) solution; CHILD (up to 10 years) using  a 2.5 mg/mL (0.25%) solution, up to lower-thoracic  (T10) 0. 3-0.4 mL/kg (0.75-1 mg/kg), up to mid-  thoracic (T6) 0.4-0. 8 mL/kg (1-2 mg/kg)   Labour, lumbar, 6-12 mL (15-30 mg) using a 2.5 mg/  mL (0.25%) or 6-12 mL (30-60 mg) using a 5 mg/mL  (0.5%) solution   The licensed doses stated above may not be appro-  priate in some settings and expert advice should be  sought   2.5 mg/mL (0.25%), net price 10 mL = 82p; 5 mg/mL  (0.5%), 10 mL = 94p   Infusion, anhydrous bupivacaine hydrochloride  1 mg/mL (0.1%), net price 100 mL = £8.41, 250 mL =  £10.59; 1.25 mg/mL (0.125%), 250 mL =£10.80  Dose continuous lumbar epidural infusion during labour (once  epidural block established), 10-15 mg/hour of 0.1% or 0.125%  solution; max. 2 mg/kg over 4 hours and total of 400 mg in 24  hours   Continuous thoracic, upper abdominal, or lower abdominal epi-  dural infusion for postoperative pain (once epidural block estab-  lished), 4-15 mg/hour of 0.1% solution, or 5-15 mg/hour of  0.125% solution; max. 2 mg/kg over 4 hours and total of 400 mg  in 24 hours; not recommended for use in children   2.5 mg/mL ( Marcain ® 0.25%), net price 10-mL  Polyamp® =£1.06; 5 mg/mL [Marcain® 0.5%), 10-  mL Polyamp® = £1.21    Marcain Heavy® (AstraZeneca) (Ml  Injection, anhydrous bupivacaine hydrochloride  5 mg/mL (0.5%), glucose 80 mg/mL, net price 4-mL  amp = £1.21   Dose intrathecal anaesthesia for surgery, 2-4 mL (10-20 mg  bupivacaine); dose may need to be reduced in elderly and in late  pregnancy   For prescribing information on adrenaline, see section  2.7.3; see also Use of Vasoconstrictors, p. 793.   2.5 mg/mL (0.25%), adrenaline 1 in 200000 (5micr-  ograms/mL), net price 10-mL amp = £1.40  Injection, anhydrous bupivacaine hydrochloride  5 mg/mL (0.5%), adrenaline 1 in 200000 (5micr-  ograms/mL), net price 10-mL amp = £1.50   Levobupivacaine, an isomer of bupivacaine, has anaes-  thetic and analgesic properties similar to bupivacaine,  but is thought to have fewer adverse effects.   Cautions see Cautions of Local Anaesthetics, p. 794;  cardiovascular disease; interactions: Appendix 1  (levobupivacaine)   Contra-indications see Contra-indications of Local  Anaesthetics, p. 794  Hepatic impairment use with caution  Pregnancy large doses during delivery can cause  neonatal respiratory depression, hypotonia, and  bradycardia after epidural block; avoid if possible in  the first trimester — toxicity in animal studies; may  cause fetal distress syndrome; do not use for para-  cervical block in obstetrics; do not use 7.5 mg/mL  strength in obstetrics   Breast-feeding amount too small to be harmful  Side-effects see Toxicity and Side-effects, p. 794; also  sweating, pyrexia, and anaemia   Lumbar epidural, 10-20 mL (50-150 mg) of 5 mg/mL  or 7.5 mg/mL solution over 5 minutes; caesarean  section, 15-30 mL (75-150 mg) of 5 mg/mL solution  over 15-20 minutes   Intrathecal, 3mL (15 mg) of 5 mg/mL solution  Peripheral nerve block, 1-40 mL of 2.5 mg/mL or  5 mg/mL solution (max. 150 mg); ilioinguinal/iliohy-  pogastric block, CHILD under 12 years 0.25-0.5 mL/kg  (0.625-2.5 mg/kg) of a 2.5 mg/mL or 5 mg/mL solu-  tion   Local infiltration, 1-60 mL (max. 150 mg) of 2.5 mg/  mL solution   Lumbar epidural, labour pain, 6-10 mL (15-25 mg) of  2.5 mg/mL solution at intervals of at least 15 minutes  or 5-12.5 mg/hour as a continuous epidural infusion;  postoperative pain, 12.5-18.75 mg/hour as a contin-  uous epidural infusion; max. 400 mg in 24 hours   The licensed doses stated above may not be appro-  priate in some settings and expert advice should be  sought   Injection, levobupivacaine (as hydrochloride) 2.5 mg/  mL, net price 10-mL amp = £1.42; 5 mg/mL, 10-mL  amp = £1.62; 7.5 mg/mL, 10-mL amp = £2.43  Note For 1.25 mg/mL concentration dilute standard solu-  tions with sodium chloride 0.9%   200 mL = £10.37; 1.25 mg/mL, net price 100 mL =  £7.26, 200 mL = £12.20   Lidocaine is effectively absorbed from mucous mem-  branes and is a useful surface anaesthetic in concentra-  tions up to 10%. Except for surface anaesthesia and  dental anaesthesia, solutions should not usually exceed  1% in strength. The duration of the block (with adrena-  line) is about 90 minutes.   Cautions See Cautions of Local Anaesthetics, p. 794  and section 2.3.2; hypertension; topical preparations  can damage plastic cuffs of endotracheal tubes  Contra-indications see notes above, Contra-indica-  tions of Local Anaesthetics, p. 794, and section 2.3.2  Hepatic impairment section 2.3.2  Renal impairment section 2.3.2  Pregnancy large doses can cause fetal bradycardia;  large doses during delivery can cause neonatal resp-  iratory depression, hypotonia, or bradycardia after  paracervical or epidural block  Breast-feeding section 2.3.2  Side-effects see Toxicity and Side-effects, p. 794 and  section 2.3.2; also methaemoglobinaemia (see under  Prilocaine (p. 797) for treatment), nystagmus, rash;  hypoglycaemia also reported following intrathecal or  extradural administration   To avoid excessive dosage in obese patients, dose may  need to be calculated on the basis of ideal body-weight   The licensed doses stated above may not be appro-  priate in some settings and expert advice should be  sought    ^ Lidocaine hydrochloride injections  Lidocaine (Non-proprietary) (MO  Injection, lidocaine hydrochloride 5 mg/mL (0.5%),  net price 10-mL amp = 35p; 10 mg/mL (1%), 2-mL  amp = 25p, 5-mL amp = 26p, 10-mL amp = 39p, 10-  mL prefilled syringe = £4.53; 20-mL amp = 75p;   20 mg/mL (2%), 2-mL amp = 32p, 5-mL amp = 3 lp   Xylocaine® (AstraZeneca) (Ml  Injection, anhydrous lidocaine hydrochloride 10 mg/  mL (1%), adrenaline 1 in 200 000 (5 micrograms/mL),  net price 20-mL vial = 99p   Injection, anhydrous lidocaine hydrochloride 20 mg/  mL (2%), adrenaline 1 in 200 000 (5 micrograms/mL),  net price 20-mL vial = £1.04    ^Lidocaine injections for dental use  A variety of lidocaine injections with adrenaline is  available in dental cartridges; brands include Ligno-  span Special ® , Rexocaine ® , and Xylocaine® .   Note Consult expert dental sources for specific advice in  relation to dose of lidocaine for dental anaesthesia   Gel, lidocaine hydrochloride 2%, chlorhexidine  gluconate solution 0.25%, in a sterile lubricant basis in  disposable syringe, net price 6-mL syringe = £1.41,  11-mL syringe = £1.58   Cystoscopy, 1 1 mL (a further instillation of 6-1 1 mL may be  required)   Solution, lidocaine hydrochloride 40 mg/mL (4%),  net price per unit (4-mL vial and disposable sterile  cannula with cover and vial injector) = £5.10  Dose anaesthesia of oropharynx, trachea, or respiratory tract,  40-200 mg (1-5 mL) as a single dose sprayed, instilled (if a cavity),  or applied with a swab (reduce dose according to size, age and  condition of patient), usual dose 160 mg (4mL); CHILD up to  3 mg/kg   Cream lidocaine 4%, net price 5-g tube = £2.98; 5 x  5-g tube with 10 occlusive dressings = £16.90   Excipients include benzyl alcohol and propylene glycol  Dose ADULT and CHILD over 1 month, anaesthesia before venous  cannulation or venepuncture, apply thick layer (1-2.5 g; CHILD  under 1 year max. 1 g) to small area (2.5 cm x 2.5 cm) of non-  irritated skin at least 30 minutes before procedure (max. 60  minutes); remove cream with gauze and perform procedure after  approximately 5 minutes   Plasters, lidocaine 5% (700 mg/medicated plaster),  net price 30 = £72.40   Excipients include hydroxybenzoates (parabens), propylene glycol  Dose postherpetic neuralgia, ADULT over 18 years, apply to  intact, dry, non-hairy, non-irritated skin once daily for up to 12  hours, followed by a 12-hour plaster-free period; discontinue if no  response after 4 weeks   Note Up to 3 plasters may be used to cover large areas; plasters  may be cut   Note The Scottish Medicines Consortium (p. 4) has advised (July  2008) that Versatis ® is accepted for restricted use within NHS  Scotland for the treatment of postherpetic neuralgia in patients  who are intolerant of first-line systemic therapies or when they  have been ineffective   Spray, lidocaine 10% (lOOmg/g) supplying 10 mg  lidocaine/dose; 500 spray doses per container, net  price 50-mL bottle = £3.13  Dose dental practice, 1-5 doses  Maxillary sinus puncture, 3 doses  During delivery in obstetrics, up to 20 doses  Bronchoscopy, laryngoscopy, oesophagoscopy, endotracheal  intubation, up to 20 doses; CHILD up to 3 mg/kg   Cream, lidocaine 2.5%, prilocaine 2.5%, net price 5-g  tube = £1.73; 30-g tube (surgical pack) = £10.25; 5 x  5-g tube with 12 occlusive dressings (premedication  pack) = £9.75   Dose ADULT and CHILD over 1 year, anaesthesia before minor  skin procedures including venepuncture, apply thick layer under  occlusive dressing 1-5 hours before procedure (2-5 hours before  procedures on large areas e.g. split skin grafting); max. 2 doses in  24 hours for CHILD 1-12 years; CHILD under 3 months or body-  weight less than 5 kg, apply max. 1 g under occlusive dressing for  max. 1 hour before procedure; max. 1 dose in 24 hours, CHILD 3-  12 months and body-weight over 5 kg, apply max. 2 g under  occlusive dressing for max. 4 hours before procedure; max. 2  doses in 24 hours   Note Shorter application time of 15-30 minutes is recommended  for children with atopic dermatitis   Anaesthesia on genital skin before injection of local anaesthetics  in adult men, apply under occlusive dressing for 15 minutes  Anaesthesia before surgical treatment of lesions on genital  mucosa in adults, apply up to 10 g 5-10 minutes before procedure   Lidocaine with phenylephrine (Non-proprietary)  Topical solution, lidocaine hydrochloride 5%,  phenylephrine hydrochloride 0.5%, net price 2.5 mL  (with nasal applicator) = £9.98  Dose anaesthesia before nasal surgery, endoscopy, laryngo-  scopy, or removal of foreign bodies from the nose, ADULT and  CHILD over 12 years, up to max. 8 sprays   Mepivacaine is an amide-type local anaesthetic used  for dental anaesthesia (see Dental Anaesthesia, p. 794).   Cautions see Cautions of Local Anaesthetics, p. 794  Contra-indications see Contra-indications of Local  Anaesthetics, p. 794   Hepatic impairment use with caution; increased risk  of side-effects in severe impairment  Renal impairment use with caution; increased risk of  side-effects   Pregnancy use with caution in early pregnancy  Breast-feeding use with caution  Side-effects see Toxicity and Side-effects, p. 794   To avoid excessive dosage in obese patients, dose may  need to be calculated on the basis of ideal body- weight   For prescribing information on adrenaline, see section  2.7.3; see also Use of Vasoconstrictors, p. 793.   Scandonest® 2% Special (Septodont) (Ml  Injection, mepivacaine hydrochloride 20mg/mL,  adrenaline 1 in 100 000 (lOmicrograms/mL), net  price 2.2-mL cartridge = 36p    Prilocaine is a local anaesthetic of low toxicity which is  similar to lidocaine. If used in high doses, methaemo-  globinaemia may occur which can be treated with an  intravenous injection of methylthioninium chloride  1% using a dose of 1-2 mg/kg given over 5 minutes.  The dose may be repeated after 30-60 minutes if no  response. Infants under 6 months are particularly sus-  ceptible to methaemoglobinaemia. A hyperbaric solu-  tion of prilocaine (containing glucose) may be used for  spinal anaesthesia.    Indications see under preparations  Cautions see Cautions of Local Anaesthetics, p. 794;  severe or untreated hypertension; concomitant use of  drugs that cause methaemoglobinaemia; acute por-  phyria (section 9.8.2); interactions: Appendix 1  (prilocaine)   Contra-indications see Contra-indications of Local  Anaesthetics, p. 794; anaemia or congenital or  acquired methaemoglobinaemia  Hepatic impairment use with caution; lower doses  may be required for intrathecal anaesthesia  Renal impairment use with caution; lower doses may  be required for intrathecal anaesthesia  Pregnancy large doses during delivery can cause  neonatal respiratory depression, hypotonia, and    bradycardia after epidural block; avoid paracervical or  pudenal block in obstetrics (neonatal methaemo-  globinaemia reported); use lower doses for intrathecal  use during late pregnancy   To avoid excessive dosage in obese patients, dose may  need to be calculated on the basis of ideal body-weight   Citanest 1%® (AstraZeneca) (Ml  Injection, prilocaine hydrochloride lOmg/mL, net  price 50-mL multidose vial = £2.01  Dose infiltration anaesthesia and nerve block, adjusted accord-  ing to site of administration and response, 100-200 mg/minute, or  in incremental doses, to max. total dose 400 mg (dose may need  to be adjusted in ELDERLY or debilitated patients); CHILD over 6  months up to 5 mg/kg   Prilotekal® (Goldshield) lMJ  Injection, prilocaine hydrochloride 20mg/mL (2%),  glucose 60mg/mL, net price 5-mL amp = £7.80  Dose intrathecal anaesthesia, ADULT over 18 years, usually 40-  60 mg, max. 80 mg (dose may need to be reduced in ELDERLY or  debilitated patients, or in late pregnancy)   Citanest 3% with Octapressin® (Dentsply) (Ml  Injection, prilocaine hydrochloride 30mg/mL, fely-  pressin 0.03unit/mL, net price 2.2-mL cartridge and  self-aspirating cartridge (both) = 47p   Ropivacaine is an amide-type local anaesthetic agent  similar to bupivacaine. It is less cardiotoxic than bupiva-  caine, but also less potent.   Cautions see Cautions of Local Anaesthetics, p. 794;  also acute porphyria (section 9.8.2); interactions:  Appendix 1 (ropivacaine)   Renal impairment caution in severe impairment;  increased risk of systemic toxicity in chronic renal  failure   Pregnancy not known to be harmful; do not use for  paracervical block in obstetrics    Side-effects see Toxicity and Side-effects, p. 794; also  hypertension, pyrexia; less commonly syncope, and  hypothermia   To avoid excessive dosage in obese patients, dose may  need to be calculated on the basis of ideal body-weight   Lumbar epidural, ADULT and CHILD over 12 years, 15-  20 mL (150-200 mg) of lOmg/mL solution or 15-  25 mL (113-188 mg) of 7.5mg/mL solution; caesar-  ean section, 15-20 mL (113-150 mg) of 7.5mg/mL  solution in incremental doses  Thoracic epidural (to establish block for postoperative  pain), ADULT and CHILD over 12 years, 5-15 mL (38-  1 13 mg) of 7.5 mg/mL solution  Major nerve block (brachial plexus block), ADULT and  CHILD over 12 years, 30-40 mL (225-300 mg) of  7.5 mg/mL solution   Field block, ADULT and CHILD over 12 years, 1-30 mL  (7.5-225 mg) of 7.5 mg/mL solution   Lumbar epidural, ADULT and CHILD over 12 years, 10-  20 mL (20-40 mg) followed by 10-15 mL (20-30 mg)  at intervals of at least 30 minutes or 6-10 mL/hour  (12-20 mg/hour) as a continuous epidural infusion  for labour pain or 6-14 mL/hour (12-28 mg/hour) as  a continuous epidural infusion for postoperative pain  Thoracic epidural, ADULT and CHILD over 12 years, 6-  14 mL/hour (12-28 mg/hour) as a continuous infu-  sion   Field block, ADULT and CHILD over 12 years, 1-100 mL  (2-200 mg)   Peripheral nerve block, ADULT and CHILD over 12 years,  5-10 mL/hour (10-20 mg/hour) as a continuous  infusion or by intermittent injection  CHILD under 12 years, consult product literature   Ropivacaine (Non-proprietary) (Ml  Infusion, ropivacaine hydrochloride 2 mg/mL, net  price 200 mL = £14.45   Injection, ropivacaine hydrochloride 2 mg/mL, net  price 10-mL Polyamp® =£1.78; 7.5 mg/mL, 10-mL  Polyamp ® = £2.65; 10 mg/mL, 10-mL Polyamp® =  £3.20   Tetracaine is an effective local anaesthetic for topical  application; a 4% gel is indicated for anaesthesia before  venepuncture or venous cannulation. It is rapidly  absorbed from mucous membranes and should never  be applied to inflamed, traumatised, or highly vascular  surfaces. It should never be used to provide anaesthesia  for bronchoscopy or cystoscopy because lidocaine is a  safer alternative.   Indications see under preparation; eye (section 11.7)  Cautions see Cautions of Local Anaesthetics, p. 794  Contra-indications see Contra-indications of Local  Anaesthetics, p. 794   Side-effects see Toxicity and Side-effects, p. 794  Important Rapid and extensive absorption may result in  systemic side-effects (see also notes above)   Gel, tetracaine 4%, net price 1.5-g tube = £1.08  Dose ADULT and CHILD over 1 month, apply contents of tube to  site of venepuncture or venous cannulation and cover with  occlusive dressing; remove gel and dressing after 30 minutes for  venepuncture and after 45 minutes for venous cannulation;  NEONATE see BNF for Children   Note ADULT and CHILD over 5 years, contents of max. 5 tubes  applied at separate sites at a single time; CHILD 1 month-5 years,  contents of max. 1 tube applied at separate sites at a single time   Two or more drugs given at the same time may exert  their effects independently or may interact. The inter-  action may be potentiation or antagonism of one drug  by another, or occasionally some other effect. Adverse  drug interactions should be reported to the Medicines  and Healthcare products Regulatory Agency (MHRA),  through the Yellow Card Scheme (see Adverse Reac-  tions to Drugs, p. 12), as for other adverse drug  reactions.   These are interactions between drugs which have simi-  lar or antagonistic pharmacological effects or side-  effects. They may be due to competition at receptor  sites, or occur between drugs acting on the same  physiological system. They are usually predictable  from a knowledge of the pharmacology of the interact-  ing drugs; in general, those demonstrated with one drug  are likely to occur with related drugs. They occur to a  greater or lesser extent in most patients who receive the  interacting drugs.   These occur when one drug alters the absorption, dis-  tribution, metabolism, or excretion of another, thus  increasing or reducing the amount of drug available to  produce its pharmacological effects. They are not easily  predicted and many of them affect only a small propor-  tion of patients taking the combination of drugs. Phar-  macokinetic interactions occurring with one drug can-  not be assumed to occur with related drugs unless their  pharmacokinetic properties are known to be similar.  Pharmacokinetic interactions are of several types:    Affecting metabolism Many drugs are metabolised  in the liver. Induction of the hepatic microsomal enzyme  system by one drug can gradually increase the rate of  metabolism of another, resulting in lower plasma con-  centrations and a reduced effect. On withdrawal of the  inducer plasma concentrations increase and toxicity  may occur. Barbiturates, griseofulvin, many antiepilep-  tics, and rifampicin are the most important enzyme  inducers. Drugs affected include warfarin and the oral  contraceptives.   Conversely when one drug inhibits the metabolism of  another higher plasma concentrations are produced,  rapidly resulting in an increased effect with risk of  toxicity. Some drugs which potentiate warfarin and  phenytoin do so by this mechanism.   Isoenzymes of the hepatic cytochrome P450 system  interact with a wide range of drugs. Drugs may be  substrates, inducers or inhibitors of the different  isoenzymes. A great deal of in-vitro information is  available on the effect of drugs on the isoenzymes;  however, since drugs are eliminated by a number of  different metabolic routes as well as renal excretion,  the clinical effects of interactions cannot be pre-  dicted accurately from laboratory data on the cyto-  chrome P450 isoenzymes. Except where a combina-  tion of drugs is specifically contra-indicated, the  BNF presents only interactions that have been  reported in clinical practice. In all cases the possi-  bility of an interaction must be considered if toxic  effects occur or if the activity of a drug diminishes.    Affecting renal excretion Drugs are eliminated  through the kidney both by glomerular filtration and  by active tubular secretion. Competition occurs  between those which share active transport mechan-  isms in the proximal tubule. For example, salicylates and  some other NSAIDs delay the excretion of metho-  trexate; serious methotrexate toxicity is possible.   Many drug interactions are harmless and many of those  which are potentially harmful only occur in a small  proportion of patients; moreover, the severity of an  interaction varies from one patient to another. Drugs  with a small therapeutic ratio (e.g. phenytoin) and those  which require careful control of dosage (e.g. anticoa-  gulants, antihypertensives, and antidiabetics) are most  often involved.   Patients at increased risk from drug interactions include  the elderly and those with impaired renal or liver func-  tion.   Serious interactions The symbol • has been placed  against interactions that are potentially serious and  where combined administration of the drugs involved  should be avoided (or only undertaken with caution and  appropriate monitoring).   Interactions that have no symbol do not usually have  serious consequences.    Affecting absorption The rate of absorption or the  total amount absorbed can both be altered by drug  interactions. Delayed absorption is rarely of clinical  importance unless high peak plasma concentrations  are required (e.g. when giving an analgesic). Reduction  in the total amount absorbed, however, may result in  ineffective therapy.   Due to changes in protein binding To a variable  extent most drugs are loosely bound to plasma proteins.  Protein-binding sites are non-specific and one drug can  displace another thereby increasing its proportion free  to diffuse from plasma to its site of action. This only  produces a detectable increase in effect if it is an  extensively bound drug (more than 90%) that is not  widely distributed throughout the body. Even so displa-  cement rarely produces more than transient potentia-  tion because this increased concentration of free drug  results in an increased rate of elimination.  Displacement from protein binding plays a part in the  potentiation of warfarin by sulfonamides and tolbut-  amide but the importance of these interactions is due  mainly to the fact that warfarin metabolism is also  inhibited.   The following is an alphabetical list of drugs and their  interactions; to avoid excessive cross-referencing each  drug or group is listed twice: in the alphabetical list and  also against the drug or group with which it interacts;  changes in the interactions lists since BNF No. 60  (September 2010) are underlined.   Antibacterials: plasma concentration of abacavir  possibly reduced by rifampicin  Antiepileptics: plasma concentration of abacavir  possibly reduced by phenytoin   Barbiturates: plasma concentration of abacavir pos-  sibly reduced by phenobarbital  Abatacept   Alcohol: enhanced hypotensive effect when ACE  inhibitors given with alcohol  Aldesleukin: enhanced hypotensive effect when ACE  inhibitors given with aldesleukin  Allopurinol: increased risk of leucopenia and hyper-  sensitivity reactions when ACE inhibitors given with  allopurinol especially in renal impairment  Alpha-blockers: enhanced hypotensive effect when  ACE inhibitors given with alpha-blockers  Anaesthetics, General: enhanced hypotensive effect  when ACE inhibitors given with general anaesthetics  Analgesics: increased risk of renal impairment when  ACE inhibitors given with NSAIDs, also hypotensive  effect antagonised   Angiotensin-ll Receptor Antagonists: increased risk  of hyperkalaemia when ACE inhibitors given with  angiotensin-II receptor antagonists  Antacids: absorption of ACE inhibitors possibly  reduced by antacids; absorption of captopril,  enalapril and fosinopril reduced by antacids  Antibacterials : plasma concentration of active meta-  bolite of imidapril reduced by rifampicin (reduced  antihypertensive effect); quinapril tablets reduce  absorption of tetracyclines (quinapril tablets contain  magnesium carbonate); possible increased risk of  hyperkalaemia when ACE inhibitors given with  trimethoprim   Anticoagulants: increased risk of hyperkalaemia when  ACE inhibitors given with heparins  Antidepressants: hypotensive effect of ACE inhibitors  possibly enhanced by MAOIs  Antidiabetics: ACE inhibitors possibly enhance hypo-  glycaemic effect of insulin, metformin and sulfony-  lureas   Antipsychotics: enhanced hypotensive effect when  ACE inhibitors given with antipsychotics  Anxiolytics and Hypnotics: enhanced hypotensive  effect when ACE inhibitors given with anxiolytics  and hypnotics   Azathioprine: increased risk of anaemia or leucopenia  when captopril given with azathioprine especially in    ACE Inhibitors  Azathioprine (continued)  renal impairment; increased risk of anaemia  when enalapril given with azathioprine especially  in renal impairment   Beta-blockers: enhanced hypotensive effect when  ACE inhibitors given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when ACE inhibitors given with calcium-  channel blockers   ACE inhibitors given with •ciclosporin  Clonidine: enhanced hypotensive effect when ACE  inhibitors given with clonidine; antihypertensive  effect of captopril possibly delayed by previous  treatment with clonidine   Corticosteroids: hypotensive effect of ACE inhibitors  antagonised by corticosteroids  Diazoxide: enhanced hypotensive effect when ACE  inhibitors given with diazoxide   inhibitors given with •diuretics; increased risk of  severe hyperkalaemia when ACE inhibitors given  with •potassium-sparing diuretics and aldosterone  antagonists (monitor potassium concentration with  low-dose spironolactone in heart failure)   Methyldopa: enhanced hypotensive effect when ACE  inhibitors given with methyldopa  Moxisylyte: enhanced hypotensive effect when ACE  inhibitors given with moxisylyte  Moxonidine: enhanced hypotensive effect when ACE  inhibitors given with moxonidine  Muscle Relaxants: enhanced hypotensive effect when  ACE inhibitors given with baclofen or tizanidine  Nitrates: enhanced hypotensive effect when ACE  inhibitors given with nitrates  Oestrogens: hypotensive effect of ACE inhibitors  antagonised by oestrogens   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when ACE inhibitors given with hydral-  azine, minoxidil or sodium nitroprusside  Acebutolol see Beta-blockers  Aceclofenac see NSAIDs  Acemetacin see NSAIDs  Acenocoumarol see Coumarins  Acetazolamide see Diuretics  Aciclovir   Note Valaciclovir interactions as for aciclovir  Ciclosporin: increased risk of nephrotoxicity when  aciclovir given with ciclosporin  Mycophenolate: plasma concentration of aciclovir  increased by mycophenolate, also plasma concen-  tration of inactive metabolite of mycophenolate  increased   Probenecid: excretion of aciclovir reduced by pro-  benecid (increased plasma concentration)  Tacrolimus: possible increased risk of nephrotoxicity  when aciclovir given with tacrolimus  Theophylline: aciclovir possibly increases plasma  concentration of theophylline   Abatacept: increased risk of side-effects when adali-  mumab given with abatacept   Note Possibility of interaction with drugs tending to impair  myocardial conduction   Anaesthetics, Local: increased myocardial depression  when anti-arrhythmics given with bupivacaine,  levobupivacaine, prilocaine or ropivacaine   mias when anti-arrhythmics that prolong the QT  interval given with •antipsychotics that prolong the  QT interval   Adrenergic Neurone Blockers  Alcohol: enhanced hypotensive effect when adrenergic  neurone blockers given with alcohol  Alpha-blockers: enhanced hypotensive effect when  adrenergic neurone blockers given with alpha-  blockers   Analgesics: hypotensive effect of adrenergic neurone  blockers antagonised by NSAIDs  Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when adrenergic neurone block-  ers given with angiotensin-II receptor antagonists  Antidepressants: enhanced hypotensive effect when  adrenergic neurone blockers given with MAOIs;  hypotensive effect of adrenergic neurone blockers  antagonised by tricyclics  Antipsychotics: hypotensive effect of adrenergic  neurone blockers antagonised by haloperidol; hypo-  tensive effect of adrenergic neurone blockers antag-  onised by higher doses of chlorpromazine; enhanced  hypotensive effect when adrenergic neurone block-  ers given with phenothiazines  Anxiolytics and Hypnotics: enhanced hypotensive  effect when adrenergic neurone blockers given with  anxiolytics and hypnotics  Beta-blockers: enhanced hypotensive effect when  adrenergic neurone blockers given with beta-block-  ers   Calcium-channel Blockers: enhanced hypotensive  effect when adrenergic neurone blockers given with  calcium-channel blockers   Clonidine: enhanced hypotensive effect when adr-  energic neurone blockers given with clonidine  Corticosteroids: hypotensive effect of adrenergic  neurone blockers antagonised by corticosteroids  Diazoxide: enhanced hypotensive effect when adr-  energic neurone blockers given with diazoxide  Diuretics: enhanced hypotensive effect when adr-  energic neurone blockers given with diuretics  Dopaminergics: enhanced hypotensive effect when  adrenergic neurone blockers given with levodopa    Adrenergic Neurone Blockers (continued)  Methyldopa: enhanced hypotensive effect when adr-  energic neurone blockers given with methyldopa  Moxisylyte: enhanced hypotensive effect when adr-  energic neurone blockers given with moxisylyte  Moxonidine: enhanced hypotensive effect when adr-  energic neurone blockers given with moxonidine  Muscle Relaxants: enhanced hypotensive effect when  adrenergic neurone blockers given with baclofen or  tizanidine   Nitrates: enhanced hypotensive effect when adrener-  gic neurone blockers given with nitrates  Oestrogens: hypotensive effect of adrenergic neurone  blockers antagonised by oestrogens  Pizotifen: hypotensive effect of adrenergic neurone  blockers antagonised by pizotifen  Prostaglandins: enhanced hypotensive effect when  adrenergic neurone blockers given with alprostadil   dine antagonised by •dexamfetamine; hypotensive  effect of adrenergic neurone blockers antagonised by  •ephedrine, •isometheptene, •metaraminol,  •methylphenidate, •noradrenaline (norepinephrine),  •oxymetazoline, •phenylephrine,   •pseudoephedrine and •xylometazoline  Vasodilator Antihypertensives: enhanced hypoten-  sive effect when adrenergic neurone blockers given  with hydralazine, minoxidil or sodium nitroprusside   Agalsidase Alfa and Beta  Anti-arrhythmics: effects of agalsidase alfa and beta  possibly inhibited by amiodarone (manufacturers of  agalsidase alfa and beta advise avoid concomitant  use)   Antibacterials: effects of agalsidase alfa and beta  possibly inhibited by gentamicin (manufacturers of  agalsidase alfa and beta advise avoid concomitant  use)   Antimalarials: effects of agalsidase alfa and beta  possibly inhibited by chloroquine and hydroxy-  chloroquine (manufacturers of agalsidase alfa and  beta advise avoid concomitant use)   by manufacturer of •artemether/lumefantrine  Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine   ACE Inhibitors: enhanced hypotensive effect when  alcohol given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when alcohol given with adrenergic neurone  blockers   Alpha-blockers: increased sedative effect when  alcohol given with indoramin; enhanced hypotensive  effect when alcohol given with alpha-blockers  Analgesics: enhanced hypotensive and sedative  effects when alcohol given with opioid analgesics  Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when alcohol given with angio-  tensin-II receptor antagonists   given with metronidazole; possibility of disulfiram-  like reaction when alcohol given with tinidazole;  increased risk of convulsions when alcohol given  with •cycloserine   SSRIs; increased sedative effect when alcohol  given with •mirtazapine, •tricyclic-related  antidepressants or •tricyclics  Antidiabetics: alcohol enhances hypoglycaemic effect  of antidiabetics; increased risk of lactic acidosis  when alcohol given with metformin  Antiepileptics : alcohol possibly increases CNS side-  effects of carbamazepine; chronic heavy consump-  tion of alcohol possibly reduces plasma concentra-  tion of phenytoin; increased sedative effect when  alcohol given with primidone  Antifungals: effects of alcohol possibly enhanced by  griseofulvin   Antihistamines: increased sedative effect when  alcohol given with antihistamines (possibly less  effect with non-sedating antihistamines)  Antimuscarinics: increased sedative effect when  alcohol given with hyoscine  Antipsychotics: increased sedative effect when  alcohol given with antipsychotics  Anxiolytics and Hypnotics: increased sedative effect  when alcohol given with anxiolytics and hypnotics  Barbiturates: increased sedative effect when alcohol  given with barbiturates   Beta-blockers: enhanced hypotensive effect when  alcohol given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when alcohol given with calcium-channel  blockers; plasma concentration of alcohol possibly  increased by verapamil   Disulfiram: disulfiram reaction when alcohol given  with disulfiram (see p. 310)   Leva mi sole: possibility of disulfiram-like reaction  when alcohol given with levamisole  Lofexidine: increased sedative effect when alcohol  given with lofexidine   Methyldopa: enhanced hypotensive effect when  alcohol given with methyldopa  Moxonidine: enhanced hypotensive effect when  alcohol given with moxonidine  Muscle Relaxants: increased sedative effect when  alcohol given with baclofen, methocarbamol or  tizanidine   formed from •acitretin (increased risk of terato-  genecity in women of child-bearing potential)  Sympathomimetics: alcohol possibly enhances effects  of methylphenidate   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when alcohol given with hydralazine,  minoxidil or sodium nitroprusside   ACE Inhibitors: enhanced hypotensive effect when  aldesleukin given with ACE inhibitors  Alpha-blockers: enhanced hypotensive effect when  aldesleukin given with alpha-blockers   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when aldesleukin given with  angiotensin-II receptor antagonists  Antivirals: aldesleukin possibly increases plasma con-  centration of indinavir   Beta-blockers: enhanced hypotensive effect when  aldesleukin given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when aldesleukin given with calcium-channel  blockers   Diazoxide: enhanced hypotensive effect when aldes-  leukin given with diazoxide  Diuretics: enhanced hypotensive effect when aldes-  leukin given with diuretics  Methyldopa: enhanced hypotensive effect when  aldesleukin given with methyldopa  Moxonidine: enhanced hypotensive effect when  aldesleukin given with moxonidine  Nitrates: enhanced hypotensive effect when aldes-  leukin given with nitrates   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when aldesleukin given with hydralazine,  minoxidil or sodium nitroprusside  Alendronic Acid see Bisphosphonates  Alfentanil see Opioid Analgesics  Alfuzosin see Alpha-blockers  Alimemazine see Antihistamines  Aliskiren   Angiotensin-ll Receptor Antagonists: plasma con-  centration of aliskiren possibly reduced by irbesartan  Anticoagulants: increased risk of hyperkalaemia when  aliskiren given with heparins  Antifungals: plasma concentration of aliskiren  increased by ketoconazole   Calcium-channel Blockers: manufacturer of aliskiren  advises avoid concomitant use with verapamil   increased by •ciclosporin — avoid concomitant use  Diuretics: aliskiren reduces plasma concentration of  furosemide; increased risk of hyperkalaemia when  aliskiren given with potassium-sparing diuretics and  aldosterone antagonists   Potassium Salts: increased risk of hyperkalaemia  when aliskiren given with potassium salts  Alitretinoin see Retinoids   Alkylating Drugs see Bendamustine, Busulfan, Car-  mustine, Cyclophosphamide, Estramustine, Ifosf-  amide, Lomustine, Melphalan, and Thiotepa  Allopurinol   ACE Inhibitors: increased risk of leucopenia and  hypersensitivity reactions when allopurinol given  with ACE inhibitors especially in renal impairment  Antibacterials: increased risk of rash when allopurinol  given with amoxicillin or ampicillin  Anticoagulants: allopurinol possibly enhances anti-  coagulant effect of coumarins   increases toxicity of •azathioprine (reduce dose of  azathioprine to one quarter of usual dose)  Ciclosporin: allopurinol possibly increases plasma  concentration of ciclosporin (risk of nephrotoxicity)   toxicity of •mercaptopurine (reduce dose of  mercaptopurine to one quarter of usual dose);   Diuretics: increased risk of hypersensitivity when  allopurinol given with thiazides and related diuretics  especially in renal impairment  Theophylline: allopurinol possibly increases plasma  concentration of theophylline  Almotriptan see 5HTj Agonists  Alpha 2 -adrenoceptor Stimulants see Apraclonidine,  Brimonidine, Clonidine and Methyldopa  Alpha-blockers   ACE Inhibitors: enhanced hypotensive effect when  alpha-blockers given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when alpha-blockers given with adrenergic  neurone blockers   Alcohol: enhanced hypotensive effect when alpha-  blockers given with alcohol; increased sedative effect  when indoramin given with alcohol  Aldesleukin: enhanced hypotensive effect when  alpha-blockers given with aldesleukin   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when alpha-blockers given with  angiotensin-II receptor antagonists   alpha-blockers given with MAOIs; manufacturer of  indoramin advises avoid concomitant use with  •MAOIs   Antifungals: plasma concentration of alfuzosin possi-  bly increased by ketoconazole  Antipsychotics: enhanced hypotensive effect when  alpha-blockers given with antipsychotics   increased by •ritonavir — avoid concomitant use  Anxiolytics and Hypnotics: enhanced hypotensive  and sedative effects when alpha-blockers given with  anxiolytics and hypnotics   alpha-blockers given with •beta-blockers, also  increased risk of first-dose hypotension with post-  synaptic alpha-blockers such as prazosin   effect when alpha-blockers given with •calcium-  channel blockers, also increased risk of first-dose  hypotension with post-synaptic alpha-blockers such  as prazosin   Clonidine: enhanced hypotensive effect when alpha-  blockers given with clonidine  Corticosteroids: hypotensive effect of alpha-blockers  antagonised by corticosteroids  Diazoxide: enhanced hypotensive effect when alpha-  blockers given with diazoxide   blockers given with •diuretics, also increased risk of  first-dose hypotension with post-synaptic alpha-  blockers such as prazosin   Dopaminergics: enhanced hypotensive effect when  alpha-blockers given with levodopa  Methyldopa: enhanced hypotensive effect when  alpha-blockers given with methyldopa   when alpha-blockers given with *moxisylyte  Moxonidine: enhanced hypotensive effect when alpha-  blockers given with moxonidine  Muscle Relaxants: enhanced hypotensive effect when  alpha-blockers given with baclofen or tizanidine  Nitrates: enhanced hypotensive effect when alpha-  blockers given with nitrates   Oestrogens: hypotensive effect of alpha-blockers  antagonised by oestrogens  Prostaglandins: enhanced hypotensive effect when  alpha-blockers given with alprostadil   blockers given with •tadalafil — see also p. 515;  enhanced hypotensive effect when doxazosin given  with •tadalafil — manufacturer of tadalafil advises  avoid concomitant use   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when alpha-blockers given with hydral-  azine, minoxidil or sodium nitroprusside  Alpha-blockers (post-synaptic) see Alpha-blockers  Alprazolam see Anxiolytics and Hypnotics  Alprostadil see Prostaglandins  Aluminium Hydroxide see Antacids  Amantadine   Antimalarials: plasma concentration of amantadine  possibly increased by quinine  Antipsychotics: increased risk of extrapyramidal side-  effects when amantadine given with antipsychotics  Bupropion: increased risk of side-effects when aman-  tadine given with bupropion   amantadine given with •memantine (manufacturer  of memantine advises avoid concomitant use);  effects of dopaminergics possibly enhanced by  memantine   Methyldopa: increased risk of extrapyramidal side-  effects when amantadine given with methyldopa;  antiparkinsonian effect of dopaminergics antago-  nised by methyldopa   Tetrabenazine: increased risk of extrapyramidal side-  effects when amantadine given with tetrabenazine  Amikacin see Aminoglycosides  Amiloride see Diuretics  Aminoglycosides   Agalsidase Alfa and Beta: gentamicin possibly  inhibits effects of agalsidase alfa and beta (manu-  facturers of agalsidase alfa and beta advise avoid  concomitant use)   Analgesics: plasma concentration of amikacin and  gentamicin in neonates possibly increased by indo-  metacin   phenoxymethylpenicillin; increased risk of nephro-  toxicity when aminoglycosides given with colistin or  polymyxins; increased risk of nephrotoxicity and  ototoxicity when aminoglycosides given with  capreomycin or •vancomycin; possible increased  risk of nephrotoxicity when aminoglycosides given  with cephalosporins   suggests that 1NR possibly altered when neomycin  (given for local action on gut) is given with  •coumarins or •phenindione  Antidiabetics: neomycin possibly enhances hypogly-  caemic effect of acarbose, also severity of gastro-  intestinal effects increased  Antifungals: increased risk of nephrotoxicity when  aminoglycosides given with amphotericin  Bisphosphonates: increased risk of hypocalcaemia  when aminoglycosides given with bisphosphonates  Cardiac Glycosides: neomycin reduces absorption of  digoxin; gentamicin possibly increases plasma con-  centration of digoxin   methotrexate; neomycin reduces bioavailability of  sorafenib; increased risk of nephrotoxicity and  possibly of ototoxicity when aminoglycosides given  with •platinum compounds   Azathioprine: possible increased risk of leucopenia  when aminosalicylates given with azathioprine  Cardiac Glycosides: sulfasalazine possibly reduces  absorption of digoxin   Cytotoxics: possible increased risk of leucopenia when  aminosalicylates given with mercaptopurine  Folates: sulfasalazine possibly reduces absorption of  folic acid   Note Amiodarone has a long half-life; there is a potential for  drug interactions to occur for several weeks (or even  months) after treatment with it has been stopped  Agalsidase Alfa and Beta: amiodarone possibly  inhibits effects of agalsidase alfa and beta (manu-  facturers of agalsidase alfa and beta advise avoid  concomitant use)   Anaesthetics, Local: increased myocardial depression  when anti-arrhythmics given with bupivacaine,  levobupivacaine, prilocaine or ropivacaine   when anti-arrhythmics given with other •anti-  arrhythmics; increased risk of ventricular arrhyth-  mias when amiodarone given with •disopyramide or  •dronedarone — avoid concomitant use; amiodarone  increases plasma concentration of •flecainide (halve  dose of flecainide)   mias when amiodarone given with parenteral  •erythromycin — avoid concomitant use; increased  risk of ventricular arrhythmias when amiodarone  given with •levofloxacin or •moxifloxacin — avoid  concomitant use; increased risk of ventricular  arrhythmias when amiodarone given with  •sulfamethoxazole and •trimethoprim (as co-trim-  oxazole) — avoid concomitant use of co-trimoxazole   •coumarins and •phenindione (enhanced anti-  coagulant effect); amiodarone increases plasma  concentration of *dabigatran etexilate (reduce dose  of dabigatran etexilate)   manufacturer of •artemether/lumefantrine (risk of  ventricular arrhythmias); increased risk of ventricular  arrhythmias when amiodarone given with •chloro-  quine and hydroxychloroquine, •mefloquine or  •quinine — avoid concomitant use   mias when anti-arrhythmics that prolong the QT  interval given with •antipsychotics that prolong the  QT interval; increased risk of ventricular arrhythmias  when amiodarone given with •benperidol — manu-  facturer of benperidol advises avoid concomitant  use; increased risk of ventricular arrhythmias when  amiodarone given with •amisulpride, •droperidol,  •haloperidol, •phenothiazines, •pimozide or  •zuclopenthixol — avoid concomitant use; increased  risk of ventricular arrhythmias when amiodarone  given with •sulpiride   sibly increased by *atazanavir; plasma concentration  of amiodarone possibly increased by •fosamprenavir  (increased risk of ventricular arrhythmias — avoid  concomitant use); plasma concentration of amio-  darone possibly increased by •indinavir — avoid  concomitant use; increased risk of ventricular  arrhythmias when amiodarone given with  •nelfinavir or ^saquinavir — avoid concomitant use;  plasma concentration of amiodarone increased by  •ritonavir (increased risk of ventricular arrhyth-  mias — avoid concomitant use)   and myocardial depression when amiodarone given  with •beta-blockers; increased myocardial depres-  sion when anti-arrhythmics given with •beta-block-  ers; increased risk of ventricular arrhythmias when  amiodarone given with •sotalol — avoid concomitant  use   concentration of •digoxin (halve dose of digoxin)  Ciclosporin: amiodarone possibly increases plasma  concentration of ciclosporin   when amiodarone given with •arsenic trioxide  Diuretics: increased cardiac toxicity with amiodarone  if hypokalaemia occurs with acetazolamide, loop  diuretics or thiazides and related diuretics; amio-  darone increases plasma concentration of eplere-  none (reduce dose of eplerenone)   Thyroid Hormones: for concomitant use of amio-  darone and thyroid hormones see p. 94  Ulcer-healing Drugs: plasma concentration of amio-  darone increased by cimetidine  Amisulpride see Antipsychotics  Amitriptyline see Antidepressants, Tricyclic  Amlodipine see Calcium-channel Blockers  Amobarbital see Barbiturates  Amoxicillin see Penicillins   Note Close monitoring required with concomitant admin-  istration of nephrotoxic drugs or cytotoxics  Antibacterials: increased risk of nephrotoxicity when  amphotericin given with aminoglycosides or poly-  myxins; possible increased risk of nephrotoxicity  when amphotericin given with vancomycin  Antifungals : amphotericin reduces renal excretion and  increases cellular uptake of flucytosine (toxicity  possibly increased); effects of amphotericin possibly  antagonised by imidazoles and triazoles; plasma  concentration of amphotericin possibly increased by  micafungin   when amphotericin given with •arsenic trioxide  Diuretics: increased risk of hypokalaemia when  amphotericin given with loop diuretics or thiazides  and related diuretics   Pentamidine Isetionate: possible increased risk of  nephrotoxicity when amphotericin given with pent-  amidine isetionate   Note See also Surgery and Long-term Medication, p. 775  ACE Inhibitors: enhanced hypotensive effect when  general anaesthetics given with ACE inhibitors   general anaesthetics given with •alpha-blockers  Analgesics: metabolism of etomidate inhibited by  fentanyl (consider reducing dose of etomidate);  effects of thiopental possibly enhanced by aspirin;  effects of intravenous general anaesthetics and  volatile liquid general anaesthetics possibly  enhanced by opioid analgesics  Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when general anaesthetics given  with angiotensin-II receptor antagonists  Antibacterials: effects of thiopental enhanced by  sulfonamides; hypersensitivity-like reactions can  occur when general anaesthetics given with intra-  venous vancomycin   Antidepressants: increased risk of arrhythmias and  hypotension when general anaesthetics given with  tricyclics   general anaesthetics given with •antipsychotics;  effects of thiopental enhanced by droperidol  Anxiolytics and Hypnotics: increased sedative effect  when general anaesthetics given with anxiolytics and  hypnotics   effect when general anaesthetics or isoflurane given  with calcium-channel blockers; general anaesthetics  enhance hypotensive effect of •verapamil (also AV  delay)   •methotrexate — avoid concomitant use  Diazoxide: enhanced hypotensive effect when general  anaesthetics given with diazoxide  Diuretics: enhanced hypotensive effect when general  anaesthetics given with diuretics   liquid general anaesthetics given with •doxapram  (avoid doxapram for at least 10 minutes after volatile  liquid general anaesthetics)   Ergot Alkaloids: halothane reduces effects of ergo-  metrine on the parturient uterus   depression and bradycardia when propofol given  with •suxamethonium; volatile liquid general anaes-  thetics enhance effects of non-depolarising muscle  relaxants and suxamethonium; ketamine enhances  effects of atracurium   Nitrates: enhanced hypotensive effect when general  anaesthetics given with nitrates  Oxytocin: oxytocic effect possibly reduced, also  enhanced hypotensive effect and risk of arrhythmias  when volatile liquid general anaesthetics given with  oxytocin   when volatile liquid general anaesthetics given with  •adrenaline (epinephrine); increased risk of hyper-  tension when volatile liquid general anaesthetics  given with •methylphenidate  Theophylline: increased risk of convulsions when  ketamine given with theophylline; increased risk of  arrhythmias when halothane given with theophylline  Vasodilator Antihypertensives: enhanced hypoten-  sive effect when general anaesthetics given with  hydralazine, minoxidil or sodium nitroprusside  Anaesthetics, General (intravenous) see Anaes-  thetics, General   Anaesthetics, Local see Bupivacaine, Levobupiva-  caine, Lidocaine, Prilocaine, and Ropivacaine  Anagrelide   of anagrelide advises avoid concomitant use with  •enoximone and •milrinone  Anakinra    Angiotensin-ll Receptor Antagonists  ACE Inhibitors: increased risk of hyperkalaemia when  angiotensin-II receptor antagonists given with ACE  inhibitors   Adrenergic Neurone Blockers: enhanced hypotensive  effect when angiotensin-II receptor antagonists  given with adrenergic neurone blockers  Alcohol: enhanced hypotensive effect when angio-  tensin-II receptor antagonists given with alcohol  Aldesleukin: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with  aldesleukin   Alpha-blockers: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with alpha-  blockers   Anaesthetics, General: enhanced hypotensive effect  when angiotensin-II receptor antagonists given with  general anaesthetics   Analgesics: increased risk of renal impairment when  angiotensin-II receptor antagonists given with  NSAIDs, also hypotensive effect antagonised  Antibacterials : plasma concentration of losartan and  its active metabolite reduced by rifampicin; possible  increased risk of hyperkalaemia when angiotensin-II  receptor antagonists given with trimethoprim  Anticoagulants: increased risk of hyperkalaemia when  angiotensin-II receptor antagonists given with  heparins   Antidepressants: hypotensive effect of angiotensin-II  receptor antagonists possibly enhanced by MAOIs  Antipsychotics: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with anti-  psychotics   Anxiolytics and Hypnotics: enhanced hypotensive  effect when angiotensin-II receptor antagonists  given with anxiolytics and hypnotics  Beta-blockers: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with beta-  blockers   Calcium-channel Blockers: enhanced hypotensive  effect when angiotensin-II receptor antagonists  given with calcium-channel blockers   Clonidine: enhanced hypotensive effect when angio-  tensin-II receptor antagonists given with clonidine  Corticosteroids: hypotensive effect of angiotensin-II  receptor antagonists antagonised by corticosteroids  Diazoxide: enhanced hypotensive effect when angio-  tensin-II receptor antagonists given with diazoxide   tensin-II receptor antagonists given with •diuretics;  increased risk of hyperkalaemia when angiotensin-II  receptor antagonists given with •potassium-sparing  diuretics and aldosterone antagonists  Dopaminergics: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with levo-  dopa   Methyldopa: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with  methyldopa   Moxisylyte: enhanced hypotensive effect when angio-  tensin-II receptor antagonists given with moxisylyte  Moxonidine: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with mox-  onidine   Muscle Relaxants: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with  baclofen or tizanidine   Nitrates: enhanced hypotensive effect when angio-  tensin-II receptor antagonists given with nitrates    Angiotensin-II Receptor Antagonists (continued)  Oestrogens: hypotensive effect of angiotensin-II  receptor antagonists antagonised by oestrogens   Prostaglandins: enhanced hypotensive effect when  angiotensin-II receptor antagonists given with  alprostadil   Tacrolimus: increased risk of hyperkalaemia when  angiotensin-II receptor antagonists given with  tacrolimus   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when angiotensin-II receptor antagonists  given with hydralazine, minoxidil or sodium nitro-  prusside   Note Antacids should preferably not be taken at the same  time as other drugs since they may impair absorption  ACE Inhibitors: antacids possibly reduce absorption of  ACE inhibitors; antacids reduce absorption of  captopril, enalapril and fosinopril  Analgesics: alkaline urine due to some antacids  increases excretion of aspirin  Antibacterials : antacids reduce absorption of azithro-  mycin, cefaclor, cefpodoxime, ciprofloxacin, isoni-  azid, levofloxacin, moxifloxacin, norfloxacin,  ofloxacin, rifampicin and tetracyclines; avoid con-  comitant use of antacids with methenamine; oral  magnesium salts (as magnesium trisilicate) reduce  absorption of nitrofurantoin  Antiepileptics: antacids reduce absorption of  gabapentin and phenytoin  Antifungals: antacids reduce absorption of  itraconazole and ketoconazole  Antihistamines: antacids reduce absorption of fex-  ofenadine   Antimalarials: antacids reduce absorption of chloro-  quine and hydroxychloroquine; oral magnesium salts  (as magnesium trisilicate) reduce absorption of  proguanil   Antipsychotics: antacids reduce absorption of  phenothiazines and sulpiride  Antivirals: antacids possibly reduce plasma concen-  tration of atazanavir; antacids reduce absorption of  tipranavir   tration of •erlotinib — give antacids at least 4 hours  before or 2 hours after erlotinib  Deferasirox: antacids containing aluminium possibly  reduce absorption of deferasirox (manufacturer of  deferasirox advises avoid concomitant use)  Dipyridamole: antacids possibly reduce absorption of  dipyridamole   Eltrombopag: antacids reduce absorption of eltrom-  bopag (give at least 4 hours apart)   Iron: oral magnesium salts (as magnesium trisilicate)  reduce absorption of oral iron  Lipid-regulating Drugs: antacids reduce absorption of  rosuvastatin   Lithium: sodium bicarbonate increases excretion of  lithium (reduced plasma concentration)  Mycophenolate: antacids reduce absorption of  mycophenolate   Polystyrene Sulphonate Resins : risk of intestinal  obstruction when aluminium hydroxide given with  polystyrene sulphonate resins; risk of metabolic   Polystyrene Sulphonate Resins (continued)  alkalosis when oral magnesium salts given with  polystyrene sulphonate resins   Antazoline see Antihistamines  Anti-arrhythmics see Adenosine, Amiodarone, Diso-  pyramide, Dronedarone, Flecainide, Lidocaine, and  Propafenone   Antibacterials see individual drugs  Antibiotics (cytotoxic) see Bleomycin, Doxorubicin,  Epirubicin, Idarubicin, Mitomycin, and Mitoxan-  trone   Anticoagulants see Coumarins, Dabigatran etexilate,  Heparins, Phenindione, and Rivaroxaban  Antidepressants see Agomelatine; Antidepressants,  SSRI; Antidepressants, Tricyclic; Antidepressants,  Tricyclic (related); MAOIs; Mirtazapine; Moclobe-  mide; Reboxetine; St John’s Wort; Tryptophan;  Venlafaxine   given with «NSAIDs or •aspirin; fluoxetine, fluvox-  amine, paroxetine and sertraline possibly increase  plasma concentration of methadone; increased risk  of CNS toxicity when SSRIs given with •tramadol   Anti-arrhythmics: fluoxetine increases plasma con-  centration of flecainide; paroxetine possibly inhibits  metabolism of propafenone (increased risk of toxi-  city)   by manufacturer of •reboxetine; possible increased  serotonergic effects when SSRIs given with dulox-  etine; fluvoxamine inhibits metabolism of  •duloxetine — avoid concomitant use; CNS effects of  SSRIs increased by *MAOIs (risk of serious toxicity);  citalopram, escitalopram, fluvoxamine, paroxetine or  sertraline should not be started until 2 weeks after  stopping •MAOIs, also MAOIs should not be started  until at least 1 week after stopping citalopram,  escitalopram, fluvoxamine, paroxetine or sertraline;  fluoxetine should not be started until 2 weeks after  stopping *MAOIs, also MAOIs should not be started  until at least 5 weeks after stopping fluoxetine;  increased risk of CNS toxicity when escitalopram  given with •moclobemide, preferably avoid conco-  mitant use; after stopping citalopram, fluvoxamine,  paroxetine or sertraline do not start •moclobemide  for at least 1 week; after stopping fluoxetine do not  start •moclobemide for 5 weeks; increased seroto-  nergic effects when SSRIs given with »St John’s  wort — avoid concomitant use; fluvoxamine inhibits  metabolism of •agomelatine (increased plasma  concentration); possible increased serotonergic  effects when fluoxetine or fluvoxamine given with  mirtazapine; SSRIs increase plasma concentration of  some •tricyclics; agitation and nausea may occur  when SSRIs given with «tryptophan; CNS toxicity  reported when fluoxetine given with tryptophan   centration of •carbamazepine; plasma concen-  tration of sertraline possibly reduced by pheny-  toin, also plasma concentration of phenytoin  possibly increased; plasma concentration of  paroxetine reduced by phenytoin and primidone;  fluoxetine and fluvoxamine increase plasma  concentration of •phenytoin  Antihistamines: antidepressant effect of SSRIs possi-  bly antagonised by cyproheptadine   by manufacturer of •artemether/lumefantrine  Antimuscarinics: paroxetine increases plasma con-  centration of darifenacin and procyclidine   fluvoxamine or sertraline advised by manufacturer of  •droperidol (risk of ventricular arrhythmias); fluox-  etine increases plasma concentration of •clozapine,  •haloperidol and risperidone; fluvoxamine possibly  increases plasma concentration of haloperidol; par-  oxetine inhibits metabolism of perphenazine (reduce  dose of perphenazine); fluoxetine and paroxetine  possibly inhibit metabolism of •aripiprazole (reduce  dose of aripiprazole); citalopram possibly increases  plasma concentration of clozapine (increased risk of  toxicity); fluvoxamine, paroxetine and sertraline  increase plasma concentration of •clozapine; flu-  voxamine increases plasma concentration of olan-  zapine; SSRIs possibly increase plasma  concentration of •pimozide (increased risk of  ventricular arrhythmias — avoid concomitant use);  paroxetine possibly increases plasma concentration  of risperidone (increased risk of toxicity)   sertraline possibly reduced by darunavir; plasma  concentration of paroxetine possibly reduced by  ritonavir; plasma concentration of SSRIs possibly  increased by •ritonavir   plasma concentration of alprazolam; fluvoxamine  increases plasma concentration of some benzodiaz-  epines; fluvoxamine increases plasma concentration  of •melatonin — avoid concomitant use; sedative  effects possibly increased when sertraline given with  zolpidem   Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine;  fluoxetine and paroxetine possibly inhibit metab-  olism of atomoxetine   Barbiturates: SSRIs antagonise anticonvulsant effect  of barbiturates (convulsive threshold lowered);  plasma concentration of paroxetine reduced by  phenobarbital   Beta-blockers: citalopram and escitalopram increase  plasma concentration of metoprolol; paroxetine  possibly increases plasma concentration of  metoprolol (enhanced effect); fluvoxamine increases  plasma concentration of propranolol  Bupropion: plasma concentration of citalopram pos-  sibly increased by bupropion  Calcium-channel Blockers: fluoxetine possibly inhi-  bits metabolism of nifedipine (increased plasma  concentration)   manufacturer of entacapone; increased risk of CNS  toxicity when SSRIs given with •rasagiline; fluvox-  amine should not be started until 2 weeks after  stopping *rasagiline; fluoxetine should not be started  until 2 weeks after stopping •rasagiline, also rasagi-  line should not be started until at least 5 weeks after  stopping fluoxetine; increased risk of hypertension  and CNS excitation when paroxetine given with  •selegiline (selegiline should not be started until 2  weeks after stopping paroxetine, avoid paroxetine for   2 weeks after stopping selegiline); increased risk  of hypertension and CNS excitation when  fluvoxamine or sertraline given with •selegiline  (selegiline should not be started until 1 week  after stopping fluvoxamine or sertraline, avoid  fluvoxamine or sertraline for 2 weeks after  stopping selegiline); increased risk of hyper-  tension and CNS excitation when fluoxetine  given with •selegiline (selegiline should not be  started until 5 weeks after stopping fluoxetine,  avoid fluoxetine for 2 weeks after stopping  selegiline); avoidance of citalopram and escita-  lopram advised by manufacturer of selegiline   frovatriptan; increased risk of CNS toxicity when  citalopram, escitalopram, fluoxetine, fluvoxamine or  paroxetine given with •sumatriptan; CNS toxicity  reported when sertraline given with sumatriptan;  fluvoxamine possibly inhibits metabolism of zolmi-  triptan (reduce dose of zolmitriptan)   concentration of •tizanidine (increased risk of  toxicity) — avoid concomitant use  Parasympathomimetics: paroxetine increases plasma  concentration of galantamine  Ranolazine: paroxetine increases plasma concentra-  tion of ranolazine   tration of •theophylline (concomitant use should  usually be avoided, but where not possible halve  theophylline dose and monitor plasma-theophylline  concentration)   Ulcer-healing Drugs: plasma concentration of citalo-  pram, escitalopram and sertraline increased by  cimetidine; fluvoxamine possibly increases plasma  concentration of lansoprazole; plasma concentration  of escitalopram increased by omeprazole  Antidepressants, SSRI (related) see Duloxetine and  Venlafaxine   Antidepressants, Tricyclic  Adrenergic Neurone Blockers: tricyclics antagonise  hypotensive effect of adrenergic neurone blockers   Alpha 2 -adrenoceptor Stimulants: avoidance of tri-  cyclics advised by manufacturer of apraclonidine and  brimonidine   Anaesthetics, General: increased risk of arrhythmias  and hypotension when tricyclics given with general  anaesthetics   tricyclics given with •tramadol; side-effects possibly  increased when tricyclics given with nefopam;  sedative effects possibly increased when tricyclics  given with opioid analgesics   thmias when tricyclics given with •amiodarone —  avoid concomitant use; increased risk of ventricular  arrhythmias when tricyclics given with  •disopyramide or •flecainide; avoidance of tricyclics  advised by manufacturer of •dronedarone (risk of  ventricular arrhythmias); increased risk of arrhyth-  mias when tricyclics given with ^propafenone   effects when amitriptyline or clomipramine given  with duloxetine; increased risk of hypertension and  CNS excitation when tricyclics given with •MAOIs,  tricyclics should not be started until 2 weeks after  stopping MAOIs (3 weeks if starting clomipramine or  imipramine), also MAOIs should not be started for at  least 1-2 weeks after stopping tricyclics (3 weeks in  the case of clomipramine or imipramine); after  stopping tricyclics do not start •moclobemide for at  least 1 week; plasma concentration of some tricyclics  increased by •SSRIs; plasma concentration of ami-  triptyline reduced by St John’s wort   effect of •antiepileptics (convulsive threshold  lowered); metabolism of tricyclics accelerated by  •carbamazepine (reduced plasma concentration and  reduced effect); plasma concentration of tricyclics  possibly reduced by •phenytoin; tricyclics antago-  nises anticonvulsant effect of •primidone (convulsive  threshold lowered), also metabolism of tricyclics  possibly accelerated (reduced plasma concentration)  Antifungals: plasma concentration of tricyclics possi-  bly increased by terbinafine  Antihistamines: increased antimuscarinic and seda-  tive effects when tricyclics given with antihistamines   by manufacturer of •artemether/lumefantrine  Antimuscarinics: increased risk of antimuscarinic side-  effects when tricyclics given with antimuscarinics   increased by •antipsychotics — possibly increased  risk of ventricular arrhythmias; avoidance of tricyc-  lics advised by manufacturer of •droperidol (risk of  ventricular arrhythmias); possibly increased anti-  muscarinic side-effects when tricyclics given with  clozapine; increased risk of antimuscarinic side-  effects when tricyclics given with phenothiazines;  increased risk of ventricular arrhythmias when  tricyclics given with •pimozide — avoid concomitant  use   Anxiolytics and Hypnotics: increased sedative effect  when tricyclics given with anxiolytics and hypnotics   when tricyclics given with •atomoxetine; possible  increased risk of convulsions when antidepressants  given with atomoxetine   effect of •barbiturates (convulsive threshold  lowered), also metabolism of tricyclics possibly  accelerated (reduced plasma concentration)   increased by labetalol and propranolol; increased  risk of ventricular arrhythmias when tricyclics given  with •sotalol   Bupropion : plasma concentration of tricyclics possibly  increased by bupropion (possible increased risk of  convulsions)   Calcium-channel Blockers: plasma concentration of  tricyclics possibly increased by diltiazem and verap-  amil; plasma concentration of imipramine increased  by diltiazem and verapamil  Cannabis Extract : possible increased risk of hyper-  tension and tachycardia when tricyclics given with  cannabis extract   Disulfiram: metabolism of tricyclics inhibited by  disulfiram (increased plasma concentration); conco-  mitant amitriptyline reported to increase disulfiram  reaction with alcohol   Diuretics: increased risk of postural hypotension when  tricyclics given with diuretics   manufacturer of entacapone; increased risk of CNS  toxicity when tricyclics given with •rasagiline; CNS  toxicity reported when tricyclics given with  •selegiline   Moxonidine : tricyclics possibly antagonise hypoten-  sive effect of moxonidine (manufacturer of moxoni-  dine advises avoid concomitant use)   Nitrates: tricyclics reduce effects of sublingual tablets  of nitrates (failure to dissolve under tongue owing to  dry mouth)   Oestrogens: antidepressant effect of tricyclics antag-  onised by oestrogens (but side-effects of tricyclics  possibly increased due to increased plasma concen-  tration)   Sodium Oxybate: increased risk of side-effects when  tricyclics given with sodium oxybate   and arrhythmias when tricyclics given with •adr-  enaline (epinephrine) (but local anaesthetics with  adrenaline appear to be safe); metabolism of  tricyclics possibly inhibited by methylphenidate;  increased risk of hypertension and arrhythmias when  tricyclics given with •noradrenaline (norepinephrine)   Thyroid Hormones: effects of tricyclics possibly  enhanced by thyroid hormones; effects of  amitriptyline and imipramine enhanced by thyroid  hormones   Ulcer-healing Drugs: plasma concentration of tricyc-  lics possibly increased by cimetidine; metabolism of  amitriptyline, doxepin, imipramine and nortriptyline  inhibited by cimetidine (increased plasma concen-  tration)   Alpha 2 -adrenoceptor Stimulants: avoidance of tri-  cyclic-related antidepressants advised by manufac-  turer of apraclonidine and brimonidine   should not be started until 2 weeks after stopping  •MAOIs, also MAOIs should not be started until at  least 1-2 weeks after stopping tricyclic-related anti-  depressants; after stopping tricyclic-related anti-  depressants do not start •moclobemide for at least 1  week   bly antagonise anticonvulsant effect of  •antiepileptics (convulsive threshold lowered);  plasma concentration of mianserin reduced by  •carbamazepine and •phenytoin; metabolism of  mianserin accelerated by •primidone (reduced  plasma concentration)   Antihistamines: possible increased antimuscarinic and  sedative effects when tricyclic-related antidepres-  sants given with antihistamines   by manufacturer of •artemether/lumefantrine  Antimuscarinics: possibly increased antimuscarinic  side-effects when tricyclic-related antidepressants  given with antimuscarinics   increased by •ritonavir (increased risk of toxicity);  increased risk of ventricular arrhythmias when  trazodone given with ©saquinavir — avoid concomi-  tant use   Anxiolytics and Hypnotics: increased sedative effect  when tricyclic-related antidepressants given with  anxiolytics and hypnotics   Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine   antagonise anticonvulsant effect of •barbiturates  (convulsive threshold lowered); metabolism of  mianserin accelerated by •phenobarbital (reduced  plasma concentration)   Diazoxide: enhanced hypotensive effect when tri-  cyclic-related antidepressants given with diazoxide  Nitrates: tricyclic-related antidepressants possibly  reduce effects of sublingual tablets of nitrates (failure  to dissolve under tongue owing to dry mouth)  Vasodilator Antihypertensives: enhanced hypoten-  sive effect when tricyclic-related antidepressants  given with hydralazine or sodium nitroprusside   Note Other oral drugs may be taken at least 1 hour before  or 4 hours after exenatide injection, or taken with a meal  when exenatide is not administered, to minimise possible  interference with absorption  ACE Inhibitors: hypoglycaemic effect of insulin,  metformin and sulfonylureas possibly enhanced by  ACE inhibitors   Alcohol: hypoglycaemic effect of antidiabetics  enhanced by alcohol; increased risk of lactic acidosis  when metformin given with alcohol  Anabolic Steroids: hypoglycaemic effect of anti-  diabetics possibly enhanced by anabolic steroids   Anti-arrhythmics: hypoglycaemic effect of gliclazide,  insulin and metformin possibly enhanced by diso-  pyr amide   possibly enhanced by neomycin, also severity of  gastro-intestinal effects increased; effects of repagli-  nide enhanced by clarithromycin; effects of gliben-  clamide possibly enhanced by norfloxacin; plasma  concentration of nateglinide reduced by rifampicin;  hypoglycaemic effect of repaglinide possibly antag-  onised by rifampicin; effects of sulfonylureas  enhanced by •chloramphenicol; metabolism of tol-  butamide accelerated by •rifamycins (reduced  effect); metabolism of sulfonylureas possibly accel-  erated by •rifamycins (reduced effect); effects of  sulfonylureas rarely enhanced by sulfonamides and  trimethoprim; hypoglycaemic effect of sulfonylureas  possibly enhanced by tetracyclines; hypoglycaemic  effect of repaglinide possibly enhanced by trimetho-  prim — manufacturer advises avoid concomitant use   coagulant effect of warfarin; hypoglycaemic effect of  sulfonylureas possibly enhanced by •coumarins, also  possible changes to anticoagulant effect  Antidepressants: hypoglycaemic effect of anti-  diabetics possibly enhanced by MAOIs; hypoglycae-  mic effect of insulin, metformin and sulfonylureas  enhanced by MAOIs   Antiepileptics : tolbutamide transiently increases  plasma concentration of phenytoin (possibility of  toxicity); plasma concentration of glibenclamide  possibly reduced by topiramate; plasma concentra-  tion of metformin possibly increased by topiramate   increased by •fluconazole and •miconazole; hypo-  glycaemic effect of gliclazide and glipizide enhanced  by •miconazole — avoid concomitant use; hypogly-  caemic effect of nateglinide possibly enhanced by  fluconazole; hypoglycaemic effect of repaglinide  possibly enhanced by itraconazole; hypoglycaemic  effect of glipizide possibly enhanced by posacona-  zole; plasma concentration of sulfonylureas possibly  increased by voriconazole   Antihistamines: thrombocyte count depressed when  metformin given with ketotifen (manufacturer of  ketotifen advises avoid concomitant use)  Antipsychotics: hypoglycaemic effect of sulfonylureas  possibly antagonised by phenothiazines  Antivirals: plasma concentration of tolbutamide pos-  sibly increased by ritonavir  Aprepitant: plasma concentration of tolbutamide  reduced by aprepitant   Beta-blockers: warning signs of hypoglycaemia (such  as tremor) with antidiabetics may be masked when  given with beta-blockers; hypoglycaemic effect of  insulin enhanced by beta-blockers   Calcium-channel Blockers: glucose tolerance occa-  sionally impaired when insulin given with nifedipine  Cardiac Glycosides: acarbose possibly reduces plasma  concentration of digoxin; sitagliptin increases plasma  concentration of digoxin  Ciclosporin: hypoglycaemic effect of repaglinide  possibly enhanced by ciclosporin  Corticosteroids: hypoglycaemic effect of antidiabetics  antagonised by corticosteroids   manufacturer of •lapatinib  Deferasirox: plasma concentration of repaglinide  increased by deferasirox  Diazoxide: hypoglycaemic effect of antidiabetics  antagonised by diazoxide  Diuretics: hypoglycaemic effect of antidiabetics  antagonised by loop diuretics and thiazides and  related diuretics   Hormone Antagonists: requirements for insulin, met-  formin, repaglinide and sulfonylureas possibly  reduced by lanreotide; requirements for insulin,  metformin, repaglinide and sulfonylureas possibly  reduced by octreotide   reduced by colesevelam; hypoglycaemic effect of  acarbose possibly enhanced by colestyramine;  hypoglycaemic effect of nateglinide possibly  enhanced by gemfibrozil; increased risk of severe  hypoglycaemia when repaglinide given with  •gemfibrozil — avoid concomitant use; plasma con-  centration of glibenclamide possibly increased by  fluvastatin; may be improved glucose tolerance and  an additive effect when insulin or sulfonylureas given  with fibrates   Oestrogens: hypoglycaemic effect of antidiabetics  antagonised by oestrogens  Orlistat: avoidance of acarbose advised by manufac-  turer of orlistat   Testosterone: hypoglycaemic effect of antidiabetics  possibly enhanced by testosterone  Ulcer-healing Drugs: excretion of metformin reduced  by cimetidine (increased plasma concentration);   Antiepileptics see Carbamazepine, Eslicarbazepine,  Ethosuximide, Gabapentin, Lacosamide, Lamotri-  gine, Levetiracetam, Oxcarbazepine, Phenytoin,  Primidone, Rufinamide, Stiripentol, Tiagabine,  Topiramate, Valproate, Vigabatrin, and Zonisamide  Antifungals see Amphotericin; Antifungals, Imidazole;  Antifungals, Triazole; Caspofungin; Flucytosine;  Griseofulvin; Micafungin; Terbinafine  Antifungals, Imidazole   ated by •rifampicin (reduced plasma concentration),  also plasma concentration of rifampicin may be  reduced by ketoconazole; plasma concentration of  ketoconazole possibly reduced by isoniazid; avoid-  ance of concomitant ketoconazole in severe renal  and hepatic impairment advised by manufacturer of  •telithromycin   increase plasma concentration of carbamazepine;  miconazole enhances anticonvulsant effect of  •phenytoin (plasma concentration of phenytoin  increased); plasma concentration of ketoconazole  reduced by •phenytoin   ketoconazole possibly increases plasma concentra-  tion of loratadine; imidazoles possibly inhibit  metabolism of •mizolastine (avoid concomitant use);  ketoconazole inhibits metabolism of •mizolastine —  avoid concomitant use; ketoconazole increases  plasma concentration of rupatadine   manufacturer of •artemether/lumefantrine; keto-  conazole increases plasma concentration of meflo-  quine   Antimuscarinics: absorption of ketoconazole reduced  by antimuscarinics; ketoconazole increases plasma  concentration of darifenacin — avoid concomitant  use; manufacturer of fesoterodine advises dose  reduction when ketoconazole given with fesotero-  dine — consult fesoterodine product literature; keto-  conazole increases plasma concentration of  solifenacin; avoidance of ketoconazole advised by  manufacturer of tolterodine   increased when ketoconazole given with darunavir;  plasma concentration of ketoconazole increased by  fosamprenavir (also plasma concentration of fosam-  prenavir possibly increased); ketoconazole increases  plasma concentration of •indinavir and •maraviroc  (consider reducing dose of indinavir and maraviroc);  plasma concentration of ketoconazole reduced by  •nevirapine — avoid concomitant use; combination of  ketoconazole with • ritonavir may increase plasma  concentration of either drug (or both); ketoconazole  increases plasma concentration of saquinavir; imi-  dazoles possibly increase plasma concentration of  saquinavir   plasma concentration of alprazolam; ketoconazole  increases plasma concentration of •midazolam (risk  of prolonged sedation)   metabolism of •felodipine (increased plasma con-  centration); avoidance of ketoconazole advised by  manufacturer of lercanidipine; ketoconazole possibly  inhibits metabolism of dihydropyridines (increased  plasma concentration)   •ciclosporin (increased plasma concentration);  miconazole possibly inhibits metabolism of  •ciclosporin (increased plasma concentration)   Cilostazol : ketoconazole increases plasma concentra-  tion of cilostazol (consider reducing dose of cilosta-  zol)   •colchicine toxicity — suspend or reduce dose of  colchicine (avoid concomitant use in hepatic or renal  impairment)   Corticosteroids: ketoconazole possibly inhibits  metabolism of corticosteroids; ketoconazole  increases plasma concentration of inhaled and oral  budesonide; ketoconazole increases plasma concen-  tration of active metabolite of ciclesonide; ketocon-  azole inhibits the metabolism of methylprednisolone;  ketoconazole increases plasma concentration of  inhaled mometasone   concentration of dasatinib; ketoconazole inhibits  metabolism of erlotinib and sunitinib (increased  plasma concentration); ketoconazole increases  plasma concentration of •everolimus, •lapatinib and  •nilotinib — avoid concomitant use; ketoconazole  increases plasma concentration of bortezomib and  imatinib; avoidance of ketoconazole advised by  manufacturer of •pazopanib; ketoconazole increases  plasma concentration of active metabolite of  •temsirolimus — avoid concomitant use; in vitro  studies suggest a possible interaction between keto-  conazole and docetaxel (consult docetaxel product  literature); ketoconazole reduces plasma concentra-  tion of •irinotecan (but concentration of active  metabolite of irinotecan increased) — avoid conco-  mitant use; ketoconazole increases plasma concen-  tration of •vinflunine — manufacturer of vinflunine  advises avoid concomitant use   centration of almotriptan (increased risk of toxicity);  ketoconazole increases plasma concentration of  •eletriptan (risk of toxicity) — avoid concomitant use   myopathy when imidazoles given with  atorvastatin or simvastatin; increased risk of myo-  pathy when ketoconazole given with •simvastatin  (avoid concomitant use); possible increased risk of  myopathy when miconazole given with  •simvastatin — avoid concomitant use  Oestrogens: anecdotal reports of contraceptive failure  when imidazoles given with oestrogens  Parasympathomimetics: ketoconazole increases  plasma concentration of galantamine   Sildenafil: ketoconazole increases plasma concentra-  tion of sildenafil — reduce initial dose of sildenafil   concentration of •theophylline  Tolvaptan: ketoconazole increases plasma concentra-  tion of tolvaptan   Ulcer-healing Drugs: absorption of ketoconazole  reduced by histamine H 2 -antagonists, proton pump  inhibitors and sucralfate   tion of •vardenafil — avoid concomitant use  Vitamins: ketoconazole possibly increases plasma  concentration of paricalcitol  Antifungals, Polyene see Amphotericin  Antifungals, Triazole   tion of celecoxib (halve dose of celecoxib); vorico-  nazole increases plasma concentration of  diclofenac and ibuprofen; fluconazole increases  plasma concentration of parecoxib (reduce dose of  parecoxib); voriconazole increases plasma concen-  tration of •alfentanil and •methadone (consider  reducing dose of alfentanil and methadone); flucon-  azole inhibits metabolism of alfentanil (risk of  prolonged or delayed respiratory depression); itra-  conazole possibly inhibits metabolism of alfentanil;  triazoles possibly increase plasma concentration of  •fentanyl   advises avoid concomitant use with •disopyramide;  avoidance of itraconazole, posaconazole and vor-  iconazole advised by manufacturer of •dronedarone   increased by clarithromycin; triazoles possibly  increase plasma concentration of •rifabutin  (increased risk of uveitis — reduce rifabutin dose);  posaconazole increases plasma concentration of  •rifabutin (also plasma concentration of posacona-  zole reduced); voriconazole increases plasma con-  centration of •rifabutin, also rifabutin reduces  plasma concentration of voriconazole (increase dose  of voriconazole and also monitor for rifabutin  toxicity); fluconazole increases plasma concentra-  tion of •rifabutin (increased risk of uveitis — reduce  rifabutin dose); plasma concentration of itraconazole  reduced by •rifabutin — avoid concomitant use;  plasma concentration of posaconazole reduced by  •rifampicin; plasma concentration of voriconazole  reduced by •rifampicin — avoid concomitant use;  metabolism of fluconazole and itraconazole accel-  erated by •rifampicin (reduced plasma concentra-  tion)   glycaemic effect of glipizide; fluconazole possibly  enhances hypoglycaemic effect of nateglinide; itra-  conazole possibly enhances hypoglycaemic effect of  repaglinide; fluconazole increases plasma concen-  tration of *sulfonylureas; voriconazole possibly  increases plasma concentration of sulfonylureas   concentration of carbamazepine; plasma concentra-  tion of voriconazole possibly reduced by  •carbamazepine and •primidone — avoid concomi-  tant use; plasma concentration of itraconazole and  posaconazole possibly reduced by •carbamazepine;  fluconazole increases plasma concentration of  •phenytoin (consider reducing dose of phenytoin);  voriconazole increases plasma concentration of  •phenytoin, also phenytoin reduces plasma concen-  tration of voriconazole (increase dose of voricona-  zole and also monitor for phenytoin toxicity); plasma  concentration of posaconazole reduced by  •phenytoin; plasma concentration of itraconazole  reduced by •phenytoin — avoid concomitant use;  plasma concentration of posaconazole possibly  reduced by •primidone   Antifungals: triazoles possibly antagonise effects of  amphotericin; plasma concentration of itraconazole  increased by micafungin (consider reducing dose of  itraconazole)   manufacturer of •art erne ther/lumefantrine  Antimuscarinics: avoidance of itraconazole advised by  manufacturer of darifenacin and tolterodine; manu-  facturer of fesoterodine advises dose reduction when  itraconazole given with fesoterodine — consult feso-  terodine product literature; itraconazole increases  plasma concentration of solifenacin   plasma concentration of haloperidol; itraconazole  possibly inhibits metabolism of •aripiprazole (reduce  dose of aripiprazole); increased risk of ventricular  arrhythmias when triazoles given with •pimozide —  avoid concomitant use; triazoles possibly increase  plasma concentration of quetiapine (reduce dose of  quetiapine)   tion of •atazanavir; plasma concentration of  itraconazole and posaconazole reduced by   •efavirenz; plasma concentration of voriconazole  reduced by •efavirenz, also plasma concentration of  efavirenz increased (increase voriconazole dose and  reduce efavirenz dose); plasma concentration of both  drugs may increase when itraconazole given with  fosamprenavir; itraconazole increases plasma con-  centration of •indinavir (consider reducing dose of  indinavir); plasma concentration of itraconazole  possibly reduced by nevirapine — consider increasing  dose of itraconazole; fluconazole increases plasma  concentration of •nevirapine, ritonavir and tiprana-  vir; plasma concentration of voriconazole reduced by  •ritonavir — avoid concomitant use; combination of  itraconazole with •ritonavir may increase plasma  concentration of either drug (or both); triazoles  possibly increase plasma concentration of saquina-  vir; fluconazole increases plasma concentration of  •zidovudine (increased risk of toxicity)   plasma concentration of alprazolam; posaconazole  increases plasma concentration of •midazolam;  fluconazole and itraconazole increase plasma con-  centration of •midazolam (risk of prolonged seda-  tion); itraconazole increases plasma concentration of  buspirone (reduce dose of buspirone)   possibly increased when itraconazole given with  calcium-channel blockers; itraconazole inhibits  metabolism of •felodipine (increased plasma con-  centration); avoidance of itraconazole advised by  manufacturer of lercanidipine; itraconazole possibly  inhibits metabolism of dihydropyridines (increased  plasma concentration)   •colchicine toxicity — suspend or reduce dose of  colchicine (avoid concomitant use in hepatic or renal  impairment)   fan (increased risk of toxicity); itraconazole possibly  increases side-effects of cyclophosphamide; itracon-  azole, posaconazole and voriconazole possibly  increase plasma concentration of •everolimus —  manufacturer of everolimus advises avoid concomi-  tant use; itraconazole increases plasma concentra-  tion of gefitinib; avoidance of itraconazole,  posaconazole and voriconazole advised by manu-  facturer of •lapatinib; avoidance of itraconazole and  voriconazole advised by manufacturer of •nilotinib;  avoidance of itraconazole and voriconazole advised  by manufacturer of •pazopanib; posaconazole pos-  sibly inhibits metabolism of •vinblastine and  •vincristine (increased risk of neurotoxicity); itra-  conazole possibly inhibits metabolism of  •vincristine and •vinorelbine (increased risk of  neurotoxicity); itraconazole possibly increases   of eplerenone (reduce dose of eplerenone); itracon-  azole increases plasma concentration of  •eplerenone — avoid concomitant use; plasma con-  centration of fluconazole increased by hydrochloro-  thiazide   tion of ivabradine — reduce initial dose of ivabradine;  itraconazole possibly increases plasma concentra-  tion of •ivabradine — avoid concomitant use   myopathy when triazoles given with atorvastatin or  simvastatin; increased risk of myopathy when  itraconazole or posaconazole given with  •atorvastatin (avoid concomitant use); fluconazole  increases plasma concentration of fluvastatin;  increased risk of myopathy when itraconazole or  posaconazole given with •simvastatin (avoid con-  comitant use)   posaconazole and voriconazole increase plasma  concentration of •tacrolimus (consider reducing  dose of tacrolimus)   conazole reduced by •cimetidine; voriconazole  possibly increases plasma concentration of esome-  prazole; voriconazole increases plasma concentra-  tion of omeprazole (consider reducing dose of  omeprazole); absorption of itraconazole reduced by  histamine H 2 -antagonists and proton pump inhi-  bitors; manufacturer of posaconazole advises avoid  concomitant use with histamine H 2 -antagonists and  proton pump inhibitors (plasma concentration of  posaconazole possibly reduced)   Note Sedative interactions apply to a lesser extent to the  non-sedating antihistamines. Interactions do not generally  apply to antihistamines used for topical action (including  inhalation)   Alcohol: increased sedative effect when antihistamines  given with alcohol (possibly less effect with non-  sedating antihistamines)   thmias when mizolastine given with •amiodarone,  •disopyramide, •flecainide or •propafenone — avoid  concomitant use   increased by erythromycin; manufacturer of lorat-  adine advises plasma concentration possibly  increased by erythromycin; metabolism of mizolas-  tine inhibited by •erythromycin — avoid concomitant  use; increased risk of ventricular arrhythmias when  mizolastine given with •moxifloxacin — avoid con-  comitant use; effects of fexofenadine possibly  reduced by rifampicin; metabolism of mizolastine  possibly inhibited by •macrolides (avoid concomi-  tant use)   Antidepressants: increased antimuscarinic and seda-  tive effects when antihistamines given with  MAOIs or tricyclics; cyproheptadine possibly antag-  onises antidepressant effect of SSRIs; possible  increased antimuscarinic and sedative effects when  antihistamines given with tricyclic-related anti-  depressants   Antidiabetics: thrombocyte count depressed when  ketotifen given with metformin (manufacturer of  ketotifen advises avoid concomitant use)   increased by ketoconazole; manufacturer of lorat-  adine advises plasma concentration possibly  increased by ketoconazole; metabolism of mizolas-  tine inhibited by ^itraconazole or •ketoconazole —  avoid concomitant use; metabolism of mizolastine  possibly inhibited by •imidazoles (avoid concomitant  use)   Antimuscarinics: increased risk of antimuscarinic side-  effects when antihistamines given with antimusca-  rinics   possibly increased by lopinavir; plasma concentra-  tion of non-sedating antihistamines possibly  increased by ritonavir; increased risk of ventricular  arrhythmias when mizolastine given with  •saquinavir — avoid concomitant use  Anxiolytics and Hypnotics: increased sedative effect  when antihistamines given with anxiolytics and  hypnotics   Histamine: antihistamines theoretically antagonise  effects of histamine — manufacturer of histamine  advises avoid concomitant use  Ulcer-healing Drugs: manufacturer of loratadine  advises plasma concentration possibly increased by  cimetidine   Antimalarials see Artemether with Lumefantrine,  Chloroquine and Hydroxychloroquine, Mefloquine,  Primaquine, Proguanil, Pyrimethamine, and  Quinine   Antimetabolites see Cytarabine, Fludarabine, Fluoro-  uracil, Gemcitabine, Mercaptopurine, Metho-  trexate, Pemetrexed, Raltitrexed, and Tioguanine   Note Many drugs have antimuscarinic effects; concomitant  use of two or more such drugs can increase side-effects such  as dry mouth, urine retention, and constipation; concomi-  tant use can also lead to confusion in the elderly. Interac-  tions do not generally apply to antimuscarinics used by  inhalation   Analgesics: increased risk of antimuscarinic side-  effects when antimuscarinics given with nefopam   thmias when tolterodine given with •amiodarone,  •disopyramide or •flecainide; increased risk of  antimuscarinic side-effects when antimuscarinics  given with disopyramide   Antibacterials: manufacturer of fesoterodine advises  dose reduction when fesoterodine given with  clarithromycin and telithromycin — consult fesotero-  dine product literature; manufacturer of tolterodine  advises avoid concomitant use with  clarithromycin and erythromycin; plasma concen-  tration of darifenacin possibly increased by erythro-  mycin; plasma concentration of active metabolite of  fesoterodine reduced by rifampicin  Antidepressants: plasma concentration of  darifenacin and procyclidine increased by par-  oxetine; increased risk of antimuscarinic side-effects  when antimuscarinics given with MAOIs or tricyc-  lics; possibly increased antimuscarinic side-effects  when antimuscarinics given with tricyclic-related  antidepressants   Antifungals: antimuscarinics reduce absorption of  ketoconazole; manufacturer of fesoterodine advises  dose reduction when fesoterodine given with  itraconazole and ketoconazole — consult fesotero-  dine product literature; plasma concentration of  darifenacin increased by ketoconazole — avoid con-  comitant use; plasma concentration of solifenacin  increased by itraconazole and ketoconazole; manu-  facturer of tolterodine advises avoid concomitant use  with itraconazole and ketoconazole; manufacturer of  darifenacin advises avoid concomitant use with  itraconazole   Antihistamines: increased risk of antimuscarinic side-  effects when antimuscarinics given with antihist-  amines   Antipsychotics: antimuscarinics possibly reduce  effects of haloperidol; increased risk of anti-  muscarinic side-effects when antimuscarinics given  with clozapine; antimuscarinics reduce plasma con-  centration of phenothiazines, but risk of anti-  muscarinic side-effects increased  Antivirals: manufacturer of fesoterodine advises dose  reduction when fesoterodine given with atazanavir,  indinavir, nelfinavir, ritonavir and saquinavir —  consult fesoterodine product literature; manufacturer  of darifenacin advises avoid concomitant use with  atazanavir, fosamprenavir, indinavir, lopinavir, nelfi-  navir, ritonavir, saquinavir and tipranavir; manufac-  turer of tolterodine advises avoid concomitant use  with fosamprenavir, indinavir, lopinavir, nelfinavir,  ritonavir and saquinavir; plasma concentration of  solifenacin increased by nelfinavir and ritonavir   mias when tolterodine given with •sotalol  Calcium-channel Blockers: manufacturer of darifena-  cin advises avoid concomitant use with verapamil  Cardiac Glycosides: darifenacin possibly increases  plasma concentration of digoxin  Ciclosporin: manufacturer of darifenacin advises avoid  concomitant use with ciclosporin  Domperidone: antimuscarinics antagonise effects of  domperidone on gastro-intestinal activity  Dopaminergics: antimuscarinics possibly reduce  absorption of levodopa   Metoclopramide: antimuscarinics antagonise effects  of metoclopramide on gastro-intestinal activity  Nitrates: antimuscarinics possibly reduce effects of  sublingual tablets of nitrates (failure to dissolve  under tongue owing to dry mouth)  Parasympathomimetics: antimuscarinics antagonise  effects of parasympathomimetics   Note Avoid concomitant use of clozapine with drugs that  have a substantial potential for causing agranulocytosis  ACE Inhibitors: enhanced hypotensive effect when  antipsychotics given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when phenothiazines given with adrenergic  neurone blockers; higher doses of chlorpromazine  antagonise hypotensive effect of adrenergic neurone  blockers; haloperidol antagonises hypotensive effect  of adrenergic neurone blockers  Adsorbents: absorption of phenothiazines possibly  reduced by kaolin   peridol given with indometacin; increased risk of  ventricular arrhythmias when antipsychotics that  prolong the QT interval given with •methadone;  increased risk of ventricular arrhythmias when  amisulpride given with •methadone — avoid conco-  mitant use; increased risk of convulsions when  antipsychotics given with tramadol; enhanced  hypotensive and sedative effects when antipsy-  chotics given with opioid analgesics  Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when antipsychotics given with  angiotensin-II receptor antagonists  Antacids: absorption of phenothiazines and sulpiride  reduced by antacids   thmias when antipsychotics that prolong the QT  interval given with ©anti-arrhythmics that prolong  the QT interval; increased risk of ventricular arrhy-  thmias when amisulpride, droperidol, haloperidol,  phenothiazines, pimozide or zuclopenthixol given  with •amiodarone — avoid concomitant use;  increased risk of ventricular arrhythmias when ben-  peridol given with •amiodarone — manufacturer of  benperidol advises avoid concomitant use; increased  risk of ventricular arrhythmias when sulpiride given  with •amiodarone or •disopyramide; possible  increased risk of ventricular arrhythmias when  haloperidol given with •disopyramide — avoid con-  comitant use; increased risk of ventricular arrhyth-  mias when amisulpride, droperidol, pimozide or  zuclopenthixol given with •disopyramide — avoid  concomitant use; increased risk of ventricular  arrhythmias when phenothiazines given with  •disopyramide; avoidance of phenothiazines advised  by manufacturer of *dronedarone (risk of ventricular  arrhythmias); increased risk of arrhythmias when  clozapine given with •flecainide   mias when pimozide given with •clarithromycin,  •moxifloxacin or •telithromycin — avoid concomi-  tant use; increased risk of ventricular arrhythmias  when amisulpride given with •erythromycin — avoid  concomitant use; plasma concentration of clozapine  possibly increased by •erythromycin (possible  increased risk of convulsions); possible increased risk  of ventricular arrhythmias when pimozide given with  •erythromycin — avoid concomitant use; increased  risk of ventricular arrhythmias when sulpiride given  with parenteral •erythromycin; increased risk of  ventricular arrhythmias when zuclopenthixol given  with parenteral •erythromycin — avoid concomitant  use; plasma concentration of clozapine increased by  ciprofloxacin; plasma concentration of olanzapine  possibly increased by ciprofloxacin; increased risk of  ventricular arrhythmias when droperidol, halo-   peridol, phenothiazines or zuclopenthixol given  with •moxifloxacin — avoid concomitant use;  increased risk of ventricular arrhythmias when  benperidol given with •moxifloxacin — manufac-  turer of benperidol advises avoid concomitant  use; plasma concentration of aripiprazole possi-  bly reduced by •rifabutin and •rifampicin —  increase dose of aripiprazole; plasma concentra-  tion of clozapine possibly reduced by rifampicin;  metabolism of haloperidol accelerated by  •rifampicin (reduced plasma concentration);  avoid concomitant use of clozapine with  •chloramphenicol or •sulfonamides (increased  risk of agranulocytosis); plasma concentration of  quetiapine possibly increased by macrolides  (reduce dose of quetiapine); manufacturer of  droperidol advises avoid concomitant use with  •macrolides (risk of ventricular arrhythmias)   possibly increased by citalopram (increased risk of  toxicity); metabolism of aripiprazole possibly inhib-  ited by •fluoxetine and •paroxetine (reduce dose of  aripiprazole); plasma concentration of clozapine,  haloperidol and risperidone increased by •fluoxetine;  manufacturer of droperidol advises avoid concomi-  tant use with •fluoxetine, •fluvoxamine,   •sertraline or •tricyclics (risk of ventricular arrhyth-  mias); plasma concentration of clozapine and olan-  zapine increased by •fluvoxamine; plasma  concentration of haloperidol possibly increased by  fluvoxamine; plasma concentration of clozapine  increased by •paroxetine, •sertraline and  •venlafaxine; plasma concentration of risperidone  possibly increased by paroxetine (increased risk of  toxicity); metabolism of perphenazine inhibited by  paroxetine (reduce dose of perphenazine); plasma  concentration of haloperidol increased by venlafax-  ine; clozapine possibly increases CNS effects of  •MAOIs; plasma concentration of pimozide possibly  increased by ©SSRIs (increased risk of ventricular  arrhythmias — avoid concomitant use); plasma con-  centration of aripiprazole possibly reduced by ©St  John’s wort — increase dose of aripiprazole;  increased risk of antimuscarinic side-effects when  phenothiazines given with tricyclics; increased risk of  ventricular arrhythmias when pimozide given with  •tricyclics — avoid concomitant use; possibly  increased antimuscarinic side-effects when clozapine  given with tricyclics; antipsychotics increase plasma  concentration of •tricyclics — possibly increased risk  of ventricular arrhythmias  Antidiabetics: phenothiazines possibly antagonise  hypoglycaemic effect of sulfonylureas   quetiapine and risperidone accelerated by carba-  mazepine (reduced plasma concentration); metab-  olism of clozapine accelerated by •carbamazepine  (reduced plasma concentration), also avoid conco-  mitant use of drugs with substantial potential for  causing agranulocytosis; plasma concentration of  aripiprazole reduced by •carbamazepine — increase  dose of aripiprazole; plasma concentration of pali-  peridone reduced by carbamazepine; antipsychotics  antagonise anticonvulsant effect of •carbamazepine,  •ethosuximide, •oxcarbazepine, •phenytoin,  •primidone and • valproate (convulsive threshold  lowered); chlorpromazine possibly increases or  decreases plasma concentration of phenytoin;  metabolism of clozapine and quetiapine accelerated  by phenytoin (reduced plasma concentration);  plasma concentration of aripiprazole possibly  reduced by •phenytoin and •primidone — increase  dose of aripiprazole; plasma concentration of halo-  peridol reduced by phenytoin; metabolism of halo-  peridol accelerated by primidone (reduced plasma   concentration); plasma concentration of quetia-  pine possibly increased by valproate; increased  risk of side-effects including neutropenia when  olanzapine given with •valproate; plasma con-  centration of clozapine possibly increased or  decreased by valproate   •ketoconazole (reduce dose of aripiprazole); metab-  olism of aripiprazole possibly inhibited by  •itraconazole (reduce dose of aripiprazole); plasma  concentration of haloperidol possibly increased by  itraconazole; increased risk of ventricular arrhyth-  mias when pimozide given with •imidazoles or  •triazoles — avoid concomitant use; plasma concen-  tration of quetiapine possibly increased by  imidazoles and triazoles (reduce dose of quetiapine)   manufacturer of •artemether/lumefantrine;  increased risk of ventricular arrhythmias when dro-  peridol given with •chloroquine and  hydroxychloroquine or •quinine — avoid concomitant  use; increased risk of ventricular arrhythmias when  pimozide given with •mefloquine or •quinine — avoid  concomitant use; possible increased risk of ventri-  cular arrhythmias when haloperidol given with  •mefloquine or •quinine — avoid concomitant use  Antimuscarinics: increased risk of antimuscarinic side-  effects when clozapine given with antimuscarinics;  plasma concentration of phenothiazines reduced by  antimuscarinics, but risk of antimuscarinic side-  effects increased; effects of haloperidol possibly  reduced by antimuscarinics   mias when amisulpride, pimozide or sulpiride given  with •droperidol — avoid concomitant use; increased  risk of ventricular arrhythmias when phenothiazines  that prolong the QT interval given with  •droperidol — avoid concomitant use; avoid conco-  mitant use of clozapine with depot formulation of  •flupentixol, •fluphenazine, •haloperidol,  •pipotiazine, •risperidone or •zuclopenthixol as  cannot be withdrawn quickly if neutropenia occurs;  increased risk of ventricular arrhythmias when sul-  piride given with •haloperidol; chlorpromazine  possibly increases plasma concentration of halo-  peridol; increased risk of ventricular arrhythmias  when droperidol given with •haloperidol — avoid  concomitant use; increased risk of ventricular  arrhythmias when pimozide given with  •phenothiazines — avoid concomitant use; increased  risk of ventricular arrhythmias when pimozide given  with •sulpiride   ited by •atazanavir, •fosamprenavir, •indinavir,  •lopinavir, •nelfinavir, •ritonavir and •saquinavir  (reduce dose of aripiprazole); plasma concentration  of pimozide possibly increased by *atazanavir —  avoid concomitant use; plasma concentration of  pimozide possibly increased by •efavirenz,  •indinavir, •nelfinavir and ©saquinavir (increased risk  of ventricular arrhythmias — avoid concomitant use);  plasma concentration of aripiprazole possibly  reduced by ©efavirenz and ©nevirapine — increase  dose of aripiprazole; plasma concentration of  pimozide increased by ©fosamprenavir and ©ritonavir  (increased risk of ventricular arrhythmias — avoid  concomitant use); plasma concentration of clozapine  increased by ©ritonavir (increased risk of toxicity) —  avoid concomitant use; plasma concentration of  antipsychotics possibly increased by ©ritonavir;  plasma concentration of olanzapine reduced by  ritonavir — consider increasing dose of olanzapine;  increased risk of ventricular arrhythmias when cloz-  apine, haloperidol or phenothiazines given with  •saquinavir — avoid concomitant use   when antipsychotics given with anxiolytics and  hypnotics; serious adverse events reported with  concomitant use of clozapine and •lorazepam  (causality not established); increased risk of hypo-  tension, bradycardia and respiratory depression  when intramuscular olanzapine given with par-  enteral •benzodiazepines; plasma concentration of  haloperidol increased by buspirone   convulsant effect of ^barbiturates (convulsive  threshold lowered); metabolism of haloperidol  accelerated by phenobarbital (reduced plasma con-  centration); plasma concentration of both drugs  reduced when chlorpromazine given with pheno-  barbital; plasma concentration of aripiprazole possi-  bly reduced by *phenobarbital — increase dose of  aripiprazole   phenothiazines given with beta-blockers; plasma  concentration of both drugs may increase when  chlorpromazine given with *propranolol; increased  risk of ventricular arrhythmias when amisulpride,  phenothiazines, pimozide or sulpiride given with  •sotalol; increased risk of ventricular arrhythmias  when droperidol or zuclopenthixol given with  •sotalol — avoid concomitant use; possible increased  risk of ventricular arrhythmias when haloperidol  given with •sotalol — avoid concomitant use   Calcium-channel Blockers: enhanced hypotensive  effect when antipsychotics given with calcium-  channel blockers   •cytotoxics (increased risk of agranulocytosis);  avoidance of pimozide advised by manufacturer of  •lapatinib; increased risk of ventricular arrhythmias  when haloperidol given with *arsenic trioxide;  increased risk of ventricular arrhythmias when anti-  psychotics that prolong the QT interval given with  •arsenic trioxide   Desferrioxamine: manufacturer of levomepromazine  advises avoid concomitant use with desferrioxamine;  avoidance of prochlorperazine advised by manufac-  turer of desferrioxamine   pride increased by hypokalaemia caused by  •diuretics; risk of ventricular arrhythmias with  pimozide increased by hypokalaemia caused by  •diuretics (avoid concomitant use); enhanced hypo-  tensive effect when phenothiazines given with diur-  etics   Dopaminergics: increased risk of extrapyramidal side-  effects when antipsychotics given with amantadine;  antipsychotics antagonise effects of apomorphine,  levodopa and pergolide; antipsychotics antagonise  hypoprolactinaemic and antiparkinsonian effects of  bromocriptine and cabergoline; manufacturer of  amisulpride advises avoid concomitant use of levo-  dopa (antagonism of effect); avoidance of antipsy-  chotics advised by manufacturer of pramipexole,  ropinirole and rotigotine (antagonism of effect)   when pimozide given with *ivabradine  Lithium : increased risk of extrapyramidal side-effects  and possibly neurotoxicity when clozapine, flupen-  tixol, haloperidol, phenothiazines or zuclopenthixol  given with lithium; possible risk of toxicity when  olanzapine given with lithium; increased risk of  extrapyramidal side-effects when sulpiride given  with lithium   Methyldopa: enhanced hypotensive effect when anti-  psychotics given with methyldopa (also increased  risk of extrapyramidal effects)   Metoclopramide: increased risk of extrapyramidal  side-effects when antipsychotics given with meto-  clopramide   Moxonidine: enhanced hypotensive effect when  phenothiazines given with moxonidine  Muscle Relaxants: promazine possibly enhances  effects of suxamethonium   arrhythmias when amisulpride or droperidol given  with •pentamidine isetionate — avoid concomitant  use; increased risk of ventricular arrhythmias when  phenothiazines given with •pentamidine isetionate  Sodium Benzoate: haloperidol possibly reduces  effects of sodium benzoate  Sodium Oxybate: antipsychotics possibly enhance  effects of sodium oxybate   Sodium Phenylbutyrate: haloperidol possibly reduces  effects of sodium phenylbutyrate  Sympathomimetics: antipsychotics antagonise hyper-  tensive effect of sympathomimetics; antipsychotic  effects of chlorpromazine possibly antagonised by  dexamfetamine; side-effects of risperidone possibly  increased by methylphenidate   Tetrabenazine: increased risk of extrapyramidal side-  effects when antipsychotics given with tetrabenazine  Ulcer-healing Drugs: effects of antipsychotics,  chlorpromazine and clozapine possibly enhanced by  cimetidine; plasma concentration of clozapine pos-  sibly reduced by omeprazole; absorption of sulpiride  reduced by sucralfate   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when phenothiazines given with hydral-  azine, minoxidil or sodium nitroprusside   Antivirals see Abacavir, Aciclovir, Adefovir, Atazanavir,  Cidofovir, Darunavir, Didanosine, Efavirenz, Emtri-  citabine, Etravirine, Famciclovir, Fosamprenavir,  Foscarnet, Ganciclovir, Indinavir, Lamivudine,  Lopinavir, Maraviroc, Nelfinavir, Nevirapine, Ralte-  gravir, Ribavirin, Ritonavir, Saquinavir, Stavudine,  Telbivudine, Tenofovir, Tipranavir, Valaciclovir, and  Zidovudine   Anxiolytics and Hypnotics  ACE Inhibitors: enhanced hypotensive effect when  anxiolytics and hypnotics given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when anxiolytics and hypnotics given with  adrenergic neurone blockers  Alcohol: increased sedative effect when anxiolytics  and hypnotics given with alcohol  Alpha-blockers: enhanced hypotensive and sedative  effects when anxiolytics and hypnotics given with  alpha-blockers   Anaesthetics, General: increased sedative effect when  anxiolytics and hypnotics given with general anaes-  thetics   Analgesics: metabolism of midazolam possibly inhib-  ited by fentanyl; increased sedative effect when  anxiolytics and hypnotics given with opioid anal-  gesics   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when anxiolytics and hypnotics  given with angiotensin-II receptor antagonists   •clarithromycin, •erythromycin and •telithromycin  (increased plasma concentration with increased  sedation); plasma concentration of buspirone  increased by erythromycin (reduce dose of buspir-  one); metabolism of zopiclone inhibited by erythro-  mycin; metabolism of benzodiazepines possibly  accelerated by rifampicin (reduced plasma concen-  tration); metabolism of diazepam accelerated by  rifampicin (reduced plasma concentration); metab-  olism of buspirone and zaleplon possibly accelerated  by rifampicin; metabolism of zolpidem accelerated  by rifampicin (reduced plasma concentration and  reduced effect); plasma concentration of zopiclone  significantly reduced by rifampicin; metabolism of  diazepam inhibited by isoniazid  Anticoagulants: chloral and triclofos may transiently  enhance anticoagulant effect of coumarins   increased by fluoxetine; plasma concentration of  melatonin increased by •fluvoxamine — avoid con-  comitant use; plasma concentration of some benzo-  diazepines increased by fluvoxamine; sedative  effects possibly increased when zolpidem given with  sertraline; manufacturer of buspirone advises avoid  concomitant use with MAOIs; avoidance of buspir-  one for 10 days after stopping tranylcypromine  advised by manufacturer of tranylcypromine; plasma  concentration of oral midazolam possibly reduced  by St John’s wort; increased sedative effect when  anxiolytics and hypnotics given with mirtazapine,  tricyclic-related antidepressants or tricyclics  Antiepileptics: plasma concentration of midazolam  reduced by carbamazepine; plasma concentration of  clonazepam often reduced by carbamazepine,  phenytoin and primidone; benzodiazepines possibly  increase or decrease plasma concentration of  phenytoin; diazepam increases or decreases plasma  concentration of phenytoin; plasma concentration of  clobazam increased by stiripentol; clobazam possibly  increases plasma concentration of valproate; plasma  concentration of diazepam and lorazepam possibly  increased by valproate; increased risk of side-effects  when clonazepam given with valproate   increased by itraconazole and ketoconazole; plasma  concentration of midazolam increased by  •fluconazole, •itraconazole and •ketoconazole (risk  of prolonged sedation); plasma concentration of  buspirone increased by itraconazole (reduce dose of  buspirone); plasma concentration of midazolam  increased by •posaconazole  Antihistamines: increased sedative effect when  anxiolytics and hypnotics given with antihistamines   anxiolytics and hypnotics given with antipsychotics;  buspirone increases plasma concentration of halo-  peridol; serious adverse events reported with con-  comitant use of lorazepam and •clozapine (causality  not established); increased risk of hypotension,  bradycardia and respiratory depression when par-  enteral benzodiazepines given with intramuscular  •olanzapine   bly increased by •atazanavir — avoid concomitant  use of oral midazolam; increased risk of prolonged  sedation when midazolam given with «efavirenz —  avoid concomitant use; plasma concentration of  midazolam possibly increased by •fosamprenavir,  •indinavir, •nelfinavir and •ritonavir (risk of pro-   longed sedation — avoid concomitant use of oral  midazolam); increased risk of prolonged sedation  when alprazolam given with •indinavir — avoid  concomitant use; plasma concentration of alpra-  zolam, diazepam, flurazepam and zolpidem  possibly increased by •ritonavir (risk of extreme  sedation and respiratory depression — avoid  concomitant use); plasma concentration of  anxiolytics and hypnotics possibly increased by  •ritonavir; plasma concentration of buspirone  increased by ritonavir (increased risk of toxicity);  plasma concentration of midazolam increased by  •saquinavir (risk of prolonged sedation — avoid  concomitant use of oral midazolam)   Aprepitant: plasma concentration of midazolam  increased by aprepitant (risk of prolonged sedation)  Barbiturates: plasma concentration of clonazepam  often reduced by phenobarbital  Beta-blockers: enhanced hypotensive effect when  anxiolytics and hypnotics given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when anxiolytics and hypnotics given with  calcium-channel blockers; midazolam increases  absorption of lercanidipine; plasma concentration of  buspirone increased by diltiazem and verapamil  (reduce dose of buspirone); metabolism of mid-  azolam inhibited by diltiazem and verapamil  (increased plasma concentration with increased  sedation)   Cardiac Glycosides: alprazolam increases plasma  concentration of digoxin (increased risk of toxicity)  Clonidine: enhanced hypotensive effect when anxio-  lytics and hypnotics given with clonidine  Cytotoxics: plasma concentration of midazolam  increased by nilotinib   Deferasirox: plasma concentration of midazolam  possibly reduced by deferasirox  Diazoxide: enhanced hypotensive effect when anxio-  lytics and hypnotics given with diazoxide  Disulfiram: metabolism of benzodiazepines inhibited  by disulfiram (increased sedative effects); increased  risk of temazepam toxicity when given with disulf-  iram   Diuretics: enhanced hypotensive effect when anxio-  lytics and hypnotics given with diuretics; adminis-  tration of chloral or triclofos with parenteral  furosemide may displace thyroid hormone from  binding sites   Grapefruit Juice: plasma concentration of buspirone  increased by grapefruit juice  Lithium : increased risk of neurotoxicity when clon-  azepam given with lithium   Lofexidine: increased sedative effect when anxiolytics  and hypnotics given with lofexidine  Methyldopa: enhanced hypotensive effect when  anxiolytics and hypnotics given with methyldopa  Moxonidine: enhanced hypotensive effect when  anxiolytics and hypnotics given with moxonidine;  sedative effects possibly increased when benzodiaz-  epines given with moxonidine  Muscle Relaxants: increased sedative effect when  anxiolytics and hypnotics given with baclofen or  tizanidine   Nabilone: increased sedative effect when anxiolytics  and hypnotics given with nabilone  Nitrates: enhanced hypotensive effect when anxio-  lytics and hypnotics given with nitrates  Oestrogens: plasma concentration of melatonin  increased by oestrogens   Probenecid: excretion of lorazepam reduced by pro-  benecid (increased plasma concentration); excretion  of nitrazepam possibly reduced by probenecid  (increased plasma concentration)   Ulcer-healing Drugs: plasma concentration of mela-  tonin increased by cimetidine; metabolism of  benzodiazepines, clomethiazole and zaleplon inhib-  ited by cimetidine (increased plasma concentration);  metabolism of diazepam possibly inhibited by  esomeprazole and omeprazole (increased plasma  concentration)   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when anxiolytics and hypnotics given with  hydralazine, minoxidil or sodium nitroprusside   Dopaminergics: effects of apomorphine possibly  enhanced by entacapone  Memantine: effects of dopaminergics possibly  enhanced by memantine   Antidepressants: manufacturer of apraclonidine  advises avoid concomitant use with MAO Is, tricyclic-  related antidepressants and tricyclics   Note Fosaprepitant is a prodrug of aprepitant  Antibacterials: plasma concentration of aprepitant  possibly increased by clarithromycin and telithro-  mycin; plasma concentration of aprepitant reduced  by rifampicin   Antiepileptics: plasma concentration of aprepitant  possibly reduced by carbamazepine and phenytoin  Antifun gals: plasma concentration of aprepitant  increased by ketoconazole   Anxiolytics and Hypnotics: aprepitant increases  plasma concentration of midazolam (risk of pro-  longed sedation)   Barbiturates: plasma concentration of aprepitant  possibly reduced by phenobarbital  Calcium-channel Blockers: plasma concentration of  both drugs may increase when aprepitant given with  diltiazem   Corticosteroids: aprepitant inhibits metabolism of  dexamethasone and methylprednisolone (reduce  dose of dexamethasone and methylprednisolone)   tive failure of hormonal contraceptives containing  •progestogens (alternative contraception recom-  mended)   mias when arsenic trioxide given with  •antipsychotics that prolong the QT interval;  increased risk of ventricular arrhythmias when  arsenic trioxide given with •haloperidol; avoid  concomitant use of cytotoxics with •clozapine  (increased risk of agranulocytosis)   trioxide increased by hypokalaemia caused by  •acetazolamide, *loop diuretics or *thiazides and  related diuretics   fantrine advises avoid concomitant use with  •amiodarone, •disopyramide or •flecainide (risk of  ventricular arrhythmias)   trine advises avoid concomitant use with  •antimalarials; increased risk of ventricular arrhyth-  mias when artemether/lumefantrine given with  •quinine   Antivirals: manufacturer of artemether/lumefantrine  advises caution with atazanavir, darunavir, fosam-  prenavir, indinavir, lopinavir, nelfinavir, ritonavir,  saquinavir and tipranavir   Grapefruit Juice: plasma concentration of artemether/  lumefantrine possibly increased by grapefruit juice  Histamine: avoidance of antimalarials advised by  manufacturer of histamine   •NSAIDs (increased side-effects); antiplatelet effect  of aspirin possibly reduced by ibuprofen  Antacids: excretion of aspirin increased by alkaline  urine due to some antacids   aspirin given with •coumarins or •phenindione (due  to antiplatelet effect); aspirin enhances anticoagulant  effect of •heparins   Corticosteroids: increased risk of gastro-intestinal  bleeding and ulceration when aspirin given with  corticosteroids, also corticosteroids reduce plasma  concentration of salicylate   (increased risk of toxicity) — but for concomitant use  in rheumatic disease see p. 647  Diuretics: aspirin antagonises diuretic effect of  spironolactone; increased risk of toxicity when high-  dose aspirin given with carbonic anhydrase inhibitors  lloprost: increased risk of bleeding when aspirin given  with iloprost   Leukotriene Receptor Antagonists: aspirin increases  plasma concentration of zafirlukast  Metoclopramide: rate of absorption of aspirin  increased by metoclopramide (enhanced effect)  Probenecid: aspirin antagonises effects of probenecid  Sulfinpyrazone: aspirin antagonises effects of sulfin-  pyrazone  Atazanavir   increased when atazanavir given with clarithro-  mycin; atazanavir increases plasma concentration of  •rifabutin (reduce dose of rifabutin); plasma con-  centration of atazanavir reduced by •rifampicin —  avoid concomitant use; avoidance of concomitant  atazanavir in severe renal and hepatic impairment  advised by manufacturer of •telithromycin  Anticoagulants: atazanavir may enhance or reduce  anticoagulant effect of warfarin; avoidance of ataza-  navir advised by manufacturer of rivaroxaban   manufacturer of artemether/lumefantrine; atazana-  vir possibly increases plasma concentration of  •quinine (increased risk of toxicity)   Anti m u sea rinics: avoidance of atazanavir advised by  manufacturer of darifenacin; manufacturer of feso-  terodine advises dose reduction when atazanavir  given with fesoterodine — consult fesoterodine  product literature   olism of •aripiprazole (reduce dose of aripiprazole);  atazanavir possibly increases plasma concentration  of •pimozide — avoid concomitant use   concomitant use with ©efavirenz (plasma concen-  tration of atazanavir reduced); avoid concomitant  use of atazanavir with ©indinavir; atazanavir  increases plasma concentration of •maraviroc (con-  sider reducing dose of maraviroc); plasma concen-  tration of atazanavir possibly reduced by  •nevirapine — avoid concomitant use; increased risk  of ventricular arrhythmias when atazanavir given  with ©saquinavir — avoid concomitant use; plasma  concentration of atazanavir reduced by tenofovir,  also plasma concentration of tenofovir possibly  increased; atazanavir increases plasma concentra-  tion of tipranavir (also plasma concentration of  atazanavir reduced)   •colchicine toxicity — suspend or reduce dose of  colchicine (avoid concomitant use in hepatic or renal  impairment)   centration of ©everolimus — manufacturer of ever-  olimus advises avoid concomitant use; avoidance of  atazanavir advised by manufacturer of ©pazopanib;  atazanavir possibly inhibits metabolism of  •irinotecan (increased risk of toxicity)   myopathy when atazanavir given with atorvastatin;  possible increased risk of myopathy when atazanavir  given with •rosuvastatin — manufacturer of rosuvas-  tatin advises avoid concomitant use; increased risk of  myopathy when atazanavir given with ©simvastatin  (avoid concomitant use)   when atomoxetine given with •methadone; possible  increased risk of convulsions when atomoxetine  given with tramadol   mias when atomoxetine given with parenteral  •erythromycin; increased risk of ventricular arrhy-  thmias when atomoxetine given with •moxifloxacin   inhibited by fluoxetine and paroxetine; possible  increased risk of convulsions when atomoxetine  given with antidepressants; atomoxetine should not  be started until 2 weeks after stopping ©MAOIs, also  MAO Is should not be started until at least 2 weeks  after stopping atomoxetine; increased risk of ventri-  cular arrhythmias when atomoxetine given with  •tricyclics   mias when atomoxetine given with •sotalol  Bupropion: possible increased risk of convulsions  when atomoxetine given with bupropion   Sympathomimetics, Beta 2 : Increased risk of cardio-  vascular side-effects when atomoxetine given with  parenteral salbutamol  Atorvastatin see Statins  Atovaquone   reduced by •rifabutin and •rifampicin (possible  therapeutic failure of atovaquone); plasma concen-  tration of atovaquone reduced by tetracycline  Antivirals: atovaquone possibly reduces plasma con-  centration of indinavir; atovaquone possibly inhibits  metabolism of zidovudine (increased plasma con-  centration)   Metoclopramide: plasma concentration of atovaquone  reduced by metoclopramide  Atracurium see Muscle Relaxants  Atropine see Antimuscarinics  Azathioprine   ACE Inhibitors: increased risk of anaemia or leuco-  penia when azathioprine given with captopril espe-  cially in renal impairment; increased risk of anaemia  when azathioprine given with enalapril especially in  renal impairment   azathioprine when given with •allopurinol (reduce  dose of azathioprine to one quarter of usual dose)  Aminosalicylates: possible increased risk of leuco-  penia when azathioprine given with aminosalicylates   city when azathioprine given with •sulfamethoxazole  (as co-trimoxazole); increased risk of haematological  toxicity when azathioprine given with •trimethoprim  (also with co-trimoxazole)   Analgesics: phenobarbital reduces plasma concentra-  tion of methadone; barbiturates possibly increase  CNS effects of opioid analgesics   of disopyramide (reduced plasma concentration);  phenobarbital possibly reduces plasma concentra-  tion of •dronedarone — avoid concomitant use   •chloramphenicol, doxycycline and metronidazole  (reduced plasma concentration); phenobarbital pos-  sibly reduces plasma concentration of rifampicin;  phenobarbital reduces plasma concentration of  •telithromycin (avoid during and for 2 weeks after  phenobarbital)   centration of paroxetine; phenobarbital accelerates  metabolism of •mianserin (reduced plasma concen-  tration); anticonvulsant effect of barbiturates possi-  bly antagonised by MAOIs and •tricyclic-related  antidepressants (convulsive threshold lowered);  anticonvulsant effect of barbiturates antagonised by  SSRIs (convulsive threshold lowered); avoid conco-   centration of carbamazepine, lamotrigine,  tiagabine and zonisamide; phenobarbital possibly  reduces plasma concentration of ethosuximide;  plasma concentration of phenobarbital increased by  oxcarbazepine, also plasma concentration of an  active metabolite of oxcarbazepine reduced; plasma  concentration of phenobarbital often increased by  phenytoin, plasma concentration of phenytoin often  reduced but may be increased; increased sedative  effect when barbiturates given with primidone;  phenobarbital possibly reduces plasma concentra-  tion of rufinamide, also plasma concentration of  phenobarbital possibly increased; plasma concen-  tration of phenobarbital increased by •stiripentol;  plasma concentration of phenobarbital increased by  valproate (also plasma concentration of valproate  reduced); plasma concentration of phenobarbital  possibly reduced by vigabatrin   concentration of itraconazole and •posaconazole;  phenobarbital possibly reduces plasma concentra-  tion of •voriconazole — avoid concomitant use;  phenobarbital reduces absorption of griseofulvin  (reduced effect)   antagonised by •antipsychotics (convulsive thresh-  old lowered); phenobarbital accelerates metabolism  of haloperidol (reduced plasma concentration);  plasma concentration of both drugs reduced when  phenobarbital given with chlorpromazine; pheno-  barbital possibly reduces plasma concentration of  •aripiprazole — increase dose of aripiprazole   barbital advised by manufacturer of etravirine; bar-  biturates possibly reduce plasma concentration of  •indinavir, •nelfinavir and •saquinavir; phenobarbital  possibly reduces plasma concentration of •indinavir,  also plasma concentration of phenobarbital possibly  increased   Anxiolytics and Hypnotics: phenobarbital often  reduces plasma concentration of clonazepam  Aprepitant: phenobarbital possibly reduces plasma  concentration of aprepitant  Beta-blockers: barbiturates reduce plasma concen-  tration of metoprolol and timolol; barbiturates  possibly reduce plasma concentration of propranolol   of •felodipine and •isradipine; barbiturates probably  reduce effects of •dihydropyridines, •diltiazem and  •verapamil   Cytotoxics: avoidance of barbiturates advised by  manufacturer of gefitinib; phenobarbital possibly  reduces plasma concentration of etoposide; pheno-  barbital reduces plasma concentration of irinotecan  and its active metabolite   Hormone Antagonists: barbiturates possibly acceler-  ate metabolism of toremifene (reduced plasma  concentration)   Leukotriene Receptor Antagonists: phenobarbital  reduces plasma concentration of montelukast  Lofexidine: increased sedative effect when barbitur-  ates given with lofexidine   •sodium oxybate (avoid concomitant use)  Sympathomimetics: plasma concentration of pheno-  barbital possibly increased by methylphenidate   Thyroid Hormones: barbiturates accelerate metab-  olism of thyroid hormones (may increase require-  ments for thyroid hormones in hypothyroidism)  Tibolone: barbiturates accelerate metabolism of tibol-  one (reduced plasma concentration)   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Bendroflumethiazide see Diuretics  Ben peri do l see Antipsychotics  Benzodiazepines see Anxiolytics and Hypnotics  Benzthiazide see Diuretics  Benzylpenicillin see Penicillins  Beta-blockers   Note Since systemic absorption may follow topical appli-  cation of beta-blockers to the eye the possibility of interac-  tions, in particular, with drugs such as verapamil should be  borne in mind   ACE Inhibitors: enhanced hypotensive effect when  beta-blockers given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when beta-blockers given with adrenergic  neurone blockers   Alcohol: enhanced hypotensive effect when beta-  blockers given with alcohol  Aldesleukin: enhanced hypotensive effect when beta-  blockers given with aldesleukin   beta-blockers given with •alpha-blockers, also  increased risk of first-dose hypotension with post-  synaptic alpha-blockers such as prazosin  Anaesthetics, General: enhanced hypotensive effect  when beta-blockers given with general anaesthetics   Analgesics: hypotensive effect of beta-blockers  antagonised by NSAIDs; plasma concentration of  esmolol possibly increased by morphine  Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when beta-blockers given with  angiotensin-II receptor antagonists   when beta-blockers given with •anti-arrhythmics;  increased risk of bradycardia, AV block and myo-  cardial depression when beta-blockers given with  •amiodarone; increased risk of ventricular arrhyth-   mias when sotalol given with •amiodarone,  •disopyramide or •dronedarone — avoid conco-  mitant use; plasma concentration of  metoprolol and propranolol possibly increased  by dronedarone; increased risk of myocardial  depression and bradycardia when beta-blockers  given with •flecainide; propranolol increases risk  of •lidocaine toxicity; plasma concentration of  metoprolol and propranolol increased by propa-  fenone   mias when sotalol given with •moxifloxacin — avoid  concomitant use; metabolism of bisoprolol and  propranolol accelerated by rifampicin (plasma con-  centration significantly reduced); plasma concentra-  tion of carvedilol, celiprolol and metoprolol reduced  by rifampicin   increased by citalopram and escitalopram; plasma  concentration of propranolol increased by fluvox-  amine; plasma concentration of metoprolol possibly  increased by paroxetine (enhanced effect);  labetalol and propranolol increase plasma concen-  tration of imipramine; enhanced hypotensive effect  when beta-blockers given with MAOIs; increased  risk of ventricular arrhythmias when sotalol given  with •tricyclics   Antidiabetics: beta-blockers may mask warning signs  of hypoglycaemia (such as tremor) with anti-  diabetics; beta-blockers enhance hypoglycaemic  effect of insulin   advised by manufacturer of •artemether/lumefan-  trine; increased risk of bradycardia when beta-  blockers given with mefloquine   mias when sotalol given with •droperidol or  •zuclopenthixol — avoid concomitant use; possible  increased risk of ventricular arrhythmias when  sotalol given with •haloperidol — avoid concomitant  use; plasma concentration of both drugs may  increase when propranolol given with  •chlorpromazine; increased risk of ventricular  arrhythmias when sotalol given with •amisulpride,  •phenothiazines, •pimozide or •sulpiride; enhanced  hypotensive effect when beta-blockers given with  phenothiazines   when sotalol given with *saquinavir — avoid conco-  mitant use; avoidance of metoprolol for heart failure  advised by manufacturer of »tipranavir  Anxiolytics and Hypnotics: enhanced hypotensive  effect when beta-blockers given with anxiolytics and  hypnotics   when sotalol given with •atomoxetine  Barbiturates: plasma concentration of metoprolol and  timolol reduced by barbiturates; plasma concentra-  tion of propranolol possibly reduced by barbiturates   effect when beta-blockers given with calcium-  channel blockers; possible severe hypotension and  heart failure when beta-blockers given with  •nifedipine; increased risk of AV block and brady-  cardia when beta-blockers given with •diltiazem;  asystole, severe hypotension and heart failure when  beta-blockers given with •verapamil (see p. 133)  Cardiac Glycosides: increased risk of AV block and  bradycardia when beta-blockers given with cardiac  glycosides   when beta-blockers given with •clonidine (withdraw  beta-blockers several days before slowly withdraw-  ing clonidine)   blockers given with diuretics; risk of ventricular  arrhythmias with sotalol increased by hypokalaemia  caused by •loop diuretics or •thiazides and related  diuretics   Dopaminergics: enhanced hypotensive effect when  beta-blockers given with levodopa  Ergot Alkaloids: increased peripheral vasoconstriction  when beta-blockers given with ergotamine and  methysergide   5HTJ Agonists: propranolol increases plasma concen-  tration of rizatriptan (manufacturer of rizatriptan  advises halve dose and avoid within 2 hours of  propranolol)   when sotalol given with •ivabradine  Methyldopa: enhanced hypotensive effect when beta-  blockers given with methyldopa   when beta-blockers given with •moxisylyte  Moxonidine: enhanced hypotensive effect when beta-  blockers given with moxonidine  Muscle Relaxants: propranolol enhances effects of  muscle relaxants; enhanced hypotensive effect when  beta-blockers given with baclofen; possible  enhanced hypotensive effect and bradycardia when  beta-blockers given with tizanidine  Nitrates: enhanced hypotensive effect when beta-  blockers given with nitrates  Oestrogens: hypotensive effect of beta-blockers  antagonised by oestrogens  Parasympathomimetics: propranolol antagonises  effects of neostigmine and pyridostigmine; increased  risk of arrhythmias when beta-blockers given with  pilocarpine   tension and bradycardia when non-cardioselective  beta-blockers given with •adrenaline (epinephrine),  also reponse to adrenaline (epinephrine) may be  reduced; increased risk of severe hypertension and  bradycardia when non-cardioselective beta-blockers  given with •dobutamine; possible increased risk of  severe hypertension and bradycardia when non-  cardioselective beta-blockers given with •noradren-  aline (norepinephrine)   Ulcer-healing Drugs: plasma concentration of labeta-  lol, metoprolol and propranolol increased by cime-  tidine   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when beta-blockers given with hydral-  azine, minoxidil or sodium nitroprusside   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Anticoagulants: bicalutamide possibly enhances anti-  coagulant effect of coumarins  Biguanides see Antidiabetics  Bile Acid Sequestrants see Colesevelam, Colestipol,  and Colestyramine  Bile Acids see Ursodeoxycholic Acid  Bisoprolol see Beta-blockers  Bisphosphonates   Antibacterials: increased risk of hypocalcaemia when  bisphosphonates given with aminoglycosides  Calcium Salts: absorption of bisphosphonates reduced  by calcium salts   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   increased by ketoconazole; plasma concentration of  bosentan possibly increased by •fluconazole — avoid  concomitant use; plasma concentration of bosentan  possibly increased by itraconazole  Antivirals: plasma concentration of bosentan possibly  increased by ritonavir   increased by •ciclosporin (also plasma concentration  of ciclosporin reduced — avoid concomitant use)  Lipid-regulating Drugs: bosentan reduces plasma  concentration of simvastatin   Antidepressants: manufacturer of brimonidine  advises avoid concomitant use with MAOIs, tricyclic-  related antidepressants and tricyclics  Brinzolamide see Diuretics  Bromocriptine   Antibacterials: plasma concentration of bromocriptine  increased by erythromycin (increased risk of toxi-  city); plasma concentration of bromocriptine possi-  bly increased by macrolides (increased risk of  toxicity)   Antipsychotics: hypoprolactinaemic and anti-  parkinsonian effects of bromocriptine antagonised  by antipsychotics   Domperidone: hypoprolactinaemic effect of bromo-  criptine possibly antagonised by domperidone  Hormone Antagonists: plasma concentration of  bromocriptine increased by octreotide  Memantine: effects of dopaminergics possibly  enhanced by memantine   Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa  Metoclopramide: hypoprolactinaemic effect of  bromocriptine antagonised by metoclopramide   criptine given with •isometheptene  Buclizine see Antihistamines  Budesonide see Corticosteroids  Bumetanide see Diuretics  Bupivacaine   plasma concentration of citalopram; manufacturer of  bupropion advises avoid for 2 weeks after stopping  •MAOIs; manufacturer of bupropion advises avoid  concomitant use with •moclobemide; bupropion  possibly increases plasma concentration of tricyclics  (possible increased risk of convulsions)  Antiepileptics: plasma concentration of bupropion  reduced by carbamazepine and phenytoin; metab-  olism of bupropion inhibited by valproate  Antivirals: plasma concentration of bupropion reduced  by ritonavir   Atomoxetine: possible increased risk of convulsions  when bupropion given with atomoxetine  Dopaminergics: increased risk of side-effects when  bupropion given with amantadine or levodopa   Analgesics: metabolism of intravenous busulfan pos-  sibly inhibited by paracetamol (manufacturer of  intravenous busulfan advises caution within 72 hours  of paracetamol)   Antiepileptics: cytotoxics possibly reduce absorption  of phenytoin; plasma concentration of busulfan  possibly reduced by phenytoin  Antifungals: metabolism of busulfan inhibited by  itraconazole (increased risk of toxicity)   Cytotoxics: increased risk of hepatotoxicity when  busulfan given with tioguanine  Buto barbital see Barbiturates  Butyrophenones see Antipsychotics  Cabergoline   Antibacterials: plasma concentration of cabergoline  increased by erythromycin (increased risk of toxi-  city); plasma concentration of cabergoline possibly  increased by macrolides (increased risk of toxicity)  Antipsychotics: hypoprolactinaemic and anti-  parkinsonian effects of cabergoline antagonised by  antipsychotics   Domperidone: hypoprolactinaemic effect of cabergo-  line possibly antagonised by domperidone  Memantine: effects of dopaminergics possibly  enhanced by memantine   Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa  Metoclopramide: hypoprolactinaemic effect of caber-  goline antagonised by metoclopramide  Calcium Salts  Note see also Antacids   Antibacterials: calcium salts reduce absorption of  ciprofloxacin and tetracycline  Bisphosphonates: calcium salts reduce absorption of  bisphosphonates   Cardiac Glycosides: large intravenous doses of  calcium salts can precipitate arrhythmias when given  with cardiac glycosides   Diuretics: increased risk of hypercalcaemia when  calcium salts given with thiazides and related diur-  etics   Eltrombopag: calcium salts possibly reduce absorp-  tion of eltrombopag (give at least 4 hours apart)  Fluorides: calcium salts reduce absorption of fluorides  Iron: calcium salts reduce absorption of oral iron  Thyroid Hormones: calcium salts reduce absorption of  levothyroxine   Zinc: calcium salts reduce absorption of zinc  Calcium-channel Blockers  Note Dihydropyridine calcium-channel blockers include  amlodipine, felodipine, isradipine, lacidipine, lercanidipine,  nicardipine, nifedipine, and nimodipine  ACE Inhibitors: enhanced hypotensive effect when  calcium-channel blockers given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when calcium-channel blockers given with  adrenergic neurone blockers  Alcohol: enhanced hypotensive effect when calcium-  channel blockers given with alcohol; verapamil  possibly increases plasma concentration of alcohol  Aldesleukin: enhanced hypotensive effect when  calcium-channel blockers given with aldesleukin  Aliskiren: avoidance of verapamil advised by manu-  facturer of aliskiren   calcium-channel blockers given with •alpha-block-  ers, also increased risk of first-dose hypotension with  post-synaptic alpha-blockers such as prazosin   when calcium-channel blockers given with general  anaesthetics or isoflurane; hypotensive effect of  verapamil enhanced by •general anaesthetics (also  A V delay)   Analgesics: hypotensive effect of calcium-channel  blockers antagonised by NSAIDs; diltiazem inhibits  metabolism of alfentanil (risk of prolonged or  delayed respiratory depression)   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when calcium-channel blockers  given with angiotensin-II receptor antagonists   verapamil given with •amiodarone; increased  risk of myocardial depression and asystole when  verapamil given with •disopyramide or  •flecainide; increased risk of bradycardia and  myocardial depression when diltiazem and  verapamil given with »dronedarone; nifedipine  increases plasma concentration of »dronedarone   inhibited by •clarithromycin and •erythromycin  (increased risk of toxicity); metabolism of felodipine  possibly inhibited by erythromycin (increased  plasma concentration); manufacturer of lercanidi-  pine advises avoid concomitant use with erythro-  mycin; metabolism of diltiazem, nifedipine,  nimodipine and verapamil accelerated by  •rifampicin (plasma concentration significantly  reduced); metabolism of isradipine and nicardipine  possibly accelerated by •rifampicin (possible signifi-  cantly reduced plasma concentration)   inhibited by fluoxetine (increased plasma concen-  tration); diltiazem and verapamil increase plasma  concentration of imipramine; enhanced hypotensive  effect when calcium-channel blockers given with  MAOIs; plasma concentration of verapamil signifi-  cantly reduced by »St John’s wort; plasma concen-  tration of nifedipine reduced by St John’s wort;  plasma concentration of amlodipine possibly  reduced by St John’s wort; diltiazem and verapamil  possibly increase plasma concentration of tricyclics  Antidiabetics: glucose tolerance occasionally  impaired when nifedipine given with insulin   nicardipine and nifedipine probably reduced by  carbamazepine; diltiazem and verapamil enhance  effects of •carbamazepine; effects of felodipine and  isradipine reduced by carbamazepine; effects of  felodipine, isradipine and verapamil reduced by  phenytoin; effects of dihydropyridines,  nicardipine and nifedipine probably reduced by  •phenytoin; diltiazem increases plasma concentra-  tion of •phenytoin but also effect of diltiazem  reduced; effects of felodipine and isradipine reduced  by •primidone; effects of dihydropyridines,  diltiazem and verapamil probably reduced by  •primidone   inhibited by itraconazole and ketoconazole  (increased plasma concentration); metabolism of  felodipine inhibited by •itraconazole and  •ketoconazole (increased plasma concentration);  manufacturer of lercanidipine advises avoid conco-  mitant use with itraconazole and ketoconazole;  negative inotropic effect possibly increased when  calcium-channel blockers given with itraconazole;  plasma concentration of nifedipine increased by  micafungin   Antimalarials: possible increased risk of bradycardia  when calcium-channel blockers given with meflo-  quine   Antimuscarinics: avoidance of verapamil advised by  manufacturer of darifenacin  Antipsychotics: enhanced hypotensive effect when  calcium-channel blockers given with antipsychotics   by *atazanavir (reduce dose of diltiazem); plasma  concentration of verapamil possibly increased by  atazanavir; plasma concentration of diltiazem  reduced by efavirenz; plasma concentration of  calcium-channel blockers possibly increased by  •ritonavir; manufacturer of lercanidipine advises  avoid concomitant use with ritonavir   Anxiolytics and Hypnotics: enhanced hypotensive  effect when calcium-channel blockers given with  anxiolytics and hypnotics; diltiazem and verapamil  inhibit metabolism of midazolam (increased plasma  concentration with increased sedation); absorption  of lercanidipine increased by midazolam;  diltiazem and verapamil increase plasma concentra-  tion of buspirone (reduce dose of buspirone)  Aprepitant: plasma concentration of both drugs may  increase when diltiazem given with aprepitant   diltiazem and verapamil probably reduced by  •barbiturates; effects of felodipine and isradipine  reduced by •barbiturates   calcium-channel blockers given with beta-blockers;  increased risk of AV block and bradycardia when  diltiazem given with •beta-blockers; asystole, severe  hypotension and heart failure when verapamil given  with •beta-blockers (see p. 133); possible severe  hypotension and heart failure when nifedipine given  with •beta-blockers   Calcium-channel Blockers: plasma concentration of  both drugs may increase when diltiazem given with  nifedipine   nicardipine increase plasma concentration of  •digoxin; verapamil increases plasma concentration  of •digoxin, also increased risk of AV block and  bradycardia; nifedipine possibly increases plasma  concentration of •digoxin   increase plasma concentration of •ciclosporin;  combination of lercanidipine with •ciclosporin may  increase plasma concentration of either drug (or  both) — avoid concomitant use; plasma concentra-  tion of nifedipine possibly increased by ciclosporin  (increased risk of toxicity including gingival hyper-  plasia)   Cilostazol : diltiazem increases plasma concentration  of cilostazol (consider reducing dose of cilostazol)  Clonidine: enhanced hypotensive effect when calcium-  channel blockers given with clonidine   risk of •colchicine toxicity — suspend or reduce dose  of colchicine (avoid concomitant use in hepatic or  renal impairment)   Corticosteroids : hypotensive effect of calcium-  channel blockers antagonised by corticosteroids;  diltiazem increases plasma concentration of  methylprednisolone   increase when verapamil given with •everolimus;  nifedipine possibly inhibits metabolism of vincristine  Diazoxide: enhanced hypotensive effect when  calcium-channel blockers given with diazoxide  Diuretics: enhanced hypotensive effect when calcium-  channel blockers given with diuretics; diltiazem and  verapamil increase plasma concentration of epler-  enone (reduce dose of eplerenone)   Dopamine rgics: enhanced hypotensive effect when  calcium-channel blockers given with levodopa  Grapefruit Juice: plasma concentration of felodipine,  isradipine, lacidipine, lercanidipine, nicardipine,  nifedipine, nimodipine and verapamil increased by  grapefruit juice; plasma concentration of amlodipine  possibly increased by grapefruit juice  Hormone Antagonists: diltiazem and verapamil  increase plasma concentration of dutasteride   possible increased risk of myopathy when amlo-  dipine given with simvastatin  Lithium: neurotoxicity may occur when diltiazem or  verapamil given with lithium without increased  plasma concentration of lithium   reported with concomitant use of nifedipine and  •parenteral magnesium in pre-eclampsia  Methyldopa: enhanced hypotensive effect when  calcium-channel blockers given with methyldopa  Moxisylyte: enhanced hypotensive effect when  calcium-channel blockers given with moxisylyte  Moxonidine: enhanced hypotensive effect when  calcium-channel blockers given with moxonidine  Muscle Relaxants : verapamil enhances effects of non-  depolarising muscle relaxants and suxamethonium;  enhanced hypotensive effect when calcium-channel  blockers given with baclofen or tizanidine; hypo-  tension, myocardial depression, and hyperkalaemia  when verapamil given with intravenous dantrolene;  possible increased risk of ventricular arrhythmias  when diltiazem given with intravenous dantrolene —  manufacturer of diltiazem advises avoid concomitant  use; calcium-channel blockers possibly enhance  effects of non-depolarising muscle relaxants  Nitrates: enhanced hypotensive effect when calcium-  channel blockers given with nitrates  Oestrogens: hypotensive effect of calcium-channel  blockers antagonised by oestrogens  Prostaglandins: enhanced hypotensive effect when  calcium-channel blockers given with alprostadil  Ranolazine: diltiazem and verapamil increase plasma  concentration of ranolazine (consider reducing dose  of ranolazine)   concentration of •tacrolimus; felodipine,  nicardipine and verapamil possibly increase plasma  concentration of tacrolimus   increase plasma concentration of •theophylline  (enhanced effect); diltiazem increases plasma con-  centration of theophylline; verapamil increases  plasma concentration of •theophylline (enhanced  effect)   Ulcer-healing Drugs: metabolism of calcium-channel  blockers possibly inhibited by cimetidine (increased  plasma concentration); plasma concentration of  isradipine increased by cimetidine (halve dose of  isradipine)   Vardenafil: enhanced hypotensive effect when nife-  dipine given with vardenafil  Vasodilator Antihypertensives: enhanced hypoten-  sive effect when calcium-channel blockers given  with hydralazine, minoxidil or sodium nitroprusside   Antidepressants : possible increased risk of hyper-  tension and tachycardia when cannabis extract given  with tricyclics   Antibacterials: increased risk of nephrotoxicity when  capreomycin given with colistin or polymyxins;  increased risk of nephrotoxicity and ototoxicity when  capreomycin given with aminoglycosides or vanco-  mycin   Cytotoxics: increased risk of nephrotoxicity and  ototoxicity when capreomycin given with platinum  compounds   •dextropropoxyphene; carbamazepine reduces  plasma concentration of methadone; carbamazepine  reduces effects of tramadol; carbamazepine possibly  accelerates metabolism of paracetamol   pine increased by •clarithromycin and  •erythromycin; plasma concentration of carba-  mazepine reduced by •rifabutin; carbamazepine  accelerates metabolism of doxycycline (reduced  effect); plasma concentration of carbamazepine  increased by •isoniazid (also possibly increased  isoniazid hepatotoxicity); carbamazepine reduces  plasma concentration of •telithromycin (avoid during  and for 2 weeks after carbamazepine)   mazepine increased by •fluoxetine and  •fluvoxamine; carbamazepine reduces plasma con-  centration of •mianserin and mirtazapine; manufac-  turer of carbamazepine advises avoid for 2 weeks  after stopping •MAOIs, also antagonism of anti-  convulsant effect; anticonvulsant effect of anti-  epileptics possibly antagonised by MAOIs and  •tricyclic-related antidepressants (convulsive  threshold lowered); anticonvulsant effect of anti-  epileptics antagonised by *SSRIs and •tricyclics  (convulsive threshold lowered); avoid concomitant  use of antiepileptics with »St John’s wort; carba-  mazepine accelerates metabolism of •tricyclics  (reduced plasma concentration and reduced effect)   reduced when carbamazepine given with eslicarba-  zepine; carbamazepine possibly reduces plasma  concentration of ethosuximide; carbamazepine often  reduces plasma concentration of lamotrigine, also  plasma concentration of an active metabolite of  carbamazepine sometimes raised (but evidence is  conflicting); possible increased risk of carbamaze-  pine toxicity when given with levetiracetam; plasma  concentration of carbamazepine sometimes reduced  by oxcarbazepine (but concentration of an active  metabolite of carbamazepine may be increased), also  plasma concentration of an active metabolite of  oxcarbazepine often reduced; plasma concentration  of both drugs often reduced when carbamazepine  given with phenytoin, also plasma concentration of  phenytoin may be increased; plasma concentration  of carbamazepine often reduced by primidone, also  plasma concentration of primidone sometimes  reduced (but concentration of an active metabolite of  primidone often increased); plasma concentration of  both drugs possibly reduced when carbamazepine  given with rufinamide; plasma concentration of  carbamazepine increased by •stiripentol; carba-  mazepine reduces plasma concentration of  tiagabine and zonisamide; carbamazepine often  reduces plasma concentration of topiramate; carba-  mazepine reduces plasma concentration of val-  proate, also plasma concentration of active  metabolite of carbamazepine increased   possibly increased by fluconazole, ketoconazole and  miconazole; carbamazepine possibly reduces plasma  concentration of itraconazole and •posaconazole;  carbamazepine possibly reduces plasma concentra-  tion of •voriconazole — avoid concomitant use;   carbamazepine possibly reduces plasma con-  centration of caspofungin — consider increasing  dose of caspofungin   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   pine antagonised by •antipsychotics (convulsive  threshold lowered); carbamazepine accelerates  metabolism of haloperidol, olanzapine,  quetiapine and risperidone (reduced plasma con-  centration); carbamazepine reduces plasma concen-  tration of •aripiprazole — increase dose of  aripiprazole; carbamazepine accelerates metabolism  of •clozapine (reduced plasma concentration), also  avoid concomitant use of drugs with substantial  potential for causing agranulocytosis; carbamaze-  pine reduces plasma concentration of paliperidone   concentration of darunavir, fosamprenavir, lopinavir,  nelfinavir, saquinavir and tipranavir; plasma con-  centration of both drugs reduced when carbamaze-  pine given with efavirenz; avoidance of  carbamazepine advised by manufacturer of etravir-  ine; carbamazepine possibly reduces plasma con-  centration of •indinavir, also plasma concentration of  carbamazepine possibly increased; carbamazepine  reduces plasma concentration of nevirapine; plasma  concentration of carbamazepine possibly increased  by •ritonavir   Anxiolytics and Hypnotics: carbamazepine often  reduces plasma concentration of clonazepam;  carbamazepine reduces plasma concentration of  midazolam   Aprepitant: carbamazepine possibly reduces plasma  concentration of aprepitant  Barbiturates: plasma concentration of carbamazepine  reduced by phenobarbital   effects of felodipine and isradipine; carbamazepine  probably reduces effects of dihydropyridines,  nicardipine and nifedipine; effects of carbamazepine  enhanced by •diltiazem and •verapamil   manufacturer of gefitinib; carbamazepine reduces  plasma concentration of •imatinib and *lapatinib —  avoid concomitant use; carbamazepine reduces  plasma concentration of irinotecan and its active  metabolite   inhibited by «danazol (increased risk of toxicity);  carbamazepine possibly accelerates metabolism of  toremifene (reduced plasma concentration)   Muscle Relaxants: carbamazepine antagonises muscle  relaxant effect of non-depolarising muscle relaxants  (accelerated recovery from neuromuscular blockade)   Retinoids: plasma concentration of carbamazepine  possibly reduced by isotretinoin  Theophylline: carbamazepine accelerates metabolism  of theophylline (reduced effect)   Thyroid Hormones: carbamazepine accelerates  metabolism of thyroid hormones (may increase  requirements for thyroid hormones in hypothyroid-  ism)   Carbapenems see Doripenem, Ertapenem, Imipenem  with Cilastatin, and Meropenem  Carbonic Anhydrase Inhibitors see Diuretics  Carboplatin see Platinum Compounds  Carboprost see Prostaglandins  Cardiac Glycosides   ACE Inhibitors: plasma concentration of digoxin  possibly increased by captopril  Alpha-blockers: plasma concentration of digoxin  increased by prazosin   Analgesics: plasma concentration of cardiac glyco-  sides possibly increased by NSAIDs, also possible  exacerbation of heart failure and reduction of renal  function   Antibacterials: plasma concentration of digoxin pos-  sibly increased by gentamicin, telithromycin and  trimethoprim; absorption of digoxin reduced by  neomycin; plasma concentration of digoxin possibly  reduced by rifampicin; plasma concentration of  digoxin increased by macrolides (increased risk of  toxicity)   reduced by «St John’s wort — avoid concomitant use  Antidiabetics: plasma concentration of digoxin possi-  bly reduced by acarbose; plasma concentration of  digoxin increased by sitagliptin  Antiepileptics: plasma concentration of digoxin pos-  sibly reduced by phenytoin   bly increased by •chloroquine and hydroxychloro-  quine; possible increased risk of bradycardia when  digoxin given with mefloquine; plasma concentra-  tion of digoxin increased by ©quinine  Antimuscarinics: plasma concentration of digoxin  possibly increased by darifenacin   Antivirals: plasma concentration of digoxin increased  by etravirine; plasma concentration of digoxin  possibly increased by ritonavir  Anxiolytics and Hypnotics: plasma concentration of  digoxin increased by alprazolam (increased risk of  toxicity)   Beta-blockers: increased risk of AV block and brady-  cardia when cardiac glycosides given with beta-  blockers   Calcium Salts: arrhythmias can be precipitated when  cardiac glycosides given with large intravenous  doses of calcium salts   digoxin increased by •diltiazem, •lercanidipine and  •nicardipine; plasma concentration of digoxin pos-  sibly increased by •nifedipine; plasma concentration  of digoxin increased by •verapamil, also increased  risk of AV block and bradycardia   digoxin given with •colchicine  Corticosteroids: increased risk of hypokalaemia when  cardiac glycosides given with corticosteroids  Cytotoxics: absorption of digoxin tablets reduced by  cytotoxics   glycosides if hypokalaemia occurs with  •acetazolamide, •loop diuretics or ©thiazides and  related diuretics; plasma concentration of digoxin  possibly increased by potassium canrenoate; plasma  concentration of digoxin increased by  •spironolactone   Lenalidomide: plasma concentration of digoxin pos-  sibly increased by lenalidomide  Lipid-regulating Drugs: absorption of cardiac glyco-  sides possibly reduced by colestipol and colestyr-  amine; plasma concentration of digoxin possibly  increased by atorvastatin  Muscle Relaxants: risk of ventricular arrhythmias  when cardiac glycosides given with suxamethonium;  possible increased risk of bradycardia when cardiac  glycosides given with tizanidine  Penicillamine: plasma concentration of digoxin pos-  sibly reduced by penicillamine  Ranolazine: plasma concentration of digoxin  increased by ranolazine   Sympathomimetics, Beta 2 : plasma concentration of  digoxin possibly reduced by salbutamol  Tolvaptan: plasma concentration of digoxin increased  by tolvaptan (increased risk of toxicity)  Ulcer-healing Drugs: plasma concentration of digoxin  possibly slightly increased by proton pump inhi-  bitors; absorption of cardiac glycosides possibly  reduced by sucralfate   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Antibacterials: plasma concentration of caspofungin  initially increased and then reduced by rifampicin  (consider increasing dose of caspofungin)  Antiepileptics: plasma concentration of caspofungin  possibly reduced by carbamazepine and phenytoin —  consider increasing dose of caspofungin  Antivirals: plasma concentration of caspofungin pos-  sibly reduced by efavirenz and nevirapine — consider  increasing dose of caspofungin   increased by •ciclosporin (manufacturer of caspo-  fungin recommends monitoring liver enzymes)  Corticosteroids: plasma concentration of caspofungin  possibly reduced by dexamethasone — consider  increasing dose of caspofungin   tion of •tacrolimus  Cefaclor see Cephalosporins  Cefadroxil see Cephalosporins  Cefalexin see Cephalosporins  Cefixime see Cephalosporins  Cefotaxime see Cephalosporins  Cefpod oxime see Cephalosporins  Cefradine see Cephalosporins  Ceftazidime see Cephalosporins  Ceftriaxone see Cephalosporins  Cefuroxime see Cephalosporins  Celecoxib see NSAIDs  Celiprolol see Beta-blockers  Cephalosporins   anticoagulant effect of •coumarins  Probenecid: excretion of cephalosporins reduced by  probenecid (increased plasma concentration)  Ulcer-healing Drugs: absorption of cefpodoxime  reduced by histamine H 2 -antagonists  Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767  Certolizumab pegol   Chlordiazepoxide see Anxiolytics and Hypnotics  Chloroquine and Hydroxychloroquine  Adsorbents: absorption of chloroquine and hydroxy-  chloroquine reduced by kaolin  Agalsidase Alfa and Beta: chloroquine and  hydroxychloroquine possibly inhibit effects of    Chloroquine and Hydroxychloroquine  Agalsidase Alfa and Beta (continued)  agalsidase alfa and beta (manufacturers of  agalsidase alfa and beta advise avoid concomi-  tant use)   mias when chloroquine and hydroxychloroquine  given with •moxifloxacin — avoid concomitant use  Antiepileptics: possible increased risk of convulsions  when chloroquine and hydroxychloroquine given  with antiepileptics   manufacturer of •artemether/lumefantrine;  increased risk of convulsions when chloroquine and  hydroxychloroquine given with •mefloquine   Lanthanum: absorption of chloroquine and hydroxy-  chloroquine possibly reduced by lanthanum (give at  least 2 hours apart)   Laronidase: chloroquine and hydroxychloroquine  possibly inhibit effects of laronidase (manufacturer of  laronidase advises avoid concomitant use)  Parasympathomimetics: chloroquine and hydroxy-  chloroquine have potential to increase symptoms of  myasthenia gravis and thus diminish effect of  neostigmine and pyridostigmine  Ulcer-healing Drugs: metabolism of chloroquine and  hydroxychloroquine inhibited by cimetidine  (increased plasma concentration)   Vaccines: antimalarials inactivate oral typhoid  vaccine-see p. 767  Chlorothiazide see Diuretics  Chlorphen amine see Antihistamines  Chlorpromazine see Antipsychotics  Chlortalidone see Diuretics  Ciclesonide see Corticosteroids  Ciclosporin   ciclosporin given with •NSAIDs; ciclosporin  increases plasma concentration of •diclofenac (halve  dose of diclofenac)   hyperkalaemia when ciclosporin given with *angio-  tensin-II receptor antagonists  Anti-arrhythmics: plasma concentration of ciclosporin  possibly increased by amiodarone and propafenone   •clarithromycin and •erythromycin (increased  plasma concentration); metabolism of ciclosporin  accelerated by •rifampicin (reduced plasma concen-  tration); plasma concentration of ciclosporin possibly  reduced by •sulfadiazine; plasma concentration of  ciclosporin possibly increased by •chloramphenicol,  •doxycycline and •telithromycin; increased risk of  nephrotoxicity when ciclosporin given with  •aminoglycosides, •polymyxins, •quinolones,  •sulfonamides or •vancomycin; increased risk of   myopathy when ciclosporin given with  •daptomycin (preferably avoid concomitant use);  metabolism of ciclosporin possibly inhibited by  •macrolides (increased plasma concentration);  increased risk of nephrotoxicity when ciclosporin  given with •trimethoprim, also plasma concen-  tration of ciclosporin reduced by intravenous  trimethoprim   by •carbamazepine and *phenytoin (reduced plasma  concentration); plasma concentration of ciclosporin  possibly reduced by oxcarbazepine; metabolism of  ciclosporin accelerated by •primidone (reduced  effect)   •fluconazole, •itraconazole, •ketoconazole,  •posaconazole and •voriconazole (increased plasma  concentration); metabolism of ciclosporin possibly  inhibited by •miconazole (increased plasma con-  centration); increased risk of nephrotoxicity when  ciclosporin given with •amphotericin; ciclosporin  increases plasma concentration of •caspofungin  (manufacturer of caspofungin recommends monitor-  ing liver enzymes); plasma concentration of ciclos-  porin possibly reduced by griseofulvin and  terbinafine; plasma concentration of ciclosporin  possibly increased by micafungin   ciclosporin given with aciclovir; plasma concentra-  tion of ciclosporin possibly increased by «atazanavir,  •nelfinavir and •ritonavir; plasma concentration of  ciclosporin possibly reduced by «efavirenz; plasma  concentration of ciclosporin increased by  •fosamprenavir and *indinavir; plasma concentration  of both drugs increased when ciclosporin given with  •saquinavir   with •lercanidipine may increase plasma concentra-  tion of either drug (or both) — avoid concomitant use;  plasma concentration of ciclosporin increased by  •diltiazem, •nicardipine and •verapamil; ciclosporin  possibly increases plasma concentration of nifedipine  (increased risk of toxicity including gingival hyper-  plasia)   and myotoxicity when ciclosporin given with  •colchicine — suspend or reduce dose of colchicine  (avoid concomitant use in hepatic or renal impair-  ment)   increased by high-dose •methylprednisolone (risk of  convulsions); ciclosporin increases plasma concen-  tration of prednisolone   neurotoxicity when ciclosporin given with  •doxorubicin; ciclosporin increases plasma con-  centration of •epirubicin, •everolimus and  •idarubicin; ciclosporin reduces excretion of  mitoxantrone (increased plasma concentration);  risk of toxicity when ciclosporin given with  •methotrexate; plasma concentration of ciclos-  porin possibly increased by imatinib; in vitro  studies suggest a possible interaction between  ciclosporin and docetaxel (consult docetaxel  product literature); ciclosporin possibly increases  plasma concentration of etoposide (increased  risk of toxicity)   increased by •acetazolamide; increased risk of  hyperkalaemia when ciclosporin given with •potas-  sium-sparing diuretics and aldosterone antagonists;  increased risk of nephrotoxicity and possibly hyper-  magnesaemia when ciclosporin given with thiazides  and related diuretics   inhibited by «danazol (increased plasma concentra-  tion); plasma concentration of ciclosporin reduced  by lanreotide and •octreotide   reduced by •colesevelam; increased risk of renal  impairment when ciclosporin given with  bezafibrate or fenofibrate; increased risk of myo-  pathy when ciclosporin given with •rosuvastatin  (avoid concomitant use); plasma concentration of  both drugs may increase when ciclosporin given with  •ezetimibe; increased risk of myopathy when  ciclosporin given with •statins  Mannitol: possible increased risk of nephrotoxicity  when ciclosporin given with mannitol   increased by •metoclopramide  Mifamurtide: avoidance of ciclosporin advised by  manufacturer of mifamurtide   •progestogens (increased plasma concentration)  Ranolazine: ciclosporin possibly increases plasma  concentration of ranolazine  S eve lamer: plasma concentration of ciclosporin pos-  sibly reduced by sevelamer  Sirolimus: ciclosporin increases plasma concentration  of sirolimus   Vitamins: plasma concentration of ciclosporin possibly  affected by vitamin E  Cidofovir   Antibacterials : plasma concentration of cilostazol  increased by erythromycin (consider reducing dose  of cilostazol)   Antifungals : plasma concentration of cilostazol  increased by ketoconazole (consider reducing dose  of cilostazol)   Calcium-channel Blockers : plasma concentration of  cilostazol increased by diltiazem (consider reducing  dose of cilostazol)   Ulcer-healing Drugs : plasma concentration of cilosta-  zol increased by omeprazole (consider reducing dose  of cilostazol)   Cinnarizine see Antihistamines  Ci profib rate see Fibrates  Ciprofloxacin see Quinolones  Cisatracurium see Muscle Relaxants  Cisplatin see Platinum Compounds  Citalopram see Antidepressants, SSRI  Clarithromycin see Macrolides  Clemastine see Antihistamines  Clindamycin   Clobazam see Anxiolytics and Hypnotics  Clomethiazole see Anxiolytics and Hypnotics  Clomipramine see Antidepressants, Tricyclic  Clonazepam see Anxiolytics and Hypnotics  Clonidine   ACE Inhibitors: enhanced hypotensive effect when  clonidine given with ACE inhibitors; previous treat-  ment with clonidine possibly delays antihypertensive  effect of captopril   Adrenergic Neurone Blockers: enhanced hypotensive  effect when clonidine given with adrenergic neurone  blockers   Anaesthetics, General: enhanced hypotensive effect  when clonidine given with general anaesthetics   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when clonidine given with  angiotensin-II receptor antagonists   clonidine given with MAOIs; hypotensive effect of  clonidine antagonised by •tricyclics, also increased  risk of hypertension on clonidine withdrawal   Anxiolytics and Hypnotics: enhanced hypotensive  effect when clonidine given with anxiolytics and  hypnotics   tension when clonidine given with •beta-blockers  (withdraw beta-blockers several days before slowly  withdrawing clonidine)   Calcium-channel Blockers: enhanced hypotensive  effect when clonidine given with calcium-channel  blockers   Corticosteroids: hypotensive effect of clonidine  antagonised by corticosteroids  Diazoxide: enhanced hypotensive effect when cloni-  dine given with diazoxide   Methyldopa: enhanced hypotensive effect when  clonidine given with methyldopa  Moxisylyte: enhanced hypotensive effect when cloni-  dine given with moxisylyte  Moxonidine: enhanced hypotensive effect when  clonidine given with moxonidine  Muscle Relaxants: enhanced hypotensive effect when  clonidine given with baclofen or tizanidine  Nitrates: enhanced hypotensive effect when clonidine  given with nitrates   when clonidine given with adrenaline  (epinephrine) or noradrenaline (norepinephrine);  serious adverse events reported with concomitant  use of clonidine and •methylphenidate (causality not  established)   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when clonidine given with hydralazine,  minoxidil or sodium nitroprusside  Clopamide see Diuretics  Clopidogrel   Analgesics: increased risk of bleeding when clopido-  grel given with NSAIDs or aspirin   avoid concomitant use with •warfarin; antiplatelet  action of clopidogrel enhances anticoagulant effect  of •coumarins and •phenindione; increased risk of  bleeding when clopidogrel given with heparins   Dipyridamole: increased risk of bleeding when clopi-  dogrel given with dipyridamole  lloprost: increased risk of bleeding when clopidogrel  given with iloprost   Prasugrel: possible increased risk of bleeding when  clopidogrel given with prasugrel   possibly reduced by •cimetidine, lansoprazole,  pantoprazole and rabeprazole; antiplatelet effect of  clopidogrel reduced by •esomeprazole and  •omeprazole   Clotrimazole see Antifungals, Imidazole  Clozapine see Antipsychotics  Co-amoxiclav see Penicillins  Co-beneldopa see Levodopa  Co-careldopa see Levodopa  Codeine see Opioid Analgesics  Co-fluampicil see Penicillins   toxicity when given with •azithromycin,  •clarithromycin, •erythromycin and  •telithromycin — suspend or reduce dose of colchi-  cine (avoid concomitant use in hepatic or renal  impairment)   when given with •atazanavir, •indinavir and  •ritonavir — suspend or reduce dose of colchicine  (avoid concomitant use in hepatic or renal impair-  ment)   colchicine toxicity when given with •diltiazem and  •verapamil — suspend or reduce dose of colchicine  (avoid concomitant use in hepatic or renal impair-  ment)   and myotoxicity when colchicine given with  •ciclosporin — suspend or reduce dose of colchicine  (avoid concomitant use in hepatic or renal impair-  ment)    Note Other drugs should be taken at least 4 hours before or  after colesevelam to reduce possible interference with  absorption   Note Other drugs should be taken at least 1 hour before or  4-6 hours after colestipol to reduce possible interference  with absorption   Cardiac Glycosides: colestipol possibly reduces  absorption of cardiac glycosides  Diuretics: colestipol reduces absorption of thiazides  and related diuretics (give at least 2 hours apart)  Thyroid Hormones: colestipol reduces absorption of  thyroid hormones   Note Other drugs should be taken at least 1 hour before or  4-6 hours after colestyramine to reduce possible interfer-  ence with absorption   Analgesics: colestyramine increases the excretion of  meloxicam; colestyramine reduces absorption of  paracetamol   Antibacterials: colestyramine possibly reduces  absorption of tetracycline; colestyramine antago-  nises effects of oral vancomycin   Antidiabetics: colestyramine possibly enhances  hypoglycaemic effect of acarbose  Antiepileptics: colestyramine possibly reduces  absorption of valproate   Cardiac Glycosides: colestyramine possibly reduces  absorption of cardiac glycosides  Diuretics: colestyramine reduces absorption of thi-  azides and related diuretics (give at least 2 hours  apart)   Leflunomide: colestyramine significantly decreases  effect of leflunomide (enhanced elimination) — avoid  unless drug elimination desired  Mycophenolate: colestyramine reduces absorption of  mycophenolate   Raloxifene: colestyramine reduces absorption of  raloxifene (manufacturer of raloxifene advises avoid  concomitant administration)   Note Interactions do not generally apply to corticosteroids  used for topical action (including inhalation) unless specified  ACE Inhibitors: corticosteroids antagonise hypoten-  sive effect of ACE inhibitors  Adrenergic Neurone Blockers: corticosteroids antag-  onise hypotensive effect of adrenergic neurone  blockers   manufacturer of •aldesleukin  Alpha-blockers: corticosteroids antagonise hypoten-  sive effect of alpha-blockers  Analgesics: increased risk of gastro-intestinal bleeding  and ulceration when corticosteroids given with  NSAIDs; increased risk of gastro-intestinal bleeding  and ulceration when corticosteroids given with  aspirin, also corticosteroids reduce plasma concen-  tration of salicylate   Angiotensin-ll Receptor Antagonists: corticosteroids  antagonise hypotensive effect of angiotensin-II  receptor antagonists   prednisolone possibly increased by clarithromycin;  metabolism of corticosteroids possibly inhibited by  erythromycin; metabolism of methylprednisolone  inhibited by erythromycin; corticosteroids possibly  reduce plasma concentration of isoniazid; metab-  olism of corticosteroids accelerated by •rifamycins  (reduced effect)   reduce anticoagulant effect of •coumarins (high-  dose corticosteroids enhance anticoagulant effect);  corticosteroids may enhance or reduce anti-  coagulant effect of phenindione  Antidiabetics: corticosteroids antagonise hypoglycae-  mic effect of antidiabetics   inhibited by itraconazole and ketoconazole; plasma  concentration of active metabolite of ciclesonide  increased by ketoconazole; plasma concentration of  inhaled mometasone increased by ketoconazole;  plasma concentration of inhaled and oral budeso-  nide increased by ketoconazole; metabolism of  methylprednisolone inhibited by ketoconazole;  increased risk of hypokalaemia when corticosteroids  given with •amphotericin — avoid concomitant use  unless corticosteroids needed to control reactions;  plasma concentration of inhaled budesonide  increased by itraconazole; metabolism of methyl-   prednisolone possibly inhibited by itraconazole;  dexamethasone possibly reduces plasma con-  centration of caspofungin — consider increasing  dose of caspofungin   concentration of indinavir, lopinavir and saquinavir;  plasma concentration of inhaled and intranasal  fluticasone possibly increased by nelfinavir; plasma  concentration of corticosteroids,  dexamethasone and prednisolone possibly increased  by ritonavir; plasma concentration of inhaled and  intranasal budesonide and fluticasone increased by  •ritonavir   Aprepitant: metabolism of dexamethasone and  methylprednisolone inhibited by aprepitant (reduce  dose of dexamethasone and methylprednisolone)   Calcium-channel Blockers : corticosteroids antagonise  hypotensive effect of calcium-channel blockers;  plasma concentration of methylprednisolone  increased by diltiazem   Cardiac Glycosides: increased risk of hypokalaemia  when corticosteroids given with cardiac glycosides   plasma concentration of •ciclosporin (risk of con-  vulsions); plasma concentration of prednisolone  increased by ciclosporin   Diuretics: corticosteroids antagonise diuretic effect of  diuretics; increased risk of hypokalaemia when  corticosteroids given with acetazolamide, loop  diuretics or thiazides and related diuretics  Histamine: avoidance of corticosteroids advised by  manufacturer of histamine   Mifamurtide: avoidance of corticosteroids advised by  manufacturer of mifamurtide  Mifepristone: effect of corticosteroids (including  inhaled corticosteroids) may be reduced for 3-4  days after mifepristone   Muscle Relaxants: corticosteroids possibly antagonise  effects of pancuronium and vecuronium  Nitrates: corticosteroids antagonise hypotensive effect  of nitrates   Oestrogens: plasma concentration of corticosteroids  increased by oral contraceptives containing oestro-  gens   Sodium Benzoate: corticosteroids possibly reduce  effects of sodium benzoate  Sodium Phenylbutyrate: corticosteroids possibly  reduce effects of sodium phenylbutyrate  Somatropin: corticosteroids may inhibit growth-pro-  moting effect of somatropin  Sympathomimetics: metabolism of dexamethasone  accelerated by ephedrine   Sympathomimetics, Beta 2 : increased risk of hypo-  kalaemia when corticosteroids given with high doses  of beta 2 sympathomimetics — see Hypokalaemia,  p. 176   Vasodilator Antihypertensives: corticosteroids  antagonise hypotensive effect of hydralazine,  minoxidil and sodium nitroprusside   Note Change in patient’s clinical condition, particularly  associated with liver disease, intercurrent illness, or drug  administration, necessitates more frequent testing. Major  changes in diet (especially involving salads and vegetables)  and in alcohol consumption may also affect anticoagulant  control   enhanced by •NSAIDs; increased risk of haemorr-  hage when anticoagulants given with intravenous  •diclofenac (avoid concomitant use, including low-  dose heparins); increased risk of haemorrhage when  anticoagulants given with •ketorolac (avoid conco-  mitant use, including low-dose heparins); anti-  coagulant effect of coumarins enhanced by  •tramadol; increased risk of bleeding when coum-  arins given with •aspirin (due to antiplatelet effect);  anticoagulant effect of coumarins possibly enhanced  by prolonged regular use of paracetamol   by •amiodarone (enhanced anticoagulant effect);  anticoagulant effect of coumarins enhanced by  •propafenone   suggests that INR possibly altered when coumarins  are given with •neomycin (given for local action on  gut); anticoagulant effect of coumarins possibly  enhanced by •azithromycin, •aztreonam,  •cephalosporins, levofloxacin, •tetracyclines,  tigecycline and trimethoprim; anticoagulant effect of  coumarins enhanced by •chloramphenicol,  •ciprofloxacin, •clarithromycin, •erythromycin,  •metronidazole, •nalidixic acid, •norfloxacin,  •ofloxacin and •sulfonamides; studies have failed to  demonstrate an interaction with coumarins, but  common experience in anticoagulant clinics is that  INR can be altered by a course of broad-spectrum  penicillins such as ampicillin; metabolism of coum-  arins accelerated by •rifamycins (reduced anti-  coagulant effect)   possibly enhanced by •venlafaxine; anticoagulant  effect of warfarin may be enhanced or reduced by  trazodone; anticoagulant effect of coumarins possi-  bly enhanced by «SSRIs; anticoagulant effect of  coumarins reduced by »St John’s wort (avoid  concomitant use); anticoagulant effect of warfarin  enhanced by mirtazapine; anticoagulant effect of  coumarins may be enhanced or reduced by  •tricyclics   enhanced by exenatide; coumarins possibly enhance  hypoglycaemic effect of •sulfonylureas, also possible  changes to anticoagulant effect   by •carbamazepine and •primidone (reduced anti-  coagulant effect); plasma concentration of warfarin  reduced by eslicarbazepine; metabolism of coum-  arins accelerated by •phenytoin (possibility of  reduced anticoagulant effect, but enhancement also  reported); anticoagulant effect of coumarins possibly  enhanced by valproate   •ketoconazole and •voriconazole; anticoagulant  effect of coumarins enhanced by •miconazole  (miconazole oral gel and possibly vaginal formula-  tions absorbed); anticoagulant effect of coumarins  reduced by •griseofulvin   Antimalarials: isolated reports that anticoagulant  effect of warfarin may be enhanced by proguanil;  plasma concentration of both drugs increased when  warfarin given with quinine   enhanced or reduced by atazanavir, •nevirapine and  •ritonavir; plasma concentration of warfarin possibly  affected by *efavirenz; anticoagulant effect of  coumarins may be enhanced or reduced by fosam-  prenavir; anticoagulant effect of coumarins possibly  enhanced by •ritonavir; anticoagulant effect of  warfarin possibly enhanced by saquinavir  Anxiolytics and Hypnotics: anticoagulant effect of  coumarins may transiently be enhanced by  chloral and triclofos   •barbiturates (reduced anticoagulant effect)  Bosentan: monitoring anticoagulant effect of coum-  arins recommended by manufacturer of bosentan   may be enhanced or reduced by •corticosteroids  (high-dose corticosteroids enhance anticoagulant  effect)   enhanced by •etoposide, •ifosfamide and •sorafenib;  anticoagulant effect of coumarins enhanced by  •fluorouracil; anticoagulant effect of warfarin possi-  bly enhanced by •gefitinib and gemcitabine; anti-  coagulant effect of coumarins possibly reduced by  •mercaptopurine and •mitotane; increased risk of  bleeding when coumarins given with •erlotinib;  replacement of warfarin with a heparin advised by  manufacturer of imatinib (possibility of enhanced  warfarin effect)   arins possibly enhanced by bicalutamide and  •toremifene; metabolism of coumarins inhibited by  •danazol (enhanced anticoagulant effect); anti-  coagulant effect of coumarins enhanced by  •flutamide and •tamoxifen  lloprost: anticoagulant effect of coumarins possibly  enhanced by iloprost   Leflunomide: anticoagulant effect of warfarin possibly  enhanced by leflunomide  Leukotriene Receptor Antagonists: anticoagulant  effect of warfarin enhanced by zafirlukast   arins may be enhanced or reduced by  •colestyramine; anticoagulant effect of warfarin may  be transiently reduced by atorvastatin; anticoagulant  effect of coumarins enhanced by •fibrates,  •fluvastatin and simvastatin; anticoagulant effect of  coumarins possibly enhanced by ezetimibe and  •rosuvastatin   enhanced or reduced by •oestrogens  Orlistat: monitoring anticoagulant effect of coumarins  recommended by manufacturer of orlistat  Prasugrel: possible increased risk of bleeding when  coumarins given with prasugrel   enhanced by •thyroid hormones  Ubidecarenone: anticoagulant effect of warfarin may  be enhanced or reduced by ubidecarenone   ited by •cimetidine (enhanced anticoagulant effect);  anticoagulant effect of coumarins possibly enhanced  by •esomeprazole, •omeprazole and pantoprazole;  absorption of coumarins possibly reduced by  •sucralfate (reduced anticoagulant effect)   enhanced by •vitamin E; anticoagulant effect of  coumarins antagonised by • vitamin K  Cranberry Juice   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Cytotoxics: intracellular concentration of cytarabine  increased by fludarabine  Cytotoxics see individual drugs  Dabigatran Etexilate   dabigatran etexilate given with •NSAIDs; increased  risk of haemorrhage when anticoagulants given with  intravenous •diclofenac (avoid concomitant use,  including low-dose heparins); increased risk of  haemorrhage when anticoagulants given with  •ketorolac (avoid concomitant use, including low-  dose heparins)   dabigatran etexilate possibly increased by  •verapamil (reduce dose of dabigatran etexilate)  Dacarbazine   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets  Dairy Products   Antibacterials: dairy products reduce absorption of  ciprofloxacin and norfloxacin; dairy products reduce  absorption of tetracyclines (except doxycycline and  minocycline)   Eltrombopag: dairy products possibly reduce absorp-  tion of eltrombopag (give at least 4 hours apart)  Dalteparin see Heparins  Danazol   Antibacterials: plasma concentration of dapsone  reduced by rifamycins; plasma concentration of both  drugs may increase when dapsone given with  trimethoprim   Probenecid: excretion of dapsone reduced by pro-  benecid (increased risk of side-effects)   Anti-arrhythmics: darunavir possibly increases plasma  concentration of lidocaine — avoid concomitant use   tration of •rifabutin (reduce dose of rifabutin);  plasma concentration of darunavir significantly  reduced by •rifampicin — avoid concomitant use  Anticoagulants: avoidance of darunavir advised by  manufacturer of rivaroxaban   concentration of paroxetine and sertraline; plasma  concentration of darunavir reduced by *St John’s  wort — avoid concomitant use  Antiepileptics: plasma concentration of darunavir  possibly reduced by carbamazepine and phenytoin  Antifungals: plasma concentration of both drugs  increased when darunavir given with ketoconazole   manufacturer of artemether/lumefantrine; darunavir  possibly increases plasma concentration of •quinine  (increased risk of toxicity)   by efavirenz and saquinavir; plasma concentration of  both drugs increased when darunavir given with  indinavir; plasma concentration of darunavir  reduced by •lopinavir, also plasma concentration of  lopinavir increased (avoid concomitant use); daru-  navir increases plasma concentration of •maraviroc  (consider reducing dose of maraviroc)   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Lipid-regulating Drugs: dasatinib possibly increases  plasma concentration of simvastatin  Ulcer-healing Drugs: plasma concentration of dasati-  nib possibly reduced by famotidine  Deferasirox   Antacids: absorption of deferasirox possibly reduced  by antacids containing aluminium (manufacturer of  deferasirox advises avoid concomitant use)  Antibacterials: plasma concentration of deferasirox  reduced by rifampicin   Anxiolytics and Hypnotics: deferasirox possibly  reduces plasma concentration of midazolam  Deflazacort see Corticosteroids  Demeclocycline see Tetracyclines  Desferrioxamine   Antipsychotics: avoidance of desferrioxamine advised  by manufacturer of levomepromazine; manufacturer  of desferrioxamine advises avoid concomitant use  with prochlorperazine  Desflurane see Anaesthetics, General  Desloratadine see Antihistamines   Loperamide: plasma concentration of oral desmo-  pressin increased by loperamide  Desogestrel see Progestogens  Dexamethasone see Corticosteroids  Dexam feta mine see Sympathomimetics  Dexibuprofen see NSAIDs  Dexketoprofen see NSAIDs  Dextromethorphan see Opioid Analgesics  Dextropropoxyphene see Opioid Analgesics  Diamorphine see Opioid Analgesics  Diazepam see Anxiolytics and Hypnotics  Diazoxide   ACE Inhibitors: enhanced hypotensive effect when  diazoxide given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when diazoxide given with adrenergic neurone  blockers   Aldesleukin: enhanced hypotensive effect when diaz-  oxide given with aldesleukin  Alpha-blockers: enhanced hypotensive effect when  diazoxide given with alpha-blockers  Anaesthetics, General: enhanced hypotensive effect  when diazoxide given with general anaesthetics  Analgesics: hypotensive effect of diazoxide antago-  nised by NSAIDs   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when diazoxide given with  angiotensin- 1 1 receptor antagonists  Antidepressants: enhanced hypotensive effect when  diazoxide given with MAOIs or tricyclic-related  antidepressants   Antiepileptics: diazoxide reduces plasma concentra-  tion of phenytoin, also effect of diazoxide may be  reduced   Antipsychotics: enhanced hypotensive effect when  diazoxide given with phenothiazines  Anxiolytics and Hypnotics: enhanced hypotensive  effect when diazoxide given with anxiolytics and  hypnotics   Beta-blockers: enhanced hypotensive effect when  diazoxide given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when diazoxide given with calcium-channel  blockers   Clonidine: enhanced hypotensive effect when diaz-  oxide given with clonidine  Corticosteroids: hypotensive effect of diazoxide  antagonised by corticosteroids  Diuretics: enhanced hypotensive and hyperglycaemic  effects when diazoxide given with diuretics  Dopamine rgics: enhanced hypotensive effect when  diazoxide given with levodopa  Methyldopa: enhanced hypotensive effect when diaz-  oxide given with methyldopa  Moxisylyte: enhanced hypotensive effect when diaz-  oxide given with moxisylyte  Moxonidine: enhanced hypotensive effect when diaz-  oxide given with moxonidine  Muscle Relaxants: enhanced hypotensive effect when  diazoxide given with baclofen or tizanidine  Nitrates: enhanced hypotensive effect when diazoxide  given with nitrates   Prostaglandins: enhanced hypotensive effect when  diazoxide given with alprostadil  Vasodilator Antihypertensives: enhanced hypoten-  sive effect when diazoxide given with hydralazine,  minoxidil or sodium nitroprusside  Diclofenac see NSAIDs  Dicycloverine see Antimuscarinics   Note Antacids in tablet formulation may affect absorption  of other drugs   bly increased by ganciclovir; increased risk of side-  effects when didanosine given with •ribavirin — avoid  concomitant use; increased risk of side-effects when  didanosine given with •stavudine; plasma concen-  tration of didanosine increased by •tenofovir  (increased risk of toxicity) — avoid concomitant use;  plasma concentration of didanosine reduced by  •tipranavir   Dienogest see Progestogens  Digoxin see Cardiac Glycosides  Dihydrocodeine see Opioid Analgesics  Diltiazem see Calcium-channel Blockers  Dimercaprol   oxide with *sulindac  Dinoprostone see Prostaglandins  Diphenoxylate see Opioid Analgesics  Dipipanone see Opioid Analgesics  Dipyridamole   enhances anticoagulant effect of •coumarins and  •phenindione; dipyridamole enhances anticoagulant  effect of heparins   Clopidogrel: increased risk of bleeding when dipyrid-  amole given with clopidogrel  Cytotoxics: dipyridamole possibly reduces effects of  fludarabine   Anaesthetics, Local: increased myocardial depression  when anti-arrhythmics given with bupivacaine,  levobupivacaine, prilocaine or ropivacaine   when anti-arrhythmics given with other •anti-  arrhythmics; increased risk of ventricular arrhyth-  mias when disopyramide given with *amiodarone or  •dronedarone — avoid concomitant use   possibly increased by •clarithromycin (increased risk  of toxicity); plasma concentration of disopyramide  increased by •erythromycin (increased risk of  toxicity); increased risk of ventricular arrhythmias  when disopyramide given with •moxifloxacin —  avoid concomitant use; metabolism of disopyramide  accelerated by •rifamycins (reduced plasma con-  centration)   thmias when disopyramide given with •tricyclics  Antidiabetics: disopyramide possibly enhances hypo-  glycaemic effect of gliclazide, insulin and metformin  Antiepileptics: plasma concentration of disopyramide  reduced by phenytoin; metabolism of disopyramide  accelerated by primidone (reduced plasma concen-  tration)   effects when disopyramide given with antimusca-  rinics; increased risk of ventricular arrhythmias when  disopyramide given with •tolterodine   mias when anti-arrhythmics that prolong the QT  interval given with •antipsychotics that prolong the  QT interval; increased risk of ventricular arrhythmias  when disopyramide given with •amisulpride,  •droperidol, •pimozide or *zuclopenthixol — avoid  concomitant use; possible increased risk of ventri-  cular arrhythmias when disopyramide given with  •haloperidol — avoid concomitant use; increased risk  of ventricular arrhythmias when disopyramide given  with •phenothiazines or •sulpiride   possibly increased by •ritonavir (increased risk of  toxicity); increased risk of ventricular arrhythmias  when disopyramide given with ©saquinavir — avoid  concomitant use   when disopyramide given with •atomoxetine  Barbiturates: metabolism of disopyramide accelerated  by barbiturates (reduced plasma concentration)   anti-arrhythmics given with •beta-blockers;  increased risk of ventricular arrhythmias when  disopyramide given with •sotalol — avoid concomi-  tant use   when disopyramide given with ©ivabradine  Nitrates: disopyramide reduces effects of sublingual  tablets of nitrates (failure to dissolve under tongue  owing to dry mouth)   Alcohol: disulfiram reaction when disulfiram given  with alcohol (see p. 310)   Antibacterials: psychotic reaction reported when  disulfiram given with metronidazole; CNS effects of  disulfiram possibly increased by isoniazid   Antidepressants: increased disulfiram reaction with  alcohol reported with concomitant amitriptyline;  disulfiram inhibits metabolism of tricyclics (increased  plasma concentration)   Anxiolytics and Hypnotics: disulfiram increases risk of  temazepam toxicity; disulfiram inhibits metabolism  of benzodiazepines (increased sedative effects)   Theophylline: disulfiram inhibits metabolism of theo-  phylline (increased risk of toxicity)   Note Since systemic absorption may follow topical appli-  cation of brinzolamide to the eye, the possibility of interac-  tions should be borne in mind   Note Since systemic absorption may follow topical appli-  cation of dorzolamide to the eye, the possibility of interac-  tions should be borne in mind   diuretics given with *ACE inhibitors; increased risk  of severe hyperkalaemia when potassium-sparing  diuretics and aldosterone antagonists given with  •ACE inhibitors (monitor potassium concentration  with low-dose spironolactone in heart failure)  Adrenergic Neurone Blockers: enhanced hypotensive  effect when diuretics given with adrenergic neurone  blockers   Aldesleukin: enhanced hypotensive effect when diur-  etics given with aldesleulan  Aliskiren: plasma concentration of furosemide  reduced by aliskiren; increased risk of hyperkalaemia  when potassium-sparing diuretics and aldosterone  antagonists given with aliskiren  Allopurinol: increased risk of hypersensitivity when  thiazides and related diuretics given with allopurinol  especially in renal impairment   diuretics given with •alpha-blockers, also increased  risk of first-dose hypotension with post-synaptic  alpha-blockers such as prazosin  Anaesthetics, General: enhanced hypotensive effect  when diuretics given with general anaesthetics   NSAIDs, also antagonism of diuretic effect; Diuretic  effect of potassium canrenoate possibly antagonised  by NSAIDs; possible increased risk of hyperkalaemia  when potassium-sparing diuretics and aldosterone  antagonists given with NSAIDs; effects of diuretics  antagonised by indometacin and ketorolac;  increased risk of hyperkalaemia when potassium-  sparing diuretics and aldosterone antagonists given  with indometacin; occasional reports of reduced  renal function when triamterene given with  •indometacin — avoid concomitant use; diuretic  effect of spironolactone antagonised by aspirin;  increased risk of toxicity when carbonic anhydrase  inhibitors given with high-dose aspirin   hypotensive effect when diuretics given with  •angiotensin-II receptor antagonists; increased risk  of hyperkalaemia when potassium-sparing diuretics  and aldosterone antagonists given with •angio-  tensin-II receptor antagonists   increased by amiodarone (reduce dose of eplere-  none); hypokalaemia caused by acetazolamide, loop  diuretics or thiazides and related diuretics increases  cardiac toxicity with amiodarone; hypokalaemia  caused by acetazolamide, loop diuretics or thiazides  and related diuretics increases cardiac toxicity with  •disopyramide; hypokalaemia caused by acetazol-  amide, loop diuretics or thiazides and related diur-  etics increases cardiac toxicity with •flecainide;  hypokalaemia caused by acetazolamide, loop  diuretics or thiazides and related diuretics antag-  onises action of •lidocaine   increased by •clarithromycin and •telithromycin —  avoid concomitant use; plasma concentration of  eplerenone increased by erythromycin (reduce dose  of eplerenone); plasma concentration of eplerenone  reduced by •rifampicin — avoid concomitant use;  avoidance of diuretics advised by manufacturer of  lymecycline; increased risk of otoxicity when loop  diuretics given with •aminoglycosides,   aemia when loop diuretics or thiazides and related  diuretics given with reboxetine; enhanced hypoten-  sive effect when diuretics given with MAOIs; plasma  concentration of eplerenone reduced by »St John’s  wort — avoid concomitant use; increased risk of  postural hypotension when diuretics given with  tricyclics   Antidiabetics: loop diuretics and thiazides and related  diuretics antagonise hypoglycaemic effect of anti-  diabetics   reduced by •carbamazepine and •phenytoin — avoid  concomitant use; increased risk of hyponatraemia  when diuretics given with carbamazepine; acetazol-  amide increases plasma concentration of  •carbamazepine; effects of furosemide antagonised  by phenytoin; acetazolamide possibly increases  plasma concentration of *phenytoin; increased risk  of osteomalacia when carbonic anhydrase inhibitors  given with phenytoin or primidone; acetazolamide  possibly reduces plasma concentration of primidone;  hydrochlorothiazide possibly increases plasma con-  centration of topiramate   increased by •itraconazole and •ketoconazole —  avoid concomitant use; increased risk of hypokal-  aemia when loop diuretics or thiazides and related  diuretics given with amphotericin; hydrochloro-  thiazide increases plasma concentration of flucon-  azole; plasma concentration of eplerenone increased  by fluconazole (reduce dose of eplerenone)   increases risk of ventricular arrhythmias with  •amisulpride; enhanced hypotensive effect when  diuretics given with phenothiazines; hypokalaemia  caused by diuretics increases risk of ventricular  arrhythmias with •pimozide (avoid concomitant use)   increased by •nelfinavir and •ritonavir — avoid con-  comitant use; plasma concentration of eplerenone  increased by saquinavir (reduce dose of eplerenone)   Anxiolytics and Hypnotics: enhanced hypotensive  effect when diuretics given with anxiolytics and  hypnotics; administration of parenteral furosemide  with chloral or triclofos may displace thyroid  hormone from binding sites   diuretics given with beta-blockers; hypokalaemia  caused by loop diuretics or thiazides and related  diuretics increases risk of ventricular arrhythmias  with •sotalol   Calcium Salts: increased risk of hypercalcaemia when  thiazides and related diuretics given with calcium  salts   Calcium-channel Blockers: enhanced hypotensive  effect when diuretics given with calcium-channel  blockers; plasma concentration of eplerenone  increased by diltiazem and verapamil (reduce dose of  eplerenone)   zolamide, loop diuretics or thiazides and related  diuretics increases cardiac toxicity with •cardiac  glycosides; spironolactone increases plasma con-  centration of •digoxin; potassium canrenoate possi-  bly increases plasma concentration of digoxin   possibly hypermagnesaemia when thiazides and  related diuretics given with ciclosporin; increased  risk of hyperkalaemia when potassium-sparing diur-  etics and aldosterone antagonists given with  •ciclosporin; acetazolamide possibly increases  plasma concentration of •ciclosporin  Clonidine: enhanced hypotensive effect when diuretics  given with clonidine   Corticosteroids: diuretic effect of diuretics antago-  nised by corticosteroids; increased risk of hypokal-  aemia when acetazolamide, loop diuretics or  thiazides and related diuretics given with corticos-  teroids   increases exceretion of methotrexate; hypokalaemia  caused by acetazolamide, loop diuretics or thiazides  and related diuretics increases risk of ventricular  arrhythmias with ©arsenic trioxide; avoidance of  spironolactone advised by manufacturer of mitotane  (antagonism of effect); increased risk of nephrotoxi-  city and ototoxicity when diuretics given with  platinum compounds   Diazoxide: enhanced hypotensive and hyperglycaemic  effects when diuretics given with diazoxide  Diuretics: increased risk of hypokalaemia when loop  diuretics or thiazides and related diuretics given with  acetazolamide; profound diuresis possible when  metolazone given with furosemide; increased risk of  hypokalaemia when thiazides and related diuretics  given with loop diuretics   Dopaminergics: enhanced hypotensive effect when  diuretics given with levodopa  Hormone Antagonists: increased risk of hypercal-  caemia when thiazides and related diuretics given  with toremifene; increased risk of hyperkalaemia  when potassium-sparing diuretics and aldosterone  antagonists given with trilostane  Lipid-regulating Drugs: absorption of thiazides and  related diuretics reduced by colestipol and colestyr-  amine (give at least 2 hours apart)   diuretics reduce excretion of •lithium (increased  plasma concentration and risk of toxicity) — loop  diuretics safer than thiazides; potassium-sparing  diuretics and aldosterone antagonists reduce excre-  tion of •lithium (increased plasma concentration and  risk of toxicity); acetazolamide increases the excre-  tion of ©lithium   Methyldopa: enhanced hypotensive effect when diur-  etics given with methyldopa  Moxisylyte: enhanced hypotensive effect when diur-  etics given with moxisylyte  Moxonidine: enhanced hypotensive effect when diur-  etics given with moxonidine  Muscle Relaxants: enhanced hypotensive effect when  diuretics given with baclofen or tizanidine  Nitrates: enhanced hypotensive effect when diuretics  given with nitrates   when potassium-sparing diuretics and aldosterone  antagonists given with ©potassium salts  Progestogens: risk of hyperkalaemia when potassium-  sparing diuretics and aldosterone antagonists given  with drospirenone (monitor serum potassium during  first cycle)   Prostaglandins: enhanced hypotensive effect when  diuretics given with alprostadil  Sympathomimetics, Beta 2 : increased risk of hypo-  kalaemia when acetazolamide, loop diuretics or  thiazides and related diuretics given with high doses  of beta 2 sympathomimetics — see Hypokalaemia,  p. 176   potassium-sparing diuretics and aldosterone  antagonists given with ©tacrolimus  Theophylline: increased risk of hypokalaemia when  acetazolamide, loop diuretics or thiazides and related  diuretics given with theophylline  Vasodilator Antihypertensives: enhanced hypoten-  sive effect when diuretics given with hydralazine,  minoxidil or sodium nitroprusside  Vitamins: increased risk of hypercalcaemia when  thiazides and related diuretics given with vitamin D  Diuretics, Loop see Diuretics  Diuretics, Potassium-sparing and Aldosterone  Antagonists see Diuretics  Diuretics, Thiazide and related see Diuretics  Dobutamine see Sympathomimetics  Docetaxel   Antibacterials: in vitro studies suggest a possible  interaction between docetaxel and erythromycin  (consult docetaxel product literature)   Antifungals: in vitro studies suggest a possible  interaction between docetaxel and ketoconazole  (consult docetaxel product literature)   Ciclosporin: in vitro studies suggest a possible  interaction between docetaxel and ciclosporin  (consult docetaxel product literature)   Cytotoxics : possible increased risk of neutropenia  when docetaxel given with lapatinib; plasma con-  centration of docetaxel increased by sorafenib  Domperidone   Analgesics: effects of domperidone on gastrointes-  tinal activity antagonised by opioid analgesics   possibly increased by ©ketoconazole  Antimuscarinics: effects of domperidone on gastro-  intestinal activity antagonised by antimuscarinics  Dopaminergics: domperidone possibly antagonises  hypoprolactinaemic effects of bromocriptine and  cabergoline   Donepezil see Parasympathomimetics  Dopamine see Sympathomimetics  Dopaminergics see Amantadine, Apomorphine,  Bromocriptine, Cabergoline, Entacapone, Levo-  dopa, Pergolide, Pramipexole, Quinagolide, Rasagi-  line, Ropinirole, Rotigotine, Selegiline, and  Tolcapone   when doxapram given with •volatile liquid general  anaesthetics (avoid doxapram for at least 10 minutes  after volatile liquid general anaesthetics)  Antidepressants: effects of doxapram enhanced by  MAO Is   Sympathomimetics: increased risk of hypertension  when doxapram given with sympathomimetics  Theophylline: increased CNS stimulation when doxa-  pram given with theophylline   with *clozapine (increased risk of agranulocytosis)  Antivirals: doxorubicin possibly inhibits effects of  stavudine   Anaesthetics, Local: increased myocardial depression  when anti-arrhythmics given with bupivacaine,  levobupivacaine, prilocaine or ropivacaine   when anti-arrhythmics given with other •anti-  arrhythmics; increased risk of ventricular arrhyth-  mias when dronedarone given with •amiodarone or  •disopyramide — avoid concomitant use   avoid concomitant use with •clarithromycin or  •telithromycin (risk of ventricular arrhythmias);  plasma concentration of dronedarone possibly  increased by •erythromycin (increased risk of  ventricular arrhythmias — avoid concomitant use);  plasma concentration of dronedarone reduced by  •rifampicin — avoid concomitant use   mias when anti-arrhythmics that prolong the QT  interval given with •antipsychotics that prolong the  QT interval; manufacturer of dronedarone advises  avoid concomitant use with •phenothiazines (risk of  ventricular arrhythmias)   concomitant use with •ritonavir; increased risk of  ventricular arrhythmias when dronedarone given  with •saquinavir — avoid concomitant use   anti-arrhythmics given with *beta-blockers; drone-  darone possibly increases plasma concentration of  metoprolol and propranolol; increased risk of  ventricular arrhythmias when dronedarone given  with •sotalol — avoid concomitant use   dronedarone increased by •nifedipine; increased risk  of bradycardia and myocardial depression when  dronedarone given with •diltiazem and •verapamil   when dronedarone given with •simvastatin  Sirolimus: manufacturer of dronedarone advises  caution with sirolimus   Tacrolimus: manufacturer of dronedarone advises  caution with tacrolimus  Droperidol see Antipsychotics  Drospirenone see Progestogens  Drotrecogin Alfa   Analgesics: possible increased serotonergic effects  when duloxetine given with pethidine or tramadol   by •fluvoxamine — avoid concomitant use; possible  increased serotonergic effects when duloxetine given  with SSRIs, St John’s wort, amitriptyline, clomipra-  mine, •moclobemide, tryptophan or venlafaxine;  duloxetine should not be started until 2 weeks after  stopping •MAOIs, also MAOIs should not be started  until at least 5 days after stopping duloxetine; after  stopping SSRI-related antidepressants do not start  •moclobemide for at least 1 week   by manufacturer of •artemether/lumefantrine  Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine  SHTj Agonists: possible increased serotonergic effects  when duloxetine given with 5HTj agonists  Dutasteride   Calcium-channel Blockers: plasma concentration of  dutasteride increased by diltiazem and verapamil  Dydrogesterone see Progestogens  Edrophonium see Parasympathomimetics  Efavirenz   Antibacterials: increased risk of rash when efavirenz  given with clarithromycin; efavirenz reduces plasma  concentration of rifabutin — increase dose of rifabu-  tin; plasma concentration of efavirenz reduced by  rifampicin — increase dose of efavirenz   of itraconazole and •posaconazole; efavirenz  reduces plasma concentration of •voriconazole, also  plasma concentration of efavirenz increased  (increase voriconazole dose and reduce efavirenz  dose); efavirenz possibly reduces plasma concentra-  tion of caspofungin — consider increasing dose of  caspofungin   concentration of •aripiprazole — increase dose of  aripiprazole; efavirenz possibly increases plasma  concentration of •pimozide (increased risk of  ventricular arrhythmias — avoid concomitant use)   facturer of *atazanavir (plasma concentration of  atazanavir reduced); efavirenz reduces plasma con-  centration of darunavir, fosamprenavir and indinavir;  efavirenz possibly reduces plasma concentration of  •etravirine — avoid concomitant use; efavirenz  reduces plasma concentration of •lopinavir — con-  sider increasing dose of lopinavir; efavirenz possibly  reduces plasma concentration of •maraviroc — con-  sider increasing dose of maraviroc; plasma concen-  tration of efavirenz reduced by nevirapine; toxicity of  efavirenz increased by ritonavir, monitor liver func-  tion tests; efavirenz significantly reduces plasma  concentration of saquinavir   Grapefruit Juice: plasma concentration of efavirenz  possibly increased by grapefruit juice  Lipid-regulating Drugs: efavirenz reduces plasma  concentration of atorvastatin, pravastatin and  simvastatin   Antacids: absorption of eltrombopag reduced by  antacids (give at least 4 hours apart)   Antivirals: plasma concentration of eltrombopag  possibly reduced by lopinavir  Calcium Salts: absorption of eltrombopag possibly  reduced by calcium salts (give at least 4 hours apart)  Dairy Products: absorption of eltrombopag possibly  reduced by dairy products (give at least 4 hours  apart)   Iron: absorption of eltrombopag possibly reduced by  oral iron (give at least 4 hours apart)   Selenium: absorption of eltrombopag possibly  reduced by selenium (give at least 4 hours apart)  Zinc: absorption of eltrombopag possibly reduced by  zinc (give at least 4 hours apart)   Antivirals: manufacturer of emtricitabine advises avoid  concomitant use with lamivudine  Enalapril see ACE Inhibitors  Enoxaparin see Heparins  Enoximone see Phosphodiesterase Inhibitors  Entacapone   caution with moclobemide, paroxetine, tricyclics and  venlafaxine; avoid concomitant use of entacapone  with non-selective •MAOIs  Dopaminergics: entacapone possibly enhances effects  of apomorphine; entacapone possibly reduces  plasma concentration of rasagiline; manufacturer of  entacapone advises max. dose of 10 mg selegiline if  used concomitantly   Iron: absorption of entacapone reduced by oral iron  Memantine: effects of dopaminergics possibly  enhanced by memantine   Methyldopa: entacapone possibly enhances effects of  methyldopa; antiparkinsonian effect of dopaminer-  gics antagonised by methyldopa  Sympathomimetics: entacapone possibly enhances  effects of adrenaline (epinephrine), dobutamine,  dopamine and noradrenaline (norepinephrine)  Enteral Foods   enteral feeds can antagonise the anticoagulant effect  of •coumarins and •phenindione  Antiepileptics: enteral feeds possibly reduce absorp-  tion of phenytoin   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   lloprost: increased risk of bleeding when eptifibatide  given with iloprost  Ergometrine see Ergot Alkaloids  Ergot Alkaloids   Anaesthetics, General: effects of ergometrine on the  parturient uterus reduced by halothane   ergotamine and methysergide given with  •macrolides or •telithromycin — avoid concomitant  use; increased risk of ergotism when ergotamine and  methysergide given with tetracyclines  Antidepressants: possible risk of hypertension when  ergotamine and methysergide given with reboxetine   possibly increased by «atazanavir — avoid concomi-  tant use; increased risk of ergotism when ergot  alkaloids given with ©efavirenz — avoid concomitant  use; increased risk of ergotism when ergotamine and  methysergide given with •fosamprenavir, •indinavir,  •nelfinavir, *ritonavir or ©saquinavir — avoid conco-  mitant use   Beta-blockers: increased peripheral vasoconstriction  when ergotamine and methysergide given with beta-  blockers   ergotamine and methysergide given with •almotrip-  tan, •rizatriptan, •sumatriptan or •zolmitriptan  (avoid ergotamine and methysergide for 6 hours after  almotriptan, rizatriptan, sumatriptan or zolmitriptan,  avoid almotriptan, rizatriptan, sumatriptan or zolmi-  triptan for 24 hours after ergotamine and methy-  sergide); increased risk of vasospasm when  ergotamine and methysergide given with •eletriptan,  •frovatriptan or •naratriptan (avoid ergotamine and  methysergide for 24 hours after eletriptan,  frovatriptan or naratriptan, avoid eletriptan,  frovatriptan or naratriptan for 24 hours after ergot-  amine and methysergide)   Sympathomimetics: increased risk of ergotism when  ergotamine and methysergide given with sympatho-  mimetics   ergotamine and methysergide given with  •cimetidine — avoid concomitant use  Ergotamine and Methysergide see Ergot Alkaloids  Erlotinib   reduced by •antacids — give antacids at least 4 hours  before or 2 hours after erlotinib  Antibacterials: plasma concentration of erlotinib  increased by ciprofloxacin; metabolism of erlotinib  accelerated by rifampicin (reduced plasma concen-  tration)   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   avoid concomitant use with •cimetidine, •esome-  prazole, •famotidine, •lansoprazole, •nizatidine,  •pantoprazole and •rabeprazole; plasma concentra-  tion of erlotinib reduced by •ranitidine — manufac-  turer of erlotinib advises give at least 2 hours before  or 10 hours after ranitidine; plasma concentration of  erlotinib reduced by •omeprazole — manufacturer of  erlotinib advises avoid concomitant use  Ertapenem   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with «St John’s wort  Antiepileptics: plasma concentration of both drugs  reduced when eslicarbazepine given with carba-  mazepine; manufacturer of eslicarbazepine advises  avoid concomitant use with oxcarbazepine; plasma  concentration of eslicarbazepine reduced by pheny-  toin, also plasma concentration of phenytoin  increased   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   Esmolol see Beta-blockers  Esomeprazole see Proton Pump Inhibitors  Estradiol see Oestrogens  Estramustine   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with «St John’s wort   possibly reduced by carbamazepine and primidone;  plasma concentration of ethosuximide possibly  reduced by •phenytoin, also plasma concentration of  phenytoin possibly increased; plasma concentration  of ethosuximide possibly increased by valproate   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   antiepileptics given with «orlistat  Etodolac see NSAIDs  Etomidate see Anaesthetics, General  Etonogestrel see Progestogens  Etoposide   with •clozapine (increased risk of agranulocytosis)  Barbiturates: plasma concentration of etoposide  possibly reduced by phenobarbital  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Ciclosporin: plasma concentration of etoposide pos-  sibly increased by ciclosporin (increased risk of  toxicity)   increased by •clarithromycin, also plasma concen-  tration of clarithromycin reduced; plasma concen-  tration of both drugs reduced when etravirine given  with •rifabutin; manufacturer of etravirine advises  avoid concomitant use with rifampicin  Antidepressants: manufacturer of etravirine advises  avoid concomitant use with St John’s wort  Antiepileptics: manufacturer of etravirine advises  avoid concomitant use with carbamazepine and  phenytoin   reduced by *efavirenz and •nevirapine — avoid con-  comitant use; etravirine increases plasma concen-  tration of •fosamprenavir (consider reducing dose of  fosamprenavir); etravirine possibly reduces plasma  concentration of •indinavir — avoid concomitant use;  etravirine possibly reduces plasma concentration of  maraviroc; etravirine possibly increases plasma  concentration of nelfinavir — avoid concomitant use;  plasma concentration of etravirine reduced by  •tipranavir, also plasma concentration of tipranavir  increased (avoid concomitant use)   Barbiturates: manufacturer of etravirine advises avoid  concomitant use with phenobarbital  Cardiac Glycosides: etravirine increases plasma con-  centration of digoxin   Lipid-regulating Drugs: etravirine possibly reduces  plasma concentration of atorvastatin  Sildenafil: etravirine reduces plasma concentration of  sildenafil   possibly increased by •clarithromycin and  •telithromycin — manufacturer of everolimus advises  avoid concomitant use; plasma concentration of  everolimus increased by •erythromycin; plasma  concentration of everolimus reduced by •rifampicin  Antidepressants: plasma concentration of everolimus  possibly reduced by St John’s wort — manufacturer of  everolimus advises avoid concomitant use  Antiepileptics: cytotoxics possibly reduce absorption  of phenytoin   bly increased by •atazanavir, •darunavir, •indinavir,  •nelfinavir, •ritonavir and •saquinavir — manufac-  turer of everolimus advises avoid concomitant use   Grapefruit Juice: manufacturer of everolimus advises  avoid concomitant use with grapefruit juice  Exemestane   increase when ezetimibe given with •ciclosporin  Lipid-regulating Drugs: increased risk of cholelithiasis  and gallbladder disease when ezetimibe given with  fibrates — discontinue if suspected  Famciclovir   Probenecid: excretion of famciclovir possibly reduced  by probenecid (increased plasma concentration)  Famotidine see Histamine H 2 -antagonists  Febuxostat   caution with •theophylline  Felodipine see Calcium-channel Blockers  Fenbufen see NSAIDs  Fenofibrate see Fibrates  Fenoprofen see NSAIDs  Fenoterol see Sympathomimetics, Beta 2  Fentanyl see Opioid Analgesics  Ferrous Salts see Iron  Fesoterodine see Antimuscarinics  Fexofenadine see Antihistamines  Fibrates   and have an additive effect with insulin or sulfony-  lureas; gemfibrozil possibly enhances hypoglycaemic  effect of nateglinide; increased risk of severe hypo-  glycaemia when gemfibrozil given with  •repaglinide — avoid concomitant use   Ciclosporin: increased risk of renal impairment when  bezafibrate or fenofibrate given with ciclosporin   and gallbladder disaese when fibrates given with  ezetimibe — discontinue if suspected; increased risk  of myopathy when fibrates given with •statins;  increased risk of myopathy when gemfibrozil given  with «statins (preferably avoid concomitant use)  Filgrastim   Note Pegfilgrastim interactions as for filgrastim  Cytotoxics: neutropenia possibly exacerbated when  filgrastim given with fluorouracil  Flavoxate see Antimuscarinics  Flecainide   Anaesthetics, Local: increased myocardial depression  when anti-arrhythmics given with bupivacaine,  levobupivacaine, prilocaine or ropivacaine   when anti-arrhythmics given with other •anti-  arrhythmics; plasma concentration of flecainide  increased by •amiodarone (halve dose of flecainide)   increased by fluoxetine; increased risk of ventricular  arrhythmias when flecainide given with •tricyclics   manufacturer of •artemether/lumefantrine (risk of  ventricular arrhythmias); plasma concentration of  flecainide increased by •quinine   mias when anti-arrhythmics that prolong the QT  interval given with •antipsychotics that prolong the  QT interval; increased risk of arrhythmias when  flecainide given with •clozapine   •lopinavir and •ritonavir (increased risk of ventri-  cular arrhythmias — avoid concomitant use);  increased risk of ventricular arrhythmias when  flecainide given with •saquinavir — avoid concomi-  tant use   and bradycardia when flecainide given with •beta-  blockers; increased myocardial depression when  anti-arrhythmics given with •beta-blockers   hypokalaemia occurs with •acetazolamide, «loop  diuretics or *thiazides and related diuretics  Ulcer-healing Drugs: metabolism of flecainide inhib-  ited by cimetidine (increased plasma concentration)  Flucloxacillin see Penicillins  Fluconazole see Antifungals, Triazole  Flucytosine   Antifungals: renal excretion of flucytosine decreased  and cellular uptake increased by amphotericin  (toxicity possibly increased)   Cytotoxics: plasma concentration of flucytosine pos-  sibly reduced by cytarabine  Fludarabine   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   centration of cytarabine; increased pulmonary toxi-  city when fludarabine given with *pentostatin  (unacceptably high incidence of fatalities)  Dipyridamole: effects of fludarabine possibly reduced  by dipyridamole   Note Capecitabine is a prodrug of fluorouracil  Note Tegafur is a prodrug of fluorouracil   Antiepileptics: fluorouracil possibly inhibits metab-  olism of phenytoin (increased risk of toxicity);  cytotoxics possibly reduce absorption of phenytoin   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Fluoxetine see Antidepressants, SSRI  Flupentixol see Antipsychotics  Fluphenazine see Antipsychotics  Flurazepam see Anxiolytics and Hypnotics  Flurbiprofen see NSAIDs  Flutamide   Antiepileptics: folates possibly reduce plasma con-  centration of phenytoin and primidone  Barbiturates: folates possibly reduce plasma concen-  tration of phenobarbital   turer of •raltitrexed  Folic Acid see Folates  Folinic Acid see Folates  Formoterol see Sympathomimetics, Beta 2  Fosamprenavir   Note Fosamprenavir is a prodrug of amprenavir  Analgesics: fosamprenavir reduces plasma concen-  tration of methadone   •flecainide and •propafenone (increased risk of  ventricular arrhythmias — avoid concomitant use);  fosamprenavir possibly increases plasma concentra-  tion of •lidocaine — avoid concomitant use   centration of •rifabutin (reduce dose of rifabutin);  plasma concentration of fosamprenavir significantly  reduced by •rifampicin — avoid concomitant use;  avoidance of concomitant fosamprenavir in severe  renal and hepatic impairment advised by manufac-  turer of •telithromycin   Anticoagulants: fosamprenavir may enhance or  reduce anticoagulant effect of coumarins; avoidance  of fosamprenavir advised by manufacturer of rivar-  oxaban   Antiepileptics: plasma concentration of fosamprenavir  possibly reduced by carbamazepine  Antifungals: fosamprenavir increases plasma concen-  tration of ketoconazole (also plasma concentration  of fosamprenavir possibly increased); plasma con-  centration of both drugs may increase when  fosamprenavir given with itraconazole   manufacturer of artemether/lumefantrine; fosam-  prenavir possibly increases plasma concentration of  •quinine (increased risk of toxicity)  Antimuscarinics: avoidance of fosamprenavir advised  by manufacturer of darifenacin and tolterodine   metabolism of •aripiprazole (reduce dose of aripi-  prazole); fosamprenavir increases plasma concen-  tration of ©pimozide (increased risk of ventricular  arrhythmias — avoid concomitant use)   reduced by efavirenz and «tipranavir; plasma con-  centration of fosamprenavir increased by •etravirine  (consider reducing dose of fosamprenavir); plasma  concentration of fosamprenavir reduced by lopinavir,  effect on lopinavir plasma concentration not pre-  dictable — avoid concomitant use; plasma concen-  tration of fosamprenavir possibly reduced by  nevirapine   myopathy when fosamprenavir given with atorvas-  tatin; possible increased risk of myopathy when  fosamprenavir given with *rosuvastatin — manufac-  turer of rosuvastatin advises avoid concomitant use;  possible increased risk of myopathy when fosam-  prenavir given with ©simvastatin — avoid concomi-  tant use   Vardenafil: fosamprenavir possibly increases plasma  concentration of vardenafil  Fosaprepitant see Aprepitant  Foscarnet   aemia when foscarnet given with parenteral ©pent-  amidine isetionate  Fosinopril see ACE Inhibitors  Fos phenytoin see Phenytoin  Framycetin see Aminoglycosides  Frovatriptan see 5HTj Agonists  Furosemide see Diuretics   myopathy when fusidic acid given with atorvastatin;  increased risk of myopathy when fusidic acid given  with •simvastatin   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by «SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with *St John’s wort   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   centration of didanosine; avoidance of intravenous  ganciclovir advised by manufacturer of lamivudine;  profound myelosuppression when ganciclovir given  with •zidovudine (if possible avoid concomitant  administration, particularly during initial ganciclovir  therapy)   Mycophenolate: plasma concentration of ganciclovir  possibly increased by mycophenolate, also plasma  concentration of inactive metabolite of mycopheno-  late possibly increased   Probenecid: excretion of ganciclovir reduced by  probenecid (increased plasma concentration and risk  of toxicity)   Tacrolimus: possible increased risk of nephrotoxicity  when ganciclovir given with tacrolimus  Gefitinib   coagulant effect of •warfarin  Antidepressants: manufacturer of gefitinib advises  avoid concomitant use with St John’s wort  Antiepileptics: manufacturer of gefitinib advises avoid  concomitant use with carbamazepine and phenytoin;  cytotoxics possibly reduce absorption of phenytoin  Antifungals: plasma concentration of gefitinib  increased by itraconazole   with •clozapine (increased risk of agranulocytosis)  Barbiturates: manufacturer of gefitinib advises avoid  concomitant use with barbiturates  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Gemeprost see Prostaglandins  Gemfibrozil see Fibrates  Gentamicin see Aminoglycosides  Gestodene see Progestogens  Glibenclamide see Antidiabetics  Gliclazide see Antidiabetics  Glimepi ride see Antidiabetics  Glipizide see Antidiabetics  Glucosamine   Glyceryl Trinitrate see Nitrates  Glycopyrronium see Antimuscarinics  Gold see Sodium Aurothiomalate  Golimumab   concentration of amiodarone; grapefruit juice  increases plasma concentration of •dronedarone —  avoid concomitant use   Antimalarials: grapefruit juice possibly increases  plasma concentration of artemether/lumefantrine  Antivirals: grapefruit juice possibly increases plasma  concentration of efavirenz   Anxiolytics and Hypnotics: grapefruit juice increases  plasma concentration of buspirone  Calcium-channel Blockers: grapefruit juice possibly  increases plasma concentration of amlodipine;  grapefruit juice increases plasma concentration of  felodipine, isradipine, lacidipine, lercanidipine,  nicardipine, nifedipine, nimodipine and verapamil   •nilotinib and «pazopanib; grapefruit juice possibly  increases plasma concentration of vinflunine —  manufacturer of vinflunine advises avoid concomi-  tant use   increases plasma concentration of atorvastatin;  grapefruit juice increases plasma concentration of  •simvastatin — avoid concomitant use   concentration of •ranolazine — manufacturer of  ranolazine advises avoid concomitant use  Sildenafil: grapefruit juice possibly increases plasma  concentration of sildenafil   Ciclosporin: griseofulvin possibly reduces plasma  concentration of ciclosporin  Oestrogens : anecdotal reports of contraceptive failure  and menstrual irregularities when griseofulvin given  with oestrogens   Progestogens : anecdotal reports of contraceptive  failure and menstrual irregularities when griseofulvin  given with progestogens   ACE Inhibitors: increased risk of hyperkalaemia when  heparins given with ACE inhibitors  Aliskiren: increased risk of hyperkalaemia when  heparins given with aliskiren   heparins given with NSAIDs; increased risk of  haemorrhage when anticoagulants given with intra-  venous •diclofenac (avoid concomitant use, includ-  ing low-dose heparins); increased risk of  haemorrhage when anticoagulants given with  •ketorolac (avoid concomitant use, including low-  dose heparins); anticoagulant effect of heparins  enhanced by •aspirin   Angiotensin-ll Receptor Antagonists: increased risk  of hyperkalaemia when heparins given with angio-  tensin-II receptor antagonists  Clopidogrel: increased risk of bleeding when heparins  given with clopidogrel   high doses of heparins with drotrecogin alfa advised  by manufacturer of •drotrecogin alfa — consult  product literature   Antidepressants: manufacturer of histamine advises  avoid concomitant use with MAOIs; effects of  histamine theoretically antagonised by tricyclics —  manufacturer of histamine advises avoid concomi-  tant use   Antihistamines: effects of histamine theoretically  antagonised by antihistamines — manufacturer of  histamine advises avoid concomitant use  Antimalarials: manufacturer of histamine advises  avoid concomitant use with antimalarials  Antipsychotics: effects of histamine theoretically  antagonised by antipsychotics — manufacturer of  histamine advises avoid concomitant use  Atovaquone: manufacturer of histamine advises avoid  concomitant use with atovaquone  Clonidine: manufacturer of histamine advises avoid  concomitant use with clonidine  Corticosteroids: manufacturer of histamine advises  avoid concomitant use with corticosteroids  Ulcer-healing Drugs: effects of histamine theoretically  antagonised by histamine H 2 -antagonists — manu-  facturer of histamine advises avoid concomitant use   centration of amiodarone and •propafenone; cime-  tidine inhibits metabolism of flecainide (increased  plasma concentration); cimetidine increases plasma  concentration of •lidocaine (increased risk of toxi-  city)   Antibacterials: histamine H 2 -antagonists reduce  absorption of cefpodoxime; cimetidine increases  plasma concentration of erythromycin (increased  risk of toxicity, including deafness); cimetidine  inhibits metabolism of metronidazole (increased  plasma concentration); metabolism of cimetidine  accelerated by rifampicin (reduced plasma concen-  tration)   •coumarins (enhanced anticoagulant effect)  Antidepressants: cimetidine increases plasma con-  centration of citalopram, escitalopram,  mirtazapine and sertraline; cimetidine inhibits  metabolism of amitriptyline, doxepin,  imipramine and nortriptyline (increased plasma  concentration); cimetidine increases plasma con-  centration of moclobemide (halve dose of moclobe-  mide); cimetidine possibly increases plasma  concentration of tricyclics   Antidiabetics: cimetidine reduces excretion of met-  formin (increased plasma concentration); cimetidine  enhances hypoglycaemic effect of sulfonylureas   tion of itraconazole and ketoconazole; avoidance of  histamine H 2 -antagonists advised by manufacturer of  posaconazole (plasma concentration of posacona-  zole possibly reduced); cimetidine reduces plasma  concentration of •posaconazole; cimetidine  increases plasma concentration of terbinafine  Antihistamines: manufacturer of loratadine advises  cimetidine possibly increases plasma concentration  of loratadine   manufacturer of •artemether/lumefantrine; cimeti-  dine inhibits metabolism of chloroquine and  hydroxychloroquine and quinine (increased plasma  concentration)   concentration of •atazanavir; histamine H 2 -antago-  nists possibly increase plasma concentration of  raltegravir — manufacturer of raltegravir advises  avoid concomitant use; cimetidine possibly increases  plasma concentration of saquinavir  Anxiolytics and Hypnotics: cimetidine inhibits  metabolism of benzodiazepines, clomethiazole and  zaleplon (increased plasma concentration); cimeti-  dine increases plasma concentration of melatonin  Beta-blockers: cimetidine increases plasma concen-  tration of labetalol, metoprolol and propranolol  Calcium-channel Blockers: cimetidine possibly inhi-  bits metabolism of calcium-channel blockers  (increased plasma concentration); cimetidine  increases plasma concentration of isradipine (halve  dose of isradipine)   pressive effects of carmustine and lomustine; cime-  tidine increases plasma concentration of •epirubicin;  cimetidine inhibits metabolism of fluorouracil  (increased plasma concentration); famotidine possi-  bly reduces plasma concentration of dasatinib;  avoidance of cimetidine, famotidine and nizatidine  advised by manufacturer of •erlotinib; ranitidine   reduces plasma concentration of •erlotinib —  manufacturer of erlotinib advises give at least 2  hours before or 10 hours after ranitidine; raniti-  dine reduces plasma concentration of •gefitinib;  histamine H 2 -antagonists possibly reduce  absorption of lapatinib   cimetidine given with •ergotamine and methy-  sergide — avoid concomitant use  Histamine: histamine H 2 -antagonists theoretically  antagonise effects of histamine — manufacturer of  histamine advises avoid concomitant use  Hormone Antagonists: absorption of cimetidine pos-  sibly delayed by octreotide  SHTj Agonists: cimetidine inhibits metabolism of  zolmitriptan (reduce dose of zolmitriptan)  Mebendazole: cimetidine possibly inhibits metabolism  of mebendazole (increased plasma concentration)  Roflumilast : cimetidine inhibits the metabolism of  roflumilast   Sildenafil: cimetidine increases plasma concentration  of sildenafil (consider reducing dose of sildenafil)   •theophylline (increased plasma concentration)  Thyroid Hormones: cimetidine reduces absorption of  levothyroxine   advised by manufacturer of •ulipristal (plasma  concentration of ulipristal possibly reduced)   Hormone Antagonists see Bicalutamide, Danazol,  Dutasteride, Exemestane, Flutamide, Lanreotide,  Octreotide, Tamoxifen, Toremifene, and Trilostane   sumatriptan given with •citalopram, •escitalopram,  •fluoxetine, •fluvoxamine or •paroxetine; metab-  olism of frovatriptan inhibited by fluvoxamine;  metabolism of zolmitriptan possibly inhibited by  fluvoxamine (reduce dose of zolmitriptan); CNS  toxicity reported when sumatriptan given with ser-  traline; possible increased serotonergic effects when  5HT! agonists given with duloxetine or venlafaxine;  increased risk of CNS toxicity when zolmitriptan  given with •MAOIs; risk of CNS toxicity when  rizatriptan or sumatriptan given with •MAOIs (avoid  rizatriptan or sumatriptan for 2 weeks after MAOIs);  risk of CNS toxicity when rizatriptan or sumatriptan  given with •moclobemide (avoid rizatriptan or  sumatriptan for 2 weeks after moclobemide); risk of  CNS toxicity when zolmitriptan given with  •moclobemide (reduce dose of zolmitriptan);  increased serotonergic effects when 5HTj agonists  given with *St John’s wort — avoid concomitant use   increased by •itraconazole and •ketoconazole (risk  of toxicity) — avoid concomitant use; plasma con-  centration of almotriptan increased by ketoconazole  (increased risk of toxicity)   increased by •indinavir, •nelfinavir and •ritonavir  (risk of toxicity) — avoid concomitant use  Beta-blockers: plasma concentration of rizatriptan  increased by propranolol (manufacturer of rizatriptan  advises halve dose and avoid within 2 hours of  propranolol)   eletriptan, frovatriptan or naratriptan given with  •ergotamine and methysergide (avoid ergotamine  and methysergide for 24 hours after eletriptan,  frovatriptan or naratriptan, avoid eletriptan,  frovatriptan or naratriptan for 24 hours after ergot-  amine and methysergide); increased risk of vasos-  pasm when almotriptan, rizatriptan, sumatriptan or  zolmitriptan given with •ergotamine and methy-  sergide (avoid ergotamine and methysergide for 6  hours after almotriptan, rizatriptan, sumatriptan or  zolmitriptan, avoid almotriptan, rizatriptan,  sumatriptan or zolmitriptan for 24 hours after  ergotamine and methysergide)   Lithium : possible risk of toxicity when sumatriptan  given with lithium   Ulcer-healing Drugs: metabolism of zolmitriptan  inhibited by cimetidine (reduce dose of zolmitriptan)  5HT 3 Antagonists   Antiepileptics: metabolism of ondansetron acceler-  ated by carbamazepine and phenytoin (reduced  effect)   Hydralazine see Vasodilator Antihypertensives  Hydrochlorothiazide see Diuretics  Hydrocortisone see Corticosteroids  Hydroflumethiazide see Diuretics  Hydromorphone see Opioid Analgesics  Hydrotalcite see Antacids  Hydroxocobalamin   Hydroxyzine see Antihistamines  Hyoscine see Antimuscarinics  Ibandronic Acid see Bisphosphonates  Ibuprofen see NSAIDs  Idarubicin   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Analgesics: increased risk of bleeding when iloprost  given with NSAIDs or aspirin  Anticoagulants: iloprost possibly enhances anti-  coagulant effect of coumarins and heparins;   Anticoagulants (continued)  increased risk of bleeding when iloprost given  with phenindione   Tirofiban: increased risk of bleeding when iloprost  given with tirofiban  Imatinib   reduced by •carbamazepine, •oxcarbazepine and  •phenytoin — avoid concomitant use; cytotoxics  possibly reduce absorption of phenytoin  Antifungals: plasma concentration of imatinib  increased by ketoconazole   Lipid-regulating Drugs: imatinib increases plasma  concentration of simvastatin  Thyroid Hormones: imatinib possibly reduces plasma  concentration of levothyroxine  Imidapril see ACE Inhibitors  Imipenem with Cilastatin   concentration of •amiodarone — avoid concomitant  use; indinavir possibly increases plasma concentra-  tion of •flecainide (increased risk of ventricular  arrhythmias — avoid concomitant use)   tion of •rifabutin — avoid concomitant use; metab-  olism of indinavir accelerated by •rifampicin  (reduced plasma concentration — avoid concomitant  use); avoidance of concomitant indinavir in severe  renal and hepatic impairment advised by manufac-  turer of •telithromycin   possibly reduced by •carbamazepine and  •phenytoin, also plasma concentration of  carbamazepine and phenytoin possibly increased;  plasma concentration of indinavir possibly reduced  by •primidone   increased by •itraconazole and •ketoconazole (con-  sider reducing dose of indinavir)   manufacturer of artemether/lumefantrine; indinavir  possibly increases plasma concentration of •quinine  (increased risk of toxicity)   Antimuscarinics: avoidance of indinavir advised by  manufacturer of darifenacin and tolterodine; manu-  facturer of fesoterodine advises dose reduction when  indinavir given with fesoterodine — consult fesoter-  odine product literature   of •aripiprazole (reduce dose of aripiprazole); indi-  navir possibly increases plasma concentration of  •pimozide (increased risk of ventricular arrhyth-  mias — avoid concomitant use)   •atazanavir; plasma concentration of both drugs  increased when indinavir given with darunavir;  plasma concentration of indinavir reduced by  efavirenz and nevirapine; plasma concentration of  indinavir possibly reduced by •etravirine — avoid  concomitant use; indinavir increases plasma con-  centration of •maraviroc (consider reducing dose of  maraviroc); combination of indinavir with nelfinavir  may increase plasma concentration of either drug (or  both); plasma concentration of indinavir increased  by ritonavir; indinavir increases plasma concentra-  tion of saquinavir   longed sedation when indinavir given with  •alprazolam — avoid concomitant use; indinavir pos-  sibly increases plasma concentration of •midazolam  (risk of prolonged sedation — avoid concomitant use  of oral midazolam)   sibly reduced by •barbiturates; plasma concentration  of indinavir possibly reduced by •phenobarbital, also  plasma concentration of phenobarbital possibly  increased   •colchicine toxicity — suspend or reduce dose of  colchicine (avoid concomitant use in hepatic or renal  impairment)   myopathy when indinavir given with atorvastatin;  possible increased risk of myopathy when indinavir  given with •rosuvastatin — manufacturer of rosuvas-  tatin advises avoid concomitant use; increased risk of  myopathy when indinavir given with •simvastatin  (avoid concomitant use)   •sildenafil — reduce initial dose of sildenafil  Tadalafil: indinavir possibly increases plasma con-  centration of tadalafil   Influenza Vaccine see Vaccines  Insulin see Antidiabetics  Interferon Alfa see Interferons  Interferon Gamma see Interferons  Interferons   Vaccines: manufacturer of interferon gamma advises  avoid concomitant use with vaccines  Ipratropium see Antimuscarinics  Irbesartan see Angiotensin-II Receptor Antagonists  Irinotecan   Antiepileptics: plasma concentration of irinotecan and  its active metabolite reduced by carbamazepine and  phenytoin; cytotoxics possibly reduce absorption of  phenytoin   by «atazanavir (increased risk of toxicity)  Barbiturates: plasma concentration of irinotecan and  its active metabolite reduced by phenobarbital  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Antacids: absorption of oral iron reduced by oral  magnesium salts (as magnesium trisilicate)  Antibacterials: oral iron reduces absorption of cipro-  floxacin, levofloxacin, moxifloxacin, norfloxacin and  ofloxacin; oral iron reduces absorption of tetracy-  clines, also absorption of oral iron reduced by  tetracyclines   Dopaminergics: oral iron reduces absorption of  entacapone; oral iron possibly reduces absorption of  levodopa   Eltrombopag: oral iron possibly reduces absorption of  eltrombopag (give at least 4 hours apart)  Methyldopa: oral iron antagonises hypotensive effect  of methyldopa   Thyroid Hormones: oral iron reduces absorption of  levothyroxine (give at least 2 hours apart)   Trientine: absorption of oral iron reduced by trientine  Zinc: oral iron reduces absorption of zinc, also  absorption of oral iron reduced by zinc  Isocarboxazid see MAOIs  Isoflurane see Anaesthetics, General   Antacids: absorption of isoniazid reduced by antacids  Antibacterials: increased risk of CNS toxicity when  isoniazid given with cycloserine   tion of •carbamazepine (also possibly increased  isoniazid hepatotoxicity); isoniazid inhibits metab-  olism of •ethosuximide (increased plasma concen-  tration and risk of toxicity); isoniazid possibly inhibits  metabolism of phenytoin (increased risk of toxicity)  Antifungals: isoniazid possibly reduces plasma con-  centration of ketoconazole  Anxiolytics and Hypnotics: isoniazid inhibits the  metabolism of diazepam   Corticosteroids: plasma concentration of isoniazid  possibly reduced by corticosteroids  Disulfiram: isoniazid possibly increases CNS effects of  disulfiram   Theophylline: isoniazid possibly increases plasma  concentration of theophylline  Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767  Isosorbide Dinitrate see Nitrates  Isosorbide Mononitrate see Nitrates  Isotretinoin see Retinoids  Isradipine see Calcium-channel Blockers  Itraconazole see Antifungals, Triazole  Ivabradine   possibly increased by •clarithromycin and  •telithromycin — avoid concomitant use; increased  risk of ventricular arrhythmias when ivabradine  given with •erythromycin — avoid concomitant use  Antidepressants: plasma concentration of ivabradine  reduced by St John’s wort — avoid concomitant use   increased by •ketoconazole — avoid concomitant  use; plasma concentration of ivabradine increased by  fluconazole — reduce initial dose of ivabradine;  plasma concentration of ivabradine possibly  increased by •itraconazole — avoid concomitant use   Antimalarials: kaolin reduces absorption of chloro-  quine and hydroxychloroquine  Antipsychotics: kaolin possibly reduces absorption of  phenothiazines   Ketamine see Anaesthetics, General  Ketoconazole see Antifungals, Imidazole  Ketoprofen see NSAIDs  Ketorolac see NSAIDs   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by *SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with *St John’s wort   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   Antibacterials: plasma concentration of lamivudine  increased by trimethoprim (as co-trimoxazole) —  avoid concomitant use of high-dose co-trimoxazole   Antivirals: avoidance of lamivudine advised by man-  ufacturer of emtricitabine; manufacturer of lamivu-  dine advises avoid concomitant use with foscamet;  manufacturer of lamivudine advises avoid concomi-  tant use of intravenous ganciclovir   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with *St John’s wort   Antiepileptics: plasma concentration of lamotrigine  often reduced by carbamazepine, also plasma con-  centration of an active metabolite of carbamazepine  sometimes raised (but evidence is conflicting);  plasma concentration of lamotrigine reduced by  phenytoin and primidone; plasma concentration of  lamotrigine increased by valproate   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   Antidiabetics: lanreotide possibly reduces require-  ments for insulin, metformin, repaglinide and sulfo-  nylureas   Antibacterials : lanthanum possibly reduces absorp-  tion of quinolones (give at least 2 hours before or 4  hours after lanthanum)   Antifungals: lanthanum possibly reduces absorption of  ketoconazole (give at least 2 hours apart)   Antimalarials: lanthanum possibly reduces absorption  of chloroquine and hydroxychloroquine (give at least  2 hours apart)   Thyroid Hormones : lanthanum reduces absorption of  levothyroxine (give at least 2 hours apart)   with •clozapine (increased risk of agranulocytosis);  manufacturer of lapatinib advises avoid concomitant  use with •pimozide   of pazopanib; possible increased risk of neutropenia  when lapatinib given with docetaxel; increased risk  of neutropenia when lapatinib given with •paclitaxel;  lapatinib increases plasma concentration of active  metabolite of •irinotecan — consider reducing dose  of irinotecan   avoid concomitant use with •grapefruit juice  Ulcer-healing Drugs: absorption of lapatinib possibly  reduced by histamine H 2 -antagonists and proton  pump inhibitors  Laronidase   Antimalarials: effects of laronidase possibly inhibited  by chloroquine and hydroxychloroquine (manufac-  turer of laronidase advises avoid concomitant use)  Leflunomide   Note Increased risk of toxicity with other haematotoxic and  hepatotoxic drugs   Antibacterials: plasma concentration of active meta-  bolite of leflunomide possibly increased by rif-  ampicin   Anticoagulants: leflunomide possibly enhances anti-  coagulant effect of warfarin  Antidiabetics: leflunomide possibly enhances hypo-  glycaemic effect of tolbutamide  Antiepileptics: leflunomide possibly increases plasma  concentration of phenytoin   Lipid-regulating Drugs: the effect of leflunomide is  significantly decreased by colestyramine (enhanced  elimination) — avoid unless drug elimination desired   Cardiac Glycosides: lenalidomide possibly increases  plasma concentration of digoxin  Lercanidipine see Calcium-channel Blockers  Leukotriene Receptor Antagonists  Analgesics: plasma concentration of zafirlukast  increased by aspirin    Leukotriene Receptor Antagonists (continued)  Barbiturates: plasma concentration of montelukast  reduced by phenobarbital   Theophylline: zafirlukast possibly increases plasma  concentration of theophylline, also plasma concen-  tration of zafirlukast reduced  Levamisole   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with «St John’s wort  Antiepileptics: levetiracetam possibly increases risk of  carbamazepine toxicity   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   Anti-arrhythmics: increased myocardial depression  when levobupivacaine given with anti-arrhythmics  Levocetirizine see Antihistamines  Levodopa   ACE Inhibitors: enhanced hypotensive effect when  levodopa given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when levodopa given with adrenergic neurone  blockers   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when levodopa given with  angiotensin-II receptor antagonists  Antibacterials: effects of levodopa possibly reduced  by isoniazid   levodopa given with •MAOIs, avoid levodopa for at  least 2 weeks after stopping MAOIs; increased risk of  side-effects when levodopa given with moclobemide  Antiepileptics: effects of levodopa possibly reduced  by phenytoin   Anti m u sea rinics: absorption of levodopa possibly  reduced by antimuscarinics  Antipsychotics: effects of levodopa antagonised by  antipsychotics; avoidance of levodopa advised by  manufacturer of amisulpride (antagonism of effect)  Anxiolytics and Hypnotics: effects of levodopa  possibly antagonised by benzodiazepines  Beta-blockers: enhanced hypotensive effect when  levodopa given with beta-blockers  Bupropion: increased risk of side-effects when levo-  dopa given with bupropion  Calcium-channel Blockers: enhanced hypotensive  effect when levodopa given with calcium-channel  blockers   Dopamine rgics: enhanced effects and increased toxi-  city of levodopa when given with selegiline (reduce  dose of levodopa)   Memantine: effects of dopaminergics possibly  enhanced by memantine  Methyldopa: enhanced hypotensive effect when  levodopa given with methyldopa; antiparkinsonian  effect of dopaminergics antagonised by methyldopa  Moxonidine: enhanced hypotensive effect when levo-  dopa given with moxonidine  Muscle Relaxants: possible agitation, confusion and  hallucinations when levodopa given with baclofen  Nitrates: enhanced hypotensive effect when levodopa  given with nitrates   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when levodopa given with hydralazine,  minoxidil or sodium nitroprusside  Vitamins: effects of levodopa reduced by pyridoxine  when given without dopa-decarboxylase inhibitor  Levofloxacin see Quinolones  Levofolinic Acid see Folates  Levomepromazine see Antipsychotics  Levonorgestrel see Progestogens  Levothyroxine see Thyroid Hormones  Lidocaine   Note Interactions less likely when lidocaine used topically  Anaesthetics, Local: increased myocardial depression  when anti-arrhythmics given with bupivacaine,  levobupivacaine, prilocaine or ropivacaine   mias when anti-arrhythmics that prolong the QT  interval given with •antipsychotics that prolong the  QT interval   increased by »atazanavir and lopinavir; plasma  concentration of lidocaine possibly increased by  darunavir and •fosamprenavir — avoid concomitant  use; increased risk of ventricular arrhythmias when  lidocaine given with «saquinavir — avoid concomi-  tant use   anti-arrhythmics given with •beta-blockers;  increased risk of lidocaine toxicity when given with  •propranolol   kalaemia caused by •acetazolamide, *loop  diuretics or *thiazides and related diuretics  Muscle Relaxants: neuromuscular blockade enhanced  and prolonged when lidocaine given with suxa-  methonium   Note Linezolid is a reversible, non-selective MAO inhibi-  tor — see interactions of MAOIs  Antibacterials: plasma concentration of linezolid  reduced by rifampicin (possible therapeutic failure of  linezolid)   Liothyronine see Thyroid Hormones  Lipid-regulating Drugs see Colestipol, Colestyramine,  Ezetimibe, Fibrates, Nicotinic Acid, and Statins  Liraglutide see Antidiabetics  Lisinopril see ACE Inhibitors  Lithium   Antacids: excretion of lithium increased by sodium  bicarbonate (reduced plasma concentration)   effects when lithium given with venlafaxine;  increased risk of CNS effects when lithium given with  •SSRIs (lithium toxicity reported); risk of toxicity  when lithium given with tricyclics  Antiepileptics: neurotoxicity may occur when lithium  given with carbamazepine or phenytoin without  increased plasma concentration of lithium; plasma  concentration of lithium possibly affected by topir-  amate   Antipsvchotics : increased risk of extrapyramidal side-  effects and possibly neurotoxicity when lithium  given with clozapine, flupentixol, haloperidol,  phenothiazines or zuclopenthixol; possible risk of  toxicity when lithium given with olanzapine;  increased risk of extrapyramidal side-effects when  lithium given with sulpiride  Anxiolytics and Hypnotics : increased risk of neuro-  toxicity when lithium given with clonazepam  Calcium-channel Blockers: neurotoxicity may occur  when lithium given with diltiazem or verapamil  without increased plasma concentration of lithium   •acetazolamide; excretion of lithium reduced by  •loop diuretics and •thiazides and related diuretics  (increased plasma concentration and risk of toxi-  city) — loop diuretics safer than thiazides; excretion  of lithium reduced by •potassium-sparing diuretics  and aldosterone antagonists (increased plasma con-  centration and risk of toxicity)   Muscle Relaxants: lithium enhances effects of muscle  relaxants; hyperkinesis caused by lithium possibly  aggravated by baclofen   Parasympathomimetics: lithium antagonises effects  of neostigmine and pyridostigmine  Theophylline: excretion of lithium increased by theo-  phylline (reduced plasma concentration)   Anxiolytics and Hypnotics: increased sedative effect  when lofexidine given with anxiolytics and hypnotics  Barbiturates: increased sedative effect when lofex-  idine given with barbiturates   Note In combination with ritonavir as Kaletra ® (ritonavir is  present to inhibit lopinavir metabolism and increase plasma-  lopinavir concentration) — see also Ritonavir   concentration of •flecainide (increased risk of  ventricular arrhythmias — avoid concomitant use);  lopinavir possibly increases plasma concentration of  lidocaine   Antihistamines: lopinavir possibly increases plasma  concentration of chlorphenamine  Antimalarials: caution with lopinavir advised by  manufacturer of artemether/lumefantrine    Antimuscarinics: avoidance of lopinavir advised by  manufacturer of darifenacin and tolterodine   •darunavir, also plasma concentration of lopinavir  increased (avoid concomitant use); plasma concen-  tration of lopinavir reduced by •efavirenz — consider  increasing dose of lopinavir; lopinavir reduces  plasma concentration of fosamprenavir, effect on  lopinavir plasma concentration not predictable —  avoid concomitant use; lopinavir increases plasma  concentration of •maraviroc (consider reducing dose  of maraviroc); plasma concentration of lopinavir  reduced by nelfinavir, also plasma concentration of  active metabolite of nelfinavir increased; plasma  concentration of lopinavir possibly reduced by  •nevirapine — consider increasing dose of lopinavir;  increased risk of ventricular arrhythmias when  lopinavir given with *saquinavir — avoid concomitant  use; lopinavir increases plasma concentration of  tenofovir; plasma concentration of lopinavir reduced  by *tipranavir   sibly reduced by *phenobarbital  Corticosteroids: plasma concentration of lopinavir  possibly reduced by dexamethasone  Eltrombopag: lopinavir possibly reduces plasma con-  centration of eltrombopag   myopathy when lopinavir given with atorvastatin;  possible increased risk of myopathy when lopinavir  given with «rosuvastatin — manufacturer of rosuvas-  tatin advises avoid concomitant use; possible  increased risk of myopathy when lopinavir given  with •simvastatin — avoid concomitant use   • Ranolazine: lopinavir possibly increases plasma con-  centration of •ranolazine — manufacturer of ranola-  zine advises avoid concomitant use    Lorazepam see Anxiolytics and Hypnotics  Lormetazepam see Anxiolytics and Hypnotics  Losartan see Angiotensin-II Receptor Antagonists  Lumefantrine see Artemether with Lumefantrine  Lymecy cline see Tetracyclines   thmias when parenteral erythromycin given with  •amiodarone — avoid concomitant use; erythromycin  increases plasma concentration of •disopyramide  (increased risk of toxicity); clarithromycin possibly  increases plasma concentration of •disopyramide  (increased risk of toxicity); erythromycin possibly  increases plasma concentration of •dronedarone  (increased risk of ventricular arrhythmias — avoid  concomitant use); avoidance of clarithromycin  advised by manufacturer of *dronedarone (risk of  ventricular arrhythmias)   mias when parenteral erythromycin given with  •moxifloxacin — avoid concomitant use; macrolides  possibly increase plasma concentration of •rifabutin  (increased risk of uveitis — reduce rifabutin dose);  clarithromycin increases plasma concentration of  •rifabutin (increased risk of uveitis — reduce rifabutin  dose); plasma concentration of clarithromycin  reduced by rifamycins   enhance anticoagulant effect of •coumarins;  azithromycin possibly enhances anticoagulant effect  of •coumarins   increase plasma concentration of •carbamazepine;  clarithromycin inhibits metabolism of phenytoin  (increased plasma concentration); erythromycin  possibly inhibits metabolism of valproate (increased  plasma concentration)   erythromycin possibly increases plasma concentra-  tion of loratadine; macrolides possibly inhibit  metabolism of •mizolastine (avoid concomitant use);  erythromycin inhibits metabolism of •mizolastine —  avoid concomitant use; erythromycin increases  plasma concentration of rupatadine   manufacturer of •artemether/lumefantrine  Anti m u sea rinics: erythromycin possibly increases  plasma concentration of darifenacin; manufacturer of  fesoterodine advises dose reduction when clarithro-  mycin given with fesoterodine — consult fesoterodine  product literature; avoidance of clarithromycin and  erythromycin advised by manufacturer of tolterodine   manufacturer of •droperidol (risk of ventricular  arrhythmias); increased risk of ventricular arrhyth-  mias when parenteral erythromycin given with  •zuclopenthixol — avoid concomitant use; increased  risk of ventricular arrhythmias when erythromycin  given with •amisulpride — avoid concomitant use;  erythromycin possibly increases plasma concentra-  tion of •clozapine (possible increased risk of con-  vulsions); increased risk of ventricular arrhythmias  when clarithromycin given with *pimozide — avoid  concomitant use; possible increased risk of ventri-  cular arrhythmias when erythromycin given with  •pimozide — avoid concomitant use; macrolides  possibly increase plasma concentration of quetiapine  (reduce dose of quetiapine); increased risk of  ventricular arrhythmias when parenteral erythro-  mycin given with •sulpiride   increased when clarithromycin given with atazana-  vir; increased risk of rash when clarithromycin given  with efavirenz; clarithromycin increases plasma  concentration of •etravirine, also plasma concentra-  tion of clarithromycin reduced; clarithromycin pos-  sibly increases plasma concentration of •maraviroc  (consider reducing dose of maraviroc); plasma  concentration of clarithromycin reduced by nevir-  apine (but concentration of an active metabolite  increased), also plasma concentration of nevirapine  increased; plasma concentration of clarithromycin  increased by •ritonavir (reduce dose of clarithro-  mycin in renal impairment); plasma concentration of  azithromycin and erythromycin possibly increased  by ritonavir; increased risk of ventricular arrhythmias  when clarithromycin or erythromycin given with  •saquinavir — avoid concomitant use; plasma con-  centration of clarithromycin increased by »tipranavir  (reduce dose of clarithromycin in renal impairment),  also clarithromycin increases plasma concentration  of tipranavir; clarithromycin tablets reduce absorp-  tion of zidovudine (give at least 2 hours apart)   erythromycin inhibit metabolism of •midazolam  (increased plasma concentration with increased  sedation); erythromycin increases plasma concen-  tration of buspirone (reduce dose of buspirone);  erythromycin inhibits the metabolism of zopiclone  Aprepitant: clarithromycin possibly increases plasma  concentration of aprepitant   inhibits metabolism of felodipine (increased plasma  concentration); avoidance of erythromycin advised  by manufacturer of lercanidipine; clarithromycin and  erythromycin possibly inhibit metabolism of  •verapamil (increased risk of toxicity)   Cardiac Glycosides: macrolides increase plasma con-  centration of digoxin (increased risk of toxicity)   •ciclosporin (increased plasma concentration);  clarithromycin and erythromycin inhibit metabolism  of •ciclosporin (increased plasma concentration)  Cilostazol : erythromycin increases plasma concentra-  tion of cilostazol (consider reducing dose of cilosta-  zol)   mycin possibly increase risk of •colchicine toxicity —  suspend or reduce dose of colchicine (avoid con-  comitant use in hepatic or renal impairment)  Corticosteroids: erythromycin possibly inhibits  metabolism of corticosteroids; erythromycin inhibits  the metabolism of methylprednisolone; clarithro-  mycin possibly increases plasma concentration of  methylprednisolone   concentration of •everolimus — manufacturer of  everolimus advises avoid concomitant use; erythro-  mycin increases plasma concentration of  •everolimus; avoidance of clarithromycin advised by  manufacturer of •nilotinib and •pazopanib; in vitro  studies suggest a possible interaction between  erythromycin and docetaxel (consult docetaxel  product literature); increased risk of ventricular  arrhythmias when erythromycin given with •arsenic  trioxide; erythromycin increases toxicity of  •vinblastine — avoid concomitant use; possible  increased risk of neutropenia when clarithromycin  given with •vinorelbine   erythromycin increases plasma concentration of  eplerenone (reduce dose of eplerenone)  Dopaminergics: macrolides possibly increase plasma  concentration of bromocriptine and cabergoline  (increased risk of toxicity); erythromycin increases  plasma concentration of bromocriptine and caber-  goline (increased risk of toxicity)   plasma concentration of •atorvastatin and prava-  statin; possible increased risk of myopathy when  erythromycin given with atorvastatin; erythromycin  increases plasma concentration of pravastatin;  erythromycin reduces plasma concentration of  rosuvastatin; increased risk of myopathy when  clarithromycin or erythromycin given with  •simvastatin (avoid concomitant use)  Parasympathomimetics: erythromycin increases  plasma concentration of galantamine   concentration of •ranolazine — manufacturer of  ranolazine advises avoid concomitant use  Sildenafil: clarithromycin possibly increases plasma  concentration of sildenafil — reduce initial dose of  sildenafil; erythromycin increases plasma concen-  tration of sildenafil — reduce initial dose of sildenafil   plasma concentration of •tacrolimus  Tadalafil: clarithromycin and erythromycin possibly  increase plasma concentration of tadalafil   concentration of theophylline; clarithromycin inhibits  metabolism of •theophylline (increased plasma  concentration); erythromycin inhibits metabolism of  •theophylline (increased plasma concentration), if  erythromycin given by mouth, also decreased  plasma-erythromycin concentration  Ulcer-healing Drugs: plasma concentration of  erythromycin increased by cimetidine (increased risk  of toxicity, including deafness); plasma concentration  of both drugs increased when clarithromycin given  with omeprazole   Vardenafil: erythromycin increases plasma concen-  tration of vardenafil (reduce dose of vardenafil)  Magnesium (parenteral)   reported with concomitant use of parenteral  magnesium and •nifedipine in pre-eclampsia  Muscle Relaxants: parenteral magnesium enhances  effects of non-depolarising muscle relaxants and  suxamethonium   Ciclosporin: possible increased risk of nephrotoxicity  when mannitol given with ciclosporin   Note For interactions of reversible MAO-A inhibitors  (RIMAs) see Moclobemide, and for interactions of MAO-B  inhibitors see Rasagiline and Selegiline; the antibacterial  Linezolid is a reversible, non-selective MAO inhibitor  ACE Inhibitors: MAOIs possibly enhance hypotensive  effect of ACE inhibitors    Adrenergic Neurone Blockers: enhanced hypotensive  effect when MAOIs given with adrenergic neurone  blockers   tension or hypotension) when MAOIs given with  •pethidine — avoid concomitant use and for 2 weeks  after stopping MAOIs; possible increased serotoner-  gic effects and increased risk of convulsions when  MAOIs given with •tramadol — some manufacturers  advise avoid concomitant use and for 2 weeks after  stopping MAOIs; avoidance of MAOIs advised by  manufacturer of •nefopam; possible CNS excitation  or depression (hypertension or hypotension) when  MAOIs given with •opioid analgesics — some manu-  facturers advise avoid concomitant use and for 2  weeks after stopping MAOIs    Angiotensin-ll Receptor Antagonists: MAOIs possibly  enhance hypotensive effect of angiotensin-II recep-  tor antagonists   • Antidepressants: increased risk of hypertension and  CNS excitation when MAOIs given with •reboxetine  (MAOIs should not be started until 1 week after  stopping reboxetine, avoid reboxetine for 2 weeks  after stopping MAOIs); after stopping MAOIs do not  start •citalopram, •escitalopram, •fluvoxamine,  •paroxetine or •sertraline for 2 weeks, also MAOIs  should not be started until at least 1 week after  stopping citalopram, escitalopram, fluvoxamine,  paroxetine or sertraline; after stopping MAOIs do not  start •fluoxetine for 2 weeks, also MAOIs should not  be started until at least 5 weeks after stopping  fluoxetine; after stopping MAOIs do not start  •duloxetine for 2 weeks, also MAOIs should not be  started until at least 5 days after stopping duloxetine;  enhanced CNS effects and toxicity when MAOIs  given with •venlafaxine (venlafaxine should not be  started until 2 weeks after stopping MAOIs, avoid  MAOIs for 1 week after stopping venlafaxine);  increased risk of hypertension and CNS excitation  when MAOIs given with other *MAOIs (avoid for at  least 2 weeks after stopping previous MAOIs and  then start at a reduced dose); after stopping MAOIs  do not start •moclobemide for at least 1 week;  MAOIs increase CNS effects of *SSRIs (risk of  serious toxicity); after stopping MAOIs do not start  •mirtazapine for 2 weeks, also MAOIs should not be  started until at least 2 weeks after stopping  mirtazapine; after stopping MAOIs do not start  •tricyclic-related antidepressants for 2 weeks, also  MAOIs should not be started until at least 1-2 weeks  after stopping tricyclic-related antidepressants;  increased risk of hypertension and CNS excitation  when MAOIs given with •tricyclics, tricyclics should  not be started until 2 weeks after stopping MAOIs (3  weeks if starting clomipramine or imipramine), also  MAOIs should not be started for at least 1-2 weeks  after stopping tricyclics (3 weeks in the case of  clomipramine or imipramine); CNS excitation and  confusion when MAOIs given with ©tryptophan  (reduce dose of tryptophan)   Antidiabetics: MAOIs possibly enhance hypoglycae-  mic effect of antidiabetics; MAOIs enhance hypo-  glycaemic effect of insulin, metformin and  sulfonylureas   convulsant effect of antiepileptics (convulsive  threshold lowered); avoidance for 2 weeks after  stopping MAOIs advised by manufacturer of  •carbamazepine, also antagonism of anticonvulsant  effect   Antihistamines: increased antimuscarinic and seda-  tive effects when MAOIs given with antihistamines   by manufacturer of •artemether/lumefantrine  Antimuscarinics: increased risk of antimuscarinic side-  effects when MAOIs given with antimuscarinics   Anxiolytics and Hypnotics : avoidance of MAOIs  advised by manufacturer of buspirone; manufacturer  of tranylcypromine advises avoid buspirone for 10  days after stopping tranylcypromine   •atomoxetine for 2 weeks, also MAOIs should not be  started until at least 2 weeks after stopping  atomoxetine; possible increased risk of convulsions  when antidepressants given with atomoxetine  Barbiturates: MAOIs possibly antagonise anti-  convulsant effect of barbiturates (convulsive thresh-  old lowered)   Calcium-channel Blockers: enhanced hypotensive  effect when MAOIs given with calcium-channel  blockers   tive MAOIs with •entacapone; risk of hypertensive  crisis when MAOIs given with •levodopa, avoid  levodopa for at least 2 weeks after stopping MAOIs;  risk of hypertensive crisis when MAOIs given with  •rasagiline, avoid MAOIs for at least 2 weeks after  stopping rasagiline; enhanced hypotensive effect  when MAOIs given with •selegiline — manufacturer  of selegiline advises avoid concomitant use; avoid  concomitant use of MAOIs with tolcapone  Doxapram: MAOIs enhance effects of doxapram  Histamine: avoidance of MAOIs advised by manufac-  turer of histamine   with •rizatriptan or •sumatriptan (avoid  rizatriptan or sumatriptan for 2 weeks after MAOIs);  increased risk of CNS toxicity when MAOIs given  with •zolmitriptan   Moxonidine: enhanced hypotensive effect when  MAOIs given with moxonidine  Muscle Relaxants: phenelzine enhances effects of  suxamethonium   Pholcodine : avoidance of pholcodine for 2 weeks after  stopping MAOIs advised by manufacturer of phol-  codine   hypertensive crisis when MAOIs given with  •methylphenidate, some manufacturers advise  avoid methylphenidate for at least 2 weeks after  stopping MAOIs   tension when MAOIs given with •tetrabenazine  Vasodilator Antihypertensives: enhanced hypoten-  sive effect when MAOIs given with hydralazine,  minoxidil or sodium nitroprusside  MAOIs, reversible see Moclobemide  Maraviroc   possibly increased by •clarithromycin and  •telithromycin (consider reducing dose of mara-  viroc); plasma concentration of maraviroc reduced  by •rifampicin — consider increasing dose of mar-  aviroc   increased by •atazanavir, •darunavir, •indinavir,  •lopinavir and ©saquinavir (consider reducing dose  of maraviroc); plasma concentration of maraviroc  possibly reduced by *efavirenz — consider increasing  dose of maraviroc; plasma concentration of mar-  aviroc possibly reduced by etravirine; plasma con-  centration of maraviroc possibly increased by  •nelfinavir (consider reducing dose of maraviroc);  plasma concentration of maraviroc increased by  ritonavir  Mebendazole   Ulcer-healing Drugs: metabolism of mebendazole  possibly inhibited by cimetidine (increased plasma  concentration)   manufacturer of •artemether/lumefantrine;  increased risk of convulsions when mefloquine given  with •chloroquine and hydroxychloroquine;  increased risk of convulsions when mefloquine given  with •quinine (but should not prevent the use of  intravenous quinine in severe cases)   arrhythmias when mefloquine given with  •haloperidol — avoid concomitant use; increased risk  of ventricular arrhythmias when mefloquine given  with •pimozide — avoid concomitant use   when mefloquine given with •atomoxetine  Beta-blockers: increased risk of bradycardia when  mefloquine given with beta-blockers  Calcium-channel Blockers: possible increased risk of  bradycardia when mefloquine given with calcium-  channel blockers   Cardiac Glycosides: possible increased risk of brady-  cardia when mefloquine given with digoxin   Antibacterials: increased risk of melphalan toxicity  when given with nalidixic acid  Antiepileptics: cytotoxics possibly reduce absorption  of phenytoin   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   memantine given with •dextromethorphan (manu-  facturer of memantine advises avoid concomitant  use)   Anticoagulants: memantine possibly enhances anti-  coagulant effect of warfarin  Antiepileptics: memantine possibly reduces effects of  primidone   of dopaminergics and selegiline; increased risk of  CNS toxicity when memantine given with  •amantadine (manufacturer of memantine advises  avoid concomitant use)   Antimalarials: mepacrine increases plasma concen-  tration of primaquine (increased risk of toxicity)  Meprobamate see Anxiolytics and Hypnotics  Meptazinol see Opioid Analgesics  Mercaptopurine   mercaptopurine when given with •allopurinol  (reduce dose of mercaptopurine to one quarter of  usual dose)   Aminosalicylates: possible increased risk of leuco-  penia when mercaptopurine given with aminosali-  cylates   city when mercaptopurine given with  •sulfamethoxazole (as co-trimoxazole); increased  risk of haematological toxicity when mercaptopurine  given with •trimethoprim (also with co-trimoxazole)   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767  Mesalazine see Aminosalicylates  Mestranol see Oestrogens  Metaraminol see Sympathomimetics  Metformin see Antidiabetics  Methadone see Opioid Analgesics  Methenamine   Potassium Salts: avoid concomitant use of methen-  amine with potassium citrate  Sodium Citrate : avoid concomitant use of methen-  amine with sodium citrate  Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767   reduced by *NSAIDs (increased risk of toxicity) — but  for concomitant use in rheumatic disease see p. 647;  excretion of methotrexate reduced by •aspirin,  •diclofenac, *ibuprofen, •indometacin, •ketoprofen,  •meloxicam and ©naproxen (increased risk of  toxicity) — but for concomitant use in rheumatic  disease see p. 647   reduced by neomycin; excretion of methotrexate  possibly reduced by ciprofloxacin (increased risk of  toxicity); increased risk of haematological toxicity  when methotrexate given with •sulfamethoxazole  (as co-trimoxazole); increased risk of methotrexate  toxicity when given with doxycycline,  sulfonamides or tetracycline; excretion of metho-  trexate reduced by penicillins (increased risk of  toxicity); increased risk of haematological toxicity  when methotrexate given with •trimethoprim (also  with co-trimoxazole)   Antiepileptics: antifolate effect of methotrexate  increased by phenytoin; cytotoxics possibly reduce  absorption of phenytoin   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   increased by •acitretin (also increased risk of  hepatotoxicity) — avoid concomitant use  Theophylline: methotrexate possibly increases plasma  concentration of theophylline  Ulcer-healing Drugs: excretion of methotrexate pos-  sibly reduced by omeprazole (increased risk of  toxicity)   ACE Inhibitors: enhanced hypotensive effect when  methyldopa given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when methyldopa given with adrenergic  neurone blockers   Aldesleukin: enhanced hypotensive effect when  methyldopa given with aldesleukin  Alpha-blockers: enhanced hypotensive effect when  methyldopa given with alpha-blockers  Anaesthetics, General: enhanced hypotensive effect  when methyldopa given with general anaesthetics  Analgesics: hypotensive effect of methyldopa antag-  onised by NSAIDs   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when methyldopa given with  angiotensin-II receptor antagonists   avoid concomitant use with •MAOIs  Antipsychotics: enhanced hypotensive effect when  methyldopa given with antipsychotics (also  increased risk of extrapyramidal effects)   Anxiolytics and Hypnotics: enhanced hypotensive  effect when methyldopa given with anxiolytics and  hypnotics   Beta-blockers: enhanced hypotensive effect when  methyldopa given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when methyldopa given with calcium-channel  blockers   Clonidine: enhanced hypotensive effect when  methyldopa given with clonidine  Corticosteroids: hypotensive effect of methyldopa  antagonised by corticosteroids  Diazoxide: enhanced hypotensive effect when  methyldopa given with diazoxide  Diuretics: enhanced hypotensive effect when methyl-  dopa given with diuretics  Dopaminergics: methyldopa antagonises anti-  parkinsonian effect of dopaminergics; increased risk  of extrapyramidal side-effects when methyldopa  given with amantadine; effects of methyldopa  possibly enhanced by entacapone; enhanced hypo-  tensive effect when methyldopa given with levodopa  Iron: hypotensive effect of methyldopa antagonised by  oral iron   Moxisylyte: enhanced hypotensive effect when  methyldopa given with moxisylyte  Moxonidine: enhanced hypotensive effect when  methyldopa given with moxonidine  Muscle Relaxants: enhanced hypotensive effect when  methyldopa given with baclofen or tizanidine  Nitrates: enhanced hypotensive effect when methyl-  dopa given with nitrates   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when methyldopa given with hydralazine,  minoxidil or sodium nitroprusside  Methylphenidate see Sympathomimetics  Methylprednisolone see Corticosteroids  Methysergide see Ergot Alkaloids  Metipranolol see Beta-blockers  Metoclopramide   Analgesics: metoclopramide increases rate of  absorption of aspirin (enhanced effect); effects of    Metoclopramide  Analgesics (continued)  metoclopramide on gastro-intestinal activity  antagonised by opioid analgesics; metoclo-  pramide increases rate of absorption of para-  cetamol   Antimuscarinics: effects of metoclopramide on gastro-  intestinal activity antagonised by antimuscarinics  Antipsychotics: increased risk of extrapyramidal side-  effects when metoclopramide given with antipsy-  chotics   Dopaminergics: metoclopramide antagonises hypo-  prolactinaemic effects of bromocriptine and caber-  goline; metoclopramide antagonises  antiparkinsonian effect of pergolide; avoidance of  metoclopramide advised by manufacturer of  ropinirole and rotigotine (antagonism of effect)  Muscle Relaxants: metoclopramide enhances effects  of suxamethonium   Tetrabenazine: increased risk of extrapyramidal side-  effects when metoclopramide given with tetraben-  azine   •phenytoin (increased plasma concentration);  metabolism of metronidazole accelerated by  primidone (reduced plasma concentration)  Barbiturates: metabolism of metronidazole acceler-  ated by barbiturates (reduced plasma concentration)   tration of «busulfan (increased risk of toxicity);  metronidazole inhibits metabolism of fluorouracil  (increased toxicity)   Disulfiram: psychotic reaction reported when metro-  nidazole given with disulfiram  Lithium: metronidazole increases risk of lithium  toxicity   Mycophenolate: metronidazole possibly reduces  bioavailability of mycophenolate  Ulcer-healing Drugs: metabolism of metronidazole  inhibited by cimetidine (increased plasma concen-  tration)   Antifungals : micafungin possibly increases plasma  concentration of amphotericin; micafungin increases  plasma concentration of itraconazole (consider  reducing dose of itraconazole)   Calcium-channel Blockers: micafungin increases  plasma concentration of nifedipine  Ciclosporin: micafungin possibly increases plasma  concentration of ciclosporin  Sirolimus: micafungin increases plasma concentration  of sirolimus   Analgesics: manufacturer of mifamurtide advises  avoid concomitant use with high doses of NSAIDs  Ciclosporin: manufacturer of mifamurtide advises  avoid concomitant use with ciclosporin  Corticosteroids: manufacturer of mifamurtide advises  avoid concomitant use with corticosteroids   Corticosteroids: mifepristone may reduce effect of  corticosteroids (including inhaled corticosteroids)  for 3-4 days   Milrinone see Phosphodiesterase Inhibitors  Minocycline see Tetracyclines  Minoxidil see Vasodilator Antihypertensives  Mirtazapine   Analgesics: possible increased serotonergic effects  when mirtazapine given with tramadol  Anticoagulants: mirtazapine enhances anticoagulant  effect of warfarin   effects when mirtazapine given with fluoxetine,  fluvoxamine or venlafaxine; mirtazapine should not  be started until 2 weeks after stopping •MAO Is, also  MAOIs should not be started until at least 2 weeks  after stopping mirtazapine; after stopping mirtaza-  pine do not start •moclobemide for at least 1 week  Antiepileptics: plasma concentration of mirtazapine  reduced by carbamazepine and phenytoin  Antifungals: plasma concentration of mirtazapine  increased by ketoconazole   by manufacturer of •artemether/lumefantrine  Anxiolytics and Hypnotics: increased sedative effect  when mirtazapine given with anxiolytics and hyp-  notics   Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine  Ulcer-healing Drugs: plasma concentration of mirta-  zapine increased by cimetidine   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Diuretics: manufacturer of mitotane advises avoid  concomitant use of spironolactone (antagonism of  effect)   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Ciclosporin: excretion of mitoxantrone reduced by  ciclosporin (increased plasma concentration)  Mivacurium see Muscle Relaxants  Mizolastine see Antihistamines  Moclobemide   (hypertension or hypotension) when moclobemide  given with •dextromethorphan or *pethidine — avoid  concomitant use; possible CNS excitation or  depression (hypertension or hypotension) when  moclobemide given with *opioid analgesics — man-  ufacturer of moclobemide advises consider reducing  dose of opioid analgesics   related antidepressants, •citalopram, •fluvox-  amine, •mirtazapine, •paroxetine, •sertraline,  •tricyclic-related antidepressants or •tricyclics;  increased risk of CNS toxicity when moclobe-  mide given with •escitalopram, preferably avoid  concomitant use; moclobemide should not be  started until 5 weeks after stopping •fluoxetine;  possible increased serotonergic effects when  moclobemide given with «duloxetine   by manufacturer of •artemether/lumefantrine  Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine   manufacturer of entacapone; increased risk of side-  effects when moclobemide given with levodopa;  avoid concomitant use of moclobemide with  •selegiline   mide given with •rizatriptan or •sumatriptan (avoid  rizatriptan or sumatriptan for 2 weeks after moclo-  bemide); risk of CNS toxicity when moclobemide  given with •zolmitriptan (reduce dose of zolmitrip-  tan)   moclobemide given with •sympathomimetics  Ulcer-healing Drugs: plasma concentration of moclo-  bemide increased by cimetidine (halve dose of  moclobemide)   ACE Inhibitors: enhanced hypotensive effect when  moxisylyte given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when moxisylyte given with adrenergic  neurone blockers   when moxisylyte given with •alpha-blockers  Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when moxisylyte given with  angiotensin-II receptor antagonists   when moxisylyte given with •beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when moxisylyte given with calcium-channel  blockers   Clonidine: enhanced hypotensive effect when mox-  isylyte given with clonidine  Diazoxide: enhanced hypotensive effect when mox-  isylyte given with diazoxide  Diuretics: enhanced hypotensive effect when moxisy-  lyte given with diuretics   Methyldopa: enhanced hypotensive effect when  moxisylyte given with methyldopa  Moxonidine: enhanced hypotensive effect when  moxisylyte given with moxonidine  Nitrates: enhanced hypotensive effect when moxisy-  lyte given with nitrates   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when moxisylyte given with hydralazine,  minoxidil or sodium nitroprusside   ACE Inhibitors: enhanced hypotensive effect when  moxonidine given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when moxonidine given with adrenergic  neurone blockers   Aldesleukin: enhanced hypotensive effect when  moxonidine given with aldesleukin  Alpha-blockers: enhanced hypotensive effect when  moxonidine given with alpha-blockers  Anaesthetics, General: enhanced hypotensive effect  when moxonidine given with general anaesthetics  Analgesics: hypotensive effect of moxonidine antag-  onised by NSAIDs   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when moxonidine given with  angiotensin-II receptor antagonists  Antidepressants : enhanced hypotensive effect when  moxonidine given with MAOIs; hypotensive effect of  moxonidine possibly antagonised by tricyclics  (manufacturer of moxonidine advises avoid conco-  mitant use)   Antipsychotics: enhanced hypotensive effect when  moxonidine given with phenothiazines  Anxiolytics and Hypnotics: enhanced hypotensive  effect when moxonidine given with anxiolytics and  hypnotics; sedative effects possibly increased when  moxonidine given with benzodiazepines  Beta-blockers: enhanced hypotensive effect when  moxonidine given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when moxonidine given with calcium-channel  blockers   Clonidine: enhanced hypotensive effect when mox-  onidine given with clonidine  Corticosteroids: hypotensive effect of moxonidine  antagonised by corticosteroids  Diazoxide: enhanced hypotensive effect when mox-  onidine given with diazoxide  Diuretics: enhanced hypotensive effect when moxo-  nidine given with diuretics  Dopaminergics: enhanced hypotensive effect when  moxonidine given with levodopa  Methyldopa: enhanced hypotensive effect when  moxonidine given with methyldopa  Moxisylyte: enhanced hypotensive effect when mox-  onidine given with moxisylyte  Muscle Relaxants: enhanced hypotensive effect when  moxonidine given with baclofen or tizanidine  Nitrates: enhanced hypotensive effect when moxoni-  dine given with nitrates   Prostaglandins: enhanced hypotensive effect when  moxonidine given with alprostadil  Vasodilator Antihypertensives: enhanced hypoten-  sive effect when moxonidine given with hydralazine,  minoxidil or sodium nitroprusside  Muscle Relaxants   ACE Inhibitors: enhanced hypotensive effect when  baclofen or tizanidine given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when baclofen or tizanidine given with adr-  energic neurone blockers  Alcohol: increased sedative effect when baclofen,  methocarbamol or tizanidine given with alcohol  Alpha-blockers: enhanced hypotensive effect when  baclofen or tizanidine given with alpha-blockers  • Anaesthetics, General: effects of atracurium   enhanced by ketamine; increased risk of myocardial  depression and bradycardia when suxamethonium  given with •propofol; effects of non-depolarising   muscle relaxants and suxamethonium enhanced  by volatile liquid general anaesthetics  Analgesics: excretion of baclofen possibly reduced by  NSAIDs (increased risk of toxicity); excretion of  baclofen reduced by ibuprofen (increased risk of  toxicity); increased sedative effect when baclofen  given with fentanyl or morphine  Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when baclofen or tizanidine given  with angiotensin-II receptor antagonists  Anti-arrhythmics: neuromuscular blockade enhanced  and prolonged when suxamethonium given with  lidocaine   relaxants and suxamethonium enhanced by pipera-  cillin; plasma concentration of tizanidine increased  by •ciprofloxacin (increased risk of toxicity) — avoid  concomitant use; plasma concentration of tizanidine  possibly increased by norfloxacin (increased risk of  toxicity); effects of non-depolarising muscle  relaxants and suxamethonium enhanced by  •aminoglycosides; effects of non-depolarising  muscle relaxants and suxamethonium enhanced by  •clindamycin; effects of non-depolarising muscle  relaxants and suxamethonium enhanced by  •polymyxins; effects of suxamethonium enhanced by  •vancomycin   increased by •fluvoxamine (increased risk of toxi-  city) — avoid concomitant use; effects of suxa-  methonium enhanced by phenelzine; muscle  relaxant effect of baclofen enhanced by tricyclics  Antiepileptics: muscle relaxant effect of non-depolar-  ising muscle relaxants antagonised by  carbamazepine and phenytoin (accelerated recovery  from neuromuscular blockade)   Anxiolytics and Hypnotics: increased sedative effect  when baclofen or tizanidine given with anxiolytics  and hypnotics   Beta-blockers: enhanced hypotensive effect when  baclofen given with beta-blockers; possible  enhanced hypotensive effect and bradycardia when  tizanidine given with beta-blockers; effects of muscle  relaxants enhanced by propranolol  Calcium-channel Blockers : enhanced hypotensive  effect when baclofen or tizanidine given with  calcium-channel blockers; effects of non-depolaris-  ing muscle relaxants possibly enhanced by calcium-  channel blockers; possible increased risk of ventri-  cular arrhythmias when intravenous dantrolene  given with diltiazem — manufacturer of diltiazem  advises avoid concomitant use; effects of non-  depolarising muscle relaxants and suxamethonium  enhanced by verapamil; hypotension, myocardial  depression, and hyperkalaemia when intravenous  dantrolene given with verapamil  Cardiac Glycosides: possible increased risk of brady-  cardia when tizanidine given with cardiac glycosides;  risk of ventricular arrhythmias when suxamethonium  given with cardiac glycosides  Clonidine: enhanced hypotensive effect when  baclofen or tizanidine given with clonidine  Corticosteroids: effects of pancuronium and vecuron-  ium possibly antagonised by corticosteroids  Cytotoxics: effects of suxamethonium enhanced by  cyclophosphamide and thiotepa  Diazoxide: enhanced hypotensive effect when  baclofen or tizanidine given with diazoxide  Diuretics: enhanced hypotensive effect when  baclofen or tizanidine given with diuretics  Dopaminergics: possible agitation, confusion and  hallucinations when baclofen given with levodopa   Lithium: effects of muscle relaxants enhanced by  lithium; baclofen possibly aggravates hyperkinesis  caused by lithium   Magnesium (parenteral): effects of non-depolarising  muscle relaxants and suxamethonium enhanced by  parenteral magnesium   Memantine: effects of baclofen and dantrolene possi-  bly modified by memantine  Methyldopa: enhanced hypotensive effect when  baclofen or tizanidine given with methyldopa  Metoclopramide: effects of suxamethonium enhanced  by metoclopramide   Moxonidine: enhanced hypotensive effect when  baclofen or tizanidine given with moxonidine  Nitrates: enhanced hypotensive effect when  baclofen or tizanidine given with nitrates  Oestrogens: plasma concentration of tizanidine pos-  sibly increased by oestrogens (increased risk of  toxicity)   Parasympathomimetics: effects of non-depolarising  muscle relaxants possibly antagonised by donepezil;  effects of suxamethonium possibly enhanced by  donepezil; effects of non-depolarising muscle relax-  ants antagonised by edrophonium, neostigmine,  pyridostigmine and rivastigmine; effects of suxa-  methonium enhanced by edrophonium, galantamine,  neostigmine, pyridostigmine and rivastigmine  Progestogens: plasma concentration of tizanidine  possibly increased by progestogens (increased risk of  toxicity)   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when baclofen or tizanidine given with  hydralazine; enhanced hypotensive effect when  baclofen or tizanidine given with minoxidil;  enhanced hypotensive effect when baclofen or  tizanidine given with sodium nitroprusside  Muscle Relaxants, depolarising see Muscle Relaxants  Muscle Relaxants, non-depolarising see Muscle  Relaxants  Mycophenolate   • Antibacterials: bioavailability of mycophenolate pos-  sibly reduced by metronidazole and norfloxacin;  plasma concentration of active metabolite of myco-  phenolate reduced by •rifampicin  Antivirals: mycophenolate increases plasma concen-  tration of aciclovir, also plasma concentration of  inactive metabolite of mycophenolate increased;  mycophenolate possibly increases plasma concen-  tration of ganciclovir, also plasma concentration of  inactive metabolite of mycophenolate possibly  increased   Sevelamer: plasma concentration of mycophenolate  possibly reduced by sevelamer  Mycophenolate Mofetil see Mycophenolate  Mycophenolate Sodium see Mycophenolate  Mycophenolic Acid see Mycophenolate  Nabilone   Anxiolytics and Hypnotics: increased sedative effect  when nabilone given with anxiolytics and hypnotics  Nabumetone see NSAIDs  Nadolol see Beta-blockers  Nalidixic Acid see Quinolones  Nandrolone see Anabolic Steroids  Naproxen see NSAIDs  Naratriptan see 5HT! Agonists  Nateglinide see Antidiabetics   avoid concomitant use with •MAOIs; side-effects  possibly increased when nefopam given with tricyc-  lics   Antimuscarinics: increased risk of antimuscarinic side-  effects when nefopam given with antimuscarinics   tion of •rifabutin (halve dose of rifabutin); plasma  concentration of nelfinavir significantly reduced by  •rifampicin — avoid concomitant use; avoidance of  concomitant nelfinavir in severe renal and hepatic  impairment advised by manufacturer of  •telithromycin   possibly reduced by carbamazepine and •primidone;  nelfinavir reduces plasma concentration of pheny-  toin   manufacturer of artemether/lumefantrine; nelfinavir  possibly increases plasma concentration of •quinine  (increased risk of toxicity)   Antimuscarinics: avoidance of nelfinavir advised by  manufacturer of darifenacin and tolterodine; manu-  facturer of fesoterodine advises dose reduction when  nelfinavir given with fesoterodine — consult fesoter-  odine product literature; nelfinavir increases plasma  concentration of solifenacin   of •aripiprazole (reduce dose of aripiprazole); nelfi-  navir possibly increases plasma concentration of  •pimozide (increased risk of ventricular arrhyth-  mias — avoid concomitant use)   increased by etravirine — avoid concomitant use;  combination of nelfinavir with indinavir or ritonavir  may increase plasma concentration of either drug (or  both); nelfinavir reduces plasma concentration of  lopinavir, also plasma concentration of active meta-  bolite of nelfinavir increased; nelfinavir possibly  increases plasma concentration of •maraviroc (con-  sider reducing dose of maraviroc); nelfinavir  increases plasma concentration of «saquinavir —  manufacturer of saquinavir advises avoid concomi-  tant use   Corticosteroids: nelfinavir possibly increases plasma  concentration of inhaled and intranasal fluticasone   centration of •everolimus — manufacturer of ever-  olimus advises avoid concomitant use; avoidance of  nelfinavir advised by manufacturer of •pazopanib;  nelfinavir increases plasma concentration of pacli-  taxel   myopathy when nelfinavir given with atorvastatin;  possible increased risk of myopathy when nelfinavir  given with •rosuvastatin — manufacturer of rosuvas-  tatin advises avoid concomitant use; increased risk of  myopathy when nelfinavir given with •simvastatin  (avoid concomitant use)   tion of clarithromycin (but concentration of an active  metabolite increased), also plasma concentration of  nevirapine increased; nevirapine possibly increases  plasma concentration of rifabutin; plasma concen-  tration of nevirapine reduced by •rifampicin — avoid  concomitant use   of •ketoconazole — avoid concomitant use; plasma  concentration of nevirapine increased by  •fluconazole; nevirapine possibly reduces plasma  concentration of caspofungin and itraconazole —  consider increasing dose of caspofungin and itra-  conazole   centration of «atazanavir and •etravirine — avoid  concomitant use; nevirapine reduces plasma con-  centration of efavirenz and indinavir; nevirapine  possibly reduces plasma concentration of fosam-  prenavir; nevirapine possibly reduces plasma con-  centration of •lopinavir — consider increasing dose of  lopinavir   Antidepressants: enhanced hypotensive effect when  nicorandil given with MAOIs; hypotensive effect of  nicorandil possibly enhanced by tricyclics   Vasodilator Antihypertensives: possible enhanced  hypotensive effect when nicorandil given with  hydralazine, minoxidil or sodium nitroprusside   concomitant use with •ritonavir  Anxiolytics and Hypnotics: nilotinib increases plasma  concentration of midazolam  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   ACE Inhibitors: enhanced hypotensive effect when  nitrates given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when nitrates given with adrenergic neurone  blockers   Aldesleukin: enhanced hypotensive effect when  nitrates given with aldesleukin  Alpha-blockers: enhanced hypotensive effect when  nitrates given with alpha-blockers  Anaesthetics, General: enhanced hypotensive effect  when nitrates given with general anaesthetics  Analgesics: hypotensive effect of nitrates antagonised  by NSAIDs   Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when nitrates given with angio-  tensin-II receptor antagonists  Anti-arrhythmics: effects of sublingual tablets of  nitrates reduced by disopyramide (failure to dissolve  under tongue owing to dry mouth)   anticoagulant effect of •heparins  Antidepressants: enhanced hypotensive effect when  nitrates given with MAOIs; effects of sublingual  tablets of nitrates possibly reduced by tricyclic-  related antidepressants (failure to dissolve under  tongue owing to dry mouth); effects of sublingual  tablets of nitrates reduced by tricyclics (failure to  dissolve under tongue owing to dry mouth)  Antimuscarinics: effects of sublingual tablets of  nitrates possibly reduced by antimuscarinics (failure  to dissolve under tongue owing to dry mouth)   Antipsychotics: enhanced hypotensive effect when  nitrates given with phenothiazines  Anxiolytics and Hypnotics: enhanced hypotensive  effect when nitrates given with anxiolytics and  hypnotics   Beta-blockers: enhanced hypotensive effect when  nitrates given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when nitrates given with calcium-channel  blockers   Dopaminergics: enhanced hypotensive effect when  nitrates given with levodopa  Methyldopa: enhanced hypotensive effect when  nitrates given with methyldopa  Moxisylyte: enhanced hypotensive effect when  nitrates given with moxisylyte  Moxonidine: enhanced hypotensive effect when  nitrates given with moxonidine  Muscle Relaxants: enhanced hypotensive effect when  nitrates given with baclofen or tizanidine  Oestrogens: hypotensive effect of nitrates antagonised  by oestrogens   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when nitrates given with hydralazine,  minoxidil or sodium nitroprusside  Nitrazepam see Anxiolytics and Hypnotics  Nitrofurantoin   Antacids: absorption of nitrofurantoin reduced by oral  magnesium salts (as magnesium trisilicate)  Antibacterials: nitrofurantoin possibly antagonises  effects of nalidixic acid   Probenecid: excretion of nitrofurantoin reduced by  probenecid (increased risk of side-effects)  Sulfinpyrazone: excretion of nitrofurantoin reduced by  sulfinpyrazone (increased risk of toxicity)   Nitroimidazoles see Metronidazole and Tinidazole  Nitrous Oxide see Anaesthetics, General  Nizatidine see Histamine H 2 -antagonists  Noradrenaline (norepinephrine) see Sympatho-  mimetics   Norethisterone see Progestogens  Norfloxacin see Quinolones  Norgestimate see Progestogens  Norgestrel see Progestogens  Nortriptyline see Antidepressants, Tricyclic  NSAIDs   ACE Inhibitors: increased risk of renal impairment  when NSAIDs given with ACE inhibitors, also  hypotensive effect antagonised  Adrenergic Neurone Blockers: NSAIDs antagonise  hypotensive effect of adrenergic neurone blockers  Aliskiren : NSAIDs possibly antagonise hypotensive  effect of aliskiren   •NSAIDs or •aspirin (increased side-effects); avoid  concomitant use of NSAIDs with •ketorolac  (increased side-effects and haemorrhage); ibuprofen  possibly reduces antiplatelet effect of aspirin   Angiotensin-ll Receptor Antagonists: increased risk  of renal impairment when NSAIDs given with  angiotensin-II receptor antagonists, also hypotensive  effect antagonised   concentration of amikacin and gentamicin in neo-  nates; plasma concentration of celecoxib,  diclofenac and etoricoxib reduced by rifampicin;  possible increased risk of convulsions when NSAIDs  given with •quinolones   intravenous diclofenac given with •anticoagulants  (avoid concomitant use, including low-dose hepar-  ins); increased risk of haemorrhage when ketorolac  given with ^anticoagulants (avoid concomitant use,  including low-dose heparins); NSAIDs possibly  enhance anticoagulant effect of •coumarins and  •phenindione; possible increased risk of bleeding  when NSAIDs given with *dabigatran etexilate or  heparins   Antifungals: plasma concentration of parecoxib  increased by fluconazole (reduce dose of parecoxib);  plasma concentration of celecoxib increased by  fluconazole (halve dose of celecoxib); plasma con-  centration of diclofenac and ibuprofen increased by  voriconazole   increased by •ritonavir (risk of toxicity) — avoid  concomitant use; plasma concentration of NSAIDs  possibly increased by ritonavir; increased risk of  haematological toxicity when NSAIDs given with  zidovudine   Cardiac Glycosides: NSAIDs possibly increase plasma  concentration of cardiac glycosides, also possible  exacerbation of heart failure and reduction of renal  function   NSAIDs given with •ciclosporin; plasma concentra-  tion of diclofenac increased by •ciclosporin (halve  dose of diclofenac)   Corticosteroids: increased risk of gastro-intestinal  bleeding and ulceration when NSAIDs given with  corticosteroids   •methotrexate (increased risk of toxicity) — but for  concomitant use in rheumatic disease see p. 647;  diclofenac, ibuprofen, indometacin, ketoprofen,  meloxicam and naproxen reduce excretion of  •methotrexate (increased risk of toxicity) — but for  concomitant use in rheumatic disease see p. 647;  increased risk of bleeding when NSAIDs given with  •erlotinib   by diuretics, also antagonism of diuretic effect;  indometacin and ketorolac antagonise effects of  diuretics; NSAIDs possibly antagonise diuretic effect  of potassium canrenoate; occasional reports of  reduced renal function when indometacin given with  •triamterene — avoid concomitant use; possible  increased risk of hyperkalaemia when NSAIDs given  with potassium-sparing diuretics and aldosterone  antagonists; increased risk of hyperkalaemia when  indometacin given with potassium-sparing diuretics  and aldosterone antagonists  lloprost: increased risk of bleeding when NSAIDs  given with iloprost   (increased risk of toxicity); ketorolac reduces excre-  tion of •lithium (increased risk of toxicity) — avoid  concomitant use   Mifamurtide: avoidance of high doses of NSAIDs  advised by manufacturer of mifamurtide  Moxonidine: NSAIDs antagonise hypotensive effect of  moxonidine   Muscle Relaxants: ibuprofen reduces excretion of  baclofen (increased risk of toxicity); NSAIDs possibly  reduce excretion of baclofen (increased risk of  toxicity)   Penicillamine: possible increased risk of nephrotoxi-  city when NSAIDs given with penicillamine   Prasugrel: possible increased risk of bleeding when  NSAIDs given with prasugrel   ketoprofen and naproxen reduced by •probenecid  (increased plasma concentration); excretion of  ketorolac reduced by •probenecid (increased plasma  concentration) — avoid concomitant use   when NSAIDs given with tacrolimus; increased risk  of nephrotoxicity when ibuprofen given with  •tacrolimus   Vasodilator Antihypertensives: NSAIDs antagonise  hypotensive effect of hydralazine, minoxidil and  sodium nitroprusside   Antidiabetics: octreotide possibly reduces require-  ments for insulin, metformin, repaglinide and sulfo-  nylureas   Dopaminergics: octreotide increases plasma concen-  tration of bromocriptine  Ulcer-healing Drugs: octreotide possibly delays  absorption of cimetidine   Note Interactions of combined oral contraceptives may  also apply to combined contraceptive patches and vaginal  rings   Adrenergic Neurone Blockers: oestrogens antagonise  hypotensive effect of adrenergic neurone blockers   Angiotensin-ll Receptor Antagonists: oestrogens  antagonise hypotensive effect of angiotensin-II  receptor antagonists   reduced by *St John’s wort (avoid concomitant use);  oestrogens antagonise antidepressant effect of tri-  cyclics (but side-effects of tricyclics possibly  increased due to increased plasma concentration)   by •carbamazepine, •eslicarbazepine,  •oxcarbazepine, •phenytoin, •primidone,  •rufinamide and •topiramate (reduced contraceptive  effect — see p. 495); oestrogens reduce plasma con-  centration of •lamotrigine — consider increasing dose  of lamotrigine; ethinylestradiol possibly reduces  plasma concentration of valproate   Antifungals : oestrogens increase plasma concentra-  tion of voriconazole; anecdotal reports of contra-  ceptive failure and menstrual irregularities when  oestrogens given with griseofulvin; anecdotal reports  of contraceptive failure when oestrogens given with  imidazoles; occasional reports of breakthrough  bleeding when oestrogens (used for contraception)  given with terbinafine   increased by atazanavir; contraceptive effect of  oestrogens possibly reduced by efavirenz; metab-  olism of oestrogens accelerated by •nelfinavir,  •nevirapine and •ritonavir (reduced contraceptive  effect — see p. 495)   Bile Acids: elimination of cholesterol in bile increased  when oestrogens given with bile acids   contraceptives containing oestrogens when given  with •bosentan (alternative contraception recom-  mended)   Corticosteroids: oral contraceptives containing  oestrogens increase plasma concentration of corti-  costeroids   Lipid-regulating Drugs: absorption of ethinylestradiol  reduced by colesevelam; plasma concentration of   Muscle Relaxants: oestrogens possibly increase  plasma concentration of tizanidine (increased risk of  toxicity)   Somatropin: oestrogens (when used as oral replace-  ment therapy) may increase dose requirements of  somatropin   Thyroid Hormones: oestrogens may increase require-  ments for thyroid hormones in hypothyroidism   Vasodilator Antihypertensives: oestrogens antago-  nise hypotensive effect of hydralazine, minoxidil and  sodium nitroprusside   Alcohol: enhanced hypotensive and sedative effects  when opioid analgesics given with alcohol   Anaesthetics, General: fentanyl inhibits metabolism  of etomidate (consider reducing dose of etomidate);  opioid analgesics possibly enhance effects of intra-  venous general anaesthetics and volatile liquid  general anaesthetics   Antibacterials: plasma concentration of alfentanil  increased by erythromycin; avoidance of premedi-  cation with opioid analgesics advised by manufac-  turer of ciprofloxacin (reduced plasma concentration  of ciprofloxacin) when ciprofloxacin used for surgi-  cal prophylaxis; metabolism of alfentanil, codeine,  fentanyl, methadone and morphine accelerated by  rifampicin (reduced effect); metabolism of oxy-  codone possibly accelerated by rifampicin; metab-  olism of oxycodone inhibited by telithromycin   possibly increased by fluoxetine, fluvoxamine,  paroxetine and sertraline; possible increased sero-  tonergic effects when pethidine or tramadol given  with duloxetine; possible increased serotonergic  effects when tramadol given with mirtazapine or  venlafaxine; possible increased serotonergic effects  and increased risk of convulsions when tramadol  given with •MAO Is — some manufacturers advise  avoid concomitant use and for 2 weeks after  stopping MAOIs; CNS excitation or depression  (hypertension or hypotension) when pethidine given  with *MAOIs — avoid concomitant use and for 2  weeks after stopping MAOIs; possible CNS excita-  tion or depression (hypertension or hypotension)  when opioid analgesics given with *MAOIs — some  manufacturers advise avoid concomitant use and for  2 weeks after stopping MAOIs; possible CNS   excitation or depression (hypertension or hypo-  tension) when opioid analgesics given with  •moclobemide — manufacturer of moclobemide  advises consider reducing dose of opioid anal-  gesics; possible CNS excitation or depression  (hypertension or hypotension) when  dextromethorphan or pethidine given with  •moclobemide — avoid concomitant use;  increased risk of CNS toxicity when tramadol  given with •SSRIs or •tricyclics; plasma con-  centration of methadone possibly reduced by St  John’s wort; sedative effects possibly increased  when opioid analgesics given with tricyclics   of •carbamazepine; effects of tramadol reduced by  carbamazepine; plasma concentration of methadone  reduced by carbamazepine; morphine increases  bioavailability of gabapentin; metabolism of metha-  done accelerated by phenytoin (reduced effect and  risk of withdrawal effects); plasma concentration of  methadone possibly reduced by primidone   by •ketoconazole (reduce dose of buprenorphine);  metabolism of alfentanil inhibited by fluconazole  (risk of prolonged or delayed respiratory depression);  metabolism of alfentanil possibly inhibited by itra-  conazole; plasma concentration of alfentanil and  methadone increased by •voriconazole (consider  reducing dose of alfentanil and methadone); plasma  concentration of fentanyl possibly increased by  •triazoles    • Antipsychotics: enhanced hypotensive and sedative  effects when opioid analgesics given with antipsy-  chotics; increased risk of ventricular arrhythmias  when methadone given with •antipsychotics that  prolong the QT interval; increased risk of con-  vulsions when tramadol given with antipsychotics;  increased risk of ventricular arrhythmias when  methadone given with •amisulpride — avoid conco-  mitant use   • Antivirals : plasma concentration of methadone possi-  bly reduced by abacavir and nevirapine; methadone  possibly reduces plasma concentration of didano-  sine; plasma concentration of methadone reduced by  efavirenz, fosamprenavir, nelfinavir and ritonavir;  plasma concentration of dextropropoxyphene  increased by •ritonavir (risk of toxicity) — avoid  concomitant use; plasma concentration of bupren-  orphine possibly increased by ritonavir; plasma  concentration of alfentanil and fentanyl increased by  •ritonavir; plasma concentration of pethidine  reduced by •ritonavir, but plasma concentration of  toxic pethidine metabolite increased (avoid conco-  mitant use); plasma concentration of morphine  possibly reduced by ritonavir; increased risk of  ventricular arrhythmias when alfentanil, fentanyl or  methadone given with «saquinavir — avoid concomi-  tant use; buprenorphine possibly reduces plasma  concentration of tipranavir; methadone possibly  increases plasma concentration of zidovudine  Anxiolytics and Hypnotics: increased sedative effect  when opioid analgesics given with anxiolytics and  hypnotics; fentanyl possibly inhibits metabolism of  midazolam    • Atomoxetine: increased risk of ventricular arrhythmias  when methadone given with •atomoxetine; possible  increased risk of convulsions when tramadol given  with atomoxetine   Barbiturates: CNS effects of opioid analgesics possibly  increased by barbiturates; plasma concentration of  methadone reduced by phenobarbital   Calcium-channel Blockers: metabolism of alfentanil  inhibited by diltiazem (risk of prolonged or delayed  respiratory depression)   methorphan with •rasagiline; risk of CNS toxicity  when pethidine given with *rasagiline (avoid pethi-  dine for 2 weeks after rasagiline); hyperpyrexia and  CNS toxicity reported when pethidine given with  •selegiline (avoid concomitant use); avoidance of  opioid analgesics advised by manufacturer of sele-  giline   Muscle Relaxants: increased sedative effect when  fentanyl or morphine given with baclofen   Ulcer-healing Drugs: metabolism of opioid analgesics  inhibited by cimetidine (increased plasma concen-  tration)   Thyroid Hormones: possible increased risk of hypo-  thyroidism when orlistat given with levothyroxine   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by «SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with «St John’s wort   Antiepileptics: oxcarbazepine sometimes reduces  plasma concentration of carbamazepine (but con-  centration of an active metabolite of carbamazepine  may be increased), also plasma concentration of an  active metabolite of oxcarbazepine often reduced;  avoidance of oxcarbazepine advised by manufacturer  of eslicarbazepine; oxcarbazepine increases plasma  concentration of phenytoin, also plasma concentra-  tion of an active metabolite of oxcarbazepine  reduced; plasma concentration of an active meta-  bolite of oxcarbazepine sometimes reduced by val-  proate   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   Barbiturates: oxcarbazepine increases plasma con-  centration of phenobarbital, also plasma concentra-    Oxcarbazepine  Barbiturates (continued)  tion of an active metabolite of oxcarbazepine  reduced   Oxprenolol see Beta-blockers  Oxybutynin see Antimuscarinics  Oxycodone see Opioid Analgesics  Oxymetazoline see Sympathomimetics  Oxytetracycline see Tetracyclines  Oxytocin   Anaesthetics, General: oxytocic effect possibly  reduced, also enhanced hypotensive effect and risk  of arrhythmias when oxytocin given with volatile  liquid general anaesthetics  Prostaglandins: uterotonic effect of oxytocin poten-  tiated by prostaglandins   Sympathomimetics: risk of hypertension when oxy-  tocin given with vasoconstrictor sympathomimetics  (due to enhanced vasopressor effect)   with •clozapine (increased risk of agranulocytosis)  Antivirals: plasma concentration of paclitaxel  increased by nelfinavir and ritonavir  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Pancuronium see Muscle Relaxants  Pantoprazole see Proton Pump Inhibitors  Papaveretum see Opioid Analgesics  Paracetamol   Anticoagulants: prolonged regular use of paracetamol  possibly enhances anticoagulant effect of coumarins  Antiepileptics: metabolism of paracetamol possibly  accelerated by carbamazepine  Cytotoxics : paracetamol possibly inhibits metabolism  of intravenous busulfan (manufacturer of intravenous  busulfan advises caution within 72 hours of para-  cetamol); caution with paracetamol advised by  manufacturer of imatinib   Anti-arrhythmics: effects of neostigmine and pyrido-  stigmine possibly antagonised by propafenone   increased by erythromycin; effects of  neostigmine and pyridostigmine antagonised by  •aminoglycosides; effects of neostigmine and   pyridostigmine antagonised by clindamycin;  effects of neostigmine and pyridostigmine  antagonised by •polymyxins  Antidepressants: plasma concentration of galanta-  mine increased by paroxetine  Antifungals: plasma concentration of galantamine  increased by ketoconazole  Antimalarials: effects of neostigmine and pyrido-  stigmine may be diminished because of potential for  chloroquine and hydroxychloroquine to increase  symptoms of myasthenia gravis  Antimuscarinics: effects of parasympathomimetics  antagonised by antimuscarinics  Beta-blockers: increased risk of arrhythmias when  pilocarpine given with beta-blockers; effects of  neostigmine and pyridostigmine antagonised by  propranolol   Muscle Relaxants: donepezil possibly enhances  effects of suxamethonium; edrophonium, galanta-  mine, neostigmine, pyridostigmine and rivastigmine  enhance effects of suxamethonium; donepezil pos-  sibly antagonises effects of non-depolarising muscle  relaxants; edrophonium, neostigmine,  pyridostigmine and rivastigmine antagonise effects  of non-depolarising muscle relaxants  Parecoxib see NSAIDs  Paricalcitol see Vitamins  Paroxetine see Antidepressants, SSRI  Pazopanib   concomitant use with •atazanavir, •indinavir,  •nelfinavir, •ritonavir and •saquinavir  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets  Penicillamine   Analgesics: possible increased risk of nephrotoxicity  when penicillamine given with NSAIDs  Antacids: absorption of penicillamine reduced by  antacids   Cardiac Glycosides: penicillamine possibly reduces  plasma concentration of digoxin  Iron: absorption of penicillamine reduced by oral iron  Sodium Aurothiomalate : manufacturer of penicill-  amine advises avoid concomitant use with sodium  aurothiomalate (increased risk of toxicity)   Allopurinol: increased risk of rash when amoxicillin or  ampicillin given with allopurinol  Antibacterials: absorption of phenoxymethylpenicillin  reduced by neomycin; effects of penicillins possibly  antagonised by tetracyclines  Anticoagulants: common experience in anticoagulant  clinics is that INR can be altered by a course of  broad-spectrum penicillins such as ampicillin,  although studies have failed to demonstrate an  interaction with coumarins or phenindione  Cytotoxics: penicillins reduce excretion of metho-  trexate (increased risk of toxicity)   Muscle Relaxants: piperacillin enhances effects of  non-depolarising muscle relaxants and suxa-  methonium   Probenecid: excretion of penicillins reduced by pro-  benecid (increased plasma concentration)  Sulfinpyrazone: excretion of penicillins reduced by  sulfinpyrazone   mias when pentamidine isetionate given with par-  enteral •erythromycin; increased risk of ventricular  arrhythmias when pentamidine isetionate given with  •moxifloxacin — avoid concomitant use   Antifungals: possible increased risk of nephrotoxicity  when pentamidine isetionate given with amphot-  ericin   mias when pentamidine isetionate given with  •amisulpride or •droperidol — avoid concomitant  use; increased risk of ventricular arrhythmias when  pentamidine isetionate given with •phenothiazines   parenteral pentamidine isetionate given with  •foscamet; increased risk of ventricular arrhythmias  when pentamidine isetionate given with  •saquinavir — avoid concomitant use   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa  Metoclopramide: antiparkinsonian effect of pergolide  antagonised by metoclopramide  Pericyazine see Antipsychotics  Perindopril see ACE Inhibitors  Perphenazine see Antipsychotics  Pethidine see Opioid Analgesics  Phenazocine see Opioid Analgesics  Phenelzine see MAOIs  Phenindione   Note Change in patient’s clinical condition particularly  associated with liver disease, intercurrent illness, or drug  administration, necessitates more frequent testing. Major  changes in diet (especially involving salads and vegetables)  and in alcohol consumption may also affect anticoagulant  control   sibly enhanced by »NSAIDs; increased risk of  haemorrhage when anticoagulants given with intra-  venous •diclofenac (avoid concomitant use, includ-  ing low-dose heparins); increased risk of  haemorrhage when anticoagulants given with  •ketorolac (avoid concomitant use, including low-  dose heparins); increased risk of bleeding when  phenindione given with •aspirin (due to antiplatelet  effect)   suggests that INR possibly altered when phenindione  is given with •neomycin (given for local action on  gut); anticoagulant effect of phenindione possibly  enhanced by levofloxacin and •tetracyclines; studies  have failed to demonstrate an interaction with  phenindione, but common experience in anti-  coagulant clinics is that INR can be altered by a  course of broad-spectrum penicillins such as ampi-  cillin; metabolism of phenindione possibly inhibited  by sulfonamides   enhanced due to antiplatelet action of •clopidogrel  Corticosteroids : anticoagulant effect of phenindione  may be enhanced or reduced by corticosteroids   indione may be enhanced or reduced by  •colestyramine; anticoagulant effect of phenindione  possibly enhanced by •rosuvastatin; anticoagulant  effect of phenindione enhanced by •fibrates   antagonised by •oestrogens  Prasugrel: possible increased risk of bleeding when  phenindione given with prasugrel    Phenobarbital see Barbiturates  Phenothiazines see Antipsychotics  Phenoxybenzamine see Alpha-blockers  Phenoxymethylpenicillin see Penicillins  Phentolamine see Alpha-blockers  Phenylephrine see Sympathomimetics  Phenytoin   Note Fosphenytoin interactions as for phenytoin  Alcohol : plasma concentration of phenytoin possibly  reduced by chronic heavy consumption of alcohol  Analgesics: phenytoin accelerates metabolism of  methadone (reduced effect and risk of withdrawal  effects); effects of phenytoin enhanced by aspirin  Antacids: absorption of phenytoin reduced by antacids   by •amiodarone (increased plasma concentration);  phenytoin reduces plasma concentration of disopyr-  amide; phenytoin possibly reduces plasma concen-  tration of •dronedarone — avoid concomitant use   clarithromycin and •metronidazole (increased  plasma concentration); plasma concentration of  phenytoin increased or decreased by ciprofloxacin;  phenytoin accelerates metabolism of doxycycline  (reduced plasma concentration); plasma concentra-  tion of phenytoin increased by •chloramphenicol  (increased risk of toxicity); metabolism of phenytoin  possibly inhibited by isoniazid (increased risk of  toxicity); metabolism of phenytoin accelerated by  •rifamycins (reduced plasma concentration); plasma  concentration of phenytoin possibly increased by  sulfonamides; phenytoin reduces plasma concentra-  tion of •telithromycin (avoid during and for 2 weeks  after phenytoin); plasma concentration of phenytoin  increased by •trimethoprim (also increased antifolate  effect)   increased by •fluoxetine and •fluvoxamine; pheny-  toin reduces plasma concentration of •mianserin,  mirtazapine and paroxetine; plasma concentration of  phenytoin possibly increased by sertraline, also  plasma concentration of sertraline possibly reduced;  anticonvulsant effect of antiepileptics possibly  antagonised by MAOIs and •tricyclic-related anti-  depressants (convulsive threshold lowered); anti-  convulsant effect of antiepileptics antagonised by  •SSRIs and •tricyclics (convulsive threshold  lowered); avoid concomitant use of antiepileptics  with «St John’s wort; phenytoin possibly reduces  plasma concentration of •tricyclics  Antidiabetics: plasma concentration of phenytoin  transiently increased by tolbutamide (possibility of  toxicity)   often reduced when phenytoin given with carba-  mazepine, also plasma concentration of phenytoin  may be increased; phenytoin reduces plasma con-  centration of eslicarbazepine, also plasma concen-  tration of phenytoin increased; plasma concentration  of phenytoin possibly increased by •ethosuximide,  also plasma concentration of ethosuximide possibly  reduced; phenytoin reduces plasma concentration of  lamotrigine, tiagabine and zonisamide; plasma con-  centration of phenytoin increased by oxcarbazepine,  also plasma concentration of an active metabolite of  oxcarbazepine reduced; phenytoin possibly reduces  plasma concentration of primidone (but concentra-  tion of an active metabolite increased), plasma  concentration of phenytoin often reduced but may  be increased; phenytoin possibly reduces plasma  concentration of rufinamide, also plasma concen-  tration of phenytoin possibly increased; plasma  concentration of phenytoin increased by •stiripentol;  plasma concentration of phenytoin increased by  •topiramate (also plasma concentration of topira-   mate reduced); plasma concentration of pheny-  toin increased or possibly reduced when given  with valproate, also plasma concentration of  valproate reduced; plasma concentration of  phenytoin reduced by vigabatrin   of •ketoconazole and •posaconazole; anticonvulsant  effect of phenytoin enhanced by •miconazole  (plasma concentration of phenytoin increased);  plasma concentration of phenytoin increased by  •fluconazole (consider reducing dose of phenytoin);  phenytoin reduces plasma concentration of  •itraconazole — avoid concomitant use; plasma con-  centration of phenytoin increased by •voriconazole,  also phenytoin reduces plasma concentration of  voriconazole (increase dose of voriconazole and also  monitor for phenytoin toxicity); phenytoin possibly  reduces plasma concentration of caspofungin — con-  sider increasing dose of caspofungin   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine; anti-  convulsant effect of phenytoin antagonised by  •pyrimethamine, also increased antifolate effect   antagonised by •antipsychotics (convulsive thresh-  old lowered); phenytoin reduces plasma concentra-  tion of haloperidol; plasma concentration of  phenytoin possibly increased or decreased by chlor-  promazine; phenytoin possibly reduces plasma con-  centration of •aripiprazole — increase dose of  aripiprazole; phenytoin accelerates metabolism of  clozapine and quetiapine (reduced plasma concen-  tration)   centration of abacavir, darunavir, lopinavir and  saquinavir; avoidance of phenytoin advised by  manufacturer of etravirine; phenytoin possibly  reduces plasma concentration of •indinavir, also  plasma concentration of phenytoin possibly  increased; plasma concentration of phenytoin  reduced by nelfinavir; phenytoin possibly reduces  plasma concentration of ritonavir, also plasma  concentration of phenytoin possibly affected; plasma  concentration of phenytoin increased or decreased  by zidovudine   Anxiolytics and Hypnotics: phenytoin often reduces  plasma concentration of clonazepam; plasma con-  centration of phenytoin increased or decreased by  diazepam; plasma concentration of phenytoin pos-  sibly increased or decreased by benzodiazepines   Barbiturates: phenytoin often increases plasma con-  centration of phenobarbital, plasma concentration of  phenytoin often reduced but may be increased   of felodipine, isradipine and verapamil; phenytoin  probably reduces effects of dihydropyridines,  nicardipine and •nifedipine; plasma concentration of  phenytoin increased by •diltiazem but also effect of  diltiazem reduced   centration of busulfan and etoposide; metabolism of  phenytoin possibly inhibited by fluorouracil  (increased risk of toxicity); phenytoin increases  antifolate effect of methotrexate; absorption of   phenytoin possibly reduced by cytotoxics;  avoidance of phenytoin advised by manufacturer  of gefitinib and •lapatinib; phenytoin reduces  plasma concentration of •imatinib — avoid con-  comitant use; phenytoin reduces plasma con-  centration of irinotecan and its active metabolite  Diazoxide: plasma concentration of phenytoin  reduced by diazoxide, also effect of diazoxide may be  reduced   increased by •acetazolamide; phenytoin antagonises  effects of furosemide; phenytoin reduces plasma  concentration of •eplerenone — avoid concomitant  use; increased risk of osteomalacia when phenytoin  given with carbonic anhydrase inhibitors  Dopamine rgics: phenytoin possibly reduces effects of  levodopa   Leflunomide: plasma concentration of phenytoin  possibly increased by leflunomide  Levamisole: plasma concentration of phenytoin pos-  sibly increased by levamisole  Lipid-regulating Drugs: absorption of phenytoin pos-  sibly reduced by colesevelam; combination of  phenytoin with fluvastatin may increase plasma  concentration of either drug (or both)   Lithium: neurotoxicity may occur when phenytoin  given with lithium without increased plasma con-  centration of lithium   Muscle Relaxants: phenytoin antagonises muscle  relaxant effect of non-depolarising muscle relaxants  (accelerated recovery from neuromuscular blockade)   increased by •sulfinpyrazone  Sympathomimetics: plasma concentration of pheny-  toin increased by methylphenidate  Tacrolimus: phenytoin reduces plasma concentration  of tacrolimus, also plasma concentration of pheny-  toin possibly increased   ited by •cimetidine (increased plasma concentra-  tion); effects of phenytoin enhanced by  •esomeprazole; effects of phenytoin possibly  enhanced by omeprazole; absorption of phenytoin  reduced by •sucralfate   Antidepressants : manufacturer of pholcodine advises  avoid for 2 weeks after stopping MAOIs  Phosphodiesterase Type-3 Inhibitors   advised by manufacturer of • anagrelide  Physostigmine see Parasympathomimetics  Pilocarpine see Parasympathomimetics  Pimozide see Antipsychotics  Pindolol see Beta-blockers  Pioglitazone see Antidiabetics  Piperacillin see Penicillins  Pipotiazine see Antipsychotics  Piroxicam see NSAIDs  Pivmecillinam see Penicillins  Pizotifen   Adrenergic Neurone Blockers: pizotifen antagonises  hypotensive effect of adrenergic neurone blockers   possibly of ototoxicity when platinum compounds  given with •aminoglycosides or •polymyxins;  increased risk of nephrotoxicity and ototoxicity when  platinum compounds given with capreomycin;  increased risk of nephrotoxicity and possibly of  ototoxicity when cisplatin given with vancomycin  Antiepileptics: cytotoxics possibly reduce absorption  of phenytoin   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Diuretics: increased risk of nephrotoxicity and oto-  toxicity when platinum compounds given with diur-  etics   Antibacterials: increased risk of nephrotoxicity when  colistin or polymyxins given with aminoglycosides;  increased risk of nephrotoxicity when colistin or  polymyxins given with capreomycin; increased risk  of nephrotoxicity when polymyxins given with  vancomycin; increased risk of nephrotoxicity and  ototoxicity when colistin given with vancomycin  Antifun gals: increased risk of nephrotoxicity when  polymyxins given with amphotericin   effects of •neostigmine and •pyridostigmine  Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767  Polystyrene Sulphonate Resins  Antacids : risk of intestinal obstruction when poly-  styrene sulphonate resins given with aluminium  hydroxide; risk of metabolic alkalosis when poly-  styrene sulphonate resins given with oral magnesium  salts   Thyroid Hormones: polystyrene sulphonate resins  reduce absorption of levothyroxine  Posaconazole see Antifungals, Triazole  Potassium Canrenoate see Diuretics  Potassium Aminobenzoate  Antibacterials: potassium aminobenzoate inhibits  effects of sulfonamides  Potassium Bicarbonate see Potassium Salts  Potassium Chloride see Potassium Salts  Potassium Citrate see Potassium Salts  Potassium Salts  Note Includes salt substitutes   when potassium salts given with *ACE inhibitors  Aliskiren: increased risk of hyperkalaemia when  potassium salts given with aliskiren   of hyperkalaemia when potassium salts given with  •angiotensin-II receptor antagonists  Antibacterials: avoid concomitant use of potassium  citrate with methenamine   Antipsychotics: manufacturer of pramipexole advises  avoid concomitant use of antipsychotics (antagonism  of effect)   Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa  Ulcer-healing Drugs: excretion of pramipexole  reduced by cimetidine (increased plasma concen-  tration)   Analgesics: possible increased risk of bleeding when  prasugrel given with NSAIDs  Anticoagulants: possible increased risk of bleeding  when prasugrel given with coumarins or phenindi-  one   Clopidogrel: possible increased risk of bleeding when  prasugrel given with clopidogrel  Pravastatin see Statins  Prazosin see Alpha-blockers  Prednisolone see Corticosteroids  Prednisone see Corticosteroids  Prilocaine   Anti-arrhythmics: increased myocardial depression  when prilocaine given with anti-arrhythmics  Antibacterials: increased risk of methaemoglobin-  aemia when prilocaine given with sulfonamides   manufacturer of •artemether/lumefantrine  Histamine: avoidance of antimalarials advised by  manufacturer of histamine  Mepacrine: plasma concentration of primaquine  increased by mepacrine (increased risk of toxicity)  Vaccines: antimalarials inactivate oral typhoid  vaccine-see p. 767  Primidone   tration of paroxetine; primidone accelerates metab-  olism of •mianserin (reduced plasma concentration);  anticonvulsant effect of antiepileptics possibly  antagonised by MAOIs and •tricyclic -related anti-  depressants (convulsive threshold lowered); anti-  convulsant effect of antiepileptics antagonised by  •SSRIs and •tricyclics (convulsive threshold  lowered); avoid concomitant use of antiepileptics  with *St John’s wort; anticonvulsant effect of  primidone antagonised by •tricyclics (convulsive  threshold lowered), also metabolism of tricyclics  possibly accelerated (reduced plasma concentration)   centration of carbamazepine, also plasma concen-  tration of primidone sometimes reduced (but  concentration of an active metabolite of primidone  often increased); primidone possibly reduces plasma  concentration of ethosuximide and rufinamide;  primidone reduces plasma concentration of  lamotrigine and tiagabine; plasma concentration of  primidone possibly reduced by phenytoin (but  concentration of an active metabolite increased),  plasma concentration of phenytoin often reduced but  may be increased; plasma concentration of primid-  one possibly increased by •valproate (plasma con-  centration of active metabolite of primidone  increased), also plasma concentration of valproate  reduced; plasma concentration of primidone possibly  reduced by vigabatrin   centration of •posaconazole; primidone possibly  reduces plasma concentration of •voriconazole —  avoid concomitant use; primidone reduces absorp-  tion of griseofulvin (reduced effect)   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   Anxiolytics and Hypnotics: primidone often reduces  plasma concentration of clonazepam  Barbiturates: increased sedative effect when primid-  one given with barbiturates   of •felodipine and •isradipine; primidone probably  reduces effects of •dihydropyridines, •diltiazem and  •verapamil   Diuretics: plasma concentration of primidone possibly  reduced by acetazolamide; increased risk of osteo-  malacia when primidone given with carbonic  anhydrase inhibitors   Hormone Antagonists: primidone accelerates metab-  olism of toremifene (reduced plasma concentration)  Leukotriene Receptor Antagonists: primidone  reduces plasma concentration of montelukast  Memantine: effects of primidone possibly reduced by  memantine   Sympathomimetics: plasma concentration of primid-  one possibly increased by methylphenidate  Theophylline: primidone accelerates metabolism of  theophylline (reduced effect)   Thyroid Hormones: primidone accelerates metabolism  of thyroid hormones (may increase requirements for  thyroid hormones in hypothyroidism)   •dexketoprofen, •indometacin, •ketoprofen and  •naproxen (increased plasma concentration); pro-  benecid reduces excretion of •ketorolac (increased  plasma concentration) — avoid concomitant use;  effects of probenecid antagonised by aspirin  Antibacterials : probenecid reduces excretion of dor-  ipenem (manufacturers of doripenem advise avoid  concomitant use); probenecid reduces excretion of  meropenem; probenecid reduces excretion of ceph-  alosporins, ciprofloxacin, nalidixic acid,  norfloxacin and penicillins (increased plasma con-  centration); probenecid reduces excretion of  dapsone and nitrofurantoin (increased risk of side-  effects); effects of probenecid antagonised by  pyrazinamide   (increased plasma concentration); probenecid possi-  bly reduces excretion of famciclovir (increased  plasma concentration); probenecid reduces excre-  tion of ganciclovir and •zidovudine (increased  plasma concentration and risk of toxicity)  Anxiolytics and Hypnotics: probenecid reduces  excretion of lorazepam (increased plasma concen-  tration); probenecid possibly reduces excretion of  nitrazepam (increased plasma concentration)   Sodium Benzoate: probenecid possibly reduces  excretion of conjugate formed by sodium benzoate  Sodium Phenylbutyrate: probenecid possibly reduces  excretion of conjugate formed by sodium phenylbu-  tyrate   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Note Interactions of combined oral contraceptives may  also apply to combined contraceptive patches and vaginal  rings   ated by •carbamazepine, •eslicarbazepine, «oxcar-  bazepine, •phenytoin, •primidone, •rufinamide and  •topiramate (reduced contraceptive effect — see  p. 495); desogestrel possibly increases plasma con-  centration of lamotrigine   Antifungals : progestogens possibly increase plasma  concentration of voriconazole; anecdotal reports of  contraceptive failure and menstrual irregularities  when progestogens given with griseofulvin; occa-  sional reports of breakthrough bleeding when pro-  gestogens (used for contraception) given with  terbinafine   bly reduced by •efavirenz and nelfinavir; metabolism  of progestogens accelerated by •nevirapine (reduced  contraceptive effect — see p. 495)   contraceptives containing progestogens when given  with •aprepitant (alternative contraception recom-  mended)   •ciclosporin (increased plasma concentration)  Diuretics: risk of hyperkalaemia when drospirenone  given with potassium-sparing diuretics and aldo-  sterone antagonists (monitor serum potassium  during first cycle)   centration of •selegiline — manufacturer of selegiline  advises avoid concomitant use  Lipid-regulating Drugs: plasma concentration of nor-  ethisterone increased by atorvastatin; plasma con-  centration of norgestrel increased by rosuvastatin  Muscle Relaxants: progestogens possibly increase  plasma concentration of tizanidine (increased risk of  toxicity)   Antacids: absorption of proguanil reduced by oral  magnesium salts (as magnesium trisilicate)  Anticoagulants: isolated reports that proguanil may  enhance anticoagulant effect of warfarin   manufacturer of •artemether/lumefantrine;  increased antifolate effect when proguanil given with  pyrimethamine   Anaesthetics, Local: increased myocardial depression  when anti-arrhythmics given with bupivacaine,  levobupivacaine, prilocaine or ropivacaine   inhibited by paroxetine (increased risk of toxicity);  increased risk of arrhythmias when propafenone  given with •tricyclics   mias when anti-arrhythmics that prolong the QT  interval given with •antipsychotics that prolong the  QT interval   sibly increased by •fosamprenavir (increased risk of  ventricular arrhythmias — avoid concomitant use);  plasma concentration of propafenone increased by  •ritonavir (increased risk of ventricular arrhyth-  mias — avoid concomitant use); increased risk of  ventricular arrhythmias when propafenone given  with «saquinavir — avoid concomitant use   anti-arrhythmics given with •beta-blockers; propa-  fenone increases plasma concentration of  metoprolol and propranolol   concentration of *digoxin (halve dose of digoxin)  Ciclosporin: propafenone possibly increases plasma  concentration of ciclosporin  Parasympathomimetics: propafenone possibly antag-  onises effects of neostigmine and pyridostigmine  Theophylline: propafenone increases plasma concen-  tration of theophylline   fenone increased by •cimetidine  Propantheline see Antimuscarinics  Propiverine see Antimuscarinics  Propofol see Anaesthetics, General  Propranolol see Beta-blockers  Prostaglandins   ACE Inhibitors: enhanced hypotensive effect when  alprostadil given with ACE inhibitors  Adrenergic Neurone Blockers: enhanced hypotensive  effect when alprostadil given with adrenergic  neurone blockers   Alpha-blockers: enhanced hypotensive effect when  alprostadil given with alpha-blockers  Angiotensin-ll Receptor Antagonists: enhanced  hypotensive effect when alprostadil given with  angiotensin-II receptor antagonists  Beta-blockers: enhanced hypotensive effect when  alprostadil given with beta-blockers  Calcium-channel Blockers: enhanced hypotensive  effect when alprostadil given with calcium-channel  blockers   Methyldopa: enhanced hypotensive effect when  alprostadil given with methyldopa  Moxonidine: enhanced hypotensive effect when  alprostadil given with moxonidine  Nitrates: enhanced hypotensive effect when alprost-  adil given with nitrates   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when alprostadil given with hydralazine,  minoxidil or sodium nitroprusside    Protein Kinase Inhibitors see Dasatinib, Erlotinib,  Everolimus, Gefitinib, Imatinib, Lapatinib, Nilotinib,  Pazopanib, Sorafenib, Sunitinib, and Temsirolimus   Antibacterials: plasma concentration of both drugs  increased when omeprazole given with clarithro-  mycin   Antidepressants: omeprazole increases plasma con-  centration of escitalopram; plasma concentration of  lansoprazole possibly increased by fluvoxamine;  plasma concentration of omeprazole possibly  reduced by St John’s wort   Antifungals: proton pump inhibitors reduce absorp-  tion of itraconazole and ketoconazole; avoidance of  proton pump inhibitors advised by manufacturer of  posaconazole (plasma concentration of posacona-  zole possibly reduced); plasma concentration of  esomeprazole possibly increased by voriconazole;  plasma concentration of omeprazole increased by  voriconazole (consider reducing dose of omeprazole)   concentration of »atazanavir — avoid or adjust dose  of both drugs (consult product literature); ome-  prazole reduces plasma concentration of  •nelfinavir — avoid concomitant use; proton pump  inhibitors possibly increase plasma concentration of  raltegravir — manufacturer of raltegravir advises  avoid concomitant use; omeprazole increases  plasma concentration of •raltegravir — avoid conco-  mitant use; esomeprazole, lansoprazole,  pantoprazole and rabeprazole possibly increase  plasma concentration of •saquinavir — manufacturer  of saquinavir advises avoid concomitant use; ome-  prazole increases plasma concentration of  •saquinavir — manufacturer of saquinavir advises  avoid concomitant use; plasma concentration of  esomeprazole and omeprazole reduced by  •tipranavir   Anxiolytics and Hypnotics: esomeprazole and ome-  prazole possibly inhibit metabolism of diazepam  (increased plasma concentration)   Cardiac Glycosides: proton pump inhibitors possibly  slightly increase plasma concentration of digoxin   Cilostazol : omeprazole increases plasma concentra-  tion of cilostazol (consider reducing dose of cilosta-  zol)   antiplatelet effect of •clopidogrel; lansoprazole,  pantoprazole and rabeprazole possibly reduce anti-  platelet effect of clopidogrel   methotrexate (increased risk of toxicity); avoidance  of esomeprazole, lansoprazole, pantoprazole and  rabeprazole advised by manufacturer of •erlotinib;  omeprazole reduces plasma concentration of  •erlotinib — manufacturer of erlotinib advises avoid  concomitant use; proton pump inhibitors possibly  reduce absorption of lapatinib   advised by manufacturer of •ulipristal (plasma  concentration of ulipristal possibly reduced)   manufacturer of •artemether/lumefantrine;  increased antifolate effect when pyrimethamine  given with proguanil   Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa  Quinapril see ACE Inhibitors  Quinine   Anticoagulants: plasma concentration of both drugs  increased when quinine given with warfarin   manufacturer of •artemether/lumefantrine;  increased risk of ventricular arrhythmias when  quinine given with •artemether/lumefantrine;  increased risk of convulsions when quinine given  with •mefloquine (but should not prevent the use of  intravenous quinine in severe cases)   mias when quinine given with •droperidol or  •pimozide — avoid concomitant use; possible  increased risk of ventricular arrhythmias when  quinine given with •haloperidol — avoid concomitant  use   increased by •atazanavir, •darunavir,  •fosamprenavir, •indinavir, •nelfinavir and  •tipranavir (increased risk of toxicity); plasma con-  centration of quinine increased by •ritonavir  (increased risk of toxicity); increased risk of ventri-  cular arrhythmias when quinine given with  •saquinavir — avoid concomitant use   Dopaminergics: quinine possibly increases plasma  concentration of amantadine  Histamine: avoidance of antimalarials advised by  manufacturer of histamine   Ulcer-healing Drugs: metabolism of quinine inhibited  by cimetidine (increased plasma concentration)   when quinolones given with •NSAIDs; manufacturer  of ciprofloxacin advises avoid premedication with  opioid analgesics (reduced plasma concentration of  ciprofloxacin) when ciprofloxacin used for surgical  prophylaxis   Antacids: absorption of ciprofloxacin, levofloxacin,  moxifloxacin, norfloxacin and ofloxacin reduced by  antacids   thmias when levofloxacin or moxifloxacin given with  •amiodarone — avoid concomitant use; increased  risk of ventricular arrhythmias when moxifloxacin  given with •disopyramide — avoid concomitant use   norfloxacin and ofloxacin enhance anticoagulant  effect of •coumarins; levofloxacin possibly enhances  anticoagulant effect of coumarins and phenindione   •duloxetine — avoid concomitant use; avoidance of  ciprofloxacin advised by manufacturer of  •agomelatine; increased risk of ventricular arrhyth-  mias when moxifloxacin given with •tricyclics —  avoid concomitant use   manufacturer of •artemether/lumefantrine;  increased risk of ventricular arrhythmias when  moxifloxacin given with •chloroquine and hydroxy-  chloroquine, •mefloquine or ©quinine — avoid con-  comitant use   mias when moxifloxacin given with •benperidol —  manufacturer of benperidol advises avoid concomi-  tant use; increased risk of ventricular arrhythmias  when moxifloxacin given with •droperidol,  •haloperidol, •phenothiazines, •pimozide or  •zuclopenthixol — avoid concomitant use; ciproflox-  acin increases plasma concentration of clozapine;  ciprofloxacin possibly increases plasma concentra-  tion of olanzapine   toxicity; ciprofloxacin possibly reduces excretion of  methotrexate (increased risk of toxicity); ciproflox-  acin increases plasma concentration of erlotinib;  increased risk of ventricular arrhythmias when  levofloxacin or moxifloxacin given with ©arsenic  trioxide   Dairy Products: absorption of ciprofloxacin and nor-  floxacin reduced by dairy products  Dopaminergics: ciprofloxacin increases plasma con-  centration of rasagiline; ciprofloxacin inhibits   5HT a Agonists: quinolones possibly inhibit metabolism  of zolmitriptan (reduce dose of zolmitriptan)   Iron: absorption of ciprofloxacin, levofloxacin, moxi-  floxacin, norfloxacin and ofloxacin reduced by oral  iron   Lanthanum : absorption of quinolones possibly  reduced by lanthanum (give at least 2 hours before  or 4 hours after lanthanum)   plasma concentration of tizanidine (increased risk of  toxicity); ciprofloxacin increases plasma concentra-  tion of •tizanidine (increased risk of toxicity) — avoid  concomitant use   Strontium Ranelate: absorption of quinolones  reduced by strontium ranelate (manufacturer of  strontium ranelate advises avoid concomitant use)   when quinolones given with •theophylline;  ciprofloxacin and norfloxacin increase plasma con-  centration of ©theophylline  Ulcer-healing Drugs: absorption of ciprofloxacin,  levofloxacin, moxifloxacin, norfloxacin and oflox-  acin reduced by sucralfate  Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767   Zinc: absorption of ciprofloxacin, levofloxacin, moxi-  floxacin, norfloxacin and ofloxacin reduced by zinc  Rabeprazole see Proton Pump Inhibitors  Raloxifene   gravir increased by •omeprazole — avoid concomi-  tant use; plasma concentration of raltegravir possibly  increased by histamine H 2 -antagonists and proton  pump inhibitors — manufacturer of raltegravir advises  avoid concomitant use  Raltitrexed   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   possibly increased by ©clarithromycin and  •telithromycin — manufacturer of ranolazine advises  avoid concomitant use; plasma concentration of  ranolazine reduced by ©rifampicin — manufacturer of  ranolazine advises avoid concomitant use   increased by •ketoconazole — avoid concomitant  use; plasma concentration of ranolazine possibly  increased by •itraconazole, •posaconazole and  •voriconazole — manufacturer of ranolazine advises  avoid concomitant use   increased by •atazanavir, •darunavir,  •fosamprenavir, •indinavir, •lopinavir, •nelfinavir,  •ritonavir, «saquinavir and *tipranavir — manufac-  turer of ranolazine advises avoid concomitant use   avoid concomitant use with *sotalol  Calcium-channel Blockers: plasma concentration of  ranolazine increased by diltiazem and verapamil  (consider reducing dose of ranolazine)   possibly increased by •grapefruit juice — manufac-  turer of ranolazine advises avoid concomitant use  Lipid-regulating Drugs: ranolazine increases plasma  concentration of simvastatin (consider reducing dose  of simvastatin)   •dextromethorphan; risk of CNS toxicity when  rasagiline given with *pethidine (avoid pethidine for  2 weeks after rasagiline)   •fluoxetine for 2 weeks, also rasagiline should not be  started until at least 5 weeks after stopping fluox-  etine; after stopping rasagiline do not start  •fluvoxamine for 2 weeks; risk of hypertensive crisis  when rasagiline given with •MAOIs, avoid MAOIs  for at least 2 weeks after stopping rasagiline;  increased risk of CNS toxicity when rasagiline given  with •SSRIs or •tricyclics   Dopaminergics: plasma concentration of rasagiline  possibly reduced by entacapone  Memantine: effects of dopaminergics possibly  enhanced by memantine   avoid concomitant use with •fluvoxamine; increased  risk of hypertension and CNS excitation when  reboxetine given with •MAOIs (MAOIs should not be  started until 1 week after stopping reboxetine, avoid  reboxetine for 2 weeks after stopping MAOIs)   by manufacturer of •artemether/lumefantrine  Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine  Diuretics: possible increased risk of hypokalaemia  when reboxetine given with loop diuretics or thi-  azides and related diuretics  Ergot Alkaloids: possible risk of hypertension when  reboxetine given with ergotamine and methysergide  Remifentanil see Opioid Analgesics  Repaglinide see Antidiabetics   of •alcohol (increased risk of teratogenecity in  women of child-bearing potential)   coagulant effect of •coumarins  Antiepileptics: isotretinoin possibly reduces plasma  concentration of carbamazepine  Antifungals: plasma concentration of alitretinoin  increased by ketoconazole   •methotrexate (also increased risk of hepatotoxi-  city) — avoid concomitant use  Lipid-regulating Drugs: alitretinoin reduces plasma  concentration of simvastatin  Vitamins: risk of hypervitaminosis A when retinoids  given with vitamin A  Ribavirin   •abacavir; increased risk of side-effects when riba-  virin given with •didanosine — avoid concomitant  use; increased risk of toxicity when ribavirin given  with •stavudine; increased risk of anaemia when  ribavirin given with •zidovudine — avoid concomitant  use   pressive effects of •azathioprine  Rifabutin see Rifamycins  Rifampicin see Rifamycins  Rifamycins   ACE Inhibitors: rifampicin reduces plasma concentra-  tion of active metabolite of imidapril (reduced  antihypertensive effect)   Analgesics: rifampicin reduces plasma concentration  of celecoxib, diclofenac and etoricoxib; rifampicin  accelerates metabolism of alfentanil, codeine,  fentanyl, methadone and morphine (reduced effect);  rifampicin possibly accelerates metabolism of oxy-  codone   Angiotensin-ll Receptor Antagonists: rifampicin  reduces plasma concentration of losartan and its  active metabolite   •disopyramide (reduced plasma concentration); rif-  ampicin reduces plasma concentration of  •dronedarone — avoid concomitant use; rifampicin  accelerates metabolism of •propafenone (reduced  effect)   tion of clarithromycin and dapsone; plasma con-  centration of rifabutin increased by •clarithromycin  (increased risk of uveitis — reduce rifabutin dose);  rifampicin reduces plasma concentration of doxycy-  cline — consider increasing dose of doxycycline; rif-  ampicin accelerates metabolism of chloramphenicol  (reduced plasma concentration); rifampicin reduces  plasma concentration of linezolid (possible thera-  peutic failure of linezolid); plasma concentration of  rifabutin possibly increased by •macrolides  (increased risk of uveitis — reduce rifabutin dose);  rifampicin reduces plasma concentration of  •telithromycin (avoid during and for 2 weeks after  rifampicin); rifampicin possibly reduces plasma  concentration of trimethoprim   •coumarins (reduced anticoagulant effect); rif-  ampicin reduces plasma concentration of rivarox-  aban   •tolbutamide (reduced effect); rifampicin reduces  plasma concentration of nateglinide; rifampicin  possibly antagonises hypoglycaemic effect of repa-  glinide; rifamycins possibly accelerate metabolism of  •sulfonylureas (reduced effect)   of •carbamazepine; rifampicin reduces plasma con-  centration of •lamotrigine; rifamycins accelerate  metabolism of •phenytoin (reduced plasma concen-  tration)   •ketoconazole (reduced plasma concentration), also  plasma concentration of rifampicin may be reduced  by ketoconazole; plasma concentration of rifabutin  increased by •fluconazole (increased risk of uveitis —  reduce rifabutin dose); rifampicin accelerates  metabolism of •fluconazole and •itraconazole  (reduced plasma concentration); rifabutin reduces  plasma concentration of •itraconazole — avoid con-  comitant use; plasma concentration of rifabutin  increased by •posaconazole (also plasma concen-  tration of posaconazole reduced); rifampicin reduces  plasma concentration of •posaconazole and  •terbinafine; plasma concentration of rifabutin  increased by •voriconazole, also rifabutin reduces  plasma concentration of voriconazole (increase dose  of voriconazole and also monitor for rifabutin  toxicity); rifampicin reduces plasma concentration of  •voriconazole — avoid concomitant use; rifampicin  initially increases and then reduces plasma concen-  tration of caspofungin (consider increasing dose of  caspofungin); plasma concentration of rifabutin  possibly increased by •triazoles (increased risk of  uveitis — reduce rifabutin dose)   tion of •mefloquine — avoid concomitant use; rif-  ampicin reduces plasma concentration of •quinine  Antimuscarinics: rifampicin reduces plasma concen-  tration of active metabolite of fesoterodine   •haloperidol (reduced plasma concentration);  rifabutin and rifampicin possibly reduce plasma  concentration of •aripiprazole — increase dose of  aripiprazole; rifampicin possibly reduces plasma  concentration of clozapine   centration of abacavir and ritonavir; rifampicin  reduces plasma concentration of •atazanavir,  •lopinavir and •nevirapine — avoid concomitant use;  plasma concentration of rifabutin increased by  •atazanavir, *darunavir, •fosamprenavir and  •tipranavir (reduce dose of rifabutin); rifampicin  significantly reduces plasma concentration of  •darunavir, •fosamprenavir and •nelfinavir — avoid  concomitant use; plasma concentration of rifabutin  reduced by efavirenz — increase dose of rifabutin;  rifampicin reduces plasma concentration of efavir-  enz — increase dose of efavirenz; plasma concentra-  tion of both drugs reduced when rifabutin given with  •etravirine; avoidance of rifampicin advised by  manufacturer of etravirine and zidovudine; rif-  ampicin accelerates metabolism of •indinavir  (reduced plasma concentration — avoid concomitant  use); plasma concentration of rifabutin increased by  •indinavir — avoid concomitant use; rifampicin  reduces plasma concentration of •maraviroc and  •raltegravir — consider increasing dose of  maraviroc and raltegravir; plasma concentration of  rifabutin increased by •nelfinavir (halve dose of  rifabutin); plasma concentration of rifabutin possibly  increased by nevirapine; plasma concentration of  rifabutin increased by •ritonavir (increased risk of  toxicity); rifampicin significantly reduces plasma  concentration of •saquinavir, also risk of hepato-  toxicity — avoid concomitant use; plasma concentra-  tion of rifabutin increased by •saquinavir (also  plasma concentration of saquinavir reduced); rif-  ampicin possibly reduces plasma concentration of  •tipranavir — avoid concomitant use   Anxiolytics and Hypnotics: rifampicin accelerates  metabolism of diazepam (reduced plasma concen-  tration); rifampicin possibly accelerates metabolism  of benzodiazepines (reduced plasma concentration);  rifampicin possibly accelerates metabolism of  buspirone and zaleplon; rifampicin accelerates  metabolism of zolpidem (reduced plasma concen-  tration and reduced effect); rifampicin significantly  reduces plasma concentration of zopiclone  Aprepitant: rifampicin reduces plasma concentration  of aprepitant   Barbiturates: plasma concentration of rifampicin  possibly reduced by phenobarbital  Beta-blockers: rifampicin accelerates metabolism of  bisoprolol and propranolol (plasma concentration  significantly reduced); rifampicin reduces plasma  concentration of carvedilol, celiprolol and metopro-  lol   erates metabolism of •isradipine and •nicardipine  (possible significantly reduced plasma concentra-  tion); rifampicin accelerates metabolism of  •diltiazem, •nifedipine, •nimodipine and •verapamil  (plasma concentration significantly reduced)   •dasatinib (reduced plasma concentration — avoid  concomitant use); rifampicin accelerates metabolism  of erlotinib and sunitinib (reduced plasma concen-  tration); rifampicin reduces plasma concentration of  •everolimus and sorafenib; rifampicin reduces  plasma concentration of •gefitinib, •imatinib and  •nilotinib — avoid concomitant use; avoidance of  rifabutin and rifampicin advised by manufacturer of  •lapatinib; avoidance of rifampicin advised by  manufacturer of *pazopanib; rifampicin reduces  plasma concentration of active metabolite of  •temsirolimus — avoid concomitant use; rifampicin  possibly reduces plasma concentration of  •vinflunine — manufacturer of vinflunine advises  avoid concomitant use   •eplerenone — avoid concomitant use  Hormone Antagonists: rifampicin possibly reduces  plasma concentration of exemestane; rifampicin  accelerates metabolism of tamoxifen (reduced  plasma concentration)   Leflunomide: rifampicin possibly increases plasma  concentration of active metabolite of leflunomide  Lipid-regulating Drugs: rifampicin possibly reduces  plasma concentration of atorvastatin and simva-  statin; rifampicin accelerates metabolism of fluvas-  tatin (reduced effect)   Roflumilast : rifampicin reduces plasma concentration  of roflumilast — consider increasing dose of roflumi-  last   Thyroid Hormones: rifampicin accelerates metabolism  of levothyroxine (may increase requirements for  levothyroxine in hypothyroidism)   Risedronate Sodium see Bisphosphonates  Risperidone see Antipsychotics  Ritodrine see Sympathomimetics, Beta 2  Ritonavir   centration of NSAIDs and buprenorphine; ritonavir  increases plasma concentration of  •dextropropoxyphene and •piroxicam (risk of toxi-  city) — avoid concomitant use; ritonavir increases  plasma concentration of •alfentanil and *fentanyl;  ritonavir reduces plasma concentration of metha-  done; ritonavir possibly reduces plasma concentra-  tion of morphine; ritonavir reduces plasma  concentration of •pethidine, but increases plasma  concentration of toxic metabolite of pethidine (avoid  concomitant use)   tration of •amiodarone and •propafenone (increased  risk of ventricular arrhythmias — avoid concomitant  use); ritonavir possibly increases plasma concentra-  tion of •disopyramide (increased risk of toxicity);  avoidance of ritonavir advised by manufacturer of  •dronedarone; ritonavir possibly increases plasma  concentration of •flecainide (increased risk of  ventricular arrhythmias — avoid concomitant use)   concentration of azithromycin and erythromycin;  ritonavir increases plasma concentration of  •clarithromycin (reduce dose of clarithromycin in  renal impairment); ritonavir increases plasma con-  centration of •rifabutin (increased risk of toxicity);  plasma concentration of ritonavir possibly reduced  by rifampicin; plasma concentration of both drugs  increased when ritonavir given with *fusidic acid —  avoid concomitant use; avoidance of concomitant  ritonavir in severe renal and hepatic impairment  advised by manufacturer of •telithromycin   anticoagulant effect of •warfarin; ritonavir possibly  enhances anticoagulant effect of •coumarins and  •phenindione; ritonavir increases plasma concen-  tration of •rivaroxaban — manufacturer of rivaroxa-  ban advises avoid concomitant use   concentration of •carbamazepine; ritonavir possibly  reduces plasma concentration of lamotrigine; plasma  concentration of ritonavir possibly reduced by  phenytoin, also plasma concentration of phenytoin  possibly affected   •itraconazole or •ketoconazole may increase plasma  concentration of either drug (or both); plasma  concentration of ritonavir increased by fluconazole;  ritonavir reduces plasma concentration of  •voriconazole — avoid concomitant use   manufacturer of artemether/lumefantrine; ritonavir  increases plasma concentration of •quinine  (increased risk of toxicity)   Antimuscarinics: avoidance of ritonavir advised by  manufacturer of darifenacin and tolterodine; manu-  facturer of fesoterodine advises dose reduction when  ritonavir given with fesoterodine — consult fesoter-  odine product literature; ritonavir increases plasma  concentration of solifenacin   concentration of •antipsychotics; ritonavir possibly  inhibits metabolism of •aripiprazole (reduce dose of  aripiprazole); ritonavir increases plasma concentra-  tion of •clozapine (increased risk of toxicity) — avoid  concomitant use; ritonavir reduces plasma concen-  tration of olanzapine — consider increasing dose of  olanzapine; ritonavir increases plasma concentration  of •pimozide (increased risk of ventricular arrhyth-  mias — avoid concomitant use)   monitor liver function tests; ritonavir increases  plasma concentration of indinavir, maraviroc and  •saquinavir; combination of ritonavir with nelfinavir  may increase plasma concentration of either drug (or  both)   increases plasma concentration of •anxiolytics and  hypnotics; ritonavir possibly increases plasma con-  centration of •alprazolam, •diazepam,   •flurazepam and •zolpidem (risk of extreme sedation  and respiratory depression — avoid concomitant use);  ritonavir possibly increases plasma concentration of  •midazolam (risk of prolonged sedation — avoid  concomitant use of oral midazolam); ritonavir  increases plasma concentration of buspirone  (increased risk of toxicity)   increases plasma concentration of •calcium-channel  blockers; avoidance of ritonavir advised by manu-  facturer of lercanidipine   •colchicine toxicity — suspend or reduce dose of  colchicine (avoid concomitant use in hepatic or renal  impairment)   concentration of corticosteroids,  dexamethasone and prednisolone; ritonavir  increases plasma concentration of inhaled and  intranasal budesonide and •fluticasone   centration of •everolimus and •vinflunine — manu-  facturer of everolimus and vinflunine advises avoid  concomitant use; avoidance of ritonavir advised by  manufacturer of •lapatinib, •nilotinib and  •pazopanib; ritonavir possibly increases plasma  concentration of *docetaxel (increased risk of  toxicity); ritonavir increases plasma concentration of  paclitaxel; ritonavir possibly increases plasma con-  centration of vinblastine   myopathy when ritonavir given with atorvastatin;  possible increased risk of myopathy when ritonavir  given with •rosuvastatin — manufacturer of rosuvas-  tatin advises avoid concomitant use; increased risk of  myopathy when ritonavir given with •simvastatin  (avoid concomitant use)   anticoagulants given with intravenous •diclofenac  (avoid concomitant use, including low-dose hepar-  ins); increased risk of haemorrhage when anticoa-  gulants given with •ketorolac (avoid concomitant  use, including low-dose heparins)   concomitant use with atazanavir, darunavir, fosam-  prenavir, indinavir, lopinavir, nelfinavir,  saquinavir and tipranavir; plasma concentration of  rivaroxaban increased by •ritonavir — manufacturer  of rivaroxaban advises avoid concomitant use  Rivastigmine see Parasympathomimetics  Rizatriptan see 5HT t Agonists  Rocuronium see Muscle Relaxants   Antibacterials : plasma concentration of roflumilast  reduced by rifampicin — consider increasing dose of  roflumilast   Theophylline : manufacturer of roflumilast advises  avoid concomitant use with theophylline  Ulcer-healing Drugs : metabolism of roflumilast inhib-  ited by cimetidine   Antibacterials: metabolism of ropinirole inhibited by  ciprofloxacin (increased plasma concentration)  Antipsychotics: manufacturer of ropinirole advises  avoid concomitant use of antipsychotics (antagonism  of effect)   Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa  Metoclopramide: manufacturer of ropinirole advises  avoid concomitant use of metoclopramide (antag-  onism of effect)   Anti-arrhythmics: increased myocardial depression  when ropivacaine given with anti-arrhythmics  Antidepressants: metabolism of ropivacaine inhibited  by fluvoxamine — avoid prolonged administration of  ropivacaine   Antipsychotics: manufacturer of rotigotine advises  avoid concomitant use of antipsychotics (antagonism  of effect)   Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa  Metoclopramide: manufacturer of rotigotine advises  avoid concomitant use of metoclopramide (antag-  onism of effect)   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with «St John’s wort  Antiepileptics : plasma concentration of both drugs  possibly reduced when rufinamide given with  carbamazepine; plasma concentration of rufinamide  possibly reduced by phenytoin, also plasma con-  centration of phenytoin possibly increased; plasma  concentration of rufinamide possibly reduced by  primidone; plasma concentration of rufinamide  possibly increased by valproate (reduce dose of  rufinamide)   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine  Barbiturates : plasma concentration of rufinamide  possibly reduced by phenobarbital, also plasma  concentration of phenobarbital possibly increased   effects when St John’s wort given with duloxetine or  venlafaxine; St John’s wort reduces plasma concen-  tration of amitriptyline; increased serotonergic  effects when St John’s wort given with ©SSRIs —  avoid concomitant use   tion of «atazanavir, •darunavir, •efavirenz,  •fosamprenavir, ©indinavir, •lopinavir, •nelfinavir,  •nevirapine, ©ritonavir and ©saquinavir — avoid con-  comitant use; avoidance of St John’s wort advised by  manufacturer of etravirine; St John’s wort possibly  reduces plasma concentration of ©maraviroc and  •tipranavir — avoid concomitant use  Anxiolytics and Hypnotics: St John’s wort possibly  reduces plasma concentration of oral midazolam   reduces plasma concentration of amlodipine; St  John’s wort reduces plasma concentration of nife-  dipine; St John’s wort significantly reduces plasma  concentration of ©verapamil   concentration of everolimus and ©vinflunine — man-  ufacturer of everolimus and vinflunine advises avoid  concomitant use; avoidance of St John’s wort  advised by manufacturer of gefitinib and ©lapatinib;  St John’s wort reduces plasma concentration of  •imatinib — avoid concomitant use; St John’s wort  accelerates metabolism of ©irinotecan (reduced  plasma concentration — avoid concomitant use)   Ivabradine: St John’s wort reduces plasma concen-  tration of ivabradine — avoid concomitant use  Lipid-regulating Drugs: St John’s wort reduces plasma  concentration of simvastatin   Salbutamol see Sympathomimetics, Beta 2  Salmeterol see Sympathomimetics, Beta 2  Saquinavir   mias when saquinavir given with ©clarithromycin,  •dapsone or ©erythromycin — avoid concomitant  use; saquinavir increases plasma concentration of  •rifabutin (also plasma concentration of saquinavir  reduced); plasma concentration of saquinavir sig-  nificantly reduced by ©rifampicin, also risk of  hepatotoxicity — avoid concomitant use; avoidance  of concomitant saquinavir in severe renal and  hepatic impairment advised by manufacturer of  •telithromycin   Anticoagulants: saquinavir possibly enhances anti-  coagulant effect of warfarin; avoidance of saquinavir  advised by manufacturer of rivaroxaban   Antifungals: plasma concentration of saquinavir  increased by ketoconazole; plasma concentration of  saquinavir possibly increased by imidazoles and  triazoles   manufacturer of artemether/lumefantrine; increased  risk of ventricular arrhythmias when saquinavir given  with ©quinine — avoid concomitant use  Antimuscarinics: avoidance of saquinavir advised by  manufacturer of darifenacin and tolterodine; manu-  facturer of fesoterodine advises dose reduction when  saquinavir given with fesoterodine — consult fesoter-  odine product literature   mias when saquinavir given with ©clozapine,  •haloperidol or ©phenothiazines — avoid concomi-  tant use; saquinavir possibly inhibits metabolism of  •aripiprazole (reduce dose of aripiprazole); saquina-  vir possibly increases plasma concentration of  •pimozide (increased risk of ventricular arrhyth-  mias — avoid concomitant use)   when saquinavir given with ©atazanavir or  •lopinavir — avoid concomitant use; saquinavir  reduces plasma concentration of darunavir; plasma  concentration of saquinavir significantly reduced by  efavirenz; plasma concentration of saquinavir  increased by indinavir and ©ritonavir; saquinavir  increases plasma concentration of ©maraviroc (con-  sider reducing dose of maraviroc); plasma concen-  tration of saquinavir increased by ©nelfinavir —  manufacturer of saquinavir advises avoid concomi-  tant use; plasma concentration of saquinavir reduced  by ©tipranavir   increased when saquinavir given with •ciclosporin  Corticosteroids: plasma concentration of saquinavir  possibly reduced by dexamethasone   Diuretics: saquinavir increases plasma concentration  of eplerenone (reduce dose of eplerenone)   myopathy when saquinavir given with atorvastatin;  possible increased risk of myopathy when saquinavir  given with *rosuvastatin — manufacturer of rosuvas-  tatin advises avoid concomitant use; increased risk of  myopathy when saquinavir given with •simvastatin  (avoid concomitant use)   navir possibly increased by cimetidine; plasma  concentration of saquinavir possibly increased by  •esomeprazole, •lansoprazole, *pantoprazole and  •rabeprazole — manufacturer of saquinavir advises  avoid concomitant use; plasma concentration of  saquinavir increased by •omeprazole — manufacturer  of saquinavir advises avoid concomitant use   when selegiline given with •pethidine (avoid con-  comitant use); manufacturer of selegiline advises  avoid concomitant use with opioid analgesics   avoid concomitant use with citalopram and escita-  lopram; increased risk of hypertension and CNS  excitation when selegiline given with •fluoxetine  (selegiline should not be started until 5 weeks after  stopping fluoxetine, avoid fluoxetine for 2 weeks  after stopping selegiline); increased risk of hyper-  tension and CNS excitation when selegiline given  with •fluvoxamine, •sertraline or *venlafaxine  (selegiline should not be started until 1 week after  stopping fluvoxamine, sertraline or venlafaxine,  avoid fluvoxamine, sertraline or venlafaxine for 2  weeks after stopping selegiline); increased risk of  hypertension and CNS excitation when selegiline   given with •paroxetine (selegiline should not be  started until 2 weeks after stopping paroxetine,  avoid paroxetine for 2 weeks after stopping  selegiline); enhanced hypotensive effect when  selegiline given with »MAOIs — manufacturer of  selegiline advises avoid concomitant use; avoid  concomitant use of selegiline with  •moclobemide; CNS toxicity reported when  selegiline given with •tricyclics  Dopaminergics: max. dose of 10 mg selegiline advised  by manufacturer of entacapone if used concomi-  tantly; selegiline enhances effects and increases  toxicity of levodopa (reduce dose of levodopa)   5HT a Agonists: manufacturer of selegiline advises  avoid concomitant use with 5HTj agonists  Memantine: effects of dopaminergics and selegiline  possibly enhanced by memantine  Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa   Eltrombopag: selenium possibly reduces absorption of  eltrombopag (give at least 4 hours apart)   Vitamins: absorption of selenium possibly reduced by  ascorbic acid (give at least 4 hours apart)   Mycophenolate: sevelamer possibly reduces plasma  concentration of mycophenolate  Tacrolimus: sevelamer possibly reduces plasma con-  centration of tacrolimus   sildenafil given with •alpha-blockers (avoid alpha-  blockers for 4 hours after sildenafil) — see also p. 515  Antibacterials: plasma concentration of sildenafil  possibly increased by clarithromycin and telithro-  mycin — reduce initial dose of sildenafil; plasma  concentration of sildenafil increased by erythro-  mycin — reduce initial dose of sildenafil  Antifungals: plasma concentration of sildenafil  increased by itraconazole and ketoconazole — reduce  initial dose of sildenafil   by «atazanavir; plasma concentration of sildenafil  reduced by etravirine; plasma concentration of  sildenafil possibly increased by fosamprenavir;  plasma concentration of sildenafil increased by  •indinavir — reduce initial dose of sildenafil; plasma  concentration of sildenafil possibly increased by  nelfinavir — reduce initial dose of sildenafil; plasma  concentration of sildenafil significantly increased by  •ritonavir — avoid concomitant use; increased risk of  ventricular arrhythmias when sildenafil given with  •saquinavir — avoid concomitant use  Bosentan: plasma concentration of sildenafil reduced  by bosentan   Calcium-channel Blockers: enhanced hypotensive  effect when sildenafil given with amlodipine  Grapefruit Juice: plasma concentration of sildenafil  possibly increased by grapefruit juice   increased by •clarithromycin and •telithromycin —  avoid concomitant use; plasma concentration of both  drugs increased when sirolimus given with  •erythromycin; plasma concentration of sirolimus  reduced by •rifabutin and •rifampicin — avoid con-  comitant use   increased by •itraconazole, •ketoconazole and  •voriconazole — avoid concomitant use; plasma  concentration of sirolimus increased by  micafungin and •miconazole; plasma concentration  of sirolimus possibly increased by posaconazole   Penicillamine : avoidance of sodium aurothiomalate  advised by manufacturer of penicillamine (increased  risk of toxicity)   Probenecid: excretion of conjugate formed by sodium  benzoate possibly reduced by probenecid  Sodium Bicarbonate see Antacids  Sodium Citrate   •opioid analgesics (avoid concomitant use)  Antidepressants: increased risk of side-effects when  sodium oxybate given with tricyclics  Antipsychotics: effects of sodium oxybate possibly  enhanced by antipsychotics   Antiepileptics: effects of sodium phenylbutyrate pos-  sibly reduced by valproate  Antipsychotics: effects of sodium phenylbutyrate  possibly reduced by haloperidol  Corticosteroids: effects of sodium phenylbutyrate  possibly reduced by corticosteroids  Probenecid: excretion of conjugate formed by sodium  phenylbutyrate possibly reduced by probenecid  Sodium Valproate see Valproate  Solifenacin see Antimuscarinics  Somatropin   Corticosteroids: growth-promoting effect of soma-  tropin may be inhibited by corticosteroids  Oestrogens: increased doses of somatropin may be  needed when given with oestrogens (when used as  oral replacement therapy)   Antibacterials: bioavailability of sorafenib reduced by  neomycin; plasma concentration of sorafenib  reduced by rifampicin   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Cytotoxics: sorafenib possibly increases plasma con-  centration of doxorubicin and irinotecan; sorafenib  increases plasma concentration of docetaxel  Sotalol see Beta-blockers  Spironolactone see Diuretics  Statins   atorvastatin and pravastatin increased by  •clarithromycin; increased risk of myopathy when  simvastatin given with •clarithromycin,  •erythromycin or •telithromycin (avoid concomitant  use); plasma concentration of rosuvastatin reduced  by erythromycin; possible increased risk of myo-  pathy when atorvastatin given with erythromycin or  fusidic acid; plasma concentration of pravastatin  increased by erythromycin; plasma concentration of  atorvastatin and simvastatin possibly reduced by  rifampicin; metabolism of fluvastatin accelerated by  rifampicin (reduced effect); increased risk of myo-  pathy when statins given with •daptomycin (pre-  ferably avoid concomitant use); increased risk of  myopathy when simvastatin given with •fusidic acid;  possible increased risk of myopathy when prava-  statin given with telithromycin; increased risk of  myopathy when atorvastatin given with  •telithromycin (avoid concomitant use)   anticoagulant effect of warfarin; fluvastatin and  simvastatin enhance anticoagulant effect of  •coumarins; rosuvastatin possibly enhances anti-  coagulant effect of •coumarins and •phenindione  Antidepressants: plasma concentration of simvastatin  reduced by St John’s wort   statin given with •itraconazole, •ketoconazole or  •posaconazole (avoid concomitant use); possible  increased risk of myopathy when simvastatin given  with •miconazole — avoid concomitant use; plasma  concentration of fluvastatin increased by flucon-  azole; increased risk of myopathy when atorvastatin  given with •itraconazole or •posaconazole (avoid  concomitant use); possible increased risk of myo-  pathy when atorvastatin or simvastatin given with  imidazoles; possible increased risk of myopathy  when atorvastatin or simvastatin given with triazoles   rosuvastatin given with •atazanavir, •darunavir,  •fosamprenavir, •indinavir, •lopinavir, •nelfinavir,  •ritonavir and •saquinavir — manufacturer of rosu-  vastatin advises avoid concomitant use; increased  risk of myopathy when simvastatin given with  •atazanavir, •indinavir, •nelfinavir, •ritonavir or  •saquinavir (avoid concomitant use); possible  increased risk of myopathy when atorvastatin given  with atazanavir, fosamprenavir, indinavir, lopinavir,  nelfinavir, ritonavir or saquinavir; plasma concen-  tration of pravastatin possibly increased by daruna-  vir; plasma concentration of atorvastatin,  pravastatin and simvastatin reduced by efavirenz;  plasma concentration of atorvastatin possibly  reduced by etravirine; possible increased risk of  myopathy when simvastatin given with  •fosamprenavir or •lopinavir — avoid concomitant  use; plasma concentration of simvastatin possibly  increased by •tipranavir — avoid concomitant use;  plasma concentration of atorvastatin possibly  increased by *tipranavir (consider reducing dose of  atorvastatin); plasma concentration of rosuvastatin  possibly increased by *tipranavir — manufacturer of  rosuvastatin advises avoid concomitant use  Bosentan: plasma concentration of simvastatin  reduced by bosentan   myopathy when simvastatin given with amlodipine;  plasma concentration of atorvastatin and simvastatin  increased by diltiazem — possible increased risk of  myopathy; increased risk of myopathy when simva-  statin given with • verapamil  Cardiac Glycosides: atorvastatin possibly increases  plasma concentration of digoxin   given with •ciclosporin; increased risk of myopathy  when rosuvastatin given with •ciclosporin (avoid  concomitant use)   statins given with •colchicine  Cytotoxics: plasma concentration of simvastatin pos-  sibly increased by dasatinib; plasma concentration of  simvastatin increased by imatinib   possibly increased by grapefruit juice; plasma con-  centration of simvastatin increased by •grapefruit  juice — avoid concomitant use   when statins given with •gemfibrozil (preferably  avoid concomitant use); increased risk of myopathy  when statins given with *fibrates; increased risk of  myopathy when statins given with •nicotinic acid  (applies to lipid regulating doses of nicotinic acid)  Oestrogen s: atorvastatin and rosuvastatin increase  plasma concentration of ethinylestradiol   Progestogens: atorvastatin increases plasma concen-  tration of norethisterone; rosuvastatin increases  plasma concentration of norgestrel  Ranolazine: plasma concentration of simvastatin  increased by ranolazine (consider reducing dose of  simvastatin)   dine given with •didanosine; increased risk of  toxicity when stavudine given with •ribavirin; effects  of stavudine possibly inhibited by ©zidovudine  (manufacturers advise avoid concomitant use)   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by «SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with •St John’s wort   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine  Anxiolytics and Hypnotics: stiripentol increases  plasma concentration of clobazam   Antibacterials: strontium ranelate reduces absorption  of quinolones and tetracyclines (manufacturer of  strontium ranelate advises avoid concomitant use)  Sucralfate   Antibacterials: sucralfate reduces absorption of  ciprofloxacin, levofloxacin, moxifloxacin, norflox-  acin, ofloxacin and tetracyclines   Cardiac Glycosides: sucralfate possibly reduces  absorption of cardiac glycosides  Theophylline: sucralfate possibly reduces absorption  of theophylline (give at least 2 hours apart)   Hormone Antagonists: response to sugammadex  possibly reduced by toremifene  Oestrogens: sugammadex possibly reduces plasma  concentration of oestrogens  Progestogens: sugammadex possibly reduces plasma  concentration of progestogens  Sulfadiazine see Sulfonamides  Sulfadoxine see Sulfonamides  Sulfamethoxazole see Sulfonamides  Sulfasalazine see Aminosalicylates   Antibacterials: sulfinpyrazone reduces excretion of  nitrofurantoin (increased risk of toxicity); sulfinpyr-  azone reduces excretion of penicillins; effects of  sulfinpyrazone antagonised by pyrazinamide   effect of •coumarins; sulfonamides possibly inhibit  metabolism of phenindione  Antidiabetics: sulfonamides rarely enhance the effects  of sulfonylureas   sulfonamides given with •ciclosporin; sulfadiazine  possibly reduces plasma concentration of  •ciclosporin   when sulfamethoxazole (as co-trimoxazole) given  with •mercaptopurine or •methotrexate; sulfona-  mides increase risk of methotrexate toxicity  Potassium Aminobenzoate: effects of sulfonamides  inhibited by potassium aminobenzoate  Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767  Sulfonylureas see Antidiabetics  Sulindac see NSAIDs  Sulpiride see Antipsychotics  Sumatriptan see 5HT! Agonists  Sunitinib   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   eptene, metaraminol, methylphenidate, noradren-  aline (norepinephrine), oxymetazoline,  phenylephrine, pseudoephedrine and xylometazoline  antagonise hypotensive effect of •adrenergic   neurone blockers; dexamfetamine antagonises  hypotensive effect of •guanethidine  Alcohol: effects of methylphenidate possibly enhanced  by alcohol   when methylphenidate given with •volatile liquid  general anaesthetics; increased risk of arrhythmias  when adrenaline (epinephrine) given with •volatile  liquid general anaesthetics   methylphenidate given with •MAOIs, some manu-  facturers advise avoid methylphenidate for at least 2  weeks after stopping MAOIs; risk of hypertensive  crisis when sympathomimetics given with  •MAOIs or •moclobemide; methylphenidate possi-  bly inhibits metabolism of SSRIs and tricyclics;  increased risk of hypertension and arrhythmias when  noradrenaline (norepinephrine) given with  •tricyclics; increased risk of hypertension and  arrhythmias when adrenaline (epinephrine) given  with •tricyclics (but local anaesthetics with adrena-  line appear to be safe)   Antiepileptics: methylphenidate increases plasma  concentration of phenytoin; methylphenidate possi-  bly increases plasma concentration of primidone  Antipsychotics: hypertensive effect of sympatho-  mimetics antagonised by antipsychotics; dexamfe-  tamine possibly antagonises antipsychotic effects of  chlorpromazine; methylphenidate possibly increases  side-effects of risperidone  Antivirals: plasma concentration of dexamfetamine  possibly increased by ritonavir  Barbiturates: methylphenidate possibly increases  plasma concentration of phenobarbital   and bradycardia when adrenaline (epinephrine)  given with non-cardioselective •beta-blockers, also  response to adrenaline (epinephrine) may be  reduced; increased risk of severe hypertension and  bradycardia when dobutamine given with non-  cardioselective •beta-blockers; possible increased  risk of severe hypertension and bradycardia when  noradrenaline (norepinephrine) given with non-car-  dioselective •beta-blockers   enaline (epinephrine) or noradrenaline (norepi-  nephrine) given with clonidine; serious adverse  events reported with concomitant use of methyl-  phenidate and •clonidine (causality not established)  Corticosteroids: ephedrine accelerates metabolism of  dexamethasone   given with •bromocriptine; effects of adrenaline  (epinephrine), dobutamine, dopamine and  noradrenaline (norepinephrine) possibly enhanced  by entacapone; avoid concomitant use of  sympathomimetics with •rasagiline; risk of hyper-  tensive crisis when dopamine given with •selegiline  Doxapram: increased risk of hypertension when  sympathomimetics given with doxapram  Ergot Alkaloids: increased risk of ergotism when  sympathomimetics given with ergotamine and  methysergide   Oxytocin: risk of hypertension when vasoconstrictor  sympathomimetics given with oxytocin (due to  enhanced vasopressor effect)   Theophylline: avoidance of ephedrine in children  advised by manufacturer of theophylline    Sympathomimetics, Beta 2  Antifungals: metabolism of salmeterol inhibited by  ketoconazole (increased plasma concentration)  Atomoxetine: Increased risk of cardiovascular side-  effects when parenteral salbutamol given with  atomoxetine   Cardiac Glycosides: salbutamol possibly reduces  plasma concentration of digoxin  Corticosteroids: increased risk of hypokalaemia when  high doses of beta 2 sympathomimetics given with  corticosteroids — see Hypokalaemia, p. 176  Diuretics: increased risk of hypokalaemia when high  doses of beta 2 sympathomimetics given with aceta-  zolamide, loop diuretics or thiazides and related  diuretics — see Hypokalaemia, p. 176  • Methyldopa: acute hypotension reported when infu-  sion of salbutamol given with •methyldopa  Muscle Relaxants: bambuterol enhances effects of  suxamethonium   Theophylline: increased risk of hypokalaemia when  high doses of beta 2 sympathomimetics given with  theophylline — see Hypokalaemia, p. 176   Note Interactions do not generally apply to tacrolimus used  topically; risk of facial flushing and skin irritation with  alcohol consumption (p. 722) does not apply to tacrolimus  taken systemically   when tacrolimus given with NSAIDs; increased risk  of nephrotoxicity when tacrolimus given with  •ibuprofen   Angiotensin-ll Receptor Antagonists: increased risk  of hyperkalaemia when tacrolimus given with  angiotensin-II receptor antagonists  Anti-arrhythmics: caution with tacrolimus advised by  manufacturer of dronedarone   increased by •clarithromycin and •erythromycin;  plasma concentration of tacrolimus possibly reduced  by rifabutin; plasma concentration of tacrolimus  reduced by •rifampicin; increased risk of nephro-  toxicity when tacrolimus given with  •aminoglycosides; plasma concentration of tacroli-  mus possibly increased by •chloramphenicol and  •telithromycin; possible increased risk of nephro-  toxicity when tacrolimus given with vancomycin   increased by •fluconazole, •itraconazole,  •ketoconazole, •posaconazole and •voriconazole  (consider reducing dose of tacrolimus); increased  risk of nephrotoxicity when tacrolimus given with  •amphotericin; plasma concentration of tacrolimus  reduced by •caspofungin; plasma concentration of  tacrolimus possibly increased by •imidazoles   when tacrolimus given with aciclovir or ganciclovir;  plasma concentration of tacrolimus possibly  increased by ©atazanavir, •nelfinavir and •ritonavir;  plasma concentration of tacrolimus possibly affected  by ©efavirenz; plasma concentration of tacrolimus  increased by ©fosamprenavir; plasma concentration  of tacrolimus increased by •saquinavir (consider  reducing dose of tacrolimus)   tacrolimus possibly increased by felodipine,  nicardipine and verapamil; plasma concentration of  tacrolimus increased by •diltiazem and •nifedipine   increased by •grapefruit juice  Hormone Antagonists: plasma concentration of  tacrolimus possibly increased by danazol  Mifamurtide: avoidance of tacrolimus advised by  manufacturer of mifamurtide  Oestrogens: plasma concentration of tacrolimus pos-  sibly increased by ethinylestradiol   when tacrolimus given with •potassium salts  Sevelamer: plasma concentration of tacrolimus pos-  sibly reduced by sevelamer  Ulcer-healing Drugs: plasma concentration of tacroli-  mus possibly increased by omeprazole  Tadalafil   sibly increased by clarithromycin and erythromycin;  plasma concentration of tadalafil reduced by  •rifampicin — manufacturer of tadalafil advises avoid  concomitant use   increased by fosamprenavir and indinavir; plasma  concentration of tadalafil increased by •ritonavir —  manufacturer of tadalafil advises avoid concomitant  use; increased risk of ventricular arrhythmias when  tadalafil given with ©saquinavir — avoid concomitant  use   Grapefruit Juice: plasma concentration of tadalafil  possibly increased by grapefruit juice   Tamsulosin see Alpha-blockers  Taxanes see Docetaxel and Paclitaxel  Tegafur with uracil see Fluorouracil  Teicoplanin   reduced by •carbamazepine, •phenytoin and  •primidone (avoid during and for 2 weeks after  carbamazepine, phenytoin and primidone)   avoid concomitant use with •ketoconazole in severe  renal and hepatic impairment  Antimuscarinics: manufacturer of fesoterodine  advises dose reduction when telithromycin given  with fesoterodine — consult fesoterodine product  literature   concomitant use with •atazanavir, •fosamprenavir,  •indinavir, •lopinavir, •nelfinavir, •ritonavir,  •saquinavir and «tipranavir in severe renal and  hepatic impairment; telithromycin possibly increases  plasma concentration of •maraviroc (consider redu-  cing dose of maraviroc)   •colchicine toxicity — suspend or reduce dose of  colchicine (avoid concomitant use in hepatic or renal  impairment)   when telithromycin given with *atorvastatin or  •simvastatin (avoid concomitant use); possible  increased risk of myopathy when telithromycin given  with pravastatin   Telmisartan see Angiotensin-II Receptor Antagonists  Temazepam see Anxiolytics and Hypnotics  Temocillin see Penicillins  Temoporfin   Antiepileptics: cytotoxics possibly reduce absorption  of phenytoin; plasma concentration of temozolomide  increased by valproate   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets  Tenofovir   concomitant use with adefovir; tenofovir reduces  plasma concentration of atazanavir, also plasma  concentration of tenofovir possibly increased; man-  ufacturers advise avoid concomitant use of tenofovir  with •cidofovir; tenofovir increases plasma concen-  tration of •didanosine (increased risk of toxicity) —  avoid concomitant use; plasma concentration of  tenofovir increased by lopinavir  Tenoxicam see NSAIDs  Terazosin see Alpha-blockers  Terbinafine   Antidepressants: terbinafine possibly increases  plasma concentration of tricyclics  Ciclosporin: terbinafine possibly reduces plasma con-  centration of ciclosporin  Oestrogens: occasional reports of breakthrough  bleeding when terbinafine given with oestrogens  (when used for contraception)   Progestogens: occasional reports of breakthrough  bleeding when terbinafine given with progestogens  (when used for contraception)   tension when tetrabenazine given with •MAOIs  Antipsychotics: increased risk of extrapyramidal side-  effects when tetrabenazine given with antipsychotics  Dopamine rgics: increased risk of extrapyramidal side-  effects when tetrabenazine given with amantadine   Metoclopramide: increased risk of extrapyramidal  side-effects when tetrabenazine given with meto-  clopramide   ACE Inhibitors: absorption of tetracyclines reduced by  quinapril tablets (quinapril tablets contain magnes-  ium carbonate)   Antibacterials: plasma concentration of doxycycline  reduced by rifampicin — consider increasing dose of  doxycycline; tetracyclines possibly antagonise  effects of penicillins   coagulant effect of •coumarins and •phenindione  Antidiabetics: tetracyclines possibly enhance hypo-  glycaemic effect of sulfonylureas  Antiepileptics: metabolism of doxycycline accelerated  by carbamazepine (reduced effect); metabolism of  doxycycline accelerated by phenytoin and primidone  (reduced plasma concentration)   Barbiturates: metabolism of doxycycline accelerated  by barbiturates (reduced plasma concentration)  Calcium Salts: absorption of tetracycline reduced by  calcium salts   Dairy Products: absorption of tetracyclines (except  doxycycline and minocycline) reduced by dairy  products   Diuretics: manufacturer of lymecycline advises avoid  concomitant use with diuretics  Ergot Alkaloids: increased risk of ergotism when  tetracyclines given with ergotamine and methy-  sergide   Iron: absorption of tetracyclines reduced by oral iron,  also absorption of oral iron reduced by tetracyclines  Lipid-regulating Drugs: absorption of tetracycline  possibly reduced by colestipol and colestyramine   Strontium Ranelate: absorption of tetracyclines  reduced by strontium ranelate (manufacturer of  strontium ranelate advises avoid concomitant use)  Ulcer-healing Drugs: absorption of tetracyclines  reduced by sucralfate and tripotassium dicitrato-  bismuthate   Zinc: absorption of tetracyclines reduced by zinc, also  absorption of zinc reduced by tetracyclines   Allopurinol: plasma concentration of theophylline  possibly increased by allopurinol  Anaesthetics, General: increased risk of convulsions  when theophylline given with ketamine; increased  risk of arrhythmias when theophylline given with  halothane   Anti-arrhythmics: theophylline antagonises anti-  arrhythmic effect of adenosine; plasma concentra-  tion of theophylline increased by propafenone   possibly increased by azithromycin and isoniazid;  metabolism of theophylline inhibited by  •clarithromycin (increased plasma concentration);  metabolism of theophylline inhibited by  •erythromycin (increased plasma concentration), if  erythromycin given by mouth, also decreased   plasma-erythromycin concentration; plasma  concentration of theophylline increased by  •ciprofloxacin and •norfloxacin; metabolism of  theophylline accelerated by rifampicin (reduced  plasma concentration); possible increased risk of  convulsions when theophylline given with  •quinolones   by carbamazepine and primidone (reduced effect);  plasma concentration of both drugs reduced when  theophylline given with •phenytoin   Anxiolytics and Hypnotics: theophylline possibly  reduces effects of benzodiazepines  Barbiturates: metabolism of theophylline accelerated  by barbiturates (reduced effect)   theophylline possibly increased by •calcium-channel  blockers (enhanced effect); plasma concentration of  theophylline increased by diltiazem; plasma con-  centration of theophylline increased by •verapamil  (enhanced effect)   Corticosteroids: increased risk of hypokalaemia when  theophylline given with corticosteroids  Cytotoxics: plasma concentration of theophylline  possibly increased by methotrexate  Disulfiram: metabolism of theophylline inhibited by  disulfiram (increased risk of toxicity)   Diuretics: increased risk of hypokalaemia when theo-  phylline given with acetazolamide, loop diuretics or  thiazides and related diuretics  Doxapram: increased CNS stimulation when theo-  phylline given with doxapram   Leukotriene Receptor Antagonists: plasma concen-  tration of theophylline possibly increased by zafirlu-  kast, also plasma concentration of zafirlukast  reduced   Oestrogens: excretion of theophylline reduced by  oestrogens (increased plasma concentration)  Pentoxifylline: plasma concentration of theophylline  increased by pentoxifylline  Roflumilast : avoidance of theophylline advised by  manufacturer of roflumilast  Sulfinpyrazone: plasma concentration of theophylline  reduced by sulfinpyrazone  Sympathomimetics: manufacturer of theophylline  advises avoid concomitant use with ephedrine in  children   Sympathomimetics, Beta 2 : increased risk of hypo-  kalaemia when theophylline given with high doses of  beta 2 sympathomimetics — see Hypokalaemia, p. 176   inhibited by •cimetidine (increased plasma concen-  tration); absorption of theophylline possibly reduced  by sucralfate (give at least 2 hours apart)   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Anti-arrhythmics: for concomitant use of thyroid  hormones and amiodarone see p. 94  Antibacterials: metabolism of levothyroxine acceler-  ated by rifampicin (may increase requirements for  levothyroxine in hypothyroidism)   coagulant effect of •coumarins and •phenindione  Antidepressants: thyroid hormones enhance effects of  amitriptyline and imipramine; thyroid hormones  possibly enhance effects of tricyclics  Antiepileptics: metabolism of thyroid hormones  accelerated by carbamazepine and primidone (may  increase requirements for thyroid hormones in  hypothyroidism); metabolism of thyroid hormones  accelerated by phenytoin (may increase require-  ments in hypothyroidism), also plasma concentration  of phenytoin possibly increased  Barbiturates: metabolism of thyroid hormones accel-  erated by barbiturates (may increase requirements  for thyroid hormones in hypothyroidism)  Beta-blockers: levothyroxine accelerates metabolism  of propranolol   Cytotoxics: plasma concentration of levothyroxine  possibly reduced by imatinib  Iron: absorption of levothyroxine reduced by oral iron  (give at least 2 hours apart)   Lanthanum : absorption of levothyroxine reduced by  lanthanum (give at least 2 hours apart)  Lipid-regulating Drugs: absorption of levothyroxine  reduced by colesevelam; absorption of thyroid  hormones reduced by colestipol and colestyramine  Oestrogens: requirements for thyroid hormones in  hypothyroidism may be increased by oestrogens  Orlistat: possible increased risk of hypothyroidism  when levothyroxine given with orlistat  Polystyrene Sulphonate Resins: absorption of  levothyroxine reduced by polystyrene sulphonate  resins   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with «St John’s wort  Antiepileptics: plasma concentration of tiagabine  reduced by carbamazepine, phenytoin and primid-  one   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   Antibacterials: metabolism of tibolone accelerated by  rifampicin (reduced plasma concentration)  Antiepileptics: metabolism of tibolone accelerated by  carbamazepine and primidone (reduced plasma  concentration); metabolism of tibolone accelerated  by phenytoin   Barbiturates: metabolism of tibolone accelerated by  barbiturates (reduced plasma concentration)  Ticarcillin see Penicillins  Tigecycline   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Cytotoxics: increased risk of hepatotoxicity when  tioguanine given with busulfan  Tiotropium see Antimuscarinics  Tipranavir   Analgesics: plasma concentration of tipranavir possi-  bly reduced by buprenorphine  Antacids: absorption of tipranavir reduced by antacids   tration of •clarithromycin (reduce dose of clarithro-  mycin in renal impairment), also plasma  concentration of tipranavir increased by clarithro-  mycin; tipranavir increases plasma concentration of  •rifabutin (reduce dose of rifabutin); plasma con-  centration of tipranavir possibly reduced by  •rifampicin — avoid concomitant use; avoidance of  concomitant tipranavir in severe renal and hepatic  impairment advised by manufacturer of  •telithromycin   Antiepileptics: plasma concentration of tipranavir  possibly reduced by carbamazepine  Antifungals: plasma concentration of tipranavir  increased by fluconazole   manufacturer of artemether/lumefantrine; tipranavir  possibly increases plasma concentration of ©quinine  (increased risk of toxicity)   •abacavir, •didanosine, •fosamprenavir, •lopinavir,  •saquinavir and •zidovudine; plasma concentration  of tipranavir increased by atazanavir (also plasma  concentration of atazanavir reduced); tipranavir  reduces plasma concentration of •etravirine, also  plasma concentration of tipranavir increased (avoid  concomitant use)   plasma concentration of •atorvastatin (consider  reducing dose of atorvastatin); tipranavir possibly  increases plasma concentration of •rosuvastatin —  manufacturer of rosuvastatin advises avoid conco-  mitant use; tipranavir possibly increases plasma  concentration of •simvastatin — avoid concomitant  use   centration of •esomeprazole and •omeprazole  Vitamins: increased risk of bleeding when tipranavir  given with high doses of vitamin E  Tirofiban   lloprost: increased risk of bleeding when tirofiban  given with iloprost  Tizanidine see Muscle Relaxants  Tobramycin see Aminoglycosides  Tocilizumab   Methyldopa: antiparkinsonian effect of dopaminergics  antagonised by methyldopa  Tolfenamic Acid see NSAIDs  Tolterodine see Antimuscarinics  Tolvaptan   Cardiac Glycosides: tolvaptan increases plasma con-  centration of digoxin (increased risk of toxicity)   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with «St John’s wort  Antidiabetics : topiramate possibly increases plasma  concentration of metformin; topiramate possibly  reduces plasma concentration of glibenclamide   often reduced by carbamazepine; topiramate  increases plasma concentration of •phenytoin (also  plasma concentration of topiramate reduced); CNS  toxicity reported when topiramate given with val-  proate   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine  Diuretics : plasma concentration of topiramate possibly  increased by hydrochlorothiazide  Lithium: topiramate possibly affects plasma concen-  tration of lithium   coagulant effect of •coumarins  Antiepileptics: metabolism of toremifene possibly  accelerated by carbamazepine (reduced plasma  concentration); metabolism of toremifene possibly  accelerated by phenytoin; metabolism of toremifene  accelerated by primidone (reduced plasma concen-  tration)   Barbiturates: metabolism of toremifene possibly  accelerated by barbiturates (reduced plasma con-  centration)   Diuretics: increased risk of hypercalcaemia when  toremifene given with thiazides and related diuretics  Sugammadex: toremifene possibly reduces response  to sugammadex   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets   Iron: trientine reduces absorption of oral iron  Zinc: trientine reduces absorption of zinc, also  absorption of trientine reduced by zinc  Trifluoperazine see Antipsychotics  Trihexyphenidyl see Antimuscarinics  Trilostane   Diuretics: increased risk of hyperkalaemia when trilo-  stane given with potassium-sparing diuretics and  aldosterone antagonists   ACE Inhibitors : possible increased risk of hyperkal-  aemia when trimethoprim given with ACE inhibitors  Angiotensin-ll Receptor Antagonists : possible  increased risk of hyperkalaemia when trimethoprim  given with angiotensin-II receptor antagonists   Antibacterials: plasma concentration of trimethoprim  possibly reduced by rifampicin; plasma concentra-  tion of both drugs may increase when trimethoprim  given with dapsone   Anticoagulants: trimethoprim possibly enhances anti-  coagulant effect of coumarins  Antidiabetics: trimethoprim possibly enhances hypo-  glycaemic effect of repaglinide — manufacturer  advises avoid concomitant use; trimethoprim rarely  enhances the effects of sulfonylureas   trimethoprim given with •ciclosporin, also plasma  concentration of ciclosporin reduced by intravenous  trimethoprim   when trimethoprim (also with co-trimoxazole) given  with •mercaptopurine or •methotrexate  Diuretics: increased risk of hyperkalaemia when  trimethoprim given with eplerenone  Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767   Trimipramine see Antidepressants, Tricyclic  Tripotassium Dicitratobismuthate  Antibacterials: tripotassium dicitratobismuthate  reduces absorption of tetracyclines  Tropicamide see Antimuscarinics  Trospium see Antimuscarinics  Tryptophan   phan given with fluoxetine; possible increased  serotonergic effects when tryptophan given with  duloxetine; CNS excitation and confusion when  tryptophan given with •MAOIs (reduce dose of  tryptophan); agitation and nausea may occur when  tryptophan given with «SSRIs   by manufacturer of •artemether/lumefantrine  Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine  Typhoid Vaccine (oral) see Vaccines  Typhoid Vaccine (parenteral) see Vaccines  Ubidecarenone   Anticoagulants: ubidecarenone may enhance or  reduce anticoagulant effect of warfarin  Ulcer-healing Drugs see Histamine H 2 -antagonists,  Proton Pump Inhibitors, Sucralfate, and Tripotass-  ium Dicitratobismuthate  Ulipristal   concomitant use with ^antacids (plasma concentra-  tion of ulipristal possibly reduced)   concomitant use with •carbamazepine and  •phenytoin (contraceptive effect of ulipristal possibly  reduced)   avoid concomitant use with •histamine H 2 -  antagonists and •proton pump inhibitors (plasma  concentration of ulipristal possibly reduced)  Ursodeoxycholic Acid   Lipid-regulating Drugs: absorption of bile acids  possibly reduced by colestipol and colestyramine  Oestrogens: elimination of cholesterol in bile  increased when bile acids given with oestrogens   Note For a general warning on live vaccines and high doses  of corticosteroids or other immunosuppressive drugs, see  p. 746 ; for advice on live vaccines and immunoglobulins,  see under Normal Immunoglobulin, p. 769   Anticoagulants: influenza vaccine possibly enhances  anticoagulant effect of warfarin  Antiepileptics: influenza vaccine enhances effects of  phenytoin   inhibited by erythromycin (increased plasma con-  centration); plasma concentration of valproate  reduced by •carbapenems — avoid concomitant use  Anticoagulants: valproate possibly enhances anti-  coagulant effect of coumarins   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with «St John’s wort   reduced by carbamazepine, also plasma concentra-  tion of active metabolite of carbamazepine  increased; valproate possibly increases plasma con-  centration of ethosuximide; valproate increases  plasma concentration of lamotrigine; valproate  sometimes reduces plasma concentration of an  active metabolite of oxcarbazepine; valproate  increases or possibly decreases plasma concentra-  tion of phenytoin, also plasma concentration of  valproate reduced; valproate possibly increases  plasma concentration of •primidone (plasma con-  centration of active metabolite of primidone  increased), also plasma concentration of valproate  reduced; valproate possibly increases plasma con-  centration of rufinamide (reduce dose of rufinamide);  CNS toxicity reported when valproate given with  topiramate   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine   antagonised by *antipsychotics (convulsive thresh-  old lowered); valproate possibly increases or  decreases plasma concentration of clozapine;  increased risk of side-effects including neutropenia  when valproate given with •olanzapine; valproate  possibly increases plasma concentration of quetia-  pine   Antivirals: valproate possibly increases plasma con-  centration of zidovudine (increased risk of toxicity)  Anxiolytics and Hypnotics: plasma concentration of  valproate possibly increased by clobazam; increased  risk of side-effects when valproate given with clon-  azepam; valproate possibly increases plasma con-  centration of diazepam and lorazepam  Barbiturates: valproate increases plasma concentra-  tion of phenobarbital (also plasma concentration of  valproate reduced)   Lipid-regulating Drugs: absorption of valproate pos-  sibly reduced by colestyramine  Oestrogens : plasma concentration of valproate possi-  bly reduced by ethinylestradiol   Anaesthetics, General: hypersensitivity-like reactions  can occur when intravenous vancomycin given with  general anaesthetics   ototoxicity when vancomycin given with  •aminoglycosides, capreomycin or colistin;  increased risk of nephrotoxicity when vancomycin  given with polymyxins   Antifungals: possible increased risk of nephrotoxicity  when vancomycin given with amphotericin   vancomycin given with •ciclosporin  Cytotoxics: increased risk of nephrotoxicity and  possibly of ototoxicity when vancomycin given with  cisplatin   Tacrolimus: possible increased risk of nephrotoxicity  when vancomycin given with tacrolimus  Vaccines: antibacterials inactivate oral typhoid  vaccine-see p. 767   Antibacterials: plasma concentration of vardenafil  increased by erythromycin (reduce dose of varde-  nafil)   increased by fosamprenavir; plasma concentration of  vardenafil increased by •indinavir and •ritonavir —  avoid concomitant use; increased risk of ventricular  arrhythmias when vardenafil given with  •saquinavir — avoid concomitant use  Calcium-channel Blockers: enhanced hypotensive  effect when vardenafil given with nifedipine   Vasodilator Antihypertensives  ACE Inhibitors: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with ACE inhibitors   Adrenergic Neurone Blockers: enhanced hypotensive  effect when hydralazine, minoxidil or sodium nitro-  prusside given with adrenergic neurone blockers  Alcohol: enhanced hypotensive effect when hydral-  azine, minoxidil or sodium nitroprusside given with  alcohol   Aldesleukin: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with aldesleukin   Alpha-blockers: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with alpha-blockers   Anaesthetics, General: enhanced hypotensive effect  when hydralazine, minoxidil or sodium nitroprusside  given with general anaesthetics  Analgesics: hypotensive effect of hydralazine,  minoxidil and sodium nitroprusside antagonised by  NSAIDs   Angiotensin-II Receptor Antagonists: enhanced  hypotensive effect when hydralazine, minoxidil or  sodium nitroprusside given with angiotensin-II  receptor antagonists   Antidepressants: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with MAOIs; enhanced hypotensive effect when  hydralazine or sodium nitroprusside given with  tricyclic-related antidepressants  Antipsychotics: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with phenothiazines   Anxiolytics and Hypnotics: enhanced hypotensive  effect when hydralazine, minoxidil or sodium nitro-  prusside given with anxiolytics and hypnotics  Beta-blockers: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with beta-blockers   Calcium-channel Blockers: enhanced hypotensive  effect when hydralazine, minoxidil or sodium nitro-  prusside given with calcium-channel blockers  Clonidine: enhanced hypotensive effect when hydral-  azine, minoxidil or sodium nitroprusside given with  clonidine   Corticosteroids: hypotensive effect of hydralazine,  minoxidil and sodium nitroprusside antagonised by  corticosteroids   Diazoxide: enhanced hypotensive effect when hydral-  azine, minoxidil or sodium nitroprusside given with  diazoxide   Diuretics: enhanced hypotensive effect when hydral-  azine, minoxidil or sodium nitroprusside given with  diuretics   Dopamine rgics: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with levodopa   Methyldopa: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with methyldopa   Moxisylyte: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with moxisylyte   Moxonidine: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with moxonidine   Muscle Relaxants: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with baclofen; enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with tizanidine   Nicorandil: possible enhanced hypotensive effect  when hydralazine, minoxidil or sodium nitroprusside  given with nicorandil   Nitrates: enhanced hypotensive effect when hydral-  azine, minoxidil or sodium nitroprusside given with  nitrates   Oestrogens: hypotensive effect of hydralazine,  minoxidil and sodium nitroprusside antagonised by  oestrogens   Prostaglandins: enhanced hypotensive effect when  hydralazine, minoxidil or sodium nitroprusside given  with alprostadil   Vasodilator Antihypertensives: enhanced hypoten-  sive effect when hydralazine given with minoxidil or  sodium nitroprusside; enhanced hypotensive effect  when minoxidil given with sodium nitroprusside   effects when venlafaxine given with St John’s wort,  duloxetine or mirtazapine; enhanced CNS effects  and toxicity when venlafaxine given with •MAOIs  (venlafaxine should not be started until 2 weeks after  stopping MAOIs, avoid MAOIs for 1 week after  stopping venlafaxine); after stopping SSRI -related  antidepressants do not start •moclobemide for at  least 1 week   Atomoxetine: possible increased risk of convulsions  when antidepressants given with atomoxetine   manufacturer of entacapone; increased risk of  hypertension and CNS excitation when venlafaxine  given with •selegiline (selegiline should not be  started until 1 week after stopping venlafaxine, avoid  venlafaxine for 2 weeks after stopping selegiline)   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by *SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with *St John’s wort   Antiepileptics: vigabatrin reduces plasma concentra-  tion of phenytoin; vigabatrin possibly reduces  plasma concentration of primidone   hydroxychloroquine; anticonvulsant effect of  antiepileptics antagonised by •mefloquine  Barbiturates: vigabatrin possibly reduces plasma  concentration of phenobarbital   with •clozapine (increased risk of agranulocytosis)  Antivirals: plasma concentration of vinblastine possi-  bly increased by ritonavir   with •clozapine (increased risk of agranulocytosis)  Calcium-channel Blockers: metabolism of vincristine  possibly inhibited by nifedipine  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets  Vinflunine   increased by •ketoconazole — manufacturer of vin-  flunine advises avoid concomitant use; plasma  concentration of vinflunine possibly increased by  •itraconazole — manufacturer of vinflunine advises  avoid concomitant use   Grapefruit Juice: plasma concentration of vinflunine  possibly increased by grapefruit juice — manufacturer  of vinflunine advises avoid concomitant use  Vinorelbine   with •clozapine (increased risk of agranulocytosis)  Cardiac Glycosides: cytotoxics reduce absorption of  digoxin tablets  Vitamin A see Vitamins  Vitamin D see Vitamins  Vitamin E see Vitamins   coagulant effect of •coumarins; vitamin K antag-  onises anticoagulant effect of •coumarins and  •phenindione   Antiepileptics: vitamin D requirements possibly  increased when given with carbamazepine,  phenytoin or primidone   Antifungals: plasma concentration of paricalcitol  possibly increased by ketoconazole  Antivirals: increased risk of bleeding when high doses  of vitamin E given with tipranavir  Barbiturates: vitamin D requirements possibly  increased when given with barbiturates  Ciclosporin: vitamin E possibly affects plasma con-  centration of ciclosporin   Diuretics: increased risk of hypercalcaemia when  vitamin D given with thiazides and related diuretics  Dopaminergics: pyridoxine reduces effects of levo-  dopa when given without dopa-decarboxylase inhi-  bitor   Retinoids: risk of hypervitaminosis A when vitamin A  given with retinoids   Selenium: ascorbic acid possibly reduces absorption  of selenium (give at least 4 hours apart)  Voriconazole see Antifungals, Triazole  Warfarin see Coumarins  Xipamide see Diuretics  Xylometazoline see Sympathomimetics  Zafirlukast see Leukotriene Receptor Antagonists  Zaleplon see Anxiolytics and Hypnotics  Zidovudine   Analgesics: increased risk of haematological toxicity  when zidovudine given with NSAIDs; plasma con-  centration of zidovudine possibly increased by  methadone   Antibacterials: absorption of zidovudine reduced by  clarithromycin tablets (give at least 2 hours apart);  manufacturer of zidovudine advises avoid concomi-  tant use with rifampicin   Antiepileptics: zidovudine increases or decreases  plasma concentration of phenytoin; plasma concen-  tration of zidovudine possibly increased by valproate  (increased risk of toxicity)   increased by •fluconazole (increased risk of toxicity)  Antimalarials: increased antifolate effect when zido-  vudine given with pyrimethamine   vudine given with •ganciclovir (if possible avoid  concomitant administration, particularly during  initial ganciclovir therapy); increased risk of anaemia  when zidovudine given with •ribavirin — avoid con-  comitant use; zidovudine possibly inhibits effects of  •stavudine (manufacturers advise avoid concomitant  use); plasma concentration of zidovudine reduced by  •tipranavir   Atovaquone: metabolism of zidovudine possibly  inhibited by atovaquone (increased plasma concen-  tration)   Antibacterials: zinc reduces absorption of ciproflox-  acin, levofloxacin, moxifloxacin, norfloxacin and  ofloxacin; zinc reduces absorption of tetracyclines,  also absorption of zinc reduced by tetracyclines  Calcium Salts: absorption of zinc reduced by calcium  salts   Eltrombopag: zinc possibly reduces absorption of  eltrombopag (give at least 4 hours apart)   Iron: absorption of zinc reduced by oral iron, also  absorption of oral iron reduced by zinc  Penicillamine: absorption of zinc reduced by penicill-  amine, also absorption of penicillamine reduced by  zinc   Trientine: absorption of zinc reduced by trientine, also  absorption of trientine reduced by zinc  Zoledronic Acid see Bisphosphonates  Zolmitriptan see 5HT! Agonists  Zolpidem see Anxiolytics and Hypnotics  Zonisamide   tics possibly antagonised by MAOIs and •tricyclic-  related antidepressants (convulsive threshold  lowered); anticonvulsant effect of antiepileptics  antagonised by •SSRIs and •tricyclics (convulsive  threshold lowered); avoid concomitant use of anti-  epileptics with •St John’s wort  Antiepileptics: plasma concentration of zonisamide  reduced by carbamazepine and phenytoin   when antiepileptics given with chloroquine and  hydroxychloroquine; anticonvulsant effect of anti-  epileptics antagonised by •mefloquine  Barbiturates: plasma concentration of zonisamide  reduced by phenobarbital   antiepileptics given with •orlistat  Zopiclone see Anxiolytics and Hypnotics  Zuclopenthixol see Antipsychotics    For general guidance on prescribing for patients with  hepatic or renal impairment, or for patients who are  pregnant or breast-feeding, see pp. 17-19. Specific  information has been moved to the relevant chapters  and is included under the individual drug or in the  prescribing notes.    Intravenous additives policies A local policy on the  addition of drugs to intravenous fluids should be drawn  up by a multi-disciplinary team in each Strategic Health  Authority (or equivalent) and issued as a document to  the members of staff concerned.   Centralised additive services are provided in a number  of hospital pharmacy departments and should be used  in preference to making additions on wards.   The information that follows should be read in conjunc-  tion with local policy documents.   1. Drugs should only be added to infusion containers  when constant plasma concentrations are needed  or when the administration of a more concentrated  solution would be harmful.    2. In general, only one drug should be added to any  infusion container and the components should be  compatible. Ready-prepared solutions should be  used whenever possible. Drugs should not normally  be added to blood products, mannitol, or sodium  bicarbonate. Only specially formulated additives  should be used with fat emulsions or amino-acid  solutions (section 9.3).   Solutions should be thoroughly mixed by shaking  and checked for absence of particulate matter  before use.   Strict asepsis should be maintained throughout and  in general the giving set should not be used for more  than 24 hours (for drug admixtures).    5. The infusion container should be labelled with the  patient’s name, the name and quantity of additives,  and the date and time of addition (and the new  expiry date or time). Such additional labelling  should not interfere with information on the manu-  facturer’s label that is still valid. When possible,  containers should be retained for a period after  use in case they are needed for investigation.   6. It is good practice to examine intravenous infusions  from time to time while they are running. If cloudi-  ness, crystallisation, change of colour, or any other  sign of interaction or contamination is observed the  infusion should be discontinued.   Microbial contamination The accidental entry and  subsequent growth of micro-organisms converts the  infusion fluid pathway into a potential vehicle for infec-  tion with micro-organisms, particularly species of Can-  dida, Enterobacter, and Klebsiella. Ready-prepared infu-  sions containing the additional drugs, or infusions    prepared by an additive service (when available) should  therefore be used in preference to making extempora-  neous additions to infusion containers on wards etc.  However, when this is necessary strict aseptic proce-  dure should be followed.    Incompatibility Physical and chemical incompatibil-  ities may occur with loss of potency, increase in toxicity,  or other adverse effect. The solutions may become  opalescent or precipitation may occur, but in many  instances there is no visual indication of incompatibility.  Interaction may take place at any point in the infusion  fluid pathway, and the potential for incompatibility is  increased when more than one substance is added to  the infusion fluid.   Common incompatibilities Precipitation reactions are  numerous and varied and may occur as a result of pH,  concentration changes, ‘salting-out’ effects, complexa-  tion or other chemical changes. Precipitation or other  particle formation must be avoided since, apart from  lack of control of dosage on administration, it may  initiate or exacerbate adverse effects. This is particularly  important in the case of drugs which have been impli-  cated in either thrombophlebitis (e.g. diazepam) or in  skin sloughing or necrosis caused by extravasation (e.g.  sodium bicarbonate and certain cytotoxic drugs). It is  also especially important to effect solution of colloidal  drugs and to prevent their subsequent precipitation in  order to avoid a pyrogenic reaction (e.g. amphotericin).   It is considered undesirable to mix beta-lactam anti-  biotics, such as semi-synthetic penicillins and cephalo-  sporins, with proteinaceous materials on the grounds  that immunogenic and allergenic conjugates could be  formed.   A number of preparations undergo significant loss of  potency when added singly or in combination to large  volume infusions. Examples include ampicillin in infu-  sions that contain glucose or lactates. The breakdown  products of dacarbazine have been implicated in  adverse effects.   Blood Because of the large number of incompatibilities,  drugs should not normally be added to blood and blood  products for infusion purposes. Examples of incompat-  ibility with blood include hypertonic mannitol solutions  (irreversible crenation of red cells), dextrans (rouleaux  formation and interference with cross-matching), glu-  cose (clumping of red cells), and oxytocin (inactivated).   If the giving set is not changed after the administration  of blood, but used for other infusion fluids, a fibrin clot  may form which, apart from blocking the set, increases  the likelihood of microbial growth.   Intravenous fat emulsions These may break down  with coalescence of fat globules and separation of  phases when additions such as antibacterials or electro-  lytes are made, thus increasing the possibility of embo-   Other infusions Infusions that frequently give rise to  incompatibility include amino acids, mannitol, and sod-  ium bicarbonate.   Bactericides Bactericides such as chlorocresol 0.1% or  phenylmercuric nitrate 0.001% are present in some  injection solutions. The total volume of such solutions  added to a container for infusion on one occasion  should not exceed 15 mL.   Ready-prepared infusions should be used whenever  available. Potassium chloride is usually available in  concentrations of 20, 27, and 40 mmol/litre in sodium  chloride intravenous infusion (0.9%), glucose intra-  venous infusion (5%) or sodium chloride and glucose  intravenous infusion. Lidocaine hydrochloride is  usually available in concentrations of 0.1 or 0.2% in  glucose intravenous infusion (5%).   When addition is required to be made extempora-  neously, any product reconstitution instructions such  as those relating to concentration, vehicle, mixing, and  handling precautions should be strictly followed using  an aseptic technique throughout. Once the product has  been reconstituted, addition to the infusion fluid should  be made immediately in order to minimise microbial  contamination and, with certain products, to prevent  degradation or other formulation change which may  occur; e.g. reconstituted ampicillin injection degrades  rapidly on standing, and also may form polymers which  could cause sensitivity reactions.   It is also important in certain instances that an infusion  fluid of specific pH be used (e.g. furosemide injection  requires dilution in infusions of pH greater than 5.5).   When drug additions are made it is important to mix  thoroughly; additions should not be made to an infusion  container that has been connected to a giving set, as  mixing is hampered. If the solutions are not thoroughly  mixed a concentrated layer of the additive may form  owing to differences in density. Potassium chloride is  particularly prone to this ‘layering’ effect when added  without adequate mixing to infusions packed in non-  rigid infusion containers; if such a mixture is adminis-  tered it may have a serious effect on the heart.   A time limit between addition and completion of admin-  istration must be imposed for certain admixtures to  guarantee satisfactory drug potency and compatibility.  For admixtures in which degradation occurs without the  formation of toxic substances, an acceptable limit is the  time taken for 10% decomposition of the drug. When  toxic substances are produced stricter limits may be  imposed. Because of the risk of microbial contamination  a maximum time limit of 24 hours may be appropriate  for additions made elsewhere than in hospital pharma-  cies offering central additive service.   Certain injections must be protected from light during  continuous infusion to minimise oxidation, e.g. amphot-  ericin, dacarbazine, and sodium nitroprusside.   Dilution with a small volume of an appropriate vehicle  and administration using a motorised infusion pump is  advocated for preparations such as unfractionated hep-  arin where strict control over administration is required.  In this case the appropriate dose may be dissolved in a    convenient volume (e.g. 24-48 mL) of sodium chloride  intravenous infusion (0.9%).   Drugs for continuous infusion must be diluted in a  large volume infusion. Penicillins and cephalosporins  are not usually given by continuous infusion because  of stability problems and because adequate plasma and  tissue concentrations are best obtained by intermittent  infusion. Where it is necessary to administer them by  continuous infusion, detailed literature should be con-  sulted.   Drugs that are both compatible and clinically suitable  may be given by intermittent infusion in a relatively  small volume of infusion over a short period of time, e.g.   100 mL in 30 minutes. The method is used if the product  is incompatible or unstable over the period necessary  for continuous infusion; the limited stability of ampicillin  or amoxicillin in large volume glucose or lactate infu-  sions may be overcome in this way.   Intermittent infusion is also used if adequate plasma and  tissue concentrations are not produced by continuous  infusion as in the case of drugs such as dacarbazine,  gentamicin, and ticarcillin.   An in-line burette may be used for intermittent infusion  techniques in order to achieve strict control over the  time and rate of administration, especially for infants  and children and in intensive care units. Intermittent  infusion may also make use of the ‘piggy-back’ techni-  que provided that no additions are made to the primary ^ ■  infusion. In this method the drug is added to a small u  secondary container connected to a Y-type injection site m  on the primary infusion giving set; the secondary solu-  tion is usually infused within 30 minutes.   Addition via the drip tubing is indicated for a number  of cytotoxic drugs in order to minimise extravasation.   The preparation is added aseptically via the rubber  septum of the injection site of a fast-running infusion.   In general, drug preparations intended for a bolus effect  should be given directly into a separate vein where  possible. Failing this, administration may be made via  the drip tubing provided that the preparation is compa-  tible with the infusion fluid when given in this manner.   Covers addition to Glucose intravenous infusion 5  and 10%, and Sodium chloride intravenous infusion  0.9%. Compatibility with glucose 5% and with sod-  ium chloride 0.9% indicates compatibility with Sod-  ium chloride and glucose intravenous infusion. Infu-  sion of a large volume of hypotonic solution should  be avoided therefore care should be taken if water  for injections is used. The information in the Table  relates to the proprietary preparations indicated; for  other preparations suitability should be checked  with the manufacturer   Reconstitute each vial with 10 mL water for injections using the  silicone-free syringe provided; dilute requisite dose in infusion  fluid to 100 mL (using the same silicone-free syringe); give over 30  minutes through a low protein-binding filter (pore size 0.2-  1.2 micron)   Continuous in Glucose 5% or Sodium chloride 0.9%  Dilute requisite dose in infusion fluid and give via infusion pump;  filter upon dilution with infusion fluid through a non-pyrogenic  low protein-binding 0.2, 0.22, or 5 micron filter or upon adminis-  tration through an in-line non-pyrogenic low protein-binding 0.2  or 0.22 micron filter   Aciclovir (as sodium salt) (Zovirax IV® \ Aciclovir IV,  Hospira; Aciclovir IV, Genus; Aciclovir Sodium,  Zurich)   For Zovirax IV ® , Aciclovir IV (Genus) initially reconstitute to  25 mg/mL in water for injections or sodium chloride 0.9% then  dilute to not more than 5 mg/mL with the infusion fluid; to be  given over 1 hour; alternatively, may be administered in a  concentration of 25 mg/mL using a suitable infusion pump and  given over 1 hour; for Aciclovir IV (Hospira) dilute to not more  than 5 mg/mL with infusion fluid; give over 1 hour   Dilute requisite dose with 100 mL infusion fluid and give over 40  minutes using an in-line filter; use within 3 hours of dilution   Reconstitute with water for injections (35 mg in 7.2 mL, 5 mg in  1.1 mL) to produce a solution containing 5 mg/mL; dilute with  infusion fluid (for doses less than 35 mg dilute with at least 50 mL;  doses 35-70 mg dilute with at least 100 mL; doses 70-100 mg  dilute with at least 250 mL; doses greater than 100 mg dilute with  500 mL) and give through an in-line low protein-binding  0.2 micron filter at an initial rate of no more than 15 mg/hour; for  subsequent infusions, infusion rate may be increased gradually  once tolerance has been established   Reconstitute 50 mg with 10.3 mL water for injections to produce  5 mg/mL solution; gently rotate vial without shaking; dilute  requisite dose with infusion fluid to give a final concentration of  0.5-4 mg/mL; give through a low protein-binding in-line filter  (0.2 micron) at an initial rate of 1 mg/kg/hour increased by 2 mg/  kg/hour every 30 minutes to max. 7 mg/kg/hour   Continuous or intermittent in Sodium chloride 0.9%  Dissolve in water for injections to a concentration of 1 mg/mL or  2 mg/mL and infuse intravenously; alternatively dilute the solu-  tion further in the infusion fluid to a concentration of not less than  200micrograms/mL; not to be infused in glucose solution   Reconstitute 500-mg vial with 9.7 mL sodium chloride 0.9% to  produce a 50 mg/mL solution   Suggested initial infusion volume 250 mL given over 20-120  minutes; for repeat infusions up to 1.2 g in max. 500 mL; infusion  in extreme emergency see section 2.7.3; should not be diluted to  less than 600 micrograms/mL; incompatible with sodium chloride  infusion; avoid equipment containing the plasticizer di-2-ethyl-  hexyphthalate (DEHP)   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstituted solutions diluted and given without delay; sug-  gested volume 100 mL given over 30-60 minutes  via drip tubing in Glucose 5% or Sodium chloride  0.9%   Allow suspension to reach room temperature, shake gently to  ensure no yellow settlement, withdraw requisite dose (using 17-  19 gauge needle) into one or more 20-mL syringes; replace needle  on syringe with a 5-micron filter needle provided (fresh needle for  each syringe) and dilute to a concentration of 1 mg/mL (2 mg/mL  can be used in fluid restriction and in children); preferably give via  an infusion pump at a rate of 2.5 mg/kg/hour (initial test dose of  1 mg given over 15 minutes); an in-line filter (pore size no less than  15 micron) may be used; do not use sodium chloride or other  electrolyte solutions, flush existing intravenous line with glucose  5% or use separate line   Reconstitute each vial with 12 mL water for injections and shake  vigorously to produce a preparation containing 4 mg/mL; with-  draw requisite dose from vial and introduce into infusion fluid  through the 5 micron filter provided to produce a final concen-  tration of 0.2-2 mg/ mL; infuse over 30-60 minutes, or if non-  anaphylactic infusion-related reactions occur infuse over 2 hours  (initial test dose 1 mg over 10 minutes); an in-line filter (pore size  no less than 1 micron) may be used; incompatible with sodium  chloride solutions, flush existing intravenous line with glucose 5%  or 10%, or use separate line   Reconstitute each vial with 10 mL water for injections and shake  immediately to produce a 5 mg/mL colloidal solution; dilute  further in infusion fluid to a concentration of 100 micrograms/mL;  pH of the glucose must not be below 4.2 (check each container —  consult product literature for details of buffer); infuse over 2-4  hours, or longer if not tolerated (initial test dose 1 mg over 20-30  minutes); begin infusion immediately after dilution and protect  from light; incompatible with sodium chloride solutions, flush  existing intravenous line with glucose 5% or use separate line; an  in-line filter (pore size no less than 1 micron) may be used   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstituted solutions diluted and given without delay; sug-  gested volume 100 mL given over 30-60 minutes  via drip tubing in Glucose 5% or Sodium chloride  0.9%   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute each 100 mg with 30 mL water for injections, allow  up to 5 minutes for reconstitution; dilute dose in infusion fluid to a  concentration of 770 micrograms/mL; give at a rate not exceed-  ing 1.1 mg/minute   Antithymocyte immunoglobulin ( Thymoglobuline ®)  Continuous in Glucose 5% or Sodium chloride 0.9%  Reconstitute each vial with 5 mL water for injections to produce a  solution of 5mg/mL; gently rotate to dissolve. Dilute requisite  dose with infusion fluid to a total volume of 50-500 mL (usually  50mL/vial); begin infusion immediately after dilution; give  through an in-line filter (pore size 0.22 micron); not to be given  with unfractionated heparin and hydrocortisone in glucose infu-  sion as precipitation reported   Diluted solution given without delay; dilute in 500 mL and give  over at least 6 hours; glass or hard plastic containers should not be  used; some loss of potency on dilution and administration   Allow vial to reach room temperature; initially reconstitute each  vial with 10.5 mL water for injections, mixing gently to dissolve  then dilute requisite dose in 250 mL infusion fluid (35- or 50-mg  doses may be diluted in 100 mL infusion fluid if necessary); give  over 60 minutes; incompatible with glucose solutions   Continuous in Glucose 5% or Sodium chloride 0.9%  Withdraw 10 mL infusion fluid from 100-mL bag and replace with  10 mL atosiban concentrate (7.5mg/mL) to produce a final con-  centration of 750 micrograms/mL   Atracurium besilate [Tracrium®, Atracurium besilate  injection, Hospira; Atracurium injection /infusion,  Genus)   Continuous in Glucose 5% or Sodium chloride 0.9%  Stability varies with diluent; dilute requisite dose with infusion  fluid to a concentration of 0.5-5 mg/mL   Azathioprine (as sodium salt) [Imuran®)  Intermittent in Sodium chloride 0.9% or Glucose 5%  Reconstitute 50 mg with 5-15 mL water for injections; dilute  requisite dose to a volume of 20-200 mL with infusion fluid   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dissolve initially in water for injections (1 g per 3 mL) then dilute  to a concentration of less than 20 mg/mL; to be given over 20-60  minutes   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute 10 mg with 2.5 mL water for injections then dilute to  at least 25 mL with infusion fluid; reconstitute 20 mg with 5 mL  water for injections then dilute to at least 50 mL with infusion  fluid; give over 20-30 minutes   Intermittent in Glucose 5% or Sodium chloride 0.9%  Suggested volume 100 mL given over 30-60 minutes  Continuous infusion not usually recommended   Betamethasone (as sodium phosphate) [Betnesol®)  Continuous or intermittent or via drip tubing in Glu-  cose 5% or Sodium chloride 0.9%   Intermittent in Glucose 5% or Sodium chloride 0.9%  or Water for injections   Suggested volume 40-100 mL given over 20-60 minutes; incom-  patible with alkaline solutions    Ceftazidime (as pentahydrate) [Fortum®, Kefadim®)  Intermittent or via drip tubing in Glucose 5 and 10%  or Sodium chloride 0.9%   Dissolve 2 g initially in 10 mL (3 g in 15 mL) infusion fluid; for  Fortum ® dilute further to a concentration of 40 mg/mL; for  Kefadim ® dilute further to a concentration of 20 mg/mL; give  over up to 30 minutes   Intermittent or via drip tubing in Glucose 5 and 10%  or Sodium chloride 0.9%    Reconstitute 2-g vial with 40 mL infusion fluid; give intermittent  infusion over at least 30 minutes (60 minutes in neonates); not to  be given simultaneously with total parenteral nutrition or infusion  fluids containing calcium, even by different infusion lines; may be  infused sequentially with infusion fluids containing calcium if  flush with sodium chloride 0.9% between infusions or give infu-  sions by different infusion lines at different sites   Intermittent or via drip tubing in Glucose 5% or  Sodium chloride 0.9%   Dissolve initially in water for injections (at least 2 mL for each  250 mg, 15 mL for 1.5 g); suggested volume 50-100 mL given over  30 minutes   Intermittent or via drip tubing in Glucose 5% or  Sodium chloride 0.9%   Dilute to a concentration of 50 mg in 20-100 mL; give intermittent  infusion over 2-6 hours; not to be used with PVC equipment   Continuous in Glucose 5% or Sodium chloride 0.9%  Reconstitute each 250-mg vial with 5 mL water for injections then  withdraw 5 mL and dilute to 50 mL with infusion fluid   Intermittent in Glucose 5% or Sodium chloride 0.9%  Suggested volume 500 mL given over 30-60 minutes; concen-  trations above 25 micrograms/mL may cause precipitation   Dilute requisite dose with 100 mL infusion fluid; infuse over 1 hour   Continuous in Glucose 5% or Sodium chloride 0.9%  Solutions of 2 mg/mL and 5 mg/ mL may be infused undiluted;  alternatively dilute with infusion fluid to a concentration of 0. 1-  2 mg/mL   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dissolve initially in water for injections (500 mg in 10 mL) then  dilute to a concentration of 2 mg/mL; give over 60 minutes   Dilute to not more than 18 mg/mL and give over 10-60 minutes  at a rate not exceeding 30 mg/minute (1.2 g over at least 60  minutes; higher doses by continuous infusion)    Dexamethasone sodium phosphate ( Dexa -  methasone, Hospira; Dexamethasone, Organon)  Continuous or intermittent or via drip tubing in Glu-  cose 5% or Sodium chloride 0.9%   Reconstitute 500 mg with 25 mL of water for injections then dilute  in 500 mL Savene ® diluent; give over 1-2 hours into a large vein  in an area other than the one affected   Reconstitute 600 mg initially with 10 mL water for injections, then  dilute with 50 mL infusion fluid; reconstitute 1.2 g initially with  20 mL water for injections, then dilute with 100 mL infusion fluid;  give over 30-40 minutes  via drip tubing in Sodium chloride 0.9%   Co-fluampicil (as sodium salts) ( Magnapen ®)  Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstituted solutions diluted and given without delay; sug-  gested volume 100 mL given over 30-60 minutes   Dilute with 50 mL infusion fluid and give over 30 minutes   Dilute contents of 1 ampoule (5mL) to 125 mL, 2 ampoules  (10 mL) to 250 mL or 3 ampoules (15 mL) to 500 mL; suggested  duration of infusion 60-90 minutes (but may be adjusted  according to fluid requirements); if fluid restriction necessary, 1  ampoule (5 mL) may be diluted with 75 mL glucose 5% and  infused over max. 60 minutes   Reconstitute 500 mg with 25 mL sodium chloride 0.9%; reconsti-  tute 1 g with 50 mL sodium chloride 0.9%    Diazepam (solution) [Diazepam, Wockhardt)  Continuous in Glucose 5% or Sodium chloride 0.9%  Dilute to a concentration of not more than 10 mg in 200 mL;  adsorbed to some extent by the plastics of bags and infusion sets   May be diluted to a max. concentration of 200 mg in 500 mL; max.  6 hours between addition and completion of administration;  adsorbed to some extent by the plastics of the infusion set  via drip tubing in Glucose 5 and 10% or Sodium  chloride 0.9%   Adsorbed to some extent by the plastics of the infusion set   Dilute 75 mg with 100-500 mL infusion fluid (previously buffered  with 0.5 mL sodium bicarbonate 8.4% solution or with 1 mL  sodium bicarbonate 4.2% solution); for intermittent infusion give  25-50 mg over 15-60 minutes or 75 mg over 30-120 minutes; for  continuous infusion give at a rate of 5 mg/hour   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute to a concentration of not more than 62.5 micrograms/mL.  To be given over at least 2 hours   Digoxin-specific antibody fragments ( Digibind ®)  Intermittent in Sodium chloride 0.9%   Dissolve initially in water for injections (4 mL/vial) then dilute  with the sodium chloride 0.9% and give through a 0.22 micron  sterile, disposable filter over 30 minutes   Reconstitute with sodium chloride 0.9% (350 mg in 7 mL, 500 mg  in 10 mL); gently rotate vial without shaking; allow to stand for at  least 10 minutes then rotate gently to dissolve; dilute requisite  dose in 50 mL infusion fluid and give over 30 minutes   Reconstitute with water for injections to a concentration of  100 mg/mL; dilute with infusion fluid   Intermittent in Glucose 5% or Sodium chloride 0.9%  For Aredia ® and Pamidronate disodium (Britannia), reconstitute  initially with water for injections (15 mg in 5 mL, 30 mg or 90 mg in  10 mL); for Aredia ® , Pamidronate disodium (Britannia),  Disodium pamidronate (Hospira), dilute with infusion fluid to a  concentration of not more than 60 mg in 250 mL; for Disodium  pamidronate (Medac) dilute with infusion fluid to a concentration  of not more than 90 mg in 250 mL; give at a rate not exceeding  1 mg/minute; not to be given with infusion fluids containing  calcium    Disopyramide (as phosphate) ( Rythmodan ®)  Continuous or intermittent in Glucose 5% or Sodium  chloride 0.9%   Max. rate by continuous infusion 20-30 mg/hour (or 400 micr-  ograms/kg/hour)   Continuous in Glucose 5% or Sodium chloride 0.9%  Dilute to a concentration of 0.5-1 mg/mL and give via a con-  trolled infusion device; give higher concentration (max. 5 mg/mL)  with infusion pump; incompatible with bicarbonate   Continuous in Glucose 5% or Sodium chloride 0.9%  Dilute to a concentration of 400 or 800micrograms/mL; max.  concentration via large peripheral vein 1 mg/mL, concentrations  up to 4 mg/mL may be infused via central vein; give via infusion  pump or other device which provides accurate control of rate;  contact with metal should be minimised; incompatible with  bicarbonate   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute 500 mg with 10 mL water for injections or sodium  chloride 0.9% then dilute with 100 mL infusion fluid; give over 1  hour (for severe hospital-acquired pneumonia or hospital-  acquired pneumonia caused by less sensitive organisms, may  extend infusion time to 4 hours using sodium chloride 0.9% as the  infusion fluid)   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute requisite dose to a concentration of 5 mg/mL and mix  gently; give over 25-45 minutes (infusion time may be increased  to 2 hours if infusion-related reactions occur)   Dilute 200-500 mg in up to 100 mL infusion fluid and give over at  least 6 minutes; dilute 0.5-1 g in up to 250 mL infusion fluid and  give over at least 15 minutes   For a filgrastim concentration of less than 1 500 000 units/mL  (15micrograms/mL) albumin solution (human albumin solution)  is added to produce a final albumin concentration of 2 mg/mL;  should not be diluted to a filgrastim concentration of less than  200 000 units/mL (2 micrograms/mL) and should not be diluted  with sodium chloride solution   Flucloxacillin (as sodium salt) ( Floxapen ®)  Intermittent in Glucose 5% or Sodium chloride 0.9%  Suggested volume lOOmL given over 30-60 minutes  via drip tubing in Glucose 5% or Sodium chloride  0.9%   Continuous or intermittent in Sodium chloride 0.9%  or Water for injections   Dilute to a concentration of 2.5 mg/mL; incompatible with glu-  cose solutions; use only plastic containers or syringes   Reconstitute using the filter and solvent (glycine buffer diluent)  provided to make a concentrate; may be diluted further (consult  product literature); for pulmonary hypertension dilute further with  glycine buffer diluent only, for renal dialysis may be diluted further  with sodium chloride 0.9%   Reconstitute 1 g with 10 mL water for injections or sodium  chloride 0.9%; dilute requisite dose in infusion fluid to a final  concentration not exceeding 20 mg/mL; give over 30 minutes;  incompatible with glucose solutions   Continuous or intermittent in Glucose 5% (neutralised  with sodium bicarbonate) or Sodium chloride 0.9%  Dissolve initially in water for injections (1 g in 20 mL) then dilute  to a concentration of 1 mg/mL for continuous infusion and 1-  5 mg/mL for intermittent infusion; give intermittent infusion over  20-60 minutes   Esomeprazole (as sodium salt) ( Nexium ®)  Continuous or intermittent in Sodium chloride 0.9%  Reconstitute 40-80 mg with up to lOOmL infusion fluid; for  intermittent infusion, give requisite dose over 10-30 minutes;  stable for 12 hours in sodium chloride 0.9%   For ST-segment elevation myocardial infarction, add requisite  dose to 25-50 mL infusion fluid and give over 1-2 minutes   Reconstitute each 1 15-mg vial with 5 mL sodium chloride 0.9%  gently without shaking to avoid foaming, then dilute in llOmL  infusion fluid; give over 15 minutes   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute to a concentration of 12 mg/mL for infusion into peripheral  vein (undiluted solution via central venous line only); infuse over  at least 1 hour (infuse doses greater than 60 mg/kg over 2 hours)   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute to a concentration of 1.5-25 mg (phenytoin sodium  equivalent)/mL   Infusion pH must be above 5.5 and rate should not exceed 4 mg/  minute; glucose solutions are unsuitable   Reconstitute with the buffer solution provided and dilute to  500 mL; give through central venous line over 2 hours (or over 6  hours if superficial vein used); incompatible in solution of pH less  than 7.4   Dilute requisite dose with infusion fluid to final volume of 250 mL  and mix gently; infuse through a 0.2 micron in-line filter; give  approx. 2.5% of the total volume over 1 hour, then infuse  remaining volume over next 3 hours; if body-weight under 20 kg  and at risk of fluid overload, dilute requisite dose in 100 mL  infusion fluid and give over at least 4 hours   Ganciclovir (as sodium salt) ( Cymevene ®)  Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute initially in water for injections (500 mg/ 10 mL) then  dilute to not more than 10 mg/mL with infusion fluid (usually  100 mL); give over 1 hour   Dilute requisite dose in 100 mL infusion fluid and mix gently (do  not shake); give over 3 hours (gradually reduced to 1 hour if no  infusion-related reactions)   Initially reconstitute with water for injections (200 units in 5.1 mL,  400 units in 10.2 mL) to give 40 units/mL solution; dilute requisite  dose with infusion fluid to a final volume of 100-200 mL and give  initial dose at a rate not exceeding 0.5 units /kg/minute, subse-  quent doses to be given at a rate not exceeding 1 unit/kg/minute;  administer within 3 hours after reconstitution    Gentamicin (as sulphate) ( Cidomycin®\ Gentamicin  Paediatric Injection, Beacon; Gentamicin Injection,  Hospira)   Intermittent or via drip tubing in Glucose 5% or  Sodium chloride 0.9%   Suggested volume for intermittent infusion 50-100 mL given over  20-30 minutes (given over 60 minutes for once daily dose regi-  men)   Dilute to a concentration of 5 mg (as imipenem) /mL; infuse 250-  500 mg (as imipenem) over 20-30 minutes, 1 g over 40-60 min-  utes    Glyceryl trinitrate ( Nitrocine ®, Nitronal®)  Continuous in Glucose 5% or Sodium chloride 0.9%  For Nitrocine ® suggested infusion concentration lOOmicr-  ograms/mL; incompatible with polyvinyl chloride infusion  containers such as Viaflex ® or Steriflex ®; use glass or  polyethylene containers or give via a syringe pump   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute 3 mL in 20-50 mL infusion fluid (up to 3 mL in 10-30 mL for  children); give over 5 minutes   Dilute requisite dose in 100 mL infusion fluid in glass bottle and  give over at least 30 minutes via large antebrachial vein; admin-  ister within 1 hour after dilution    Hydralazine hydrochloride (Apresoline®)  Continuous in Sodium chloride 0.9%  Suggested infusion volume 500 mL   Reconstitute each 100-mg vial with lOmL water for injections  using a 21 -gauge or smaller needle; gently swirl vial without  shaking to dissolve; allow to stand for 5 minutes; dilute requisite  dose with infusion fluid to a final volume of 250 mL and give  through a low protein-binding filter (1.2 micron or less) over at  least 2 hours (patients being treated for rheumatoid arthritis who  have tolerated 3 initial 2-hour infusions may be given subsequent  infusions of up to 6 mg/kg over at least 1 hour); start infusion  within 3 hours of reconstitution   Continuous in Sodium chloride 0.9% or Glucose 5%  Dilute to 0.05-1 unit/mL with infusion fluid; adsorbed to some  extent by plastics of infusion set   Dilute to 1 unit/mL with infusion fluid; use a co-extruded  polyolefin/ polyamide plastic infusion bag with a dedicated  infusion line   Continuous or intermittent or via drip tubing in Glu-  cose 5% or Sodium chloride 0.9%   Continuous or intermittent or via drip tubing in Glu-  cose 5% or Sodium chloride 0.9%   Reconstitute each 2.5g-vial with 100 mL infusion fluid; gently  invert vial for at least 30 seconds to mix; do not shake   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute requisite dose in 500 mL infusion fluid and give over 1-2  hours   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute 100-200 mg in 100 mL infusion fluid; give 25 mg over 15  minutes as a test dose initially, then give at a rate not exceeding  6.67mg/minute; total dose infusion diluted in 500 mL infusion  fluid and given over 4-6 hours (initial test dose 25 mg over 15  minutes)   Dilute 100 mg in up to 100 mL infusion fluid; give 25 mg over 15  minutes as a test dose initially, then give at a rate not exceeding  3.33 mg/minute    Isosorbide dinitrate ( Isoket 0.05%®, Isoket 0.1%®)  Continuous in Glucose 5% or Sodium chloride 0.9%  Adsorbed to some extent by polyvinyl chloride infusion contain-  ers; preferably use glass or polyethylene containers or give via a  syringe pump; Isoket 0.05%® can alternatively be administered  undiluted using a syringe pump with a glass or rigid plastic syringe   Dilute 250 mg in 50 mL infusion fluid and infuse only 60 mL  through an in-line filter (0.2 micron) over 60 minutes   Continuous in Glucose 5% or Sodium chloride 0.9%  Dilute to 1 mg/mL; microdrip infusion for maintenance of  anaesthesia   Dilute to a concentration of 1 mg/mL; suggested volume 200 mL;  adjust rate with in-line burette   Body-weight under 20 kg, use 100 mL infusion fluid; body-weight  over 20 kg use 250 mL infusion fluid; withdraw volume of infusion  fluid equivalent to volume of laronidase concentrate being added;  give through an in-line filter (0.22 micron) at an initial rate of  2 units/kg/hour then increasing gradually every 15 minutes to  max. 43 units/kg/hour   Initially reconstitute with 1 mL water for injection provided (do  not shake vigorously) then dilute with up to 50 mL infusion fluid  for each vial of Granocyte-13 or up to 100 mL infusion fluid for  Granocyte-34\ give over 30 minutes   Continuous in Glucose 5% or Sodium chloride 0.9%  Reconstitute initially with water for injections or sodium chloride  0.9% then dilute to a concentration of 2 mg/mL with infusion fluid   Continuous infusion recommended; loading dose, dilute with 50-  100 mL and give over 15-20 minutes; maintenance dose, dilute  with 500 mL and give over 8-12 hours; for intermittent infusion  dilute with at least 50 mL and give over at least 15 minutes   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute each vial with 5 mL infusion fluid; gently rotate vial,  without shaking, to dissolve; dilute requisite dose with infusion  fluid to 100 mL (final concentration 0.5-2 mg/mL); protect infu-  sion from light; give over 60 minutes   Continuous in Glucose 5% or Sodium chloride 0.9%  For neonates and children under 15 kg dilute to a max. concen-  tration of 1 mg/mL   Continuous in Glucose 5% or Sodium chloride 0.9%  Dilute to a concentration of 500 micrograms/mL; may also be  given undiluted   Reconstitute each 500-mg vial with 14mL glucose 5% and dilute  the contents of 2 vials in 140 mL infusion fluid; give over 2 hours   Dilute to a concentration of 200 micrograms/mL and administer  via an infusion pump, see Emergency Treatment of Poisoning   Dilute 300 mg in 100 mL infusion fluid; gently invert to mix, do not  shake. Use within 8 hours of dilution and give over 1 hour   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute requisite dose with at least 100 mL of infusion fluid; give  over 15 minutes   Continuous in Glucose 5% or Sodium chloride 0.9%  Suggested concentration up to 200 mg/mL; max. rate 150 mg/  minute   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute dose in infusion fluid to a final concentration of 1-20 mg/  mL; give over 15-30 minutes   Continuous or via drip tubing in Glucose 5% or  Sodium chloride 0.9%   Continuous or intermittent or via drip tubing in Glu-  cose 5% or Sodium chloride 0.9%   Reconstitute initially with water for injections; doses up to 250 mg  should be given over at least 5 minutes, high doses over at least 30  minutes    Not to be added to infusion container; administer via an infusion  pump through a Y-piece into a central catheter; incompatible with  polyvinyl chloride giving sets or containers; protect infusion from  light   For continuous infusion, dilute 300 mg in 150 mL and give at a rate  of 10 mg/hour; for intermittent infusion, dilute 100 mg in 50 mL  and give over 15 minutes   Give via controlled infusion device; for administration via syringe  pump, dilute 4 mg noradrenaline acid tartrate (2 mL solution) with  48 mL; for administration via drip counter dilute 40 mg (20 mL  solution) with 480 mL; give through a central venous catheter;  incompatible with alkalis   Reconstitute each 40 mg vial with infusion fluid and dilute to  100 mL; for intermittent infusion, give 40 mg over 20-30 minutes;  stable for 3 hours in glucose 5% or 12 hours in sodium chloride  0.9%   Ondansetron (as hydrochloride) ( Zofran ®)  Continuous or intermittent in Glucose 5% or Sodium  chloride 0.9%   For intermittent infusion, dilute 32 mg in 50-100 mL and give over  at least 15 minutes   Continuous in Glucose 5% or Sodium chloride 0.9%  Preferably given via a variable-speed infusion pump in a con-  centration appropriate to the pump; if given by drip infusion for  induction or enhancement of labour, dilute 5 units in 500 mL  infusion fluid or for higher doses, 10 units in 500 mL; for treatment  of postpartum uterine haemorrhage dilute 40 units in 500 mL; if  high doses given for prolonged period (e.g. for inevitable or  missed abortion or for postpartum haemorrhage), use low volume  of an electrolyte-containing infusion fluid (not Glucose 5%) given  at higher concentration than for induction or enhancement of  labour; close attention to patient’s fluid and electrolyte status  essential   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute 40 mg with 10 mL sodium chloride 0.9% and dilute  with 100 mL of infusion fluid; give 40 mg over 15 minutes   Intermittent in Sodium chloride 0.9% or Glucose 5%  Dilute to a concentration of 1 mg/mL and use within 1 hour; may  also be given undiluted   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dissolve initially in water for injections (300 mg in 3-5 mL) then  dilute in 50-250 mL; give over at least 60 minutes   Dilute in 200-500 mL infusion; give over at least 2 hours; max. 4  hours between dilution and completion of administration   Flush intravenous line with Sodium chloride 0.9% before and after  infusion; dilute in 50-100 mL infusion fluid (final concentration  not to exceed 10 mg/mL) and give into a large vein through an in-  line filter (0.22-0.50 micron) at a rate not exceeding 50 mg/  minute (neonates, give at a rate of 1-3 mg/kg/minute); complete  administration within 1 hour of preparation   Dilute with 55 mL; may be injected into lower part of infusion  apparatus   Intermittent in Glucose 5% or Sodium chloride 0.9%  or Water for injections   Reconstitute initially (2.25 g in 10 mL, 4.5 g in 20 mL) with water  for injections, or glucose 5% (Tazocin® brand only), or sodium  chloride 0.9%, then dilute to 50-150 mL with infusion fluid (to  max. 50 mL with water for injections); give over 20-30 minutes   Propofol (emulsion) ( Diprivan ®; Abbott; Baxter;  Propofol-Lipuro® , Propofen®, Braun; Hospira;  Fresenius Kabi)   Continuous in Glucose 5% (or Sodium chloride 0.9%  for Propofol-Lipuro®, Propofen®, Braun, and  Fresenius Kabi brands only)   Dilute to a concentration not less than 2 mg/mL; microbiological  filter not recommended; administer using suitable device to  control infusion rate; use glass or PVC containers (if PVC bag used  it should be full — withdraw volume of infusion fluid equal to that  of propofol to be added); give within 6 hours of preparation;  propofol may alternatively be infused undiluted using a suitable  infusion pump   Reconstitute with solvent provided; gently swirl vial without  shaking to dissolve; dilute requisite dose to 50 mL with infusion  fluid and give over 30 minutes   Reconstitute with infusion fluid to a concentration of 1 mg/mL  then dilute further to a concentration of 20-250 micrograms/mL  (50micrograms/mL recommended for general anaesthesia, 20-  25 micrograms/mL recommended for children 1-12 years; 20-  50 micrograms/mL recommended when used with target con-  trolled infusion (TCI) device)   Give via controlled infusion device, preferably a syringe pump; if  syringe pump available dilute to a concentration of 3 mg/mL; if  syringe pump not available dilute to a concentration of  300 micrograms/mL; close attention to patient’s fluid and  electrolyte status essential   Dilute to 1-4 mg/mL and gently invert bag to avoid foaming   Continuous or via drip tubing in Glucose 5% or  Sodium chloride 0.9%    Salbutamol (as sulphate) ( Ventolin ® For Intra-  venous Infusion )   For bronchodilatation dilute to a concentration of 200 micr-  ograms/mL with glucose 5% or sodium chloride 0.9%; for pre-  mature labour dilute with glucose 5% to a concentration of  200 micrograms/mL for use in a syringe pump or for other  infusion methods (preferably via controlled infusion device),  dilute to a concentration of 20 micrograms/mL; close attention to  patient’s fluid and electrolyte status essential   Continuous in Glucose 5% or Sodium chloride 0.9%  Dilute to a concentration of not more than 3%; suggested volume  250-500 mL given over at least 1 hour   Intermittent or via drip tubing in Glucose 5% or  Sodium chloride 0.9%   For adult intermittent infusion suggested volume 50-100 mL  (children proportionately smaller volume) given over 20-60  minutes   Dilute requisite dose to a volume of 100 mL with infusion fluid and  give over 1 hour   Continuous in Glucose 5% or Sodium chloride 0.9%  Dilute concentrate in infusion fluid to a final concentration of 4-  100 micrograms/mL; give over 24 hours; incompatible with PVC   Intermittent in Glucose 5% or 10% or Sodium chlor-  ide 0.9%   Reconstitute 1 g with 10 mL water for injections then dilute with  50-150 mL infusion fluid; give over 30-40 minutes   For bronchodilatation dilute 1. 5-2.5 mg with 500 mL glucose 5%  or sodium chloride 0.9% and give over 8-10 hours; for premature  labour dilute in glucose 5% and give via controlled infusion device  preferably a syringe pump; if syringe pump available dilute to a  concentration of 100 micrograms/mL; if syringe pump not avail-  able dilute to a concentration of 10 micrograms/mL; close  attention to patient’s fluid and electrolyte status essential    Vancomycin (as hydrochloride) ( Vancocin ®)  Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute each 500 mg with 10 mL water for injections and  dilute with infusion fluid to a concentration of up to 5 mg/ mL  (lOmg/mL in fluid restriction but increased risk of infusion-  related effects); give over at least 60 minutes (rate not to exceed  10 mg/minute for doses over 500 mg); use continuous infusion  only if intermittent not feasible    Reconstitute each vial with 5 mL water for injections to give 2 mg/  mL solution; alternatively reconstitute with up to 10 mL glucose  5% or sodium chloride 0.9% or water for injections — unsuitable  for further dilution if not reconstituted with water for injections.  For continuous intravenous infusion, dilute to a concentration up  to 40 micrograms/mL   Reconstitute each 400-unit vial with 4.3 mL water for injec-  tions to produce a lOOunits/mL solution; dilute requisite  dose in 100 mL infusion fluid; give over 60 minutes through a  0.22 micron filter; start infusion within 24 hours of reconsti-  tution   Reconstitute each 15 mg with 7 mL water for injections to produce  a 2 mg/mL solution then dilute requisite dose with infusion fluid  to a final volume of 30 mL and give over 10 minutes; protect  infusion from light and administer within 4 hours of reconstitution.  Incompatible with sodium chloride infusion    Ticarcillin sodium with clavulanic acid ( Timentin ®)  Intermittent in Glucose 5% or Water for injections  Suggested volume (depending on dose) glucose 5% 100-150 mL  or water for injections 50-100 mL; given over 30-40 minutes   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute each vial with 5.3 mL infusion fluid to produce a  10 mg/mL solution; dilute requisite dose in 100 mL infusion fluid;  give over 30-60 minutes   Continuous in Glucose 5% or Sodium chloride 0.9%  Withdraw 50 mL infusion fluid from 250-mL bag and replace with  50 mL tirofiban concentrate (250 micrograms/mL) to give a final  concentration of 50 micrograms/mL    Vitamins B & C ( Pabrinex ® I /V High potency)  Intermittent or via drip tubing in Glucose 5% or  Sodium chloride 0.9%   Ampoule contents should be mixed, diluted, and administered  without delay; give over 30 minutes (see MHRA/CHM advice,  section 9.6.2)   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dissolve initially in 5 mL water for injections (or infusion fluid)  (Solivito N®)   Suggested volume 500-1000 mL given over 2-3 hours; see also  section 9.3   Intermittent in Glucose 5% or Sodium chloride 0.9%  Reconstitute each 200 mg with 19 mL water for injections to  produce a lOmg/mL solution; dilute dose in infusion fluid to  concentration of 0.5-5 mg/mL; give at a rate not exceeding 3 mg/  kg/hour   Dilute to a concentration of 2 mg/mL or 4 mg/ mL and give over 1  hour   Intermittent in Glucose 5% or Sodium chloride 0.9%  Dilute requisite dose with 100 mL infusion fluid; infuse over at  least 15 minutes; administer as a single intravenous solution in a  separate infusion line; do not mix with calcium or other divalent  cation-containing infusion solutions such as lactated Ringer’s  solution    In certain conditions some foods (and toilet prepara-  tions) have characteristics of drugs and the Advisory  Committee on Borderline Substances (ACBS) advises  as to the circumstances in which such substances may  be regarded as drugs. Prescriptions issued in accor-  dance with the Committee’s advice and endorsed  ACBS’ will normally not be investigated.    General Practitioners are reminded that the ACBS  recommends products on the basis that they may be  regarded as drugs for the management of specified  conditions. Doctors should satisfy themselves that  the products can safely be prescribed, that patients  are adequately monitored and that, where necessary,  expert hospital supervision is available.    Foods which may be prescribed on FP10, GP10  (Scotland), or WP10 (Wales) All the food products  listed in this appendix have ACBS approval. The clinical  condition for which the product has been approved is  included with each entry.   Note Foods included in this appendix may contain cariogenic  sugars and patients should be advised to take appropriate oral  hygiene measures.    Enteral feeds and supplements For most enteral  feeds and nutritional supplements, the main source of  carbohydrate is either maltodextrin or glucose syrup;  other carbohydrate sources are listed in the relevant  table, below. Feeds containing residual lactose (less than  1 g lactose/ 100 mL formula) are described as ‘clinically  lactose-free’ or ‘lactose-free’ by some manufacturers.   The presence of lactose (including residual lactose) in  feeds is indicated in the relevant table, below. The  primary sources of protein or amino acids are included  with each product entry. The fat or oil content is derived  from a variety of sources such as vegetables, soya bean,  com, palm nuts, and seeds; where the fat content is ^ ■  derived from animal or fish sources, this information is  included in the relevant table, below. The presence of I  medium chain triglycerides (MCT) is also noted where  the quantity exceeds 30% of the fat content.   Enteral feeds and nutritional supplements can contain  varying amounts of vitamins, minerals, and trace ele-  ments — the manufacturer’s product literature should be  consulted for more detailed information. For further  information on enteral nutrition, see section 9.4.2.   Feeds containing vitamin K may affect the INR in  patients receiving warfarin; see interactions: Appendix  1 (vitamins).   The suitability of food products for patients requiring a  vegan, kosher, halal, or other compliant diet should be  confirmed with individual manufacturers.   For details of enteral feeds, nutritional supplements, and  specialised formulas suitable for infants and children  under 12 years see BNF for Children (Appendix 2)   100 mL fibre should be avoided in children unless recom-  mended by an appropriate specialist or dietician.   Standard ACBS indications  Disease-related malnutrition, intractable malabsorp-  tion, pre-operative preparation of malnourished  patients, dysphagia, proven inflammatory bowel dis-  ease, following total gastrectomy, short-bowel  syndrome, bowel fistula   A7.1.1.1 Enteral feeds: 1 kcal/mL and less than 5g protein/100 mL   Not suitable for use in child under 1 year; not recommended for child 1-6 years unless otherwise stated   Short bowel syndrome, intractable  malabsorption, proven inflamm-  atory bowel disease, bowel fistula   Short bowel syndrome, intractable  malabsorption, proven inflamm-  atory bowel disease, bowel fistula    A7. 1.1.2 Enteral feeds: Less than 1 kcal/mL and less than 5 g protein/100 mL   Not suitable for use in child under 1 year; not recommended for child 1-6 years unless otherwise stated   Powder provides protein equivalent 12.5 g, carbohydrate 59 g, fat 17.45 g, energy 1871 kJ (443kcal)/100g   Not suitable for use in child under 1 year; not recommended for child 1-6 years unless otherwise stated   Banana, black currant, cappucci-  no, chocolate, lemon, neutral,  strawberry, tropical fruits, vanilla   2. Strawberry flavour may contain traces of wheat starch and egg   Not suitable for child under 2 years;  not recommended for child 2-10  years    A7. 1.2.1 Enteral feeds: 1.5kcal/mL and 5 g (or more) protein/100 mL (product list continued)  Not suitable for use in child under 1 year; not recommended for child 1-6 years unless otherwise stated   Bottle: 4 x 200 mL = £6.97  Apricot, banana, chocolate, cof-  fee, strawberry-raspberry, vanilla    A7. 1.2.2 Enteral feeds: Less than 1.5kcal/mL and 5g (or more) protein/100 mL   Not suitable for use in child under 1 year; not recommended for child 1-6 years unless otherwise stated   Not suitable for child under 2 years; 1000 mL = £9.16  not recommended for child 2-10 1500 mL = £13.75   Not suitable for child under 2 years;  not recommended for child 2-10  years   Not suitable for child under 2 years;  not recommended for child 2-10  years    Disease-related malnutrition in Flexible pack: 1000 mL = £8.85  patients with low energy and/or low  fluid requirements   Short bowel syndrome, intractable  malabsorption, proven inflamm-  atory bowel disease, bowel fistula  Not suitable for child under 3 years    Bottle: 500 mL = £4.80  Flexible pack: 1000 mL = £9.59  1500 mL = £14.41    Flexible pack: 500 mL = £4.18  1000 mL = £8.06  1500 mL = £12.07    A7. 1.2.3 Enteral feeds: More than 1.5kcal/mL and 5g (or more) protein/100 mL   Not suitable for use in child under 1 year; not recommended for child 1-6 years unless otherwise stated   Not suitable for use in child under 1 year; use with caution in child 1-5 years unless otherwise stated    A7.2.1.2 Nutritional supplements: More than 1 kcal/mL and less than 5g protein/100 mL   Not suitable for use in child under 1 year; use with caution in child 1-5 years unless otherwise stated    A7. 2.2.1 Nutritional supplements: 1.5kcal/mL and 5 g (or more) protein/100 mL   Not suitable for use in child under 1 year; use with caution in child 1-5 years unless otherwise stated    A7. 2.2.1 Nutritional supplements: 1.5kcal/mL and 5 g (or more) protein/100 mL (product list continued)   Not suitable for use in child under 1 year; use with caution in child 1-5 years unless otherwise stated   Banana, black currant, caramel,  chocolate, coffee, fruits of the  forest, orange, peach, raspberry,  strawberry, vanilla, neutral   Starter pack (5-10 day’s supply), contains: Ensure ® Plus Milkshake Style (various flavours), 1 pack (10 x 220-mL)   Bottle, 4 x Fortijuce ®, 2 x Fortisip ® Yogurt Style, 1 pack (10 x 200 mL) = £18.50.   Bottle: 200 mL = £1.82  Cappuccino, chocolate, straw-  berry, tropical fruits, vanilla   Not suitable for child under 3 years;  use with caution in child 3-4 years    A7 .2.2.2 Nutritional supplements: Less than 1.5 kcal/mL and 5 g (or more) protein/100 mL   year; use with caution in child 1-5 years unless otherwise stated   Standard dilution  of powder (74 g  in 250 mL water)  (sip feed)   Preoperative nutritional supplement  for malnourished patients or  patients at risk of malnourishment  Not suitable for child under 3 years    Powder provides: protein 16.8 g, carbohydrate 40.2 g, fat 8.3 g, fibre 3g, energy 1276 kJ (303 kcal)/74 g    A7. 2.2.2 Nutritional supplements: Less than 1.5kcal/mL and 5 g (or more) protein/100 mL (product list continued)   Not suitable for use in child under 1 year; use with caution in child 1-5 years unless otherwise stated    A7.2.2.3 Nutritional supplements: More than 1.5kcal/mL and 5g (or more) protein/100 mL   Not suitable for use in child under 1 year; use with caution in child 1-5 years unless otherwise stated   Powder 57 g reconstituted with 200 mL whole milk provides: protein 15.6 g, carbohydrate 44.5 g, fat 16.4 g, energy 1621kJ (387 kcal)   = 3 heaped tablespoonfuls in 250 mL water provides: protein 12.5 g, carbohydrate 32.7 g, fat 7.6 g, energy 1048 kJ (249 kcal)   = 4 heaped tablespoonfuls in 250 mL water provides: protein 12.3 g, carbohydrate 38 g, fat 7.5 g, fibre 5g, energy 1 137 kJ (270 kcal)   Bottle: 200 mL = £1.73  Apricot-peach, cappuccino, fruits  of the forest, toffee, vanilla   Pot: 4 x 125 g = £7.08  Cappuccino, chocolate, praline,  strawberry, vanilla   Not suitable for child under 6 years;  use with caution in child 6-10 years   Sachet: 12 x 110 g = £36.26  Apple, chocolate, honey, orange   Sachet: 12 x 110 g = £50.76  Chicken, chickpea, fish, fish-  vegetable, ham, lentil, veal,  vegetable, winter vegetable   Powder provides: protein 15g, carbohydrate 58 g, fat 17.5 g, energy 1889 kJ (450kcal)/100g   Not suitable for child under 1 year;  use as nutritional supplement only  in children 1-6 years.   Nutritional supplement in patients  with lung cancer undergoing  chemotherapy, or with pancreatic  cancer   76 g  protein  equivalent  (whey pro-  tein, plus  branched  chain amino  acids)   Nutritional supplement for use in  chronic liver disease and/or porto-  hepatic encephalopathy   Enteral feed or nutritional supple-  ment in children over 1 year with  hepatic disorders   Powder provides: protein equivalent 11 g, carbohydrate 62 g, fat 19 g, energy 1944 kJ (463kcal)/100g   Powder provides: protein 11.1 g, carbohydrate 64.2 g, fat 19.9 g, energy 2016 kJ (480kcal)/100g   ment as part of ketogenic diet in  management of epilepsy resistant to  drug therapy, in children overl year,   only on the advice of secondary care  physician with experience of keto-  genic diet    Powder provides: protein 15.25 g, carbohydrate 3 g, fat 73 g,   Powder provides: protein 7.5 g, carbohydrate 59 g, fat 26.3 g, energy 2104 kJ (504kcal)/100g   Powder provides: protein 18 g, carbohydrate 54 g, fat 23 g, 2070 kJ (500kcal)/100g   Not suitable for child under 1 year;  use with caution in child 1-5 years   Not suitable for child under 1 year;  use with caution in child 1-4 years   Powder provides: protein 7.5 g, carbohydrate 63 g, fat 23.2 g, energy 2053 kJ (491kcal)/100g    management of disease-related  malnutrition in patients with chronic  obstructive pulmonary disease and  body-mass index less than 20.   Enteral feed or nutritional supple-  ment in patients with chronic or  acute renal failure who are not  undergoing dialysis, or with chronic  or acute liver disease with fluid  restriction; other conditions requir-  ing high energy, low protein, low  electrolyte, low volume enteral feed  Not suitable for child under 1 year;  use with caution in child 1-5 years   Enteral feed or nutritional supple-  ment in patients with pancreatic  cancer or with lung cancer under-  going chemotherapy   Not suitable for child under 1 year;  use with caution in child 1-4 years   Flavoured carbohydrate supplements are not suitable for child under 1 year; liquid supplements should be diluted before use in child under 5 years    ACBS Indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high or readily available carbohydrate supplement   Flavoured carbohydrate supplements are not suitable for child under 1 year; liquid supplements should be diluted before use in child under 5 years    ACBS Indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high or readily available carbohydrate supplement   Contents of each sachet should be reconstituted with water to a total volume of 200 mL    For use as an emergency regimen in  the dietary management of inborn  errors of metabolism in adults and  children from birth   Sachets: 30 x 21 g (S.O.S. 10) =  £6.30; 30 x 31 g (S.O.S. 15) =  £9.30; 30 x 42 g (S.O.S. 20) =  £12.60; 30 x 52 g (S.O.S. 25) =  £15.60   Liquid supplements should be diluted before use in child under 5 years   ACBS indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high fat (or fat and carbohydrate) supplement   Powder provides: carbohydrate 66.7 g, fat 25 g, energy 2059 kJ (492kcal)/100 g   lymphangiectasia, intestinal sur-  gery, chronic liver disease, liver  cirrhosis, other proven malabsorp-  tion syndromes, ketogenic diet in  epilepsy, and in type 1 lipoprotei-  naemia   Nutritional supplement for steator-  rhoea associated with cystic fibrosis  of the pancreas, intestinal lymph-  angiectasia, intestinal surgery,  chronic liver disease and liver cirrh-  osis, other proven malabsorption  syndromes, ketogenic diet in man-  agement of epilepsy, type 1 hyper-  lipoproteinaemia   With vitamins, minerals, energy, vitamins, minerals, and  and trace elements trace elements following a protein-   ACBS indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high fat or   Hypoproteinaemia, chronic renal  failure, wound fistula leakage with  excessive protein loss, conditions  requiring a controlled nitrogen  intake, and haemodialysis   Powder provides: protein equivalent 25 g, carbohydrate 65 g, vitamin C 125 mg, energy 1530 kJ (360kcal)/100 g   Powder: one sachet reconstituted with 240 mL whole milk provides approx. 2 kcal/mL and protein 12 g   Powder: one sachet reconstituted with 240 mL whole milk provides approx. 2 kcal/mL and protein 16 g   Powder 15 g provides: protein 2g, carbohydrate 4g, fat 8.4 g, energy 418 kJ (100 kcal)    Powder 13 g provides: protein 600 mg, carbohydrate 2.2 g, fat 10 g, energy 418 kJ (100 kcal)    Powder: 85 g reconstituted with 240 mL whole milk provides: protein 1 1.7 g, carbohydrate 66.8 g, fat 30.4 g, energy 2457 kJ (588 kcal)   ACBS indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high fat or carbohydrate (with protein) supplement    Vitamin and mineral supplement in  infants and children with restrictive  therapeutic diets   For the relief of symptoms associated with lactose intolerance in  infants, provided that lactose intolerance is confirmed by the  presence of reducing substances and/ or excessive acid in stools, a  low concentration of the corresponding disaccharide enzyme on  intestinal biopsy or by breath hydrogen test or lactose intolerance  test. For dosage and administration details, consult product lit-  erature   Powder, containing 8 strains of live, freeze-dried, lactic acid  bacteria. Contains traces of soya, gluten, and lactose. Net  price 30 x 4.4-g sachets = £32.98   Nutritional supplement for use under the supervision of a physi-  cian, for the maintenance of remission of ileoanal pouchitis  induced by antibacterials in adults. For dosage and administration  details, consult product literature   Powder, modified maize starch, gluten- and lactose-free, Net  price 20 x 9-g sachets = £5.88; 225 g = £4.51.   For thickening of foods in dysphagia. Not suitable for children  under 3 years   Liquid, carbohydrate 22 g, energy: orange 382 kJ (90kcal);  apple 375kJ (89kcal)/100mL. Syrup and custard consis-  tencies. Gluten- and lactose-free, net price 12 x 114-mLcups  = £7.44   Powder, modified maize starch. Gluten- and lactose-free, net  price 227 g = £4.35; 75 x 4.5-g sachet = £16.66  For thickening of foods in dysphagia. Not suitable for children  under 1 year   Powder, carbohydrate content varies with flavour and cho-  sen consistency (3 consistencies available), see product  literature. Flavours: black currant, lemon, orange; (hot  drinks) chocolate, white coffee, net price 25 x 115mL =  £7.50.   Nutritional supplement for patient hydration in the dietary man-  agement of dysphagia. Not suitable for children under 3 years   Powder. Modified maize starch, net price 225-g can = £4.46;  100 x 9-g sachets = £26.35; 4.54 kg = £70.53.   Thickened Juices, liquid, modified food starch. Flavours:  apple, orange, net price 118-mL pot = 58p; apple, black  currant, cranberry, kiwi-strawberry, and orange, 1.42-litre  bottle = £3.61.   For thickening of foods in dysphagia. Not suitable for children  under 1 year except in cases of failure to thrive   For thickening of foods in dysphagia. Not suitable for children  under 1 year except in cases of failure to thrive   Powder. Modified maize starch. Net price 300 g = £6.66; 2 kg  = £33.91; 6 kg = £87.83.   For thickening of foods in dysphagia. Not suitable for children  under 1 year except in cases of failure to thrive   Powder, flavours: banana, chocolate, coffee, lemon-lime,  strawberry. Net price 60 g = £6.85   Powder, flavours: black currant, lemon, orange, tropical or  raspberry, net price 30 x 4-g sachets = £11.54  For use with Vitaflo’s range of unflavoured protein substitutes for  metabolic diseases   Powder, flavours: black currant, orange, pineapple, 100 g =  £10.24; cherry-vanilla, grapefruit, lemon-lime, 20 x 5-g  sachets = £10.24   For use with unflavoured SHS products based on peptides or  amino acids; not suitable for child under 6 months    ACBS indications: established gluten-sensitive  enteropathies including steatorrhoea due to gluten  sensitivity, coeliac disease, and dermatitis herpeti-  formis.   Gluten-free. Loaf, multigrain 500 g = £4.83. Loaf, sliced,  wholemeal 500 g = £3.36. Loaf, sliced, part-baked, country-  style 250 g = £3.69. Loaf, sliced, part-baked, white 550 g =  £4.88. Rice bread, brown 500 g = £4.83; white 500 g = £4.83   Gluten-free. Loaf, sliced, multigrain, brown 400 g = £3.01;  white 400 g = £3.01.   Gluten-free. Loaf, sliced Seattle brown 600 g = £5.28. Rice  bread, sliced, brown 474 g = £4.59; white 456 g = £4.59. Rice  loaf, sliced 612 g = £4.59. Tapioca bread, sliced 480 g = £4.59   Gluten-free. Loaf, unsliced, brown 400 g = £2.49; white 400 g  = £2.49   Gluten-free. Loaf, sliced, fibre 400 g = £3.41; white 400 g =  £3.41   Gluten-free. Loaf, sliced, fresh, brown 400 g = £3.25; white  400 g = £3.25. Loaf, sliced, fibre 400 g = £3.12; white 400 g =  £3.12. Loaf, seeded 400 g = £3.39.   Gluten-free. Loaf, sliced, fresh, fibre 400 g = £2.97; white  400 g = £3.23. Loaf, sliced, white 400 g = £3.10; fibre 400 g =  £3.10. Loaf, white 400 g = £3.10; fibre 400 g = £3.10. Loaf,  part-baked, fibre 400 g = £3.33; white 400 g = £3.46   Gluten-free. Loaf, sliced, brown 400 g = £2.82; high fibre  400 g = £2.82; white 400 g = £2.82. Loaf, brown 400 g =  £2.82; high fibre 400 g = £2.82; white 400 g = £2.82   Gluten-free. Loaf, sliced, brown (seeded) 200 g = £2.25;  white 200 g = £2.25   Gluten-free. Loaf, sandwich, sliced, white 260 g = £3.29;  rustic, sliced, white 260 g = £3.29.   Gluten-free. Loaf, sliced, white 165 g = £2.30; sandwich  155 g = £2.32. Rice bread, brown 220 g = £2.30; sandwich  220 g = £2.30.   Gluten-free. Loaf, mixed grain, sour dough 400 g = £1.91  Ultra® (Ultrapharm)   Gluten-free. Loaf, part-baked, white 400 g = £2.46; high fibre  500 g = £3.35   Gluten-free. Loaf, sliced 600 g = £4.95; unsliced 600 g =  £4.85   Gluten-free. Baguette, part-baked 200 g = £3.69. Rolls, part-  baked 2 x 100 g = £3.30; 6 x 50 g = £3.69   Gluten-free. Baguette, part-baked, white 160 g = £1.99. Rolls,  part-baked, white 2 x 80 g = 2.39; rustic, part-baked, white 2  x 105 g =£2.39   Gluten-free. Baguette, part-baked 2 x 125 g = £3.24. Buns 4  x 50 g = £3.26. Lunch rolls, white 8 x 34 g = £3.26. Rolls,  part-baked, white, dinner 4 x 35 g = £2. 18; hotdog 3 x 35 g =  £2.24; long 3 x 83 g = £2.95.   Gluten-free. Baguette, part-baked 2 x 200 g = £2.46. Rolls,  part-baked 4 x 70 g = £2.46   Gluten-free. Burger buns 4 x 75 g =£3.95. Rolls 4 x 70 g =  £3.65   Gluten-free. Flat bread (pitta) 4 = £3.00. Tear-drop shape  (naan) 2 x 90 g = £3.00   Gluten-free. Flat bread (pitta), part-baked 3 x 40 g = £4.36   Gluten-free. Biscuits, coffee-style 200 g = £2.86; digestive  175 g = £2.20   Gluten-free. Biscuits, plain 200 g = £3.77; digestive 150g =  £1.94; savoury 125 g = £1.94; savoury shorts 150 g = £2.65;  shortbread 100 g = £1.60; sweet (without chocolate or sul-  tanas) 150 g = £1.94; tea 150 g = £1.94   Gluten-free. Biscuits, digestive 150 g = £2.67; savoury 150 g  = £3.35; sweet 150 g = £2.52, tea 150 g = £2.67   Gluten-free. Rolls, dinner x 6 = £3.1 1; white, long 4 x 55 g =  £2.50; round 4 x 55 g = £2.50   Gluten-free. Baguette 2 x 175 g = £3.20. Rolls, fibre 4 x 50 g  = £3.41; white 4 x 50g = £3.41   Gluten-free. Rolls, fibre 4 x 65 g = £3.25; white 4 x 65 g =  £3.25. Rolls, part-baked, white 4 x 50 g = £3.35; long 2 x 75 g  = £2.56   Gluten-free. Rolls, fresh, fibre 5 x 85 g = £4.17; white 5 x  85 g = £4.17. Rolls, fibre 5 x 85 g = £4.18; white 5 x 85 g =  £4.18. Rolls, part-baked, fibre 5 x 75 g = £4.33; white 5 x  75 g = £4.33   Gluten-free. Rolls, brown 5 x 80 g = £2.82; high fibre 5 x  80 g = £2.82; white 5 x 80 g = £2.82   Gluten-free. Baguette, white 250 g = £2.50. Buns, toasting 4  x 50 g = £2.50. Rolls, white 4 = £2.25. Rolls, part-baked,  circle (bagel) 2 x 90 g = £2.50; dinner (square) 2 x 80 g =  £2.09   Gluten-free. Crackers, high fibre 200 g = £2.64; plain 200 g =  £3.16; mini 175g = £2.70.   Gluten-free. Flour mix, bread 500 g = £5.74. Plain 750 g =  £5.88   Gluten-free. Flour mix, bread, white 500 g = £5.33. Cake,  white 750 g = £5.33. Plain, white 500 g = £5.33   Gluten-free. Flour mix, bread, brown 375 g = £1.99 (seeded);  bread, white and pizza 375 g = £1.99   Gluten-free. Flour mix, fibre 500 g = £5.91; white 500 g =  £5.91   Gluten-free. Flour mix, bread, fibre 500 g = £6.06; white  500 g = £6.06. Cake 500 g = £6.06. Fibre 500 g = £6.06; white  500 g = £5.91. Pastry 500 g = £6.06   Gluten-free. Flour mix, organic, bread, standard 500 g =  £8.30; high fibre 500 g = £8.30   Gluten-free. Flour mix, bread, white 500 g = £5.25. Cake,  white 500 g = £5.25. Pizza base 500 g = £5.25   Gluten-free. Flour mix, fibre 500 g = £6.44; plain 500 g =  £6.44; harvest 500 g = £6.44   Gluten-free. Flour mix, bread 450 g = £3.10. Self-raising  500 g = £3.10. Pastry and pizza 375 g = £3.80   Gluten-free. Flour mix, blended 1kg = £3.90. Potato starch  500 g = £1.55. Rice, brown 500 g = £1.45; white 500 g =  £1.55. Tapioca starch 500 g = £2.08. Teff, brown 1 kg = £4.40;  white 1 kg = £4.40   Gluten-free. Flour mix, teff, brown 1 kg = £2.95; white 1 kg =  £2.95   Gluten-free. Flour mix, bread, brown 1 kg = £6.60; white 2 kg  = £13.20. Plain 2 kg = £13.20   Gluten-free. Pasta, animal shapes 500 g = £4.95; macaroni  500 g = £4.95; spaghetti 500 g = £4.95; spirals 500 g = £4.95;  tagliatelle 500 g = £4.95. Buckwheat, penne 250 g = £2.48;  spirals 250 g = £2.48   Gluten-free. Pasta, potato-based, gnocchi 500 g = £5.59;  perle di gnocchi 500 g = £5.60. Tubetti 500 g = £5.90   Gluten-free. Pasta, fusilli 500 g = £3.44; penne 500 g = £3.44;  spaghetti 500 g = £3.44   Gluten-free. Pasta, rice-based, lasagne 454 g = £4.27;  macaroni 454 g = £4.27; shells, small 454 g = £4.27; spaghetti  454 g = £4.27; vermicelli 300 g = £4.27   Gluten-free. Pasta, lasagne 250 g = £3.21; macaroni penne  500 g = £6.13; shells 500 g = £6.13; spirals 500 g = £6.13;  spaghetti, long 500g = £6.13; tagliatelle 250g = £3.21   Gluten-free. Pasta, fusilli 500 g = £6.31; lasagne 250 g =  £3.22; macaroni 500 g = £6.31; spaghetti 500 g = £6.31;  tagliatelle 250 g = £3.04. Fibre, linguine 500 g = £5.79; penne  500 g =£5.79   Gluten-free. Pasta, rice and com, lasagne 200 g = £3.03;  macaroni 250 g = £2.35. Spirals, buckwheat 250 g = £2.35;  com 250 g = £2.35; rice and com 250 g = £2.35; rice and  millet 250 g = £2.35   Gluten-free. Pasta, macaroni 500 g = £2.99; elbow 500 g =  £2.99; spaghetti 500 g = £2.99.   Gluten-free. Pasta, macaroni penne 250 g = £2.95; puntini 2  x 250 g = £5.90; spaghetti, short 2 x 250 g = £5.90; spirals  250 g = £2.59   Gluten-free. Pasta, brown rice, fusilli 500 g = £2.60; lasagne  375 g = £2.60; penne 500 g = £2.60; spaghetti 500 g = £2.60   Gluten-free. Pasta, fusilli 250 g = £2.95; penne 250 g = £2.95;  spaghetti 250 g = £2.95   Gluten-free. Pizza crust, rice, brown 150 g = £4.21; white  150 g =£4.21   Gluten-free, wheat-free. Bread loaf, six flour 576 g = £3.60.  Rolls, Seattle brown, round (hamburger) 4 x 1 19 g = £3.00;  long (hot dog) 4 x 1 19 g = £3.00. Pizza base, 3 x 124 g =  £3.75   Gluten-free, wheat-free. Flour mix, bread 500 g = £6.06;  fibre 500 g = £6.06. Cake mix 500 g = £6.06. Crispbread 150 g  = £3.82   Gluten-free, wheat-free. Flour mix, organic, bread, fibre  500 g = £8.30. Bread and cake mix 500 g = £6.33   Low-protein. Jelly, orange 4 x 80 g = £7.43, cherry 4 x 80 g  = £7.43    ACBS indications: inherited metabolic disorders,  renal or liver failure, requiring a low-protein diet   Low-protein. Dessert mix, caramel 6 x 36.5 g = £5.77;  custard 6 x 36.5 g = £5.77; chocolate and banana 6 x 36.5 g  = £5.77; strawberry and vanilla 6 x 36.5 g = £5.77. Rice  pudding imitation, apple 4 x 69 g = £5.77; banana 4 x 69 g =  £5.77; original 4 x 69 g = £5.77; strawberry 4 x 69 g = £5.77   Low protein. Loaf, sliced 400 g = £3.19. Rolls 5 x 70 g =  £3.96   Low protein. Loaf, sliced 400 g = £3.35. Rolls, white 4 x 65 g  = £3.12; part-baked 4 x 65 g = £3.52   Low-protein. Cookies, cinnamon 125 g = £6.67; chocolate  chip 1 10 g = £6.67; orange 125 g = £6.67   Low-protein. Crunch bar 8 x 41 g = £11.92. Wafers, cho-  colate 100 g = £2.17; vanilla 100 g = £2.17. Crackers 150 g =  £3.05, herb 150g = £3.05   Low-protein. Aminex ® biscuits 200 g = £4.67; cookies 150 g  = £4.67. Cookies, chocolate chip 150 g = £4.67; cinnamon  150 g = £4.67; orange 150 g = £4.67. Rusks 200 g = £4.67.  Cripsbread 75 g = £2.24   Low-protein. Cake bars, apricot 6 x 40 g = £5.77, lemon 6 x  40 g = £5.51, pear 6 x 40 g = £5.77   Low protein. Bar, protein 30 mg (less than 2.5 mg phenyla-  lanine), carbohydrate 15.35 g, fat 8.4 g, energy 572 kJ  (137kcal)/25g. Chocolate flavoured, 25 g = £1.02.   Low-protein. Breakfast cereal flakes, apple 375 g = £6.70;  chocolate 375 g = £6.70; strawberry 375 g = £6.70. Cereal  loops 375 g = £6.95   Low-protein. Hot breakfast (powder sachets), apple and  cinnamon 6 x 57 g = £7.35, banana 6 x 57 g = £7.35,  chocolate 6 x 57 g = £7.35; original 6 x 56 g = £7.35   Low-protein. Powder, chocolate 150 g = £4.10; strawberry  150 g = £4.10; vanilla 150g = £4.10   Low protein. All purpose mix 500 g = £6.66. Cake mix, 2 x  250 g = £6.66; chocolate-flavour 2 x 250 g = £6.66   Low-protein. Mix, plain 500 g = £7.09; chocolate 500 g =  £7.50; lemon 500 g = £7.50. Egg replacer 2 x 250 g = £13.03.  Egg-white replacer lOOg = £8.38   Low-protein. Flour mix 750 g = £9.91. Egg replacer 350 g =  £4.67   Low-protein. Pasta, animal shapes 500 g = £7.13; conchigle  500 g = £7.15; spirals 500 g = £7.42; gnoccetti sardi 500 g =  £7.15; lasagne 250 g = £3.61; macaroni elbows 250 g = £3.56;  penne 500 g = £7.42; spaghetti 500 g = £7.42; tagliatelle 250 g  = £3.56; vermicelli 250 g = £3.69. Rice, imitation 500 g =  £7.20   Low-protein. Pasta, alphabet shapes 500 g = £6.48; lasagne  sheets 200 g = £2.76; macaroni 500 g = £6.48; noodles, flat  500 g = £6.48; shells 500 g = £6.48; spaghetti, short-cut 500 g  = £6.48; spirals 500 g = £6.48. Rice, imitation 500 g = £6.48.  Tricolour pasta, alphabet shapes 500 g = £6.48; shells 500 g  = £6.48; spirals 500 g = £6.48.   Low-protein. Burger mix 2 x 62 g = £5.77; lamb & mint 2 x  62 g = £5.77. Couscous 500 g = £6.48. Pasta elbows in cheese  and broccoli sauce 4 x 66 g = £7.54. Pasta meal 500 g =  £6.48. Pasta shells in tomato, pepper, and herb sauce 4 x 72 g  = £7.54. Pasta spirals in Moroccan sauce 4 x 72 g = £7.54.  Sausage mix, apple & sage 4 x 30 g = £6.49; original 4 x 30 g  = £6.49; tomato & basil 4 x 30 g = £6.49   Powder, protein equivalent (essential and non-essential  amino acids except lysine, and low tryptophan) 13.1 g,  carbohydrate 49.5 g, fat 23 g, fibre 5.3 g, energy 1915 kJ  (457kcal)/100g, with vitamins, minerals, and trace ele-  ments; standard dilution (15%) provides protein equivalent  2 g, carbohydrate 7.4 g, fat 3.5 g, fibre 800 mg, energy 287 kJ  (69 kcal)/ 100 mL. Unflavoured, net price 400 g = £32.70 (5-g  measuring scoop provided)   Nutritional supplement for the dietary management of proven  glutaric aciduria (type 1) in children from birth to 3 years   Gel, protein equivalent (essential and non-essential amino  acids except lysine, and low tryptophan) 8.4 g, carbohydrate  8.6 g, fat trace, energy 286 kJ (68kcal)/20g, with vitamins,  minerals, and trace elements. Unflavoured (flavouring: see  FlavourPac® , p. 925), net price 30 x 20-g sachets = £149.04  Nutritional supplement for dietary management of type 1 glutaric  aciduria in children 1-10 years   Liquid, protein (essential and non-essential amino acids  except methionine) 15 g, carbohydrate 7g, fat 500 mg,  energy 386 kJ (92 kcal)/130 mL, with vitamins, minerals and  trace elements. Orange or red flavour, net price 30 x 130-mL  pouch = £277.20   A methionine-free protein substitute for use as a nutritional  supplement in patients over 3 years of age with homocystinuria   Powder, protein (essential and non-essential amino acids  except methionine) 15 g, carbohydrate 3.8 g, fat 30 mg,  energy 315 kJ (75.3kcal)/25g with vitamins, minerals and  trace elements. Unflavoured (flavouring: see FlavourPac ®,  p. 925), net price 30 x 25-g sachets = £271.88  A methionine-free protein substitute for use as a nutritional  supplement in patients over 8 years of age with homocystinuria   Powder, protein (essential and non-essential amino acids  except methionine) 8.4 g, carbohydrate 8.6 g, fat 30 mg,  energy 286 kJ (68kcal)/20g with vitamins, minerals and  trace elements. Unflavoured (flavouring: see FlavourPac ® ,  p. 925), net price 30 x 20-g sachets = £151.93  A methionine-free protein substitute for use as a nutritional  supplement for the dietary management of children 1-10 years  with homocystinuria   Powder, protein equivalent (essential and non-essential  amino acids except lysine, and low tryptophan) 25 g,  carbohydrate 51 g, fat less than 500 mg, energy 1311 kJ  (309 kcal)/ 100 g, with vitamins, minerals, and trace ele-  ments. Unflavoured, (flavouring: see Modjul ® Flavour  System, p. 925), net price 500 g = £82.57  Nutritional supplement for the dietary management of type 1  glutaric aciduria   Powder, protein equivalent (essential and non-essential  amino acids except lysine and tryptophan) 79 g, carbohy-  drate 4g, energy 141 1 kJ (332 kcal)/ 100 g. Unflavoured  (flavouring: see Modjul ® Flavour System, p. 925), net price 2  x 500g = £312.84   Nutritional supplement for the dietary management of type 1  glutaric aciduria in children and adults; requires additional source  of vitamins, minerals, and trace elements   Powder, protein 200 mg, carbohydrate (maize starch) 47.6 g,  fat 100 mg, fibre less than 600 mg, energy 803 kJ (192 kcal)/  60 g, net price 30 x 60-g sachets = £92.03  Nutritional supplement for use in the dietary management of  glycogen storage disease and other metabolic conditions where a  constant supply of glucose is essential. Not suitable for children  under 2 years   Powder, protein equivalent (essential and non-essential  amino acids except methionine) 13.1 g, carbohydrate 49.5 g,  fat 23 g, fibre 5.3 g, energy 1915 kJ (457 kcal)/ 100 g, with  vitamins, minerals, and trace elements; standard dilution  (15%) provides protein equivalent 2 g, carbohydrate 7.4 g, fat  3,5 g, fibre 800 mg, energy 287 kJ (69 kcal)/ 100 mL. Unfla-  voured, net price 400 g = £32.70 (5-g measuring scoop  provided)   Nutritional supplement for the dietary management of proven  vitamin B 6 non-responsive homocystinuria or hypermethionin-  aemia in children from birth to 3 years   Powder, protein (essential and non-essential amino acids  except methionine) 20 g, carbohydrate 2.5 g, fat 190 mg,  energy 390 kJ (92kcal)/27.8-g sachet, with vitamins,  minerals and trace elements. Unflavoured (flavouring: see  Modjul ® Flavour System, p. 925) or tropical flavour (for-  mulation varies slightly), net price 30 x 27.8-g sachets =  £434.40   A nutritional supplement for the dietary management of hyper-  methioninaemia or vitamin B 6 non-responsive homocystinuria in  patients over 8 years.   Powder, protein equivalent (essential and non-essential  amino acids except methionine) 77 g, carbohydrate 4.5 g, fat  nil, energy 1386 kJ (326 kcal)/ 1 00 g. Unflavoured  (flavouring: see Modjul® Flavour system, p. 925), net price  500 g = £156.42   Nutritional supplement for the dietary management of hyper-  methioninaemia or homocystinuria in children and adults   Powder, protein equivalent (essential and non-essential  amino acids except methionine) 25 g„ carbohydrate 51 g, fat  less than 500 mg, energy 1311 kJ (309 kcal)/ 1 00 g, with  vitamins, minerals, and trace elements. Unflavoured  (flavouring: see Modjul® Flavour Sytem, p. 925), net price  500 g = £82.57   Nutritional supplement for the dietary management of hyper-  methioninaemia or homocystinuria   Powder, protein equivalent (essential and non-essential  amino acids except methionine) 39 g, carbohydrate 34 g, fat  less than 500 mg, energy 1260 kJ (297 kcal)/ 100 g, with  vitamins, minerals, and trace elements. Unflavoured  (flavouring: see Modjul® Flavour System, p. 925), net price  500 g = £132.36   Nutritional supplement for the dietary management of hyper-  methioninaemia or homocystinuria   Powder, protein equivalent (essential and non-essential  amino acids except lysine) 13.1 g, carbohydrate 49.5 g, fat  23 g, fibre 5.3 g, energy 1915 kJ (457 kcal)/ 100 g, with vita-  mins, minerals, and trace elements; standard dilution (15%)  provides protein equivalent 2 g, carbohydrate 7.4 g, fat 3.5 g,  fibre 800 mg, energy 287 kJ (69 kcal)/ 100 mL. Unflavoured,  net price 400 g = £32.70 (5-g measuring scoop provided)  Nutritional supplement for the dietary management of proven  hyperlysinaemia in children from birth to 3 years    1. Maxamaid products are generally intended for use in  children 1-8 years    2. Maxamum products are generally intended for use in  children over 8 years and adults   Powder, protein equivalent (essential and non-essential  amino acids except lysine) 25 g, carbohydrate 51 g, fat less  than 500 mg, energy 1311 kJ (309kcal)/100g, with vitamins,  minerals, and trace elements. Unflavoured (flavouring: see  Modjul ® Flavour System , p. 925), net price 500 g = £82.57  Nutritional supplement for the dietary management of hyper-  lysinaemia   Powder, protein equivalent (essential and non-essential  amino acids except leucine) 13.1 g, carbohydrate 49.5 g, fat  23 g, fibre 5.3 g, energy 1915 kJ (457kcal)/100g, with vita-  mins, minerals, and trace elements; standard dilution (15%)  provides protein equivalent 2 g, carbohydrate 7.4 g, fat 3.5 g,  fibre 800 mg, energy 287 kJ (69kcal)/100mL. Unflavoured,  net price 400 g = £32.70 (5-g measuring scoop provided)  Nutritional supplement for the dietary management of proven  isovaleric acidaemia or other proven disorders of leucine metab-  olism in children from birth to 3 years   Powder, protein equivalent (essential and non-essential  amino acids except leucine) 77 g, carbohydrate 4.5 g, fat nil,  energy 1386 kJ (326kcal)/100g. Unflavoured (flavouring:  see Modjul ® Flavour System, p. 925), net price 200 g =  £62.55   Powder, protein equivalent (essential and non-essential  amino acids except leucine) 25 g, carbohydrate 51 g, fat less  than 500 mg, energy 1311 kJ (309kcal)/100g, with vitamins,  minerals, and trace elements. Unflavoured (flavouring: see  Modjut Flavour System, p. 925), net price 500 g = £82.57  Nutritional supplement for the dietary management of isovaleric  acidaemia   Powder, isoleucine 50 mg, carbohydrate 4g, fat nil, energy  64 kJ (15kcal)/4g, net price 30 x 4-g sachets = £44.48  Nutritional supplement for the dietary management of maple  syrup urine disease and other inborn errors of amino acid  metabolism in children over 1 year and adults   Powder, protein equivalent (essential and non-essential  amino acids except isoleucine, leucine, and valine) 77 g,  carbohydrate 4.5 g, energy 1386 kJ (326kcal)/100g. Unfla-  voured, (flavouring: see Modjul ® Flavour System, p. 925),  net price 500 g = £156.42   Nutritional supplement for the dietary management of maple  syrup urine disease and related conditions in children and adults  where it is necessary to limit the intake of branched chain amino  acids   Powder, protein equivalent (essential and non-essential  amino acids except isoleucine, leucine, and valine) 13.1 g,  carbohydrate 49.5 g, fat 23 g, fibre 5.3 g, energy 1915 kJ  (457kcal)/100g, with vitamins, minerals, and trace ele-  ments; standard dilution (15%) provides protein equivalent  2 g, carbohydrate 7.4 g, fat 3.5 g, fibre 800 mg, energy 287 kJ  (69kcal)/100mL. Unflavoured, net price 400 g = £32.70 (5-g  measuring scoop provided)   Nutritional supplement for the dietary management of proven  maple syrup urine disease in children from birth to 3 years    1. Maxamaid products are generally intended for use in  children 1-8 years   Powder, protein equivalent (essential and non-essential  amino acids except isoleucine, leucine, and valine) 8.4 g,  carbohydrate 1 1 g, fat 3.9 g, energy 474 kJ (113kcal)/29-g  sachet, with vitamins, minerals, and trace elements. Unfla-  voured (flavouring: see Modjul ® Flavour System, p. 925),  net price 30 x 29-g sachets = £166.73.   Nutritional supplement for the dietary management of maple  syrup urine disease in children 1-10 years   Liquid, protein equivalent (essential and non-essential amino  acids except isoleucine, leucine, and valine) 10g, carbohy-  drate 8.8 g, fat 4.8 g, fibre 310mg, energy 497kJ (118kcal)/  125 mL, with vitamins, minerals, and trace elements. Lact-  ose-free. Orange flavour, net price 125-mL carton = £7.58  Nutritional supplement for the dietary management of maple  syrup urine disease in children 1-10 years   Powder, protein equivalent (essential and non-essential  amino acids except leucine, isoleucine, and valine) 15g,  carbohydrate 3.8 g, fat less than 100 mg, energy 315kJ  (75kcal)/25g with vitamins, minerals, and trace elements.  Unflavoured (flavouring: see FlavourPac ® sachets, p. 925),  net price 30 x 25-g sachets = £271.88.   Nutritional supplement for the dietary management of maple  syrup urine disease in children over 8 years and adults   Liquid, protein equivalent (essential and non-essential amino  acids except leucine, isoleucine, and valine) 15g, carbohy-  drate 7 g, fat 500 mg, energy 386 kJ (92kcal)/130-mL pouch,  with vitamins, minerals, and trace elements. Orange or red  flavour, net price 30 x 130-mL = £277.20  Nutritional supplement for the dietary management of maple  syrup urine disease in children over 3 years and adults   Powder, protein equivalent (essential and non-essential  amino acids except leucine, isoleucine, and valine) 8.4 g,  carbohydrate 8.6 g, fat less than 100 mg, energy 286 kJ  (68kcal)/20g with vitamins, minerals, and trace elements.  Unflavoured (flavouring: see FlavourPac ® sachets, p. 925),  net price 30 x 20-g sachets = £151.93.   Nutritional supplement for the dietary management of maple  syrup urine disease in children 1-10 years   Powder, protein equivalent (essential and non-essential  amino acids except isoleucine, leucine, and valine) 25 g,  carbohydrate 51 g, fat less than 500 mg, energy 1311 kJ  (309kcal)/100g, with vitamins, minerals, and trace ele-  ments. Unflavoured, (flavouring: see Modjul ® Flavour  System, p. 925), net price 500 g = £82.57  Nutritional supplement for the dietary management of maple  syrup urine disease   Powder, protein equivalent (essential and non-essential  amino acids except isoleucine, leucine, and valine) 39g,  carbohydrate 34 g, fat less than 500 mg, energy 1260 kJ  (297kcal)/100g, with vitamins, minerals, and trace ele-  ments. Orange flavour or unflavoured (flavouring: see  Modjul ® Flavour System, p. 925), net price 500 g = £132.36  Nutritional supplement for the dietary management of maple  syrup urine disease   Powder, valine 50 mg, carbohydrate 4 g, fat nil, energy 64 kJ  (15kcal)/4g, net price 30 x 4-g sachets = £44.48  Nutritional supplement for the dietary management of maple  syrup urine disease and other inborn errors of amino acid  metabolism in children over 1 year and adults    2. Maxamum products are generally intended for use in  children over 8 years and adults   Powder, protein equivalent (essential and non-essential  amino acids except methionine, threonine, and valine, and  low isoleucine) 13.1 g, carbohydrate 49.5 g, fat 23 g, fibre  5.3 g, energy 1915 kJ (457kcal)/100g, with vitamins,  minerals, and trace elements; standard dilution (15%) pro-  vides protein equivalent 2 g, carbohydrate 7.4 g, fat 3.5 g,  fibre 800 mg, energy 287 kJ (69kcal)/100mL. Unflavoured,  net price 400 g = £32.70 (5-g measuring scoop provided)  Nutritional supplement for the dietary management of proven  methylmalonic acidaemia or propionic acidaemia in children from  birth to 3 years   Powder, protein equivalent (essential and non-essential  amino acids except methionine, threonine, and valine, and  low isoleucine) 77 g, carbohydrate 4.5 g, fat nil, energy  1386kJ (326kcal)/100g. Unflavoured, (flavouring: see  Modjul ® Flavour System, p. 925), net price 200 g = £62.55  Nutritional supplement for the dietary management of methyl-  malonic acidaemia or propionic acidaemia in children and adults   Powder, protein equivalent (essential and non-essential  amino acids except methionine, threonine, and valine, and  low isoleucine) 25 g, carbohydrate 51 g, fat less than 500 mg,  energy 1311 kJ (309kcal)/100g, with vitamins, minerals,  and trace elements. Unflavoured, (flavouring: see Modjul ®  Flavour System, p. 925), net price 500 g = £82.57  Nutritional supplement for the dietary management of methyl-  malonic acidaemia or propionic acidaemia   Powder, protein equivalent (essential and non-essential  amino acids except methionine, threonine, and valine, and  low isoleucine) 39 g, carbohydrate 34 g, fat less than 500 mg,  energy 1260 kJ (297kcal)/100g, with vitamins, minerals,  and trace elements. Unflavoured (flavouring: see Modjul ®  Flavour System, p. 925), net price 500 g = £132.36  Nutritional supplement for the dietary management of methyl-  malonic acidaemia or propionic acidaemia   Powder, leucine 100 mg, carbohydrate 4g, fat nil, energy  64 kJ (15kcal)/4g, net price 30 x 4-g sachets = £44.48  Nutritional supplement for the dietary management of inborn  errors of amino acid metabolism in children over 1 year and adults   Powder, protein (cows’ milk) 4.5 g (phenylalanine 100 mg),  carbohydrate 59.5 g, fat 29.9 g, fibre nil, energy 2194kJ  (528kcal)/100g, with vitamins, minerals, and trace ele-  ments. Contains lactose. Net price 400 g = £7.76 (5-g mea-  suring scoop provided)   Nutritional supplement for the dietary management of inborn  errors of amino acid metabolism in adults and children over 1 year   Powder, phenylalanine 50 mg, carbohydrate 3.8 g, energy  64 kJ (15kcal)/4g, net price 30 x 4-g sachets = £43.18  Nutritional supplement for use in the dietary management of  inborn errors of metabolism only   Liquid, carbohydrate 8.1 g (of which sugars 3.5 g), fat 3.8 g,  energy 278 kJ (66kcal)/100mL. Contains lactose. Net price  18 x 250 mL = £22.50; 6 x 1 litre = £30.00  A protein-free nutritional supplement for the dietary management  of inborn errors of metabolism in children over 6 months and  adults   Powder, protein equivalent (containing essential and non-  essential amino acids except phenylalanine) lOg, carbohy-  drate nil, fat 5.1 g, energy 359 kJ (86kcal)/18.2-g sachet,  with vitamins, minerals, and trace elements. Unflavoured  (flavouring: see Modjul ** Flavour System, p. 925), net price  60 x 18.2-g sachets = £315.60.   Nutritional supplement for the dietary management of proven  phenylketonuria. Not suitable for children under 4 years   Powder, cystine 500 mg, carbohydrate 3.4 g, fat nil, energy  63 kJ (15kcal)/4g, net price 30 x 4-g sachets = £44.48  Nutritional supplement for the dietary management of inborn  errors of amino acid metabolism in adults and children over 1 year   Powder, protein (cows’ milk, soya protein) 100 mg, carbo-  hydrate 3.2 g, fat 500 mg (of which docosahexaenoic acid  200 mg), fibre nil, energy 74 kJ (18kcal)/4g, with minerals,  net price 30 x 4-g sachets = £32.20  Nutritional supplement for the dietary management of inborn  errors of metabolism for adults and children from birth   Powder, protein equivalent (essential amino acids) 5 g,  carbohydrate 4 g, fat nil, energy 151 kJ (36 kcal)/ 1 2.5 g, with  vitamins, minerals, and trace elements. Tropical flavour, net  price 50 x 12. 5-g sachets = £174.48  Nutritional supplement for the dietary management of disorders  of protein metabolism including urea cycle disorders. Not suitable  for children under 3 years   Powder, protein (cows’ milk, soya) 170 mg, carbohydrate  2.8 g, fat 800 mg (of which arachidonic acid 200 mg, doco-  sahexaenoic acid 100 mg), energy 80 kJ (19 kcal) /4g, net  price 30 x 4-g sachet = £32.92   A nutritional supplement for the dietary management of inborn  errors of metabolism    1. Maxamaid products are generally intended for use in  children 1-8 years   Liquid, protein equivalent (containing essential and non-  essential amino acids except phenylalanine) 6.7 g, carbohy-  drate 5.1 g, fat 2g, energy 275 kJ (65 kcal)/ 100 mL with  vitamins, minerals, and trace elements. Forest berries fla-  vour, net price 250-mL carton = £8.11.   Nutritional supplement for the dietary management of proven  phenylketonuria. Not suitable for children under 8 years   Powder, protein equivalent (containing essential and non-  essential amino acids except phenylalanine) 20 g, carbohy-  drate 2.5 g, fat 60 mg, fibre 220 mg, energy 1 2 3 385 kJ (91 kcal)/  27.8-g sachet, with vitamins, minerals, and trace elements.  Flavours: berry, orange or unflavoured, net price 30 x 27.8-g  sachets = £243.60   Nutritional supplement for the dietary management of proven  phenylketonuria in children over 8 years and adults including  pregnant women   Liquid, protein (cows’ milk) 400 mg (phenylalanine 10 mg),  lactose 9.4 g, fat 2g, energy 165 kJ (40 kcal)/ 100 mL. Net  price 200-mL carton = 61p.   Nutritional supplement for the dietary management of phenyl-  ketonuria in children over 1 year and adults   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 60 g, carbohydrate lOg,  fat nil, energy 1190kJ (280 kcal)/ 100 g, with vitamins,  minerals, and trace elements. Vanilla flavour, net price 500 g  = £131.68   Nutritional supplement for the dietary management of phenyl-  ketonuria in children 1-8 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 70 g, carbohydrate 6.8 g,  fat nil, energy 1306 kJ (307kcal)/100g, with vitamins,  minerals, and trace elements. Vanilla flavour, net price 500 g  = £153.62   Nutritional supplement for the dietary management of phenyl-  ketonuria in children 9-14 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 70 g, carbohydrate 4.7 g,  fat nil, energy 1270 kJ (299kcal)/100g, with vitamins,  minerals, and trace elements. Vanilla flavour, net price 500 g  = £153.62   Nutritional supplement for the dietary management of phenyl-  ketonuria in patients 15 years and over   Capsules, protein equivalent (essential and non-essential  amino acids except phenylalanine) 416.5 mg/capsule. Net  price 200-cap pack = £35.77   Tablets, protein equivalent (essential and non-essential  amino acids except phenylalanine), 833 mg/tablet. Net price  75-tab pack = £23.17   Drink Mix, powder, protein equivalent (essential and non-  essential amino acids except phenylalanine) 8.33 g, carbo-  hydrate 8.8 g/20-g sachet. Apple-black currant, citrus, or  tropical flavour. Net price 30 x 20-g sachet = £107.86  Nutritional supplement for the dietary management of phenyl-  ketonuria   Powder, vitamins, minerals, and trace elements, net price 30  X 7-g sachets = £60.00   Tablets, vitamins, minerals, and trace elements, net price  180-tab pack = £68.26   For use as a vitamin and mineral component of restricted ther-  apeutic diets in children 1 1 years and over and adults with  phenylketonuria and similar amino acid abnormalities   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 79 g, carbohydrate 4.5 g,   Nutritional supplement for the dietary management of phenyl-  ketonuria in children and adults   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 13.1 g, carbohydrate  49.5 g, fat 23 g, fibre 5.3 g, energy 1915kJ (457kcal)/100g,  with vitamins, minerals, and trace elements; standard dilu-  tion (15%) provides protein equivalent 2g, carbohydrate  7.4 g, fat 3.5 g, fibre 800 mg, energy 287 kJ (69kcal)/100mL.  Unflavoured, net price 400 g = £29.72 (5-g measuring scoop  provided)   Nutritional supplement for the dietary management of proven  phenylketonuria in children from birth to 3 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 8.4 g, carbohydrate 9.9 g,  fat 3.9 g, energy 455 (108kcal)/29-g sachet, with vitamins,  minerals, and trace elements. Chocolate, pineapple-vanilla.  Unflavoured (carbohydrate 11 g, energy 474 kJ (113kcal)/  29-g sachet), net price 30 x 29-g sachets = £106.20  Nutritional supplement for the dietary management of phenyl-  ketonuria in children 1-10 years   Liquid, protein equivalent (essential and non-essential amino  acids except phenylalanine) lOg, carbohydrate 8.8 g, fat  4.8 g, fibre 310 mg, energy 497 kJ (118kcal)/125mL, with  vitamins, minerals, and trace elements. Lactose-free. Fla-  vours: Berry, orange, or unflavoured, net price 125-mL  carton = £4.72   Nutritional supplement for the dietary management of phenyl-  ketonuria in children 1-10 years   Liquid, protein equivalent (essential and non-essential amino  acids except phenylalanine) lOg, carbohydrate 5.1 g, energy  258 kJ (62 kcal)/87-mL pouch, with vitamins, minerals, and  trace elements. Unflavoured (white) or flavoured (orange,  purple, or red), net price 30 x 87 mL = £1 12.80.   Nutritional supplement for the dietary management of phenyl-  ketonuria. Not recommended for children under 3 years   Liquid, protein equivalent (essential and non-essential amino  acids except phenylalanine) 15 g, carbohydrate 7.8 g, energy  386 kJ (92kcal)/130-mL pouch, with vitamins, minerals, and  trace elements. Unflavoured (white) or flavoured (orange,  purple, or red), net price 30 x 130 mL = £168.00.   Nutritional supplement for the dietary management of phenyl-  ketonuria, not recommended for children under 3 years   Liquid, protein equivalent (essential and non-essential amino  acids except phenylalanine) 20 g, carbohydrate 10.2 g,  energy 517kJ (124kcal)/174-mL pouch, with vitamins,  minerals, and trace elements. Unflavoured (white) or fla-  voured (orange, purple, or red), net price 30 x 174 mL =  £225.60.   Nutritional supplement for the dietary management of phenyl-  ketonuria. Not recommended for children under 3 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 1 5 g, carbohydrate 3.8 g,  energy 315 kJ (76kcal)/25-g sachet, with vitamins, minerals,  and trace elements. Lemon, orange, tropical or unflavoured  (flavouring: see Flavour Pad ® , p. 925), net price 30 x 25-g  sachets = £164.84.   Nutritional supplement for the dietary management of phenyl-  ketonuria. Not recommended for children under 8 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 8.4 g, carbohydrate 8.6 g,  fat less than 100 mg, energy 286 kJ (68kcal)/20-g sachet  with vitamins, minerals and trace elements. Orange, rasp-  berry, or unflavoured (flavouring: see Flavour Pac®, p. 925),  net price 30 x 20-g sachets = £95.03.   Nutritional supplement for use as part of the low-protein dietary  management of phenylketonuria in children 1-10 years.   Liquid, protein equivalent (containing essential and non-  essential amino acids except phenylalanine) 10 g, carbohy-  drate 4.4 g, fibre 170 mg, energy 245 kJ (58kcal)/62.5mL,  with vitamins, minerals, and trace elements. Flavours: berry,  citrus, orange, or tropical, net price 62.5-mL carton = £4.35  Nutritional supplement for dietary management of phenylketon-  uria in children over 4 years and adults including pregnant women   Liquid, protein equivalent (containing essential and non-  essential amino acids except phenylalanine) 20 g, carbohy-  drate 8.8 g, fibre 340 mg, energy 490 kJ (115kcal)/125mL,  with vitamins, minerals, and trace elements. Flavours: berry,  citrus, orange, or tropical, net price 3 x 125 mL = £26.04  Nutritional supplement for the dietary management of phenyl-  ketonuria in children over 4 years and adults including pregnant  women   Liquid, protein equivalent (essential and non-essential amino  acids except phenylalanine) 2 g, carbohydrate 8.3 g, fat 2.9 g,  energy 286 kJ (68kcal)/100mL with vitamins, minerals, and  trace elements. Contains lactose and fish oil. Net price 500-  mL bottle = £5.58   Nutritional supplement for the dietary management of phenyl-  ketonuria in children under 1 year   Liquid, protein (cows’ milk) 220 mg (phenylalanine 12.5 mg),  carbohydrate 8g, fat 3.8 g, energy 273 kJ (65kcal)/100mL.  Contains lactose. Net price 200 mL= £1.05p  Nutritional supplement for the dietary management of phenyl-  ketonuria, chronic renal failure, and other inborn errors of amino  acid metabolism   For use as a supplement in maternal phenylketonurics who have  low plasma tyrosine concentrations   Powder, tyrosine 1 g, carbohydrate 2.9 g, energy 62 kJ  (15kcal)/4-g sachet, net price 30 x 4-g sachets = £4.08.  Nutritional supplement for the dietary management of phenyl-  ketonuria and other inborn errors of amino acid metabolism   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 25 g, carbohydrate 51 g,  fat less than 500 mg, energy 1311 kJ (309 kcal)/ 100 g, with  vitamins, minerals, and trace elements. Orange flavour or  unflavoured (flavouring: see Modjul ® Flavour System ,  p. 925), net price 500 g = £48.85   Nutritional supplement for the dietary management of phenyl-  ketonuria in children 1-8 years   Liquid, protein equivalent (essential and non-essential amino  acids except phenylalanine and tyrosine) 10 g, carbohydrate  8.8g, fat 4.8g, fibre 310mg, energy 500 kJ (119kcal)/   125 mL, with vitamins, minerals, and trace elements. Orange  flavour, net price 36 x 125-mL bottle = £272.79  Nutritional supplement for the dietary management of tyrosin-  aemia type 1 (when nitisinone (NTBC) is used, see section 9.8.1),  type II, and type III, in children over 1 year   Liquid, protein equivalent (essential and non-essential amino  acids except tyrosine and phenylalanine) 15 g, carbohydrate  7 g, fat 500 mg, energy 386 kJ (92kcal)/130mL, with vita-  mins, minerals, and trace elements. Orange or red flavour,  net price 30 x 130-mL pouch = £277.20  Nutritional supplement for the dietary management of tyrosin-  aemia in children over 8 years and adults   Powder, protein equivalent (essential and non-essential  amino acids except tyrosine and phenylalanine) 15g,  carbohydrate 3.8 g, fat less than 100 mg, energy 315 kJ  (76kcal)/25g, with vitamins, minerals, and trace elements.  Unflavoured (flavouring: see FlavourPac ® sachets, p. 925),  net price 30 x 25-g sachets = £271.88  Nutritional supplement for the dietary management of tyrosin-  aemia. Not recommended for children under 8 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine) 39 g, carbohydrate 34 g,  fat less than 500 mg, energy 1260 kJ (297 kcal)/ 100 g, with  vitamins, minerals, and trace elements. Flavours: orange,  unflavoured (flavouring: see Modjul ® Flavour System,  p. 925). Net price 30 x 50-g sachets = £226.50, 500 g =  £75.54   Nutritional supplement for the dietary management of phenyl-  ketonuria in children over 8 years and adults   Powder, protein equivalent (essential and non-essential  amino acids except methionine, phenylalanine, and tyrosine)  13.1 g, carbohydrate 49.5 g, fat 23 g, fibre 5.3 g, energy  1915 kJ (457kcal)/100g, with vitamins, minerals, and trace  elements; standard dilution (15%) provides protein equiva-  lent 2g, carbohydrate 7.4 g, fat 3.5 g, fibre 800 mg, energy  287 kJ (69kcal)/100mL. Unflavoured, net price 400 g =  £32.70 (5-g measuring scoop provided)   Nutritional supplement for the dietary management of proven  tyrosinaemia type 1 in children from birth to 3 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine, and tyrosine) 13.1 g,  carbohydrate 49.5 g, fat 23 g, fibre 5.3 g, energy 1915 kJ  (457kcal)/100g, with vitamins, minerals, and trace ele-  ments; standard dilution (15%) provides protein equivalent  2 g, carbohydrate 7.4 g, fat 3.5 g, fibre 800 mg, energy 287 kJ  (69kcal)/100mL. Unflavoured, net price 400 g = £32.70 (5-g  measuring scoop provided)   Nutritional supplement for the dietary management of proven  tyrosinaemia where plasma-methionine concentrations are nor-  mal in children from birth to 3 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine and tyrosine) 8.4 g,  carbohydrate 1 1 g, fat 3.9 g, energy 475 kJ (113kcal)/29-g  sachet, with vitamins, minerals, and trace elements. Unfla-  voured, net price 30 x 29-g sachets = £173.32  Nutritional supplement for the dietary management of proven  tyrosinaemia in children 1-10 years    1. Maxamaid products are generally intended for use in  children 1-8 years   2. Maxamum products are generally intended for use in  children over 8 years and adults   Gel, protein equivalent (essential and non-essential amino  acids except tyrosine and phenylalanine) 8.4 g, carbohydrate  8.6 g, fat less than 100 mg, energy 286 kJ (68 kcal)/20 g, with  vitamins, minerals and trace elements. Unflavoured  (flavouring: see Flavourpac ® sachets, p. 925), net price 30 x  20-g sachets = £151.93   Nutritional supplement for the dietary management of tyrosin-  aemia in children 1-10 years    Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine and tyrosine) 25 g,  carbohydrate 51 g, fat less than 500 mg, energy 131 lkJ  (309 kcal)/ 100 g with vitamins, minerals, and trace elements.  Unflavoured (flavouring: see Modjul ® Flavour System,  p. 925). Net price 500 g = £82.57   Nutritional supplement for the dietary management of tyrosin-  aemia in children 1-8 years   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine and tyrosine) 77 g,  carbohydrate 4.5 g, fat nil, energy 1386 kJ (326 kcal)/ 100 g.  Unflavoured (flavouring: see Modjul ® Flavour System,  p. 925). Net price 500 g = £156.42  Nutritional supplement for the dietary management of tyrosin-  aemia in children and adults where plasma-methionine concen-  trations are normal   Powder, protein equivalent (essential and non-essential  amino acids except phenylalanine, tyrosine, and methionine)  77 g, carbohydrate 4.5 g, fat nil, energy 1386 kJ (326 kcal)/  100 g. Unflavoured (flavouring: see Modjul ® Flavour  System, p. 925). Net price 500 g = £156.42  Nutritional supplement for the dietary management of tyrosin-  aemia type 1 in children and adults where plasma-methionine  concentrations are above normal   Nutritional supplement for the dietary management of urea cycle  disorders other than arginase deficiency, such as hyperammo-  naemia types I and II, citrullaemia, arginosuccinic aciduria, and  deficiency of N-acetyl glutamate synthetase   Dermatitis Aveeno® Bath Oil; Aveeno® Cream;  Aveeno® Colloidal; Aveeno® Lotion; E45® Emollient  Bath Oil; E45® Emollient Wash Cream; E45® Lotion   Disfiguring skin lesions (birthmarks, mutilating  lesions, scars, vitiligo) Covermark® classic founda-  tion and finishing powder; Dermacolor® Camouflage  cream and fixing powder; Keromask® masking cream  and finishing powder; Veil® Cover cream and Finishing  Powder. (Cleansing Creams, Cleansing Milks, and  Cleansing Lotions are excluded)   Disinfectants (antiseptics) May be prescribed on an  FP10 only when ordered in such quantities and with  such directions as are appropriate for the treatment of  patients, but not for general hygenic purposes.   Dry mouth (xerostomia) For patients suffering from  dry mouth as a result of having (or having undergone)  radiotherapy, or sicca syndrome.   AS Saliva Orthana® \ Biotene Oralbalance® \ BioXtra® ',  Glandosane® \ Saliveze® ', Salivix®.   Photodermatoses (skin protection in) Delph® Sun  Lotion SPF 30; Sunsense® Ultra; Uvistat® Lipscreen  SPF 50, Uvistat® Suncream SPF 30 and 50.    Wound dressings The correct dressing for wound  management depends not only on the type of wound but  also on the stage of the healing process.    The ideal dressing for moist wound healing needs to  ensure that the wound remains:   As wound healing passes through its different stages,  different types of dressings may be required to satisfy  better one or other of these requirements. Under normal  circumstances, a moist environment is a necessary part  of the wound healing process; exudate provides a moist  environment and promotes healing, but excessive exu-  date can cause maceration of the wound and surround-  ing healthy tissue. The volume and viscosity of exudate  changes as the wound heals. There are certain circum-  stances where moist wound healing is not appropriate  (e.g. gangrenous toes associated with vascular disease).  Advanced wound dressings, (section A8.2) are  designed to control the environment for wound healing,  for example to donate fluid (hydrogels), maintain  hydration (hydrocolloids), or to absorb wound exudate  (alginates, foams).    Practices such as the use of irritant cleansers and  desloughing agents may be harmful and are largely  obsolete; removal of debris and dressing remnants  should need minimal irrigation with lukewarm sterile  sodium chloride 0.9% solution or water.   Hydrogel, hydrocolloid, and medical grade honey dres-  sings can be used to deslough wounds by promoting  autolytic debridement; there is insufficient evidence to  support any particular method of debridement for diffi-  cult-to-heal surgical wounds. Sterile larvae (maggots)  are also available for biosurgical removal of wound  debris.   There have been few clinical trials able to establish a  clear advantage for any particular product. The choice  between different dressings depends not only on the  type and stage of the wound, but also on patient pre-  ference or tolerance, site of the wound, and cost. For  further information, see Buyers’ Guide: Advanced  wound dressings (October 2008); NHS Purchasing and  Supply Agency, Centre for Evidence-based Purchasing.   The table below gives suggestions for choices of pri-  mary dressing depending on the type of wound (a  secondary dressing may be needed in some cases).   Low adherence dressings are used as interface layers  under secondary absorbent dressings. Placed directly  on the wound bed, non-absorbent, low adherence dres-  sings are suitable for clean, granulating, lightly exuding  wounds without necrosis, and protect the wound bed  from direct contact with secondary dressings. Care must  be taken to avoid granulation tissue growing into the  weave of these dressings   Tulle dressings are manufactured from cotton or vis-  cose fibres which are impregnated with white or yellow  soft paraffin to prevent the fibres from sticking, but this  is only partly successful and it may be necessary to  change the dressings frequently. The paraffin reduces  absorbency of the dressing. Dressings with a reduced  content (light loading) of soft paraffin are less liable to   Symptoms or signs of infection, see Wounds with signs of infection   Symptoms or signs of infection, see Wounds with signs of infection   Consider systemic antibacterials if appropriate; also consider odour-absorbent dressings (section A8.2.8)   For malodourous wounds with slough or necrotic tissue, consider mechanical or autolytic debridement   Low adherence with honey A8.3.1  Low adherence with iodine A8.3.2  Low adherence with silver A8.3.3  Hydrocolloid with silver A8.3.3  Honey— topical A8.3.1   Note In each section of this table the dressings are listed in order of increasing absorbency.    interfere with absorption; dressings with ‘normal load-  ing’ (such as Jelonet®) have been used for skin graft  transfer.   Knitted viscose primary dressing is an alternative to  tulle dressings for exuding wounds; it can be used as the  initial layer of multi-layer compression bandaging in the  treatment of venous leg ulcers.   N-A Dressing®, 9.5 cm x 9.5 cm = 35p, 9.5 cm x 19 cm =  67p (Systagenix)   N-A Ultra® (silicone-coated), 9.5 cm x 9.5 cm = 33p, 9.5 cm  x 19 cm = 6 3p (Systagenix)   (Tulle Gras). Fabric of leno weave, weft and warp threads of  cotton and/or viscose yam, impregnated with white or  yellow soft paraffin, 10 cm x 10 cm, (light loading) = 25p;  (normal loading) = 37p (most suppliers including Synergy  Healthcare — Paranet ® (light loading); BSN Medical —  Cuticell ® Classic (normal loading); S&N Hlth. — Jelonet! 6  (normal loading); Neomedic — Neotulle ® (normal loading); C  D Medical — Paragauze ® (normal loading))   Non-adherent knitted polyester primary dressing impreg-  nated with neutral triglycerides, 5 cm x 5 cm = 24p, 7.5 cm x  10 cm = 26, 10 cm x 20 cm = 58, 20 cm x 30 cm = £1.58    Perforated film absorbent dressings are suitable only  for wounds with mild to moderate amounts of exudate;  they are not appropriate for leg ulcers or for other  lesions that produce large quantities of viscous exudate.  Dressings with an absorbent cellulose or polymer wad-  ding layer are suitable for use on moderately to heavily  exuding wounds.   Low-adherence primary dressing consisting of viscose and  rayon absorbent pad with adhesive border.   Cosmopor E®, 5 cm x 7.2 cm = 8p, 8 cm x 10 cm = 16p,   8 cm x 15 cm = 26p, 10 cm x 20 cm = 42p, 10 cm x 25 cm =  52p, 10 cm x 35 cm = 72p (Hartmann)   Cutiplast® Steril, 5 cm x 7.2 cm = 5p, 8 cm x 10 cm = lOp,   8 cm x 15 cm = 23p, 10 cm x 20 cm = 29p, 10 cm x 25 cm =  3 Op, 10 cm x 30 cm = 40p (S&N Hlth.)   Leukomed®, 7.2cm x 5cm = 8p, 8 cm x 10 cm = 17p, 8 cm  x 15 cm = 30p, 10 cm x 20 cm = 40p, 10 cm x 25 cm = 45p,  10 cm x 30 cm = 58p, 10 cm x 35 cm = 67p (BSN Medical)   Medipore® + Pad, 5 cm x 7.2 cm = 7p, 10 cm x 10 cm =  15p, 10 cm x 15 cm = 24p, 10 cm x 20 cm = 36p, 10 cm x  25 cm = 45p, 10 cm x 35 cm = 62p (3M)   Medisafe®, 6 cm x 8 cm = 8p, 8 cm x 10 cm = 13p, 8 cm x  12 cm = 23p, 9 cm x 15 cm = 29p, 9 cm x 20 cm = 34p, 9 cm  x 25 cm = 36p (Neomedic)   Mepore®, 7 cm x 8 cm = lOp, 10 cm x 11 cm = 21p, 11cm  x 15 cm = 34p, 9 cm x 20 cm = 42p, 9 cm x 25 cm = 58p,   9 cm x 30 cm = 67p, 9 cm x 35 cm = 73p (Molnlycke)   PremierPore®, 5 cm x 7 cm = 5p, 10 cm x 10cm = 12p,   10 cm x 15 cm = 18p, 10 cm x 20 cm = 32p, 10 cm x 25 cm  = 36p, 10 cm x 30 cm = 45p, 10 cm x 35 cm = 52p  (Shermond)   Primapore®, 6 cm x 8.3 cm = 17p, 8 cm x 10 cm = 18p,   8 cm x 15 cm = 31p, 10 cm x 20 cm = 41p, 10 cm x 25 cm =  47p, 10 cm x 30 cm = 59p, 10 cm x 35 cm = 91p (S&N Hlth)    Softpore®, 6 cm x 7 cm = 6p, 10 cm x 10 cm = 13p, 10 cm  x 15 cm = 20p, 10 cm x 20 cm = 35p, 10 cm x 25 cm = 40p,  10 cm x 30 cm = 49p, 10 cm x 35 cm = 58p (Richardson)   Sterifix®, 5 cm x 7 cm = 18p, 7 cm x 10 cm = 30p, 10 cm x  14 cm = 54p (Hartmann)   Telfa® Island, 5 cm x 10 cm = 8p, 10 cm x 12.5 cm = 27p,  10 cm x 20 cm = 35p, 10 cm x 25.5 cm = 44p, 10 cm x  35 cm = 61p (Covidien)   Low-adherence primary dressing consisting of 3 layers —  perforated polyester film wound contact layer, absorbent  cotton pad, and hydrophobic backing. Where no size speci-  fied by the prescriber, the 5 cm size to be supplied   Askina® Pad, 5 cm x 5 cm = 13p, 10 cm x 10 cm = 20p,   Cutisorb® l_A, 5 cm x 5 cm = 8p, 10 cm x 10 cm = 14p,   Interpose®, 5 cm x 5 cm = 9p, 10 cm x 10 cm = 15p, 10 cm  x 20 cm = 32p (Frontier)   Melolin®, 5 cm x 5 cm = 16p, 10 cm x 10 cm = 26p, 20 cm  x 10 cm = 5 lp (S&N Hlth)   Release®, 5 cm x 5 cm = 14p, 10 cm x 10 cm = 23p, 20 cm  x 10 cm = 44p (Systagenix)   Skintact®, 5 cm x 5 cm = lOp, 10 cm x 10 cm = 17p, 20 cm  x 10 cm = 34p (Robinson)   Solvaline N®, 5 cm x 5 cm = 9p, 10 cm x 10 cm = 17p,   Telfa®, 5 cm x 7.5 cm = 12p, 10 cm x 7.5 cm = 15p, 15 cm x  7.5 cm = 17p, 20 cm x 7.5 cm = 29p (Covidien)   Eclypse®, 15 cm x 15 cm = 97p, 20 cm x 30 cm = £2.14,  60 cm x 40 cm = £8.15, 80 cm x 50 cm = £9.35, 60 cm x  70 cm (boot-shape) = £13.54 (Advancis)   Exu-Dry®, 10 cm x 15 cm = £1.06, 15 cm x 23 cm = £2.17,  23 cm x 38 cm = £5.04 (S&N Hlth.)    Mesorb®, cellulose wadding pad with gauze wound contact  layer and non- woven repellent backing, 10 cm x 10 cm =  59p, 10 cm x 15 cm = 77p, 10 cm x 20 cm = 95p, 15 cm x  20 cm = £1.36, 20 cm x 25 cm = £2.14, 20 cm x 30 cm =  £2.43 (Molnlycke)   Telfa Max®, 22.8 cm x 38 cm = £4.62, 38 cm x 45.7 cm =  £5.61, 38 cm x 60.9 cm = £8.16 (Covidien)    Zetuvit® E, non-sterile, 10 cm x 10 cm = 6p, 10 cm x 20 cm  = 8p, 20 cm x 20 cm = 13p, 20 cm x 40 cm = 26p; sterile,  10 cm x 10 cm = 20p, 10 cm x 20 cm = 23p, 20 cm x 20 cm  = 37p, 20 cm x 40 cm = £1.02(Hartmann)   10 cm x 10 cm = £1.99, 20 cm x 20 cm = £6.25, 10 cm x  20 cm = £3.33, 20 cm x 30 cm = £9.42   10 cm x 10 cm = £1.99, 20 cm x 20 cm = £6.16, 10 cm x  20 cm = £3.28, 20 cm x 30 cm = £8.86   Super absorbent polyacrylate primary dressing, 10 cm x  10 cm = 90p, 10cm x 22 cm = £1.19, 20cm x 22cm = £2.10,  20 cm x 30 cm = £2.40   Super absorbent cellulose primary dressing, 10 cm x  10 cm = 60p, 10 cm x 20 cm = 83p, 15 cm x 20 cm =  95p, 20 cm x 25 cm = £1.30, 20 cm x 40 cm = £2.00   Advanced wound dressings can be used for both acute  and chronic wounds. Categories for dressings in this  section (A8.2) start with the least absorptive, moisture-  donating hydrogel dressings, followed by increasingly  more absorptive dressings. These dressings are classi-  fied according to their primary component; some dres-  sings are comprised of several components.   Hydrogel dressings are most commonly supplied as an  amorphous, cohesive topical application that can take  up the shape of a wound. A secondary, non-absorbent  dressing is needed. These dressings are generally used  to donate liquid to dry sloughy wounds and facilitate  autolytic debridement of necrotic tissue; some also have  the ability to absorb very small amounts of exudate.  Hydrogel products that do not contain propylene glycol  should be used if the wound is to be treated with larval  therapy.   Hydrogel sheets have a fixed structure and limited fluid-  handling capacity; hydrogel sheet dressings are best  avoided in the presence of infection, and are unsuitable  for heavily exuding wounds.   X Hydrogel dressing, 5 cm x 6.5 cm = £1.70, 10 cm x 10 cm =   -q £2.49, 20 cm x 20 cm = £7.51, 10 cm x 15 cm = £3.58   Hydrogel dressing, 7.5 cm diameter = £2.55, 12 cm diameter  = £5.26   Hydrogel dressing (without adhesive border) 10 cm x 10 cm  = £1.60, 15 cm x 15 cm = £3.20   Absorbent, transparent, hydrogel sheets containing poly-  urethane polymers covered with a semi-permeable film,   5 cm x 7.5 cm = £1.46; 10 cm x 10 cm = £2.09; 20 cm x  20 cm = £6.26   4.5 cm x 6.5 cm = £1.73; 7.5 cm x 10 cm = £2.29; 12.5 cm x   Soft non-woven dressing impregnated with Intrasite ® gel,  10 cm x 10 cm = £1.70; 10 cm x 20 cm = £2.30; 10 cm x  40 cm = £4.10   30 cm x 30 cm, standard = £13.00, thin = £12.27; 5 cm x   7.5 cm = £1.95; 15 cm x 20 cm = £5.86; 20 cm x 40 cm =  £11.16; 7.5 cm diameter = £2.79   Non-adherent, hydrogel coated polyester net dressing, 10 cm  x 10 cm = £1.93, 10 cm x 15 cm = £2.86   Hydrogel containing guar gum and propylene glycol, 15 g =  £1.39   Hydrogel containing modified starch copolymer, 8 g = £1.58,  15 g = £1.93   Hydrogel, 8 g = £1.56, 15 g = £1.90, 25 g = £2.80   Hydrogel containing carboxymethylcellulose, pectin, and  propylene glycol, 15 g = £2.19   Hydrogel containing modified carmellose polymer and pro-  pylene glycol, 8-g sachet = £1.70, 15-g sachet = £2.28, 25-g  sachet = £3.38   Hydrogel containing carboxymethylcellulose and calcium  alginate, 8g = £1.64, 15 g = £2.14   Vapour-permeable films and membranes allow the pas-  sage of water vapour and oxygen but are impermeable  to water and micro-organisms, and are suitable for  lightly exuding wounds. They are highly conformable,  provide protection, and a moist healing environment;  transparent film dressings permit constant observation  of the wound. Water vapour loss can occur at a slower  rate than exudate is generated, so that fluid accumulates  under the dressing, which can lead to tissue maceration  and to wrinkling at the adhesive contact site (with risk of  bacterial entry). Newer versions of these dressings have  increased moisture vapour permeability. Despite these  advances, vapour-permeable films and membranes are  unsuitable for infected, large heavily exuding wounds,  and chronic leg ulcers.   Vapour-permeable films and membranes are suitable for  partial-thickness wounds with minimal exudate, or  wounds with eschar. Most commonly, they are used as  a secondary dressing over alginates or hydrogels; film  dressings can also be used to protect the fragile skin of  patients at risk of developing minor skin damage caused  by friction or pressure.   Extensible, waterproof, water vapour-permeable polyurethane  film coated with synthetic adhesive mass; transparent. Supplied  in single-use pieces.   Film dressing, 6 cm x 7 cm = 32p, 10 cm x 12.7 cm = 74p,  15 cm x 17.8 cm = £1.81   Film dressing, 6 cm x 7 cm = 35p, 10 cm x 12 cm = £1.02,  10 cm x 20 cm = £1.94, 15 cm x 20 cm = £2.35, 20 cm x  30 cm = £4.20   Film dressing, 6 cm x 7 cm = 38p, 10 cm x 12 cm = £1.02,  12 cm x 12 cm = £1.07, 15 cm x 20 cm = £2.32   Film dressing, 12 cm x 12 cm = £1.10, 12 cm x 35 cm =  £2.75, 15 cm x 20 cm = £2.10   Film dressing, 6 cm x 7 cm = 21p, 10 cm x 12.5 cm = 39p,  10 cm x 15 cm = 49p, 10 cm x 25 cm = 76p, 12 cm x 25 cm  = 80p, 15 cm x 20 cm = 90p, 20 cm x 30 cm = £1.49   OpSite® Plus, film dressing, with absorbent pad, 6.5 cm x  5 cm = 30p, 9.5 cm x 8.5 cm = 83p, 10 cm x 12 cm = £1.13,  10 cm x 20 cm = £1.90, 35 cm x 10 cm = £3.15  OpSite® Post-op, film dressing, with absorbent pad, 8.5 cm  x 9.5 cm = 82p, 8.5 cm x 15.5 cm =£1.13, 10 cm x 12 cm =  £1.11, 10 cm x 20 cm = £1.86, 10 cm x 25 cm = £2.35, 10 cm  x 30 cm = £2.78, 10 cm x 35 cm = £3.09   Film dressing, with absorbent pad, 8.5 cm x 15.5 cm = 20p,  10 cm x 25 cm = 38p, 10 cm x 30 cm = 58p   Film dressing, 7.2 cm x 5 cm = 35p, 8 cm x 10 cm = 65p,  10 cm x 12.5 cm = 95p, 11 cm x 14 cm = £1.15, 15 cm x  20 cm = £2.20, 15 cm x 25 cm = £2.35   Film dressing, 6 cm x 7 cm = 44p, 10 cm x 12 cm = £1.18,  10 cm x 25 cm = £2.29, 15 cm x 20 cm = £2.91   Film dressing, 5 cm x 1 m = £3.69, 10 cm x 1 m = £6.22;  OpSite ® Flexigrid, 6 cm x 7 cm = 37p, 12 cm x 12 cm =  £1.06, 15 cm x 20 cm = £2.69   Film dressing, with absorbent pad, 5 cm x 7 cm = 13p, 6 cm  x 7 cm = 21p, 10 cm x 10 cm = 16p, 10 cm x 15 cm = 24p,  10 cm x 20 cm = 36p, 10 cm x 25 cm = 38p, 10 cm x 30 cm  = 57p, 10 cm x 35 cm = 69p   Film dressing, with absorbent pad, 5 cm x 7 cm = 25p, 9 cm  x 10 cm = 62p, 9 cm x 15 cm = 92p, 9 cm x 20 cm = £1.34,  9 cm x 25 cm = £1.51, 9 cm x 35 cm = £2.50  Tegaderm® Absorbent Clear, film dressing, with clear  acrylic polymer oval-shaped pad, 7.6 cm x 9.5 cm = £2.99,  11.1cm x 12.7 cm = £3.87, 14.2cm x 15.8cm = £5.45;  rectangular pad, 14.9 cm x 15.2 cm = £8.26, 20 cm x  20.3 cm = £13.26; 16.8 cm x 19 cm (sacral) = £9.89   Film dressing, 4 cm x 4 cm = 36p, 5 cm x 7 cm = 39p, 10 cm  x 12 cm = £1.01, 10 cm x 20 cm = £2.00, 15 cm x 20 cm =  £2.31, 20 cm x 25 cm = £4.03   Film dressing, 6cm x 7cm = lip, 10cm x 12cm = 20p,   Film dressing, 5 cm x 7 cm = 31p, 10 cm x 12 cm = 75p, 15  cm x 20 cm = £2.33   Film dressing, 6 cm x 7 cm = 38p, 12 cm x 12 cm = £1.08,  15 cm x 20 cm = £2.34   Film dressing, 6 cm x 7 cm = 40p, 10 cm x 12 cm = £1.06,  10 cm x 25 cm = £2.06, 15 cm x 20 cm = £2.19   Vapour-permeable transparent film dressing with adhesive  foam border, 16 cm x 7 cm (central venous catheter) = 94p,  16 cm x 8.8 cm (central venous catheter) = £1.03   Vapour-permeable transparent film dressing with adhesive  foam border, 7 cm x 7.5 cm (intravenous peripheral cannula)  = 38p   Vapour-permeable, transparent, adhesive film dressing, 5 cm  x 6 cm (1-hand) = 40p, 6 cm x 7 cm (non-winged peripheral  catheter) = 52p, 7 cm x 9 cm (ported peripheral catheter) =  69p, 9 cm x 12 cm (PICC line) =£1.37, 10 cm x 12 cm  (central venous catheter) = £1.32   Vapour-permeable, transparent, adhesive film dressing, 5 cm  x 5.5 cm = 29p, 8 cm x 9 cm = 38p, 10 cm x 1 1 cm = 99p   Film dressing, with absorbent pad, 10 cm x 10 cm = 91p,   15 cm x 15 cm = £1.98, 15 cm x 20 cm = £2.44   Film dressing, with absorbent pad, 6 cm x 7 cm = 12p, 6 cm  x 10 cm = 15p, 10 cm x 10 cm = 20p, 15 cm x 10 cm = 24p,  20 cm x 10 cm = 36p, 25 cm x 10 cm = 40p   Film dressing, with absorbent pad, 5 cm x 7.2 cm = 15p,   9 cm x 10 cm = 2 Op, 9 cm x 15 cm = 22p, 10 cm x 20 cm =  34p, 10 cm x 25 cm = 36p, 10 cm x 30 cm = 53p   Film dressing, with absorbent pad, 7.2 cm x 5 cm = 25p, 8 cm  x 10 cm = 50p, 8 cm x 15 cm = 75p, 10 cm x 20 cm = £1.25,   10 cm x 25 cm = £1.40, 10 cm x 30 cm = £2.35, 10 cm x 35 cm  = £2.85   4 cm x 5 cm = 23p, 5 cm x 7 cm = 24p, 9 cm x 10 cm = 61p,  9 cm x 15 cm = 90p, 9 cm x 20 cm = £1.31, 9 cm x 25 cm =  £1.47, 9 cm x 30 cm = £1.97, 9 cm x 35 cm = £2.45  Mepore® Ultra, film dressing, with absorbent pad, 6 cm x  7 cm = 28p, 7 cm x 8 cm = 39p, 9 cm x 10 cm = 6 lp, 9 cm x  15 cm = 92p, 9 cm x 20 cm = £1.43, 9 cm x 25 cm = £1.58,  9 cm x 30 cm = £2.61, 10 cm x 1 1 cm = 75p, 11cm x 15 cm  = £1.12   Non-woven fabric dressing with viscose-rayon pad, 7 cm x  8.5 cm (intravenous ported peripheral catheter) = 19p   8.5 cm x 7 cm = 7p, 6 cm x 7 cm (ported peripheral cannula)  = 8p, 7 cm x 9 cm (peripheral cannula, hand) = 17p   Vapour-permeable, transparent, adhesive film dressing, 7 cm  x 8.5 cm (peripheral catheter) = 57p, 8.5 cm x 10.5 cm  (central venous catheter) = £1.11, 10 cm x 15.5 cm (per-  ipherally inserted central venous catheter) = £1.60   Dressings with soft polymer, often a soft silicone poly-  mer, in a non-adherent or gently adherent layer are  suitable for use on lightly to moderately exuding  wounds. For moderately to heavily exuding wounds,  an absorbent secondary dressing can be added, or a  soft polymer dressing with an absorbent pad can be  used.   Wound contact dressings coated with soft silicone have  gentle adhesive properties and can be used on fragile  skin areas or where it is beneficial to reduce the fre-  quency of primary dressing changes.    Soft polymer dressings should not be used on heavily  bleeding wounds; blood clots can cause the dressing to  adhere to the wound surface.   Soft silicone, semi-transparent wound contact dressing. 5 cm  x 7 cm = £1.57, 8 cm x 10 cm = £3.13, 12 cm x 15 cm =  £6.34, 20 cm x 30 cm = £16.61   Mepitel® One, soft silicone, thin, transparent wound contact  dressing, 6 cm x 7 cm = £1.77, 9 cm x 10 cm = £3.32, 13 cm  x 15 cm = £6.47, 24 cm x 27.5 cm = £16.60   Non-adherent soft polymer wound contact dressing, 10 cm x  10 cm = £2.13, 15 cm x 20 cm = £6.50   Soft silicone polymer wound contact dressing, 13 cm x  13 cm = £3.52, 13 cm x 25 cm = £5.47, 28 cm x 30 cm =  £7.37   Soft silicone-coated polyester wound contact dressing, 5 cm  x 7 cm = £1.25, 8 cm x 10 cm = £2.55, 12 cm x 15 cm =  £5.15, 20 cm x 30 cm = £13.25, 35 cm x 60 cm = £39.54   Absorbent soft silicone dressing with polyurethane foam film  backing, 10 cm x 1 1 cm = £2.57, 11cm x 20 cm = £4.24,   15 cm x 16 cm = £4.66, 20 cm x 21 cm = £7.03, 20 cm x  50 cm = £27.44, 13 cm x 20 cm (heel) = £5.22, 15 cm x   Mepilex® Border, absorbent soft silicone dressing with  polyurethane foam and adhesive border, 7 cm x 7.5 cm =  £1.33, 10 cm x 12.5 cm = £2.63, 10 cm x 20 cm = £3.56,   10 cm x 30 cm = £5.36, 15 cm x 17.5 cm = £4.53, 17 cm x  20 cm = £5.87, 18 cm x 18 cm (sacrum) = £4.69, 23 cm x   Mepilex® Border Lite, thin absorbent soft silicone dressing  with polyurethane foam and adhesive border, 4 cm x 5 cm =  91p, 7.5 cm x 7.5 cm = £1.37, 5 cm x 12.5 cm = £1.98, 10 cm  x 10 cm = £2.49, 15 cm x 15 cm = £4.06  Mepilex® Lite, thin absorbent soft silicone dressing with  polyurethane foam, 6 cm x 8.5 cm = £1.74, 10 cm x 10 cm =  £2.08, 15 cm x 15 cm = £4.03, 20 cm x 50 cm = £25.46  Mepilex® Transfer, soft silicone exudate transfer dressing,   7.5 cm x 8.5 cm = £2.13, 10 cm x 12 cm = £3.35, 15 cm x  20 cm = £10.16, 20 cm x 50 cm = £25.97   Non-adherent polyethylene wound contact dressing with  absorbent core, 8.5 cm x 8.5 cm = £5.00, 12 cm x 12 cm =  £6.78, 12 cm x 22 cm = £12.56, 22 cm x 22 cm = £20.14   Non-adherent soft polymer wound contact dressing, 7.5 cm  x 10 cm = £2.14, 7.5 cm x 20 cm = £4.20, 20 cm x 25 cm =  £10.23   Non-adherent soft polymer wound contact dressing, 5 cm x  5cm = £1.50, 10 cm x 10 cm = £3.00, 10 cm x 40 cm =  £10.08, 11cm x 11 cm = £3.02, 15 cm x 20 cm = £8.49,   16 cm x 21 cm = £8.55, 20 cm x 30 cm = £13.65   Non-adherent, soft polymer wound contact dressing with  absorbent pad, 5 cm x 10 cm = £2.33, 10 cm x 12 cm =  £3.61, 15 cm x 20 cm = £8.38   Urgotul® Duo Border, soft polymer wound contact dressing  with absorbent pad and adhesive polyurethane film backing,  8 cm x 8 cm = £2.27, 10 cm x 12 cm = £3.52, 15 cm x 20 cm  = £8.17   Soft gel wound contact dressing, with polyurethane foam  film backing, 5 cm x 5 cm = £1.24, 10 cm x 10 cm = £2.45,  10 cm x 20 cm = £3.94, 15 cm x 15 cm = £4.43, 20 cm x  20 cm = £6.57   Allevyn® Gentle Border, silicone gel wound contact  dressing, with polyurethane foam film backing, 7.5 cm x   7.5 cm = £1.44, 10 cm x 10 cm = £2.46, 12.5 cm x 12.5 cm =  £3.17, 17.5 cm x 17.5 cm = £6.16, 23 cm x 23.2 cm (heel) =  £9.08   Soft silicone wound contact dressing, with polyurethane  foam film backing, 5 cm x 6 cm = £1.23, 10 cm x 10 cm =  £2.30, 10 cm x 20 cm = £3.80, 15 cm x 15 cm = £4.30, 20 cm  x 20 cm = £6.52, 16 cm x 24 cm (heel) = £6.77; with  adhesive border, 17.5 cm x 17.5 cm (sacrum) = £4.31   Cutimed® Siltec B, with adhesive border, for lightly to  moderately exuding wounds, 7.5 cm x 7.5 cm = £1.43,   12.5 cm x 12.5 cm = £3.03, 15 cm x 15 cm = £4.66, 17.5 cm  x 17.5 cm = £4.91   Cutimed® Siltec L, for lightly to moderately exuding  wounds, 5 cm x 6 cm = 98p, 10 cm x 10 cm = £1.98, 15 cm  x 15 cm = £3.26   Soft silicone wound contact layer with absorbent pad and  film-backing, 10 cm x 10 cm = £2.99, 10 cm x 20 cm = £3.75,  15 cm x 15 cm = £4.99, 20 cm x 30 cm = £9.99, 17 cm x  19 cm (sacral) = £3.76, 22 cm x 23 cm (sacral) = £6.23   Soft silicone wound contact dressing, with polyurethane  foam film backing, 7.5 cm x 7.5 cm = £1.19, 10 cm x 10 cm  = £2.16, 10 cm x 20 cm = £2.90, 10 cm x 30 cm = £4.25,   15 cm x 15 cm = £3.15, 15 cm x 20 cm = £4.10   Absorbent polymer dressing with non-adherent wound  contact layer, 10 cm x 10 cm = £2.12, 20 cm x 20 cm =  £6.68, 10 cm x 20 cm = £3.55, 20 cm x 30 cm = £9.45   Absorbent polymers in cellulose matrix, hypoallergenic  fleece envelope (for moderately to heavily exuding wounds),   7.5 cm x 7.5 cm = £1.75, 10 cm x 10 cm = £2.22, 10 cm x  10 cm (drainage) = £2.64, 20 cm x 20 cm = £6.90, 20 cm x  10 cm = £3.68, 30 cm x 10 cm = £5.29, 30 cm x 20 cm =  £9.92, 12 cm x 5 cm = £1.86   Biosynthetic cellulose fibre dressing (for lightly to moder-  ately exuding wounds), 5 cm x 5 cm = £1.90, 9 cm x 9 cm =  £3.95, 14 cm x 20 cm = £7.83; 2 cm x 21 cm (rope) = £6.08   Hydrocolloid dressings are usually presented as a  hydrocolloid layer on a vapour-permeable film or foam  pad. Semi-permeable to water vapour and oxygen, these  dressings form a gel in the presence of exudate to  facilitate rehydration in lightly to moderately exuding  wounds and promote autolytic debridement of dry,  sloughy, or necrotic wounds; they are also suitable for  promoting granulation.   Hydrocolloid-fibrous dressings made from modified  carmellose fibres resemble alginate dressings; hydro-  colloid-fibrous dressings are more absorptive and sui-  table for moderately to heavily exuding wounds.   Semi-permeable polyurethane film backing, hydrocolloid  wound contact layer, 5 cm x 7.5 cm = 76p, 10 cm x 10 cm =  £1.55, 15 cm x 15 cm = £3.37, 15 cm x 18 cm (sacral) =  £3.91; with polyurethane foam layer, 5 cm x 7.5 cm = 96p,  10 cm x 10 cm = £1.52, 15 cm x 15 cm = £2.86, 15 cm x  18 cm (sacral) = £3.30   Semi-permeable hydrocolloid dressing without adhesive  border, 10 cm x 10 cm = £3.01, 12.5 cm x 12.5 cm = £4.14,  12 cm x 20 cm = £5.44, 15 cm x 15 cm = £5.24, 20 cm x  20 cm = £7.82   Semi-permeable, polyurethane film dressing with hydro-  colloid adhesive, 10 cm x 10 cm = £1.02, 15 cm x 15 cm =  £2.3 1, 20 cm x 20 cm = £3.02   Hydrocolloid dressings containing carmellose sodium and  calcium alginate, contour, 6 cm x 8 cm = £2.08, 9 cm x  11cm = £3.61; ulcer, 4 cm x 6 cm = 90p, 10 cm x 10 cm =  £2.29, 15 cm x 15 cm = £4.91, 18 cm x 20 cm (triangular) =  £5.35, 20 cm x 20 cm = £7.08; transparent, 5 cm x 7 cm =  63p, 5 cm x 15 cm = £1.48, 5 cm x 25 cm = £2.41, 9 cm x   14 cm = £2.28, 9 cm x 25 cm = £3.24, 10 cm x 10 cm =  £1.20, 15 cm x 15 cm = £3.12, 15 cm x 20 cm = £3.17, 20 cm  x 20 cm = £3.19; pressure relieving, 7 cm diameter = £3.24,  10 cm diameter = £4.34, 15 cm diameter = £6.54   7.5 cm x 7.5 cm = 75p, 10 cm x 10 cm = £1.24, 9 cm x   15 cm = £1.66, 9 cm x 25 cm = £2.66, 9 cm x 35 cm = £3.72,  15 cm x 15 cm = £2.68   DuoDERM® Signal, hydrocolloid dressing with Time to  change’ indicator, 10 cm x 10 cm = £1.98, 14 cm x 14 cm =  £3.48, 20 cm x 20 cm = £6.91, 11cm x 19 cm (oval) =£3.01,   18.5 cm x 19.5 cm (heel) = £4.86, 22.5 cm x 20 cm (sacral) =  £5.68   Semi-permeable hydrocolloid dressing without adhesive  border, 10 cm x 10 cm = £2.19; thin, 10 cm x 10 cm = £1.08   Hydrocolloid wound contact layer bonded to plastic foam  layer, with outer semi-permeable polyurethane film, 10 cm x  10 cm = £2.64, 15 cm x 15 cm = £5.00, 15 cm x 20 cm =  £5.42, 20 cm x 20 cm = £7.52   Hydrocolloid dressing with absorbent wound contact pad,  10 cm x 10 cm = £2.28; thin, 7.5 cm x 7.5 cm = 65p, 10 cm x  10 cm = £1.07, 15 cm x 15 cm = £2.42   Semi-permeable hydrocolloid dressing, 5 cm x 5 cm = 85p,  10 cm x 10 cm = £1.56, 15 cm x 15 cm = £3.18, 20 cm x  20 cm = £6.36, 8 cm x 12 cm (heel/elbow) = £3.18, 15 cm x  18 cm (sacral) = £4.45; thin, 10 cm x 10 cm = £1.06   Hydrocolloid dressing with adhesive border, 10 cm x 12 cm  (oval) = £2.26, 13 cm x 15 cm (oval) = £4.22; 17.1 cm x  16.1 cm (sacral) = £4.71; thin, semi-permeable, clear film  dressing with hydrocolloid, 10 cm x 12 cm (oval) = £1.50;  13 cm x 15 cm (oval) = £2.81   Semi-permeable hydrocolloid dressing with adhesive border,  21cm x 21 cm = £4.58, 15 cm x 18 cm (sacral) = £3.23,   Soft non-woven pad containing hydrocolloid-fibres, 4 cm x  10 cm = £1.40, 4 cm x 20 cm = £2.07, 4 cm x 30 cm = £3.11,  5 cm x 5 cm = £1.10; 10 cm x 10 cm = £2.61; 15 cm x 15 cm  = £4.91; 2 cm x 45 cm (ribbon) = £2.64   7.5 cm x 7.5 cm = £1.39, 11cm x 11 cm = £2.31, 15 cm x  15 cm = £4.26, 20 cm x 20 cm = £6.37; with adhesive border,  10 cm x 10 cm = £2.36, 14 cm x 14 cm = £3.19, 19 cm x  19 cm = £5.09, 22 cm x 22 cm = £5.65, 18.5 cm x 20.5 cm  (heel) = £5.65, 21 cm x 25 cm (sacral) = £6.06   Polyurethane matrix with absorbent particles and waterproof  polyurethane film, 5 cm x 6 cm = £1.19, 10 cm x 10 cm =  £2.40, 15 cm x 20 cm = £5.07   Dressings containing hydrophilic polyurethane foam  (adhesive or non-adhesive), with or without plastic  film-backing, are suitable for all types of exuding  wounds, but not for dry wounds; some foam dressings  have a moisture-sensitive film backing with variable  permeability dependant on the level of exudate   Foam dressings vary in their ability to absorb exudate;  some are suitable only for lightly to moderately exuding  wounds, others have greater fluid-handing capacity and  are suitable for heavily exuding wounds. Saturated foam  dressings can cause maceration of healthy skin if left in  contact with the wound.   Hydrocolloid dressing without adhesive border, 10 cm x  10 cm = £2.30, 15 cm x 15 cm = £4.46; thin, semi-permeable,  clear film dressing with hydrocolloid, 10 cm x 10 cm = £1.51   Semi-permeable hydrocolloid dressing; without adhesive  border 10 cm x 10 cm = £2.23, 15 cm x 15 cm = £4.36,   Semi-permeable hydrocolloid dressing with adhesive border,  10 cm x 10 cm = £3.01, 12.5 cm x 12.5 cm = £4.14, 12 cm x  20 cm = £5.44, 15 cm x 15 cm = £5.24, 20 cm x 20 cm =  £7.82   Hydrocolloid wound contact layer bonded to plastic foam  layer, with outer semi-permeable polyurethane film, 6 cm x  6 cm = £1.66, 10 cm x 10 cm = £3.14, 15 cm x 15 cm =  £5.99, 10 cm x 13 cm (triangular) =£3.71, 15 cm x 18 cm  (triangular) = £5.78   Hydrocolloid dressing with adhesive border and absorbent  wound contact pad, 5 cm x 5 cm = 94p, 7.5 cm x 7.5 cm =  £1.54, 10 cm x 10 cm = £2.25, 15 cm x 15 cm = £4.22; 8 cm  x 12 cm (concave) = £1.98; 12 cm x 18 cm (sacral) = £3.36    Foam dressings can be used in combination with other  primary wound contact dressings. If used under com-  pression bandaging or compression garments, the fluid-  handling capacity of the foam dressing may be reduced.  Foam dressings can also be used to provide a protective  cushion for fragile skin.   Tielle® Lite, 1 1 cm x 1 1 cm = £2.28; 7 cm x 9 cm = £1.21;  8 cm x 15 cm = £2.81; 8 cm x 20 cm = £2.97 (Systagenix)   Lyofoam®, 7.5 cm x 7.5 cm = £1.05, 10 cm x 10 cm = £1.20,  10 cm x 17.5 cm = £1.94, 15 cm x 20 cm = £2.61  (Molnlycke)   Suprasorb® M, 10 cm x 10 cm = £1.78, 10 cm x 20 cm =  £3.14, 20 cm x 20 cm = £5.23 (Activa)   Suprasorb® R 7.5 cm x 7.5 cm = £1.20, 10 cm x 10 cm =  £1.29, 15 cm x 15 cm = £2.32 (Activa)    Tielle®, 1 1 cm x 11 cm = £2.38; 15 cm x 15 cm = £3.89,   18 cm x 18 cm = £4.95, 7 cm x 9 cm = £1.28, 15 cm x 20 cm  = £4.87, 18 cm x 18 cm (sacral) = £3.60 (Systagenix)    Trufoam®, 11 cm x 11 cm = £2.18, 15 cm x 15 cm = £3.64,  7 cm x 9 cm = £1.14, 15 cm x 20 cm = £4.57 (Aspen  Medical)   10 cm x 10 cm = £1.74, 15 cm x 20 cm = £3.70; 20 cm x  20 cm = £5.06; 10 cm x 30 cm = £3.63 (MedLogic)   Allevyn® Lite, 5 cm x 5 cm = £1.06; 10 cm x 10 cm = £1.93;  10 cm x 20 cm = £3.31; 15 cm x 20 cm = £4.13 (S&N Hlth.)   Allevyn® Thin, self-adhesive, 5 cm x 6 cm = £1.00, 10 cm x  10 cm = £2.03, 15 cm x 15 cm = £3.35, 15 cm x 20 cm =  £4.06 (S&N Hlth)   Suprasorb® P, 5 cm x 5 cm = 93p, 7.5 cm x 7.5 cm = 99p,  10 cm x 10 cm = £1.17, 15 cm x 15 cm = £3.12 (Activa)   Transorbent®, self-adhesive, 5 cm x 7 cm = £1.01; 10 cm x  10 cm = £1.90; 15 cm x 15 cm = £3.50; 20 cm x 20 cm =  £5.59 (Braun)   UrgoCell® TLC, soft-adherent, 6 cm x 6 cm = £1.74, 10 cm x  10 cm = £2.53, 15 cm x 20 cm = £5.47, 12 cm x 19 cm (heel)  = £4.52 (Urgo)   Copa®, 5 cm x 5 cm = 70p, 7.5 cm x 7.5 cm = £1.19, 10 cm  x 10 cm = £1.04, 12.5 cm x 12.5 cm = £1.77, 15 cm x 15 cm  = £2.55, 20 cm x 20 cm = £2.95, 10 cm x 20 cm = £2.01,   Cutimed® Cavity, 5 cm x 6 cm = £1.74, 10 cm x 10 cm =  £2.89, 15 cm x 2 cm = £1.61, 15 cm x 15 cm = £4.34 (BSN  Medical)   ActivHeal® Foam Island, 7.5 cm x 7.5 cm = £1.18, 10cm x  10 cm = £1.60, 12.5 cm x 12.5 cm = £1.68, 15 cm x 15 cm =  £2.15, 20 cm x 20 cm = £4.42 (MedLogic)   Advazorb® Border, 6 cm x 10 cm = £1.10, 8 cm x 12 cm =  £1.90 (Advancis)   ■ Allevyn® Adhesive, 7.5 cm x 7.5 cm = £1.43, 10 cm x 10 cm  = £2.10, 12.5 cm x 12.5 cm = £2.57, 17.5 cm x 17.5 cm =  £5.07, 12.5 cm x 22.5 cm = £4.00, 22.5 cm x 22.5 cm =  £7.38; (sacral) 17 cm x 17 cm = £3.80, 22 cm x 22 cm = £5.47  (S&N Hlth.)   17.5 cm x 17.5 cm = £6.10; 12.5 cm x 22.5 cm = £5.60;  (sacral) 17 cm x 17 cm = £4.61, 22 cm x 22 cm = £6.67 (S&N  Hlth)   12.5 cm = £2.41, 18 cm x 18 cm = £4.86, 18 cm x 28 cm =  £7.20, 23 cm x 23 cm (sacral) = £4.16, 19 cm x 20 cm (heel)  = £4.85; 17 cm diameter (contour) = £4.67 (Coloplast)   Biatain® Silicone, 7.5 cm x 7.5 cm = £1.41, 10 cm x 10 cm  = £2.27, 12.5 cm x 12.5 cm = £2.90, 15 cm x 15 cm = £3.98,   Copa® Island, 10 cm x 10 cm = £1.51, 15 cm x 15 cm =  £2.84, 20 cm x 20 cm = £5.36 (Coviden)   PermaFoam®, 16.5 cm x 18 cm (concave) = £ 3.76; 18 cm x  18 cm (sacral) = £3.09; 22 cm x 22 cm (sacral) = £3.55;  PermaFoam Comfort ® 8 cm x 8 cm = £1.04, 10 cm x 20 cm  = £3.13, 11cm x 11cm = £1.98, 15cm x 15cm = £3.23,  20 cm x 20 cm = £4.69 (Hartmann)   PolyMem®, 5 cm x 7.6 cm = £1.10, 8.8 cm x 12.7 cm =  £1.95, 10 cm x 13 cm = £2.08, 15 cm x 15 cm = £2.80,   16.5 cm x 20.9 cm = £6.42, 18.4 cm x 20 cm (sacral) = £4.32  (Aspen Medical)   14.3 cm x 14.3 cm = £3.40, 14.3 cm x 15.6 cm = £4.08,   19 cm x 22.5 cm = £6.69, 13.9 cm x 13.9 cm (heel) =£4.09  (3M)   Tielle® Plus, 11cm x 11 cm = £2.63; 15cm x 15cm = £4.30;  15 cm x 20 cm = £5.39; 15 cm x 15 cm (sacrum) = £3.13;  20 cm x 26.5 cm (heel) = £4.45 (Systagenix)   ActivHeal® Foam Non-Adhesive, 5 cm x 5cm = 73p, 10 cm  x 10cm = £l.ll, 10cm x 17.8 cm = £2.30, 20cm x 20 cm =  £3.85, 18 cm x 12 cm (heel) = £3.48 (MedLogic)   Advazorb® Plus, 5 cm x 7.5 cm = 70p, 10 cm x 10 cm =  £1.08, 15cm x 15cm = £2.10, 20cm x 20cm = £3.75  (Advancis)   Allevyn® Cavity, circular, 5 cm diameter = £3.97, 10 cm  diameter = £9.46; tubular, 9 cm x 2.5 cm = £3.85, 12 cm x  4 cm = £6.78 (S&N Hlth.)   Allevyn® Compression, 5 cm x 6 cm = £1.18; 10cm x  10 cm = £2.43; 15 cm x 15 cm = £4.12, 15 cm x 20 cm =  £4.62 (S&N Hlth.)   Allevyn® Non-Adhesive, 5 cm x 5 cm = £1.21, 10 cm x  10 cm = £2.40, 10 cm x 20 cm = £3.86, 20 cm x 20 cm =  £6.44, 10.5 cm x 13.5 cm (heel) = £4.81 (S&N Hlth.)   Allevyn® Plus Cavity, 5 cm x 6 cm = £1.78, 10 cm x 10 cm =  £2.97, 15 cm x 20 cm = £5.95 (S&N Hlth.)   Askina® Foam, 10 cm x 10 cm = £2.06, 10 cm x 20cm =  £3.25, 20 cm x 20 cm = £5.43, 12 cm x 20 cm (heel) = £4.40;  cavity dressing, 2.4 cm x 40 cm = £2.30 (Braun)   Biatain® Non-Adhesive, 10 cm x 10 cm = £2.24, 10 cm x  20 cm = £3.70, 15 cm x 15 cm = £4.13, 20 cm x 20 cm =  £6.13; 5 cm x 7 cm =£1.23; Biatain ® Soft-Hold , 10 cm x  10 cm = £2.44, 15 cm x 15 cm = £4.05, 5 cm x 7 cm = £1.22,  10 cm x 20 cm = £3.70 (Coloplast)   Copa® Plus, 5 cm x 5 cm = 80p, 7.5 cm x 7.5 cm = £1.39,  10 cm x 10 cm = £1.44, 15 cm x 15 cm = £3.32, 20 cm x  20 cm = £3.96, 10 cm x 20 cm = £2.64, 8.5 cm x 7.5 cm  (fenestrated) = £1.22 (Covidien)   Kerraboot®, (clear or white), foot-shaped, extra small =  £14.38, small = £14.66, large = £14.66, extra large = £14.38  (Ark)   Lyofoam® Extra, 10 cm x 10 cm = £2.08, 17.5 cm x 10 cm =  £3.52, 20 cm x 15 cm = £4.56 (Medlock)   PermaFoam®, 10 cm x 10 cm = £1.98, 10 cm x 20 cm =  £3.39, 15 cm x 15 cm = £3.76, 20 cm x 20 cm = £5.74; 6 cm  diameter = £1.02, 8 cm x 8 cm (fenestrated) = £1.17; cavity  dressing, 10 cm x 10 cm = £1.85 (Hartmann)   PolyMem®, 8 cm x 8 cm = £1.51, 10 cm x 10 cm = £2.35,  13 cm x 13 cm = £3.93, 17 cm x 19 cm = £5.80, 10 cm x  61 cm = £12.49; PolyWic ® 8 cm x 8 cm (cavity) = £3.52;  Poly Max® 11cm x 11 cm = £2.83 (Aspen Medical)   10 cm x 10 cm = £2.10, 10 cm x 20 cm = £3.57, 20 cm x  20 cm = £5.69, 10 cm x 60 cm = £12.05 (3M)   Tielle® Plus Borderless, 11cm x 11 cm = £3.04; 15 cm x  20 cm = £5.51 (Systagenix)   Tielle® Xtra, 1 1 cm x 1 1 cm = £2.24; 15 cm x 15 cm = £3.37,  15 cm x 20 cm = £5.51 (Systagenix)   Trufoam® NA, 5 cm x 5 cm = £1.09, 10 cm x 10 cm = £2.07,  15 cm x 15 cm = £3.81 (Aspen Medical)   Soft, conforming cavity wound dressing prepared by mixing  thoroughly for 15 seconds immediately before use and  allowing to expand its volume within the cavity. 20 g =  £18.62   Non-woven or fibrous, non-occlusive, alginate dres-  sings, made from calcium alginate, or calcium sodium  alginate, derived from brown seaweed, form a soft gel in  contact with wound exudate.   Alginate dressings are highly absorbent and suitable for  use on exuding wounds, and for the promotion of    autolytic debridement of debris in very moist wounds.  Alginate dressings also act as a haemostatic, but caution  is needed because blood clots can cause the dressing to  adhere to the wound surface. Alginate dressings should  not be used if bleeding is heavy and extreme caution is  needed if used for tumours with friable tissue.   Alginate sheets are suitable for use as a wound contact  dressing for moderately to heavily exuding wounds and  can be layered into deep wounds; alginate rope can be  used in sinus and cavity wounds to improve absorption  of exudate and prevent maceration. If the dressing does  not have an adhesive border or integral adhesive plastic  film backing, a secondary dressing will be required.   Activheal® Alginate, calcium sodium alginate dressing, 5 cm  x 5 cm = 58p, 10 cm x 10 cm = £1.13, 10 cm x 20 cm =  £2.78; cavity dressing, 2 cm x 30 cm = £2.09  ActivHeal Aquafiber®, non-woven, calcium sodium alginate  dressing, 5 cm x 5 cm = 74p, 10 cm x 10 cm = £1.77, 15 cm  x 15 cm = £3.34; cavity dressing, 2 cm x 42 cm = £1.78   Calcium alginate fibre, non-woven dressing, 5 cm x 5 cm =  87p, 10 cm x 10 cm = £1.80, 15 cm x 20 cm = £4.84; cavity  dressing, 2 cm x 30 cm = £3.27   Calcium alginate dressing. 5 cm x 5 cm = 87p, 10 cm x  10 cm = £1.98, 10 cm x 20 cm = £3.34; cavity dressing, 2g,  30 cm = £3.57   Calcium alginate dressing, 5 cm x 5 cm = 70p, 10 cm x  10 cm = £1.49, 10 cm x 14 cm = £2.41, 10 cm x 20 cm =  £2.93, 15 cm x 25 cm = £5.15, 30 cm x 61 cm = £27.03;  cavity dressing, 30 cm = £2.84, 61 cm = £4.98, 91 cm = £5.36  Curasorb® Plus, calcium alginate dressing, 10 cm x 10 cm =  £2.04   Curasorb® Zn, calcium alginate and zinc dressing, 5 cm x  5 cm = 80p, 10 cm x 10 cm = £1.68, 10 cm x 20 cm = £3.30   Calcium alginate fibre, non-woven, 5 cm x 5 cm, = 90p,   7.5 cm x 12 cm = £1.96, 10 cm x 20 cm = £3.84, 15 cm x  25 cm = £6.61; cavity dressing, 2 g = £3.60   Calcium sodium alginate fibre, highly absorbent, gelling  dressing, non-woven, 5 cm x 5 cm = 86p, 10 cm x 10 cm =  £1.79, 10 cm x 20 cm = £3.36; cavity dressing, 32 cm x  2.2 cm, (2 g) = £3.39   Alginate and carboxymethylcellulose dressing, highly  absorbent, gelling dressing, 5 cm x 5 cm = 91p, 10 cm x  10 cm = £2.18, 15 cm x 15 cm = £4.13; gelling filler, 44 cm =  £2.57   Calcium alginate dressing, 5 cm x 5 cm = 76p, 10 cm x  10 cm = £1.59; Sorbalgon ® T, cavity dressing, 2g, 30 cm =  £3.24   Calcium alginate dressing, 5 cm x 5 cm = 58p, 10 cm x  10 cm = £1.14; cavity dressing, 30 cm (2g) = £2.11   Calcium alginate dressing, 5 cm x 5 cm = 77p, 10 cm x  10 cm = £1.62; cavity dressing, 2 cm x 30.4 cm = £2.70   Alginate and carboxymethylcellulose dressing without  adhesive border, 5 cm x 5 cm = 83p, 10 cm x 10 cm = £1.99,  10 cm x 20 cm = £3.64; cavity dressing, 30 cm = £2.65   Capillary-action dressings consist of an absorbent core  of hydrophilic fibres sandwiched between two low-  adherent wound-contact layers to ensure no fibres are  shed on to the wound surface. Wound exudate is taken  up by the dressing and retained within the highly absor-  bent central layer.   The dressing may be applied intact to relatively super-  ficial areas, but for deeper wounds or cavities it may be  cut to shape to ensure good contact with the wound  base. Multiple layers may be applied to heavily exuding  wounds to further increase the fluid-absorbing capacity  of the dressing. A secondary adhesive dressing is neces-  sary.   Capillary-action dressings are suitable for use on all  types of exuding wounds, but particularly on sloughy  wounds where removal of fluid from the wound aids  debridement; capillary-action dressings are contra-indi-  cated for heavily bleeding wounds or arterial bleeding.   Non-adherent dressing consisting of a soft viscose and  polyester absorbent pad with central wicking layer between  two perforated permeable wound contact layers. 5 cm x  7.5 cm = 56p, 10 cm x 10 cm = 87p, 10 cm x 15 cm = £1.17,  15 cm x 20 cm = £1.54  Advadraw Spiral®, 0.5 cm x 40 cm = 81p   Non-adhesive wound contact sachet containing ceramic  spheres, 5 cm x 5 cm = 70p, 10 cm x 10 cm = £1.56, 10 cm x  15 cm = £2.08; cavity dressing, 10 cm x 10 cm = £2.10,   Cerdak® Aerocloth, non-adhesive wound contact sachet  containing ceramic spheres, with non-woven fabric adhesive  backing, 5 cm x 5 cm = £1.37, 5 cm x 10 cm = £1.94  Cerdak® Aerofilm, non-adhesive wound contact sachet  containing ceramic spheres, with waterproof transparent  adhesive film backing, 5 cm x 5 cm = £1.51, 5 cm x 10 cm =  £2.07   Sorbsan® Flat, calcium alginate fibre, highly absorbent, flat  non-woven pads, 5 cm x 5 cm = 79p, 10 cm x 10 cm = £1.66,  10 cm x 20 cm = £3.10   Sorbsan® Plus, alginate dressing bonded to a secondary  absorbent viscose pad, 7.5 cm x 10 cm = £1.67, 10 cm x  15 cm = £2.96, 10 cm x 20 cm = £3.77, 15 cm x 20 cm =  £5.24   Sorbsan® Plus SA, alginate dressing with adhesive border  and absorbent backing, 11.5 cm x 14 cm = £2.92, 14 cm x  19 cm = £4.25, 14 cm x 24 cm = £5.14, 19 cm x 24 cm =  £6.45   Sorbsan® Ribbon, 40 cm (with probe) = £2.01  Sorbsan® Surgical Packing, 30 cm (2 g, with probe) = £3.41   Sumar® Lite, for light to moderately exuding wounds and  cavities, 5 cm x 5 cm = 93p, 10 cm x 10 cm = £1.59, 10 cm x  15 cm = £2.12   Sumar® Max, for heavily exuding wounds, 5 cm x 5 cm =  95p, 10 cm x 10 cm = £1.61, 10 cm x 15 cm = £2.15  Sumar®Spiral, 0.5 cm x 40 cm = £1.57   Low-adherent dressing consisting of two external polyester  wound contact layers with central wicking polyester/ cotton  mix absorbent layer. 5 cm x 5 cm = 94p, 10 cm x 10 cm =  £1.66, 10 cm x 15 cm = £2.23, 10 cm x 20 cm = £2.68, 15 cm  x 20 cm = £3.14, 20 cm x 20 cm = £4.28   Dressings containing activated charcoal are used to  absorb odour from wounds. The underlying cause of  wound odour should be identified. Wound odour is most  effectively reduced by debridement of slough, reduction  in bacterial levels, and frequent dressing changes.  Fungating wounds and chronic infected wounds pro-  duce high volumes of exudate which can reduce the  effectiveness of odour absorbent dressings. Many odour  absorbent dressings are intended for use in combination  with other dressings; odour absorbent dressings with a  suitable wound contact layer can be used as a primary  dressing.   Activated charcoal and non-woven viscose rayon dressing,  10 cm x 10 cm = £2.72, 10 cm x 20 cm = £5.25   Dressing in 5 layers: wound-facing absorbent layer contain-  ing alginate and hydrocolloid; water-resistant second layer;  third layer containing activated charcoal; non-woven absor-  bent fourth layer; water-resistant backing layer. 10 cm x  10 cm = £2.98, 8 cm x 15 cm = £3.57, 15 cm x 20 cm = £6.77   Activated charcoal non-absorbent dressing, 10 cm x 10 cm  = £1.59, 10 cm x 20 cm = £2.15   Activated charcoal cloth enclosed in viscose rayon with  outer polyamide coating. 10 cm x 10 cm = £1.78, 10 cm x  20 cm = £2.37, 15 cm x 25 cm = £3.81   Lyofoam sheet with layer of activated charcoal cloth and  additional outer envelope of polyurethane foam. 10 cm x  10 cm = £2.93, 15 cm x 20 cm = £6.65   Alginate dressing with activated carbon, 7.5 cm x 10 cm =  £2.44, 10 cm x 15 cm = £4.73, 10 cm x 20 cm = £5.66, 15 cm  x 20 cm = £6.52    Spreading infection at the wound site requires treatment  with systemic antibacterials.   For local wound infection, a topical antimicrobial dres-  sing can be used to reduce the level of bacteria at the  wound surface but will not eliminate a spreading infec-  tion. Some dressings are designed to release the anti-  microbial into the wound, others act upon the bacteria  after absorption from the wound. The amount of exu-  date present and the level of infection should be taken  into account when selecting an antimicrobial dressing.  Medical grade honey (section A8.3.1), has anti-  microbial and anti-inflammatory properties. Dressings  impregnated with iodine (section A8.3.2), can be used  to treat clinically infected wounds. Dressings containing  silver (section A8.3.3), should be used only when clin-  ical signs or symptoms of infection are present.  Dressings containing other antimicrobials (section  A8.3.4) such as polihexanide (polyhexamethylene  biguanide) or dialkylcarbamoyl chloride are available  for use on infected wounds. Although hypersensitivity is  unlikely with chlorhexidine impregnated tulle dressing,  the antibacterial efficacy of these dressings has not been  established.   Medical grade honey has antimicrobial and anti-  inflammatory properties and can be used for acute or  chronic wounds. Medical grade honey has osmotic  properties, producing an environment that promotes  autolytic debridement; it can help control wound mal-  odour. Honey dressings should not be used on patients  with extreme sensitivity to honey, bee stings or bee  products. Patients with diabetes should be monitored  for changes in blood-glucose concentrations during  treatment with topical honey or honey-impregnated  dressings.   Knitted viscose impregnated with medical grade manuka  honey and manuka oil, 10 cm x 10 cm = 95p, 10 cm x 20 cm  = £1.85   Knitted viscose impregnated with medical grade manuka  honey, 5 cm x 5 cm = £1.78, 10 cm x 10 cm = £3.01  Where no size stated by the prescriber the 5 cm size to be supplied   Absorbent, non-adherent calcium alginate dressing impreg-  nated with medical grade manuka honey, 5 cm x 5 cm =  £2.09, 10 cm x 10 cm = £3.53   Antibacterial Honey Tulle, woven fabric impregnated with  medical grade manuka honey, 10 cm x 10 cm = £2.98  Gel sheet, sodium alginate dressing impregnated with  medical grade honey, 5 cm x 5 cm = £1.75, 10 cm x 10 cm =  £4.20   Antibacterial Honey Apinate®, non-adherent calcium  alginate dressing, impregnated with medical grade honey,   Knitted viscose impregnated with medical grade honey  (Bulgarian, mountain flower) 45% in a basis containing  polyethylene glycol, 10 cm x 10 cm = £2.10   Acetate wound contact layer impregnated with buckwheat  honey 75% in ointment basis, 5 cm x 6 cm = £4.82, 8 cm x  10 cm = £9.90, 8 cm x 20 cm = £19.79   Hydrogel, semi-permeable dressing impregnated with med-  ical grade honey, 10 cm x 10 cm = £2.51, 10 cm x 17.5 cm =  £4.52, 15 cm x 20 cm = £5.22; with adhesive border, 10 cm x  10 cm = £2.61, 15 cm x 13 cm (sacral) = £4.42, 15 cm x  15 cm = £4.62   Mesitran® Mesh, hydrogel, non-adherent wound contact  layer, without adhesive border, 10 cm x 10 cm = £2.41   4 Honey-based topical application  Medical grade honey is applied directly to the wound  and covered with a primary low adherence wound  dressing; an additional secondary dressing may be  required for exuding wounds.   Manuka honey, (medical grade), 25-g tube = £1.99  MANUKApli® (Manuka Medical)   Antibacterial Medical Honey, honey (medical grade, Lep-  tospermum sp.), 20-g tube = £3.96, 50-g tube = £9.90  Antibacterial Wound Gel, honey (medical grade, Leptos-  permum sp.), 80% in natural waxes and oils, 10-g tube =  £2.69, 20-g tube = £4.02   Note Antibacterial Wound Gel is not recommended for use  in deep wounds or body cavities where removal of waxes  may be difficult   Honey, (medical grade; Bulgarian, mountain flower) 45% in  basis containing polyethylene glycol, 20-g tube = £4.49, 50-g  tube = £8.50   Ointment, honey (medical grade) 47%, 15-g tube = £3.47,  50-g tube = £9.55  Excipients include lanolin   Ointment S, honey (medical grade) 40%, 15-g tube = £3.46  Excipients include lanolin   (Drug Tariff specification 43). Knitted viscose primary dres-  sing impregnated with povidone-iodine ointment 10%, 5 cm  x 5 cm = 32p; 9.5 cm x 9.5 cm = 48p (Systagenix — Inad-  ine ®)   Uses wound contact layer for abrasions and superficial bums  Cautions iodine may be absorbed particularly if large wounds  treated; children under 6 months; thyroid disease  Contra-indications severe renal impairment; pregnancy; breast-  feeding   Cadexomer-iodine, like povidone-iodine, releases free  iodine when exposed to wound exudate. The free iodine  acts as an antiseptic on the wound surface, the cadex-  omer absorbs wound exudate and encourages de-  sloughing.   Two-component hydrogel dressings containing glucose  oxidase and iodide ions generate a low level of free  iodine in the presence of moisture and oxygen.   Povidone-iodine fabric dressing is a knitted viscose  dressing with povidone-iodine incorporated in a hydro-  philic polyethylene glycol basis; this facilitates diffusion  of the iodine into the wound and permits removal of the  dressing by irrigation. The iodine has a wide spectrum  of antimicrobial activity but it is rapidly deactivated by  wound exudate.   Systemic absorption of iodine may occur, particularly  from large wounds or with prolonged use.   Paste, iodine 0.9% as cadexomer-iodine in a paste basis with  gauze backing, 5-g unit = £3.82; 10 g = £7.62; 17 g = £12.08  Uses for treatment of chronic exuding wounds; max. single  application 50 g, max. weekly application 150 g; max. duration up  to 3 months in any single course of treatment  Cautions iodine may be absorbed, particularly from large  wounds or during prolonged use; severe renal impairment; history  of thyroid disorder   Ointment, iodine 0.9% as cadexomer-iodine in an ointment  basis, 10 g = £4.21; 20 g = £8.43   Uses for treatment of chronic exuding wounds; max. single  application 50 g, max. weekly application 150 g; max. duration up  to 3 months in any single course of treatment  Cautions iodine may be absorbed, particularly from large  wounds or during prolonged use; severe renal impairment; history  of thyroid disorder   Hydrogel (two-component dressing containing glucose oxi-  dase and iodide ions), 6.5 cm x 5 cm = £7.50, 10 cm x 10 cm  = £12.50   Cautions children; pregnancy and breast-feeding  Contra-indications thyroid disorders; patients receiving lithium   Hydrogel (two-component dressing containing glucose oxi-  dase and iodide ions), 6.5 cm x 5 cm = £6.00, 10 cm x 10 cm  = £ 10.00   Uses non-infected, dry to moderately exuding wounds  Cautions children; pregnancy and breast-feeding  Contra-indications thyroid disorders; patients receiving lithium   Antimicrobial dressings containing silver should be  used only when infection is suspected as a result of  clinical signs or symptoms (see also p. 944). Silver ions  exert an antimicrobial effect in the presence of wound  exudate; the volume of wound exudate as well as the  presence of infection should be considered when select-  ing a silver-containing dressing. Silver-impregnated  dressings should not be used routinely for the manage-  ment of uncomplicated ulcers. It is recommended that  these dressings should not be used on acute wounds as  there is some evidence to suggest they delay wound  healing.   Dressings impregnated with silver sulfadiazine have  broad antimicrobial activity; if silver sulfadiazine is  applied to large areas, or used for prolonged periods,  there is a risk of blood disorders and skin discoloration  (see section 13.10.1.1). The use of silver sulfadiazine-  impregnated dressings is contra-indicated in neonates,  in pregnancy, and in patients with significant renal or  hepatic impairment, sensitivity to sulphonamides, or  G6PD deficiency. Large amounts of silver sulfadiazine  applied topically may interact with other drugs — see  Appendix 1 (sulphonamides).   Three-layer antimicrobial barrier dressing consisting of a  polyester core between low adherent silver-coated high  density polyethylene mesh (for 3-day wear), 5 cm x 5 cm =  £3.30, 10 cm x 10 cm = £8.07, 10 cm x 20 cm = £12.62,   Acticoat® 7 five-layer antimicrobial barrier dressing con-  sisting of a polyester core between low adherent silver-  coated high density polyethylene mesh (for 7-day wear),   5 cm x 5 cm = £5.74, 10 cm x 12.5 cm = £17.11, 15 cm x  15 cm = £30.76    Acticoat® Flex 3, conformable antimicrobial barrier dressing  consisting of a polyester core between low adherent silver-  coated high density polyethylene mesh (for 3-day wear),   5 cm x 5 cm = £3.28, 10 cm x 10 cm = £8.01, 10 cm x 20 cm  = £12.52, 20 cm x 40 cm = £42.85  Acticoat® Flex 7, conformable antimicrobial barrier dressing  consisting of a polyester core between low adherent silver-  coated high density polyethylene mesh (for 7-day wear),   5 cm x 5 cm = £5.70, 15 cm x 15 cm = £30.53, 10 cm x  12.5 cm = £16.98   Non-adherent polyamide fabric impregnated with silver and  neutral triglycerides, 5 cm x 5 cm = 47p, 10 cm x 10 cm =  £1.15, 10 cm x 20 cm = £2.25   Knitted fabric of activated charcoal, with one-way stretch,  with silver residues, within spun-bonded nylon sleeve. 6.5 cm  x 9.5 cm = £1.64, 10.5 cm x 10.5 cm = £2.58, 10.5 cm x  19 cm = £4.70   Soft polymer wound contact dressing, with silver sulfadiazine  impregnated polyurethane foam layer, with adhesive border,   7.5 cm x 7.5 cm = £3.99, 10 cm x 10 cm = £5.99, 12.5 cm x   12.5 cm = £7.71, 17.5 cm x 17.5 cm = £14.69; without  adhesive border, 5 cm x 5 cm = £3.12, 10 cm x 10 cm =  £5.82, 10 cm x 20 cm = £9.62, 15 cm x 15 cm = £10.83,   Soft silicone wound contact dressing with polyurethane foam  film backing, with silver, 10 cm x 10 cm = £5.85, 10 cm x  20 cm = £9.64, 15 cm x 15 cm = £10.85, 20 cm x 20 cm =  £16.08, 20 cm x 50 cm = £60.17   Non-adherent soft polymer wound contact dressing, with  silver, 10 cm x 12 cm = £3.34, 15 cm x 20 cm = £9.09  Urgotul® Duo Silver, non-adherent, soft polymer wound  contact dressing, with silver, 5 cm x 7 cm = £1.95, 1 1 cm x  1 1 cm = £3.87, 15 cm x 20 cm = £9.35   Non-adherent, soft polymer wound contact dressing, with  silver sulfadiazine, 1 1 cm x 1 1 cm = £2.99, 16 cm x 2 1 cm =  £8.48   Soft non-woven pad containing hydrocolloid fibres, (silver  impregnated), 4 cm x 10 cm = £2.70, 4 cm x 20 cm = £3.52,  4 cm x 30 cm = £5.27, 5 cm x 5 cm = £1.86, 10 cm x 10 cm  = £4.44, 15 cm x 15 cm = £8.36, 20 cm x 30 cm = £20.73;   Semi-permeable, antimicrobial barrier dressing with ionic  silver (silver sodium thiosulphate), 10 cm x 10 cm = £6.72,  15 cm x 15 cm = £13.44   Non-adherent polyester fabric with hydrocolloid and silver  sulfadiazine, 10 cm x 10 cm = £2.14  Contra-indications see notes above   Three layer polyurethane dressing consisting of a silver  coated layer, a foam layer, and a waterproof layer, 5 cm x  5 cm = £6.76, 10 cm x 10 cm = £15.82, 10 cm x 20 cm =  £30.82   Silver sulfadiazine impregnated polyurethane foam film  dressing with adhesive border, 7.5 cm x 7.5 cm = £3.24,   10 cm x 10 cm = £5.10, 12.5 cm x 12.5 cm = £6.70, 17.5 cm  x 17.5 cm = £12.89, 17 cm x 17 cm (sacral) = £10.06, 22 cm  x 22 cm (sacral) = £13.48; without adhesive border, 5 cm x  5 cm = £3.02, 10 cm x 10 cm = £5.69, 15 cm x 15 cm =  £10.79, 20 cm x 20 cm = £15.81, 10.5 cm x 13.5 cm (heel) =  £9.97   Silver impregnated polyurethane foam film dressing with  adhesive border, 12.5 cm x 12.5 cm = £8.71, 18 cm x 18 cm  = £17.47, 19 cm x 20 cm (heel) = £17.23, 23 cm x 23 cm  (sacral) = £18.31; without adhesive border, 10 cm x 10 cm =  £7.61, 5 cm x 7 cm = £3.13, 10 cm x 20 cm = £13.99, 15 cm  x 15 cm = £15.28, 20 cm x 20 cm = £21.55; 5 cm x 8 cm  (cavity) = £3.79   Silver impregnated polyurethane foam film dressing, with  adhesive border, 5 cm x 7.6 cm (oval) =£2.17, 12.7 cm x   10.8 cm = £8.45, 17 cm x 19 cm = £16.93; 8 cm x 8 cm  (cavity) = £6.72   Non-adherent, polyurethane foam film dressing with silver in  wound contact layer, 6 cm x 6 cm = £4. 1 1, 10 cm x 10 cm =  £5.65, 15 cm x 20 cm = £10.17   Calcium alginate dressing with a silver coated antimicrobial  barrier, 5 cm x 5 cm = £5.04, 10 cm x 12.5 cm = £12.11;   Calcium alginate dressing, with silver, 5 cm x 5 cm = £1.54,  10 cm x 10 cm = £3.85, 10 cm x 20 cm = £7.09; 2 g, 30 cm  (cavity) = £5.32   Alginate and carboxymethylcellulose dressing, with ionic  silver, 5 cm x 5 cm = £1.71, 10 cm x 10 cm =£3.43, 15 cm x  15 cm = £7.25; 3 cm x 44 cm (cavity) = £4.32   Alginate and carboxymethylcellulose dressing, with ionic  silver, 5 cm x 5 cm = £1.53, 10 cm x 10 cm =£3.74, 15 cm x  15 cm = £6.12; 3 cm x 44 cm (cavity) = £4.05   Alginate and carboxymethylcellulose dressing impregnated  with silver, 2.5 cm x 30.5 cm = £4.45, 5 cm x 5 cm = £1.68,  10 cm x 20 cm = £7.68, 11 cm x 11 cm = £4.14  Silvercel® Non-adherent, alginate and carboxymethylcel-  lulose dressing with film wound contact layer, impregnated  with silver, 5 cm x 5 cm = £1.80, 1 1 cm x 1 1 cm = £4.32,  10 cm x 20 cm = £8.05; 2.5 cm x 30.5 cm (cavity) = £4.37   Sorbsan® Silver Flat, calcium alginate fibre, highly absor-  bent, flat non-woven pads, with silver, 5 cm x 5 cm = £1.54,  10 cm x 10 cm = £3.91, 10 cm x 20 cm = £7.13  Sorbsan® Silver Plus, calcium alginate dressing with  absorbent backing, with silver, 7.5 cm x 10 cm = £3.25,   10 cm x 15 cm = £5.41, 10 cm x 20 cm = £6.58, 15 cm x  20 cm = £8.82   Sorbsan® Silver Plus SA, calcium alginate dressing with  absorbent backing and adhesive border, with silver, 11.5 cm  x 14 cm = £5.28, 14 cm x 19 cm = £7.60, 14 cm x 24 cm =  £8.36, 19 cm x 24 cm = £9.32   Sorbsan® Silver Ribbon, with silver, 40 cm (with probe) =  £4.08   Sorbsan® Silver Surgical Packing, with silver, 30 cm (2g,  with probe) = £5.55   Calcium alginate dressing, with silver, 5 cm x 5 cm = £1.51,  10 cm x 10 cm = £3.80, 10 cm x 20 cm = £7.02; cavity  dressing, 30 cm (2g) = £5.62   Calcium alginate and carboxymethylcellulose dressing, with  silver, 5 cm x 5 cm = £1.35, 10 cm x 10 cm = £3.15; cavity  dressing 3 cm x 30 cm = £3.60   Alginate and carboxymethylcellulose dressing, impregnated  with silver, 5 cm x 5 cm = £1.44, 10 cm x 10 cm = £3.44,   10 cm x 20 cm = £6.48; cavity dressing, 2.5 cm x 30 cm =  £3.46   Fabric of leno weave, weft and warp threads of cotton and/  or viscose yam, impregnated with ointment containing  chlorhexidine acetate, 5 cm x 5 cm = 27p; 10 cm x 10 cm =  57p (S&N Hlth. — Bactigras ®)   Low adherence acetate tissue impregnated with dialkylcar-  bamoyl chloride, (dressing pad) 7 cm x 9 cm = £3.20, 10 cm  x 10 cm = £5.00, 10 cm x 20 cm = £7.80; (swabs) 4 cm x    6 cm = £1.50, 7 cm x 9 cm = £2.50, (round swabs) 3 cm, 5  pad pack = £3.00; (ribbon gauze, cotton) 2 cm x 50 cm =  £3.74, 5cm x 2m =£7.37   Gel, hydrogel dressing impregnated with dialkylcarbamoyl  chloride, 7.5 cm x 7.5 cm = £2.46, 7.5 cm x 15 cm = £4.15   Soft adherent polymer matrix containing nano-oligosac-  charide factor (NOSF), with polyurethane foam film backing,  6 cm x 6 cm = £4.30, 10 cm x 10 cm = £5.95, 15 cm x 20 cm  = £10.70, 12 cm x 19 cm (heel) = £8.20   Forte gel, alginate with glucose oxidase and lactoperoxidase,  for moderately to heavily exuding wounds, 15 g = £7.18, 50 g  = £23.77   Hydro gel, alginate with glucose oxidase and lactoperoxi-  dase, for lightly to moderately exuding wounds, 15 g = £7. 18,  50 g = £23.77   Foam dressing with polihexanide, without adhesive border,  5 cm x 5 cm = £2.45, 10 cm x 10 cm = £4.62, 15 cm x 15 cm  = £8.75, 20 cm x 20 cm = £12.82, 8.8 cm x 7.5 cm (fene-  strated) = £4.15, 10 cm x 20 cm = £8.75   Kendall AMD® Plus 10 cm x 10 cm = £4.85, 8.8 cm x 7.5 cm  (fenestrated) = £4.35   Wound gel, hydroxyethylcellulose and propylene glycol,  with octenidine hydrochloride, 20 mL = £4.78   Biosynthetic cellulose fibre dressing with polihexanide, 5 cm  x 5 cm = £2.38, 9 cm x 9 cm = £4.73, 14 cm x 20 cm =  £10.76; 2 cm x 21 cm (rope) = £6.70   Low adherence absorbent perforated plastic film faced  dressing with polihexanide, 7.5 cm x 10 cm = 17p, 7.5 cm x  20 cm = 28p   Telfa® AMD Island, low adherence dressing with adhesive  border and absorbent pad, with polihexanide, 10 cm x  12.5 cm = 58p, 10 cm x 20 cm = 85p, 10 cm x 25.5 cm =  96p, 10 cm x 35 cm = £1.19   Protease-modulating matrix dressings alter the activity  of proteolytic enzymes in chronic wounds; the clinical  significance of this approach is yet to be demonstrated.  Cadesorb® (S8iN Hlth.)   Collagen and oxidised regenerated cellulose matrix, applied  directly to wound and covered with suitable dressing, 28 cm 2  (hexagonal) = £5.19, 123 cm 2 (hexagonal) = £15.62  Promogran® Prisma® Matrix, collagen, silver and oxidised  regenerated cellulose matrix, applied directly to wound and  covered with suitable dressing, 28 cm 2 (hexagonal) = £6.31,  123 cm 2 (hexagonal) = £17.98   Collagen, 4 cm x 6 cm = £2.64, 6 cm x 8 cm = £4.04, 8 cm x  12 cm = £7.92   Cellulose acetate matrix, impregnated with polyhydrated  ionogens ointment in polyethylene glycol basis, 5 cm x 6 cm  = £4.75, 8 cm x 10 cm = £9.75   Non-adherent soft polymer wound contact dressing con-  taining nano-oligosaccharide factor (NOSF), 5 cm x 7 cm =  £2.80, 1 1 cm x 11 cm = £3.98, 16 cm x 21 cm = £9.50   Gel, alginate and propylene glycol with extracellular matrix  proteins (amelogenins), 0.5-mL syringe = £56.00, 1-mL  syringe = £98.00   Silicone gel and gel sheets are used to reduce or prevent  hypertrophic and keloid scarring. They should not be  used on open wounds. Application times should be  increased gradually. Silicone sheets can be washed  and reused.   Self-adhesive silicone gel sheet with polyurethane film  backing, 10 cm x 10 cm = £5.20, 10 cm x 15 cm = £9.17   Soft, self-adhesive, semi-occlusive silicone gel sheet with  backing. 6 cm x 12 cm = £13.79; 15 cm x 12 cm = £26.89   Silicone gel sheet, 10 cm x 10 cm = £7.50, 15 cm x 15 cm =  £14.00, 10 cm x 20 cm = £12.50   4 cm x 13 cm = £6.61, 13 cm x 13 cm = £15.17, 13 cm x  25 cm = £27.41, 20 cm x 30 cm = £49.92   Self-adhesive silicone gel sheet with polyurethane film  backing, 5 cm x 7 cm = £3.23, 9 cm x 18 cm = £12.62, 4 cm  x 31 cm = £10.19   Self-adhesive, transparent, silicone gel sheet, 10 cm x 20 cm  = £16.00, 25.5 cm x 30.5 cm = £60.00, 3.75 cm x 22.5 cm =  £12.00, 7.5 cm diameter = £8.50, 22.5 cm x 14.5 cm = £12.00   Silicone gel sheet, 10 cm x 10 cm = £13.50; 20 cm x 20 cm =  £40.00; 40 cm x 40 cm = £144.00; 10 cm x 5 cm = £7.50;   15 cm x 10 cm = £19.50; 30 cm x 5 cm = £19.50; 10 cm x  30 cm = £31.50; 25 cm x 15 cm (submammary) = £21.12;  46 cm x 8.5 cm (abdominal) = £39.46; 5.5 cm diameter  (circular) = £4.00   Silicone gel, 15 g = £17.50, 60 g = £50.00  Dermatix® (Meda)   Silicone gel, 15 g = £17.88, 60 g = £51.00  Silicone spray, 100 mL = £51.00   Surgical absorbents applied directly to the wound have  many disadvantages — dehydration of and adherence to  the wound, shedding of fibres, and the leakage of  exudate (‘strike through’) with an associated risk of  infection. Gauze and cotton absorbent dressings can  be used as secondary layers in the management of  heavily exuding wounds (but see also Capillary-action  dressings, section A8.2.7). Absorbent cotton gauze fab-  ric can be used for swabbing and cleaning skin. Ribbon  gauze can be used post-operatively to pack wound  cavities, but adherence to the wound bed will cause  bleeding and tissue damage on removal of the dres-  sing — an advanced wound dressing (e.g. hydrocolloid-  fibrous (section A.8.2.4), foam (section A8.2.5), or algi-  nate (section A8.2.6)) layered into the cavity is often  more suitable.   Carded cotton fibres of not less than 10 mm average staple  length, available in rolls and balls, 25 g = 71p; 100 g = £1.61;  500 g = £5.43 (most suppliers).   As for absorbent cotton but lower quality materials, shorter  staple length etc. 100 g = £1.12; 500 g = £3.54 (most sup-  pliers)   Cotton fabric of plain weave, in rolls and as swabs (see  below), usually Type 13 light, sterile, 90 cm (all) x 1 m =  £1.06; 3m = £2.22; 5m = £3.46; 10m = £6.62 (most suppli-  ers). 1-m packet supplied when no size stated  Note Drug Tariff also includes unsterilised absorbent cotton  gauze, 25 m roll = £14.93   Woven fabric in ribbon form with fast selvedge edges, warp  threads of cotton, weft threads of viscose or combined  cotton and viscose yam, sterile. 5 m (both) x 1.25 cm = 79p;  2.5 cm = 87p   Consists of absorbent cotton enclosed in absorbent cotton  gauze type 12 or absorbent cotton and viscose gauze type 2.  500 g = £6.89 (most suppliers, including Robinsons —  Gamgee Tissue ® (blue label))   Cotton cloth of plain weave with nap raised on one side from  warp yams. 25 g = 88p; 100 g = £2.69; 500 g = £1 1.32 (most  suppliers).   PremierPad®, 10 cm x 20 cm = 18p, 20 cm x 20 cm = 25p  (Shermond)   Xupad®, 10 cm x 20 cm = 17p, 20 cm x 20 cm = 28p, 20 cm  x 40 cm = 40p (Richardson)   J Surgipad® (Systagenix) (Ml  Absorbent pad of absorbent cotton and viscose in sleeve of  non- woven viscose fabric, pouch 12 cm x 10 cm = 18p,   20 cm x 10 cm = 25p, 20 cm x 20 cm = 30p, 40 cm x 20 cm  = 41p; non sterile pack 12 cm x 10 cm = 5p, 20 cm x 10 cm  = lOp, 20 cm x 20 cm = 17p, 40 cm x 20 cm = 28p  1. (£*§ Except in Sterile Dressing Pack with Non- woven Pads   Wound drainage pouches can be used in the manage-  ment of wounds and fistulas with significant levels of  exudate.   Draina S Fistula, wound drainage pouch, mini (cut to  20 mm), 150-mL capacity = £2.44; medium (cut to 50 mm),  350-mL capacity = £3.64; large (cut to 88 mm), 500-mL  capacity = £4.48   Draina S Vision, wound drainage pouch, (cut to 50 mm),  150-mL capacity = £9.39; (cut to 88 mm), 250-mL capacity =  £9.92; (cut to 100 mm), 300-mL capacity = £11.51   Pouch, small (wound size up to 9 cm x 16 cm) = £15.60;  medium (wound size up to 15 cm x 27 cm) = £20.80   Wound pouch, fold and tuck closure, small (wound size up  to 45 mm x 30 mm) = £4.50; medium (wound size up to  110 mm x 75 mm) = £6.50; large (wound size up to 175 mm  x 110 mm) = £8.50; extra large (horizontal wound up to  245 mm x 160 mm) =£15.00   Wound pouch, bung closure, small (wound size up to 45 mm  x 30 mm) = £5.00; medium (wound size up to 110 mm x  75 mm) = £7.00; large (wound size up to 175 mm x 1 10 mm)  = £9.50; extra large (horizontal or vertical wound up to  245 mm x 160 mm) = £17.00, (vertical incision wound up to  290 mm x 130 mm) = £17.00; (horizontal wound up to  245 mm x 160 mm), with access window = £19.00   Wound Manager, extra small (wound size up to 90 mm x  180 mm) = £11.00; small (horizontal wound size up to  245 mm x 160 mm) = £12.23; medium (vertical wound size  up to 90 mm x 260 mm) = £12.50; large (wound size up to  160 mm x 260 mm) = £14.90; square (vertical wound up to  160 mm x 200 mm) = £13.05   Wound Manager, with access port, extra small (wound size  up to 90 mm x 180 mm) = £12.02; small (horizontal wound  size up to 245 mm x 160 mm) = £12.77; medium (vertical  wound size up to 90 mm x 260 mm) = £13.05; large (wound  size up to 160 mm x 260 mm) = £15.93; square (vertical  wound size up to 160 mm x 200 mm) = £13.59   Wound Manager, cut-to-fit, small (10-30 mm) = £2.25,  medium (10-50 mm) = £2.49, large (10-50 mm) = £2.61   Fistula bag, wound manager, cut-to-fit (wound size up to  40 mm x 70 mm) = £2.54   Pouch, drainable, small (wound size up to 76 mm) = £7.45,  medium (wound size up to 95 mm) = £8. 13, large (wound size  up to 100 mm x 200 mm) = £16.10   Topical negative pressure (or vacuum-assisted) therapy  requires specific wound dressings for use with the  vacuum-pump equipment.   Other complex adjunct therapies include sterile larvae  (maggots), and growth factors such as becalpermin (see  section 13.11.7).   Dressing kit, Kit 1 (small wound, low exudate) = £28.04; Kit 2  (large wound, heavy exudate) = £35.83; Kit 3 (large wound,  medium to low exudate) = £35.83; Kit 4 (small wound, heavy  exudate) = £28.04   Dressing kit, foam dressing with round drain (plus port,  drapes and fixation film), small = £19.15, medium = £22.25,  large = £26.39, extra large = £45.28   Dressing kit, non-adherent gauze and transparent film  dressing, with flat drain, small = £16.64, medium = £20.86,  large = £26.48; round drain, small = £16.64, large = £26.48;  channel drain, medium = £20.86   GranuFoam® dressing kit, polyurethane foam dressing  (with adhesive drapes and pad connector), 10 cm x 7.5 cm x  3.3 cm (small) =£21.73, 18 cm x 12.5 cm x 3.3 cm (medium)  = £25.87, 26 cm x 15 cm x 3.3 cm (large) = £30.01; bridge  dressing kit (for diabetic foot wound) = £30.10; with silver,  small = £31.50, medium = £36.54  Simplace® dressing kit, spiral-cut polyurethane foam  dressings, vapour-permeable adhesive film dressings (with  adhesive drapes and pad connector), small = £24.99,  medium = £28.73   WhiteFoam®, polyvinyl alcohol foam dressing 10 cm x  7.5 cm (small) = £10.00, 10 cm x 15 cm (large) = £16.01;  dressing kit (with adhesive drape and pad connector), 10 cm  x 7.5 cm (small) = £24.34, 10 cm x 15 cm (large) = £31.51   Wound sealing kit, flat drain, standard = £15.00, large =  £17.50; channel drain = £15.00   Dressing kit, flat drain, small = £16.98, medium = £21.27,  large = £27.01; round drain, small = £16.98, large = £27.01;  channel drain, medium = £21.27   Wound pack, small-medium = £20.81, medium-large =  £23.85, extra large = £34.05; channel drain, small-medium =  £20.81, medium-large = £23.85   Canister kit (with solidifier), 300 mL = £18.77, 750 mL =  £25.88   Canister kit, (with solidifier) = £12.50; Compact canister kit  (with solidifier) = £12.50   Canister kit, 250 mL (with solidifier) = £19.15, 800 mL (with  solidifier) = £21.27   Port for foam dressing = £9.31, Y-connector = £3.10  V.A.C.® (KCI Medical)   Drape = £8.82. Gel for canister = £3.53. Sensa T.R.A.C. pad =  £10.29. T.R.A.C. Y-connector = £2.94   Gel patches, adhesive, pack of 5 = £15.00. Y-connector, pack  of 5 = £15.00   The role of dressing packs is very limited. They are used  to provide a clean or sterile working surface; some  packs shown below include cotton wool balls, which  are not recommended for use on wounds.   (Drug Tariff). Contains absorbent cotton, absorbent cotton  gauze type 13 light (sterile), open-wove bandages (banded). 1  pack = £4.02   Dressit® contains vitrex gloves, large apron, disposable bag,  paper towel, softswabs, adsorbent pad, sterile field = 60p  (Richardson)   Nurse It® contains powder-free vinyl gloves, sterile lami-  nated paper sheet, large apron, non-woven swabs, paper  towel, disposable bag, compartmented tray, plastic forceps =  52p (Medicare)   Polyfield® Nitrile Patient Pack contains powder-free nitrile  gloves, laminate sheet, non-woven swabs, towel, polythene  disposable bag, apron = 52p (Shermond)   Propax® SDP contains paper towel, disposable bag, gauze  swabs, dressing pad, sterile field = 45p (BSN Medical)   Woundcare® contains nitrile gloves, sterile field, compart-  mented tray, large apron, disposable bag, non-woven swabs,  drape = 44p (Frontier)   (Drug Tariff specification 10). Contains gauze and cotton  tissue pad, gauze swabs, absorbent cotton wool balls,  absorbent paper towel, water repellent inner wrapper. 1 pack  = 50p (Synergy Healthcare — Vernaid ®)   (Drug Tariff specification 35). Contains non-woven fabric  covered dressing pad, non-woven fabric swabs, absorbent  cotton wool balls, absorbent paper towel, water repellent  inner wrapper. 1 pack = 49p (Synergy Healthcare —  Vemaid ®)   Consists of absorbent cotton gauze type 13 light or absor-  bent cotton and viscose gauze type 1 folded into squares or  rectangles of 8-ply with no cut edges exposed, sterile, 7.5 cm  x 7.5 cm 5-pad packet = 38p; non-sterile, 10 cm x 10 cm,  100-pad packet = £1.34 (most suppliers)   As for Gauze Swab, but with thin layer of Absorbent Cotton  enclosed within, non-sterile, 10 cm x 10 cm, 100-pad packet  = £3.60 (Synergy Healthcare — Cotfil ®)   7.5 cm x 7.5 cm, 5-pad packet = 25p; non-sterile, 10 cm x  10 cm, 100-pad packet = 78p   (Drug Tariff specification 29). Film of viscose fibres enclosed  within non-woven viscose fabric folded 8-ply, non-sterile,   Adhesive tapes are useful for retaining dressings on  joints or awkward body parts. These tapes, particularly  those containing rubber, can cause irritant and allergic  reactions in susceptible patients; synthetic adhesives  have been developed to overcome this problem, but  they, too, may sometimes be associated with reactions.  Synthetic adhesive, or silicon adhesive, tapes can be  used for patients with skin reactions to plasters and  strapping containing rubber, or undergoing prolonged  treatment.    Adhesive tapes that are occlusive may cause skin  maceration. Care is needed not to apply these tapes  under tension, to avoid creating a tourniquet effect. If  applied over joints they need to be orientated so that the  area of maximum extensibility of the fabric is in the  direction of movement of the limb.   (Elastic Adhesive Plaster). Woven fabric, elastic in warp  (crepe-twisted cotton threads), weft of cotton and/or viscose  threads, spread with adhesive mass containing zinc oxide.   Hypafix®, 5 cm x 5 m = £1.34, 10 cm x 5 m = £2.25, 10 m  (all): 2.5 cm = £1.56, 5 cm = £2.48, 10 cm = £4.33, 15 cm =  £6.42, 20 cm = £8.51, 30 cm = £12.31 (BSN Medical)   Mefix®, 5 m (all): 2.5 cm = 98p, 5 cm = £1.72; 10 cm = £2.76,  15 cm = £3.76, 20 cm = £4.82, 30 cm = £6.91 (Molnlycke)   Omnifix®, 10 m (all): 5 cm = £2.24, 10 cm = £3.77, 15 cm =  £5.57 (Hartmann)   Primafix® , 5 cm x 10 m = £1.50, 10 cm x 10 m = £2.20,   15 cm x 10 m = £3.25, 20 cm x 10 m = £4.00 (S&N Hlth.)   Backing of paper-based or non-woven textile material spread  with a polymeric adhesive mass:   Clinipore®, 5 m (all) 1.25 cm = 35p, 2.5 cm = 59p, 5 cm =  99p; 2.5 cm x 10 m = 73p (Clinisupplies)   Leukofix®, 5 m (all) 1.25 cm = 52p, 2.5 cm = 83p, 5 cm =  £1.45 (BSN Medical)   Leukopor®, 5 m (all) 1.25 cm = 46p, 2.5 cm = 72p, 5 cm =  £1.26 (BSN Medical)   Mediplast®, 5 m (all) 1.25 cm = 30p, 2.5 cm = 50p  (Neomedic)   Micropore®, 5 m (all) 1.25 cm = 60p, 2.5 cm = 89p, 5 cm =  £1.57 (3M)   Scanpor®, 5m (all) 1.25 cm = 40p, 2.5 cm = 65p, 5 cm =  £1.12; 10 m (all), 1.25 cm = 52p, 2.5 cm = 87p, 5 cm = £1.65,   Where no brand stated by prescriber, net price of tape supplied  not to exceed 35p (1.25 cm), 59p (2.5 cm), 99p (5 cm)   Non-extensible closely woven fabric, spread with a poly-  meric adhesive. 5 m (all): 1.25 cm = 78p; 2.5 cm = £1.15; 5 cm  = £1.99 (Beiersdorf — Leukosilk ®)   Insil®, 2 cm x 3 m = £5.60, 4 cm x 1.5 m = £5.60 (Insight)   Mepitac®, 2 cm x 3 m = £6.56, 4 cm x 1.5 m = £6.56  (Molnlycke)   Siltape®, 2 cm x 3 m = £5.60, 4 cm x 1.5 m = £5.60  (Advancis)   (Zinc Oxide Plaster). Fabric, plain weave, warp and weft of  cotton and /or viscose, spread with an adhesive containing  zinc oxide. 5 m (all): 1.25 cm = 95p; 2.5 cm = £1.38; 5 cm =  £2.33; 7.5 cm = £3.51 (most suppliers)   Mediplast®, 5 m (all), 1.25 cm = 82p, 2.5 cm = £1.19, 5 cm =  £1.99, 7.5 cm = £2.99 (Neomedic)   Strappal®, 5 m (all): 1.25 cm = 89p, 2.5 cm = £1.29, 5 cm =  £2.17, 7.5 cm = £3.27 (BSN Medical)   Extensible water-impermeable plastic film spread with an  adhesive mass. 2.5 cm x 3 m = £1.33; 2.5 cm x 5 m = £1.99;  5 cm x 5 m = £2.53; 7.5 cm x 5 m = £3.67 (BSN Medical —  Sleek®)   Extensible water-impermeable plastic film spread with a  polymeric adhesive mass. 5 m (both): 2.5 cm = £1.72; 5 cm =  £3.27 (3M — Blenderm®)   Adhesive dressings (also termed ‘island dressings’) have  a limited role for minor wounds only. The inclusion of an  antiseptic is not particularly useful and may cause skin  irritation in susceptible subjects.   (former Drug Tariff tide: Semipermeable Waterproof Plastic  Wound Dressing). Consists of absorbent pad, may be dyed  and impregnated with suitable antiseptic (see under Elastic  Adhesive Dressing), attached to piece of semi-permeable  waterproof surgical adhesive tape, to leave suitable adhesive  margin; both pad and margin covered with suitable protec-  tor.(S&N Hlth — Elastoplast Airstrip®)   Skin closure strips are used as an alternative to sutures  for minor cuts and lacerations. Skin tissue adhesive  (section 13.10.5) can be used for closure of minor skin  wounds and for additional suture support.   Skin closure strips, sterile  Leukostrip®, 6.4 mm x 76mm, 3 strips per envelope. 10  envelopes = £5.95 (S&N Hlth.)   Omnistrip®, 6 mm x 76mm, 3 strips per envelope. 50  envelopes = £22.50 (Hartmann)   Steri-strip®, 6 mm x 75 mm, 3 strips per envelope. 12  envelopes = £8.52 (3M)   Drug Tariff specifies that these are specifically for personal  administration by the prescriber    According to their structure and performance bandages  are used for dressing retention, for support, and for  compression.   Bandages made from non-extensible, woven fabrics  have generally been replaced by more conformable  products, therefore their role is now extremely limited.  Triangular calico bandage has a role as a sling.  Open-wove Bandage, Type 1 BP 1988  Cotton cloth, plain weave, warp of cotton, weft of cotton,  viscose, or combination, one continuous length. 5 m (all):  2.5 cm = 31p; 5 cm = 52p; 7.5 cm = 74p; 10 cm = 96p (most  suppliers)   Unbleached calico right-angled triangle, 90 cm x 90 cm x  1.27 m = £1.15 (most suppliers)   Lightweight conforming bandages are used for dressing  retention, with the aim of keeping the dressing close to  the wound without inhibiting movement or restricting  blood flow. The elasticity of conforming-stretch ban-  dages (also termed contour bandages) is greater than  that of cotton conforming bandages.   Fabric, plain weave, warp of polyamide, weft of viscose.  4 m stretched (all):   Hospiform®, 6 cm = 13p, 8 cm = 16p, 10 cm = 18p, 12 cm =  22p (Hartmann)   Cotton fabric, plain weave, treated to impart some elasticity  to warp and weft. 3.5 m (all): type A, 5 cm = 63p, 7.5 cm -  77p, 10 cm = 96p, 15 cm = £1.30 (BSN Medical — Easifix  Crinx ®)   Fabric, knitted warp of polyamide filament, weft of  cotton or viscose, fast edges, one continuous length.   Easifix K®, 2.5 cm = 9p, 5 cm = lOp, 7.5 cm = 15p, 10 cm =  17p, 15 cm = 30p (BSN Medical)   K-Band®, 5 cm = 19p, 7 cm = 24p, 10 cm = 27p, 15 cm = 47p  (Urgo)   Knit-Band®, 5 cm = lOp, 7 cm = 15p, 10 cm = 17p, 15 cm =  30p (CliniMed)   Knit Fix®, 5 cm = 12p, 7 cm = 17p, 10 cm = 17p, 15 cm = 33p  (Steraid)   Peha-haft®, cohesive, latex-free, 4 m (all) 2.5 cm = 68p, 4 cm  = 44p, 6 cm = 52p, 8 cm = 62p, 10 cm = 7 lp, 12 cm = 84p  (Hartmann)   PremierBand®, 4 m (all); 5 cm = 12p, 7.5 cm = 14p, 10 cm =  17p, 15 cm = 25p (Shermond)   Polyamide and Cellulose Contour Bandage, BP 1988  (Nylon and Viscose Stretch Bandage)   Fabric, plain weave, warp of polyamide filament, weft of  cotton or viscose, fast edges, one continuous length, 4  m stretched (all):   Acti-Wrap®, cohesive, latex-free, 6 cm = 44p, 8 cm = 64p,   Easifix®, 5 cm = 33p, 7.5 cm = 40p, 10 cm = 47p, 15 cm =  80p (BSN Medical)   Kontour®, cohesive, 5 cm = 28p, 7.5 cm = 35p, 10 cm = 40p,  15 cm = 66p (Easigrip)   Mollelast®, latex-free, 4 cm = 28p, 6 cm = 34p (Activa)   Slinky®, 7.5 cm = 57p, 10 cm = 68p, 15 cm = 98p  (Molnlycke)   Stayform®, 5 cm = 29p, 7.5 cm = 36p, 10 cm = 40p, 15 cm =  68p (Robinsons)   Tubular bandages are available in different forms,  according to the function required of them. Some are  used under orthopaedic casts and some are suitable for  protecting areas to which creams or ointments (other  than those containing potent corticosteroids) have been  applied. The conformability of the elasticated versions  makes them particularly suitable for retaining dressings  on difficult parts of the body or for soft tissue injury, but  their use as the only means of applying pressure to an  oedematous limb or to a varicose ulcer is not appro-  priate, since the pressure they exert is inadequate.  Compression hosiery (section A8.9.1) reduces the  recurrence of venous leg ulcers and should be consid-  ered for use after wound healing.   Silk clothing is available as an alternative to elasticated  viscose stockinette garments, for use in the manage-  ment of severe eczema and allergic skin conditions (see  below).   (Drug Tariff specification 25). Fabric as for Elasticated Tub-  ular Bandage with polyurethane foam lining. Heel, elbow,  knee, small = £2.86, medium = £3.09, large = £3.30; sacral,  medium, and large (all) = £14.76 (Medlock — Tubipad ®)  Uses relief of pressure and elimination of friction in relevant  area; porosity of foam lining allows normal water loss from skin  surface   (formerly Elasticated Surgical Tubular Stockinette). Knitted  fabric, elasticated threads of rubber-cored polyamide or  polyester with cotton or cotton and viscose yam, tubular.  Lengths 50 cm and 1 m, widths 6.25 cm, 6.75 cm, 7.5 cm,  8.75 cm, 10 cm, 12 cm; Synergy — Comfigrip®] Easigrip —  EasiGRIP ®; Sallis — Eesiban®\ Medlock — Tubigrip ®. Where  no size stated by prescriber the 50 cm length should be  supplied and width endorsed   Acti-Fast®, 3.5 cm red line (small limb), length 1 m = 62p;   5 cm green line (medium limb), length 1 m = 65p, 3 m =  £1.90, 5 m = £3.30; 7.5 cm blue line (large limb), length 1 m =  90p, 3 m = £2.50, 5 m = £4.40; 10.75 cm yellow line (child  trunk), length 1 m = £1.45, 3 m =£4.10, 5 m =£7.10; 17.5 cm  beige line (adult trunk), length 1 m = £2.15 (Activa)   5 cm green line (medium limb), length 1 m = 58p, 3 m =  £1.62, 5 m = £2.81; 7.5 cm blue line (large limb), length 1 m =  77p, 3 m = £2.13, 5 m = £3.74; 10.75 cm yellow line (child  trunk), length 1 m = £1.20, 3 m = £3.49, 5 m = £6.04; 17.5 cm  beige line (adult trunk), length 1 m = £1.83; vest (long-  sleeved), 6-24 months = £7.13, 2-5 years = £9.50, 5-8 years  = £10.69, 8-11 years = £11.88, 11-14 years = £11.88, adult,  small, = £12.75, medium = £14.54, large = £16.58; vest (short-  sleeved), adult, small = £12.50, medium = £14.25, large =  £16.25; tights (pair) 6-24 months = £7. 13; leggings (pair) 2-5  years = £9.50, 5-8 years = £10.69, 8-11 years = £11.88, 11-  14 years = £11.88, adult, small, = £12.75, medium = £14.54,  large = £16.58; cycle shorts, adult, small = £12.50, medium =  £14.25, large = £16.25; socks (pair) up to 8 years = £2.97, 8-  14 years = £2.97; mittens (pair) up to 24 months = £2.97, 2-8  years = £2.97, 8-14 years = £2.97; gloves, child, small,  medium, large = £4.99, adult, small, medium, large = £4.99;  clava, 6 months-5 years = £5.85, 5-14 years = £6.75  (Clinisupplies)   Comfifast®, 3.5 cm red line (small limb), length 1 m = 56p;  5 cm green line (medium limb), length 1 m = 58p, 3 m =  £1.62, 5 m = £2.81; 7.5 cm blue line (large limb), length 1 m =  77p, 3m = £2.13, 5m = £3.74; 10.75 cm yellow line (child  trunk), length 1 m = £1.20, 3 m = £3.49, 5 m = £6.04; 17.5 cm  beige line (adult trunk), length 1 m = £1.83 (Synergy)   Comfifast® Easy Wrap, vest (long-sleeved), 6-24 months =  £7.13, 2-5 years = £9.50, 5-8 years = £10.69, 8-11 years =  £11.88, 11-14 years = £11.88, adult, small = £12.75, medium  = £14.54, large = £16.58; tights (pair), 6-24 months = £7.13;  leggings (pair), 2-5 years = £9.50, 5-8 years = £10.69, 8-11  years = £11.88, 11-14 years = £11.88, adult, small = £12.75,  medium = £14.54, large = £16.58; socks (pair), up to 8 years  = £2.97, 8-14 = £2.97; mittens (pair), up to 24 months =  £2.97, 2-8 years = £2.97, 8-14 years = £2.97; clava, 6  months-5 years = £5.85, 5-14 years = £6.75 (Synergy)   Comfifast® Multistretch, 3.5 cm red line (small limb), length  1 m = 72p; 5 cm green line (medium limb), length 1 m = 78p,  3 m = £2.23, 5 m = £3.82; 7.5 cm blue line (large limb), length  1 m = £1.05, 3 m = £2.93, 5 m = £5.12; 10.75 cm yellow line  (child trunk), length 1 m = £1.67, 3 m = £4.78, 5 m = £8.21;  17.5 cm beige line (adult trunk), length 1 m = £2.49 (Synergy  Healthcare)   5 cm green line (medium limb), length 1 m = 80p, 3 m =  £2.34, 5 m = £4.03; 7.5 cm blue line (large limb), length 1 m =  £1.11, 3m = £2.65, 5m =£5.25; 10.75cm yellow line (child  trunk), length 1 m = £1.75, 3 m = £5.04, 5 m = £8.86; 17.5 cm  beige line (adult trunk), length 1 m = £2.34 (Hartmann)   5 cm green line (medium limb), length 1 m = 69p, 3 m =  £1.95, 5 m = £3.40; 7.5 cm blue line (large limb), length 1 m =  94p, 3 m = £2.60, 5 m = £4.50; 10.75 cm yellow line (child  trunk), length 1 m = £1.50, 3 m = £4.25, 5 m = £7.20; 17.5 cm  beige line (adult trunk), length 1 m = £1.90 (Easigrip)   Skinnies®, body-suit, premature, 0-3 months, or 3-6  months = £15.90, 6-12 months = £17.90; clava, 6 months-5  years = £6.62, 5-14 years = £7.60; gloves child (small) =  £5.20, (medium or large) = £5.25, adult (small) = £5.20,  (medium or large) = £5.25; leggings (pair), 6-24 months =  £10.30, 2-5 years = £13.50, 5-8 years = £15.25, 8-1 1 years or  11-14 years = £16.90, adult (small) = £20.90, (medium) =  £22.80, (large) = £24.70; mittens, 0-24 months, 2-8 years, or  8-14 years = £3.80; socks, ankle (pair), 6 months-8 years or  8-14 years = £4.20; socks, knee (pair), child (small, medium,  or large, up to shoe size 4) = £13.70, adult (shoe size 4-6, 6-8,  8-1 1, or size 11+) = £13.70; vest (long-sleeved), 6-24 months  = £10.30, 2-5 years = £13.50, 5-8 years = £15.25, 8-1 1 years  or 11-14 years = £16.90, adult (small) = £20.90, (medium) =  £22.80, (large) = £24.70; vest (short-sleeved), 6-24 months =  £10.20, 2-5 years = £13.40, 5-8 years = £15.10, 8-1 1 years or  11-14 years = £16.80, adult (small) = £20.80, (medium) =    £22.70, (large) = £24.60; vest (sleeveless), 6-24 months =  £10.20, 2-5 years = £13.40, 5-8 years = £15.15, 8-11 years =  £16.80, 11-14 years = £16.80, adult (small) = £20.80,  (medium) = £22.70, (large) = £24.60 (Skinnies)   Tubifast® 2-way stretch, 3.5 cm red line (small limb), length  1 m = 88p; 5 cm green line (medium limb), length 1 m = 95p,  3 m = £2.70, 5 m = £4.61; 7.5 cm blue line (large limb), length  1 m = £1.26, 3 m = £3.55, 5 m = £6.19; 10.75 cm yellow line  (child trunk), length 1 m = £2.02, 3 m = £5.78, 5 m = £9.92;  20 cm purple line (large adult trunk), length 1 m = £3.27, 5 m  = £16.00; vest (long-sleeved), 6-24 months = £10.97, 2-5  years =£14.63, 5-8 years =£16.46, 8-11 years = £18.28, 11-  14 years = £18.28; tights (pair), 6-24 months = £10.97;  leggings (pair), 2-5 years = £14.63, 5-8 years = £16.46, 8-1 1  years = £18.28, 11-14 years = £18.28; socks (pair), one-size  = £4.58; gloves, (small-medium or medium-large adult, extra  small or small child) = £5.50 (Molnlycke)   Knitted fabric, cotton yam, tubular length, 1 m (all), 2.5 cm =  34p; 5 cm = 53p; 7.5 cm = 63p; 6m x 10 cm = £4.32 (J&J,  Medlock)   Uses 1 m lengths, basis (with wadding) for Plaster of Paris ban-  dages etc.; 6 m length, compression bandage   Knitted fabric of 1:1 ribbed structure, singles yam spun from  blend of two-thirds cotton and one-third viscose fibres,  tubular. Length 5 m (all):   Type A (lightweight): arm/leg (child), arm (adult) 5 cm = £2.45;  arm (OS adult), leg (adult) 7.5 cm = £3.22; leg (OS adult) 10 cm =  £4.27; trunk (child) 15 cm = £6.15; trunk (adult) 20 cm = £7.11;  trunk (OS adult) 25 cm = £8.50 (Molnlycke)   Type B (heavyweight): sizes as for Type A, net price £2.30-£7.97  (Sallis — Eesiban ®)   Drug Tariff specifies various combinations of sizes to provide  sufficient material for part or full body coverage  Uses protective dressings with tar-based and other non-steroid  ointments   Knitted, medical grade silk clothing can be used as an  adjunct to normal treatment for severe eczema and  allergic skin conditions. When used in combination  with medical creams and ointments, care should be  taken to ensure that the medication is fully absorbed  into the skin before the silk clothing is worn; silk  garments are not suitable for use in direct contact  with emollients used in ‘wet wrapping techniques’.   Knitted silk fabric, hypoallergenic, sericin-ffee, body suit,  child 0-3 months (height 62 cm) = £36.18, 3-6 months  (height 68 cm) = £35.65, 6-9 months (height 74 cm) = £36.67,  9—12 months (height 74 cm) = 38.25, 12-18 months (height  86 cm) = £36.69, 18-24 months (height 92 cm) = £39.29, 2-3  years (height 98 cm) = £38.71, 3-4 years (height 110 cm) =  £39.73; boxer shorts, adult (male), small-XXXL =£39.95;  briefs, 3-4 years = £20.95, 5-6 years = £20.95, 7-8 years =  £20.95, 10-12 years = £20.95, adult (female), smaU-XXL =  £29.39; facial mask, child (head circumference up to 47 cm)  = £15.30, child (head circumference up to 50 cm) = £15.30,  teen or adult = £20. 19; gloves, adult (small, medium, large, or  extra large) = £19.33, child (small or medium) = £13.98;  leggings, child 0-3 months (height 62 cm) = £25.83, 3-6  months (height 68 cm) = £25.45, 6-9 months (height 74 cm)  = £26.47, 9-12 months (height 74 cm) = £27.90, 12-18  months (height 86 cm) = £27.49, 18—24 months (height  92 cm) = £28.94, 2-3 years (height 98 cm) = £28.51, 3-4  years (height 110 cm) = £29.53, adult (male), small-XXL =  £75.60, adult (female), small-XXL = £75.60; pyjamas, child  3-4 years (height 110 cm) = £66.25, 5-6 years (height  120 cm) = £70.33, 7-8 years (height 135 cm) = £73.39, 10-12  years (height 150 cm) = £76.45; shirt, roll-neck, 3-4 years =  £45.56, 5-6 years = £48.49, 7-8 years = £50.51, 10-12 years  = £52.54, adult, small-XXL = £74.72; shirt, round-neck, adult  (male), small-XXL = £74.72, adult (female), small-XXL =  £74.72; sleeves (tubular), length 33 cm = £25.45, 50 cm =  £32.50; undersocks, (heel-less), 2 pairs standard or longer    length = £22.95; undersocks, adult shoe-size 5Vz— 6Vi, 7-8'/2,  9-1014, 1 1-13, child shoe-size 3-8, 9-1, 2-5, 2 pairs = £17.45   Knitted silk fabric, hypoallergenic, sericin-ffee, with  methyacrylate copolymer and zinc-based antibacterial, body  suit (with foldaway mitts), child up to 6 months = £35.65, 6-  9 months = £36.67, 9-12 months = £37.20, 12-18 months =  £37.69, 2-3 years = £38.71, 3-4 years = £39.73; briefs or  fitted boxers, 3-4 years = £20.95, 5-6 years = £20.95, 7-8  years = £20.95, 9-10 years = £20.95, 11-12 years = £20.95,  adult (male) small-XXL = £32.95, adult (female) small-XXL  = £30.95; eye mask, one size = £9.95; gloves, child (small or  medium) = £13.98, adult (small, medium, large, or extra  large) = £19.62; head mask, child up to 1 year (head  circumference 39-45cm) = £15.30, child 1-8 years (head  circumference 48-50cm) = £15.30, child 12-18 years =  £19.96, adult = £19.96; leggings (with foldaway feet), child  up to 6 months = £25.45, 6-9 months = £26.47, 9-12 months  = £26.98, 12-18 months = £27.49, 2-3 years = £28.51, 3-4  years = £29.53; leggings (without feet; male or female styles),  3-4 years = £29.53, 5-6 years = £30.99, 7-8 years = £31.49,  9-10 years = £31.99, 1 1-12 years = £32.49, adult small-XXL  = £74.74; pyjamas (male or female styles), 3-4 years =  £66.25, 5-6 years = £70.33, 7-8 years = £73.39, 9-10 years =  £74.95, 11-12 years = £76.45; shirt, polo-neck, long-sleeved  (male or female styles), 3-4 years = £44.94, 5-6 years =  £47.94, 7-8 years = £49.94, 9- 10 years = £50.94, 11-12  years = £51.94, adult small-XXL = £73.87; shirt, round-neck,  long-sleeved (male or female styles), 3-4 years = £44.95, 5-6  years = £46.95, 7-8 years = £48.95, 9-10 years = £49.95, 1 1-  12 years = £50.95, adult small-XXL = £73.87; sleeves, (tub-  ular), pair, length 33 cm = £25.83, 50 cm = £32.13; tights,  adult (female) small-XL = £22.95; undersocks, (liner socks), 2  pairs, child shoe-size 3-5'/2, 6-8V2, 9-12, 12'/2-3 l /2, 4-5'/2, =  £17.58, adult (male) shoe-size 6-8V2, 9-11 = £17.58, adult  (female) shoe-size 4-51/2, 6-SV2 = £17.58; undersocks (heel-  less), one size = £23.12   Light support bandages, which include the various  forms of crepe bandage, are used in the prevention of  oedema; they are also used to provide support for mild  sprains and joints but their effectiveness has not been  proven for this purpose. Since they have limited exten-  sibility, they are able to provide light support without  exerting undue pressure. For a warning against injudi-  cious compression see section A8.8.7.   Fabric, plain weave, warp of wool threads and crepe-twisted  cotton threads, weft of cotton threads; stretch bandage. 4.5 m  stretched (all): 5 cm = 92p; 7.5 cm = £1.29; 10 cm = £1.68;  15 cm = £2.44 (most suppliers)   Fabric, plain weave, warp of crepe-twisted cotton threads,  weft of cotton and/or viscose threads; stretch bandage.   4.5 m stretched (both): 7.5 cm = £2.88; 10 cm = £3.70 (most  suppliers)   Fabric, cotton, polyamide, and elastane; light support ban-  dage (Type 2), 4.5 m stretched (all)   Hospilite®, 5 cm = 34p, 7.5 cm = 47p, 10 cm = 57p, 15 cm =  84p (Hartmann)   Neosport®, 5 cm = 54p, 7.5cm = 73p, 10 cm = 91p, 15 cm =  £1.12 (Neomedic)   Profore® #2, 10 cm = £1.27, latex-free = £1.35 (S&N Hlth)  Setocrepe®, 10 cm = £1.13 (Molnlycke)   Soffcrepe®, 5 cm = 64p, 7.5 cm = 91p, 10 cm = £1.16, 15 cm  = £1.67 (BSN Medical)   Fabric, plain weave, warp of crepe-twisted cotton threads,  weft of cotton threads; stretch bandage, lighter than cotton  crepe, 4.5 m stretched (all):   Hospicrepe® 233, 5 cm = 52p; 7.5 cm = 72p; 10 cm = 96p;  15 cm = £1.36 (Steraid)   PremierBand®, 5 cm = 45p, 7.5 cm = 63p, 10 cm = 79p,   (Drug Tariff). Type 1: cotton net bag with draw tapes and  webbing waistband; small, medium, and large (all) = £1.59,  extra large = £1.68. Type 2: cotton net bag with elastic edge  and webbing waistband; small = £1.76, medium = £1.81,  large = £1.88, extra large = £1.95. Type 3: cotton net bag with  elastic edge and webbing waistband with elastic insertion;  small, medium, and large (all) = £1.90; extra large = £1.96.  Type supplied to be endorsed   CliniLite®, 4.5 m (all), 5 cm = 44p, 7.5 cm = 61p, 10 cm =  80p, 15 cm = £1.16 (Clinisupplies)   K-Lite®, 4.5 m stretched, 5 cm = 52p, 7 cm = 73p, 10 cm =  95p, 15 cm = £1.38; 5.2 m stretched, 10 cm = £1.09 (Urgo)   Knit-Firm®, 4.5 m stretched, 5 cm = 3 6p, 7cm = 5 lp, 10cm =  66p, 15 cm = 96p (Steraid)   Elset®, 6 m stretched, 10 cm = £2.46, 15 cm = £2.66; 8 m  stretched, 10 cm = £3.14; 12 m stretched, 15 cm = £5.27  (Molnlycke)   K-Plus®, 8.7 m stretched, 10 cm = £2.14; long, 10.25 m  stretched, 10 cm = £2.47 (Urgo)   Profore® #3, 8.7 m stretched, 10 cm = £3.70, latex-free =  £4.02 (S&N Hlth.)   Elastic adhesive bandages are used to provide com-  pression in the treatment of varicose veins and for the  support of injured joints; they should no longer be used  for the support of fractured ribs and clavicles. They have  also been used with zinc paste bandage in the treat-  ment of venous ulcers, but they can cause skin reactions  in susceptible patients and may not produce sufficient  pressures for healing (significantly lower than those  provided by other compression bandages).   Woven fabric, elastic in warp (crepe-twisted cotton threads),  weft of cotton and/ or viscose threads spread with adhesive  mass containing zinc oxide. 4.5 m stretched (all): 5 cm =  £3.39; 7.5 cm = £4.90; 10 cm = £6.52 (BSN Medical—  Elastoplast ® Bandage).   Cohesive bandages adhere to themselves, but not to  the skin, and are useful for providing support for sports  use where ordinary stretch bandages might become  displaced and adhesive bandages are inappropriate.  Care is needed in their application, however, since the  loss of ability for movement between turns of the  bandage to equalise local areas of high tension carries  the potential for creating a tourniquet effect. Cohesive  bandages can be used to support sprained joints and as    an outer layer for multi-layer compression bandaging;  they should not be used if arterial disease is suspected.   Bandage, cohesive, 6 m (all), 4 cm = £2.25, 6 cm = £2.64,  8 cm = £3.03, 10 cm = £3.15, 12 cm = £4.02   Bandage, 5 m (all), 6 cm = £2.52; 8 cm = £2.96; 10 cm =  £3.18; 12 cm = £3.87   Bandage, 6.5 m x 10 cm (0, short) = £2.78; 7.5 m, 18-25 cm  ankle circumference, 8 cm = £3.06, 10 cm = £3.25, 12 cm =  £4.09; 10.5 m, 25-32 cm ankle circumference, 8 cm = £3.33,  10 cm = £3.55, 12 cm = £4.48   Bandage, 5 m (all), 4cm = £1.76, 6cm = £2.45, 8 cm = £2.93,  10 cm = £3.20, 12 cm = £3.88; 10m x 10cm = £5.57   Bandage, 5 m (all), 8 cm = £3.00; 10 cm = £3.39   High compression products are used to provide the high  compression needed for the management of gross vari-  ces, post-thrombotic venous insufficiency, venous leg  ulcers, and gross oedema in average-sized limbs. Their  use calls for an expert knowledge of the elastic proper-  ties of the products and experience in the technique of  providing careful graduated compression. Incorrect  application can lead to uneven and inadequate pres-  sures or to hazardous levels of pressure. In particular,  injudicious use of compression in limbs with arterial  disease has been reported to cause severe skin and  tissue necrosis (in some instances calling for amputa-  tion). Doppler testing is required before treatment with  compression. Oral pentoxifylline (section 2.6.4) can be  used as adjunct therapy if a chronic venous leg ulcer  does not respond to compression bandaging [unli-  censed indication].   Viscose, elastane, and cotton compression (high) extensible  bandage, 3 m unstretched (both); 7.5 cm = £2.53; 10 cm =  £3.25 (S&N — Tensopress® )   Cotton, viscose, nylon, and Lycra® extensible bandage, 3 m  (unstretched), 10 cm = £3.42 (ConvaTec — SurePress ®); 3 m  (unstretched), 10 cm = £2.66 (Urgo — K-ThreeC ®); 3.5 m  (unstretched), 10 cm = £1.82 (Advancis — Adva-Co®)   Woven, elastomer, cohesive, extensible, compression ban-  dage, 3 m (unstretched), 10 cm (red) = £5.51, 10 cm (yellow)  = £6.02, 10 cm (green) = £6.52    JlShort stretch compression bandage  Short stretch bandages help to reduce oedema and  promote healing of venous leg ulcers. They are also  used to reduce swelling associated with lymphoede-  ma. They are applied at full stretch over padding [see  Sub-compression Wadding Bandage below) which  protects areas of high pressure and sites at high risk  of pressure damage.   Bandage, 5 m (all), 8 cm = £3.16; 10 cm = £3.40; 12 cm =  £4.14   Padding, 2.75 m unstretched (all): 5 cm = 29p, 7.5 cm = 35p;  10 cm = 43p; 15 cm = 55p   Padding, absorbent, 3.5 m unstretched, 10 cm = 43p; 4.5 m  unstretched, 10 cm = 53p   Padding, 5 m x 10 cm (0, short) = £3.76; 6 m, 18-25 cm  ankle circumference, 8 cm = £4.26, 10 cm = £4.51, 12 cm =  £5.69; 7.3 m, 25-32 cm ankle circumference, 8 cm = £4.64,  10 cm = £4.92, 12 cm = £6.21   Padding, 10 cm x 3.5 cm unstretched = 37p  Profore® #1 (S&N Hlth.)   Padding, viscose fleece, 3.5 m unstretched, 10 cm = 66p,  latex-free = 72p   Padding, absorbent, 3.5 m unstretched, 10 cm = 60p  SurePress® (ConvaTec)   Multi-layer compression bandaging systems are an  alternative to High Compression Bandages (section  A8.8.7) for the treatment of venous leg ulcers. Compres-  sion is achieved by the combined effects of two or three  extensible bandages applied over a layer of orthopaedic  wadding and a wound contact dressing.   K-Four ® # 1 ( K-Soft ® — see Sub-compression Wadding  Bandage, above); K-Four ® # 2 ( K-Lite ® — see Knitted  Elastomer and Viscose Bandage, p. 953); K-Four ® # 3 [K-  PIus ® — see Knitted Elastomer and Viscose Bandage, p. 953);  K-Three C® — see High compression bandages, above; K-  Four ® # 4 ( Ko-Flex ®), 6 m (stretched), 10 cm = £2.84; 7 m  (stretched), 10 cm = £3.25    Multi-layer compression bandaging kit, four layer system,  for ankle circumference up to 18 cm = £6.73, 18-25 cm =  £6.44, 25-30 cm = £6.44, above 30 cm = £8.87; reduced  compression, 18 cm and above = £4.21   Profore ® wound contact layer (see Knitted Viscose Primary  Dressing, p. 937); Profore ® #1 (see Sub-compression  Wadding Bandage, p. 954); Profore ® #2 (see Cotton, Poly-  amide and Elastane Bandage, p. 953); Profore ® # 3 (see  Knitted Elastomer and Viscose Bandage, p. 953); Profore ®  #4 (see Cohesive bandages, p. 954); Profore ® Plus 3 m  (unstretched), 10 cm = £3.46, latex-free = £3.70  Multi-layer compression bandaging kit, four layer system,  for ankle circumference up to 18 cm = £9.58, 18-25 cm =  £8.92, 25-30 cm = £7.41, above 30 cm = £11.09, latex-free,  18-25 cm = £9.53; Profore Lite® above 18 cm = £5.15, latex-  free = £5.60    such as chronic eczema (ichthammol often being pre-  ferred since its action is considered to be milder). They  are also used with calamine in milder eczematous skin  conditions.   Cotton fabric, plain weave, impregnated with suitable paste  containing zinc oxide; requires additional bandaging, 6 m x   Cotton fabric, plain weave, impregnated with suitable paste  containing zinc oxide and ichthammol; requires additional  bandaging, 6m x 7.5 cm = £3.47 S&N Hlth. — Ichthopaste ®  (6/2%), excipients: include cetostearyl alcohol  Uses see section 13.5   System 4® #1 ( Softexe ® — see Sub-compression Wadding  Bandage, p. 954); System 4® #2 ( Setocrepe ® — see Cotton,  Polyamide and Elastane Bandage, p. 953); System 4® #3  (Elset® — see Knitted Elastomer and Viscose Bandage,  p. 953); System 4® #4 ( Meban ®)   Multi-layer compression bandaging kit, four layer system,  for ankle circumference 18-25 cm = £7.46   Ultra Four® #1 ( Ultra Soft® — see Sub-compression Wad-  ding Bandage, p. 954); Ultra Four® #2 (Ultra Lite®) 10 cm x   Multi-layer compression bandaging kit, four layer system,  for ankle circumference up to 18 cm = £6.41, 18-25 cm =  £5.67; Ultra Four® RC (reduced compression) 18-25 cm =  £4.14   Multi-layer compression bandaging kit, two layer system  (latex-free, foam bandage and cohesive compression ban-  dage), one size = £8.08; Coban® 2 Lite (reduced compres-  sion), one size = £8.08   K-Tech® (see Sub-compression Wadding Bandages,  p. 954); K-Press® (see Cohesive Bandages, p. 954)  Multi-layer compression bandaging kit, two layer system,  size 0 (short) = £6.55; 18-25 cm ankle circumference, 8 cm =  £7.32, 10 cm = £7.76, 12 cm = £9.78; 25-32 cm ankle cir-  cumference, 8 cm = £7.96, 10 cm = £8.48, 12 cm = £10.69   K-Two® Start, Urgotul® Start (see Protease-modulating  matrix, p. 947); K-Tech® (see Sub-compression Wadding  Bandages, p. 954); K-Press® (see Cohesive Bandages, p. 954)  Multi-layer compression bandaging kit, two-layer system,  for ankle circumference 18-25cm = £9.68; 25-32cm = £10.33   ProGuide® wound contact layer (see Absorbent dressings,  p. 937); ProGuide® #1 (see Sub-compression Wadding  Bandage, p. 954); ProGuide® #2 (see High Compression  Bandages, p. 954)   Multi-layer compression bandaging kit, two layer system,  for ankle circumference 18-22 cm (red) = £9.23; 22-28 cm  (yellow) = £9.75; 28-32 cm (green) = £10.24   Zinc Paste Bandage has been used with compression  bandaging for the treatment of venous leg ulcers. How-  ever, paste bandages are associated with hypersensi-  tivity reactions and should be used with caution.   Zinc paste bandages are also used with coal tar or  ichthammol in chronic lichenified skin conditions   Cotton fabric, selvedge weave impregnated with paste con-  taining zinc oxide (requires additional bandaging), 6 m x   Sterile rayon stocking impregnated with ointment containing  zinc oxide 20%. 4-pouch carton = £12.52; 10-pouch carton =  £31.30   Note Can be used under appropriate compression bandages or  hosiery in chronic venous insufficiency   Compression (elastic) hosiery is used to treat condi-  tions associated with chronic venous insufficiency, to  prevent recurrence of thrombosis, or to reduce the risk  of further venous ulceration after treatment with com-  pression bandaging (section A8.8.7). Doppler testing to  confirm arterial sufficiency is required before recom-  mending the use of compression hosiery.   Before elastic hosiery can be dispensed, the quantity  (single or pair), article (including accessories), and com-  pression class must be specified by the prescriber. There  are different compression values for graduated com-  pression hosiery and lymphoedema garments (see table  below). All dispensed elastic hosiery articles must state  on the packaging that they conform with Drug Tariff  technical specification No. 40, for further details see  Drug Tariff.   Hosiery, compression at ankle 14-17 mmHg, thigh length or  below knee with knitted in heel. 1 pair, circular knit (stan-  dard), thigh length = £7.61, below knee = £6.95, (made-to-  measure), thigh length = £37.79, below knee = £23.64;  lightweight elastic net (made-to-measure), thigh length =  £20.38, below knee =£15.91   Hosiery, compression at ankle 18-24 mmHg, thigh length or  below knee with knitted in heel. 1 pair, circular knit (stan-  dard), thigh length = £11.31, below knee = £10.16, (made-to-  measure), thigh length = £37.79, below knee = £23.64; net  (made-to-measure), thigh length = £20.38, below knee =  £15.91; flat bed (made-to-measure, only with closed heel and  open toe), thigh length = £37.79, below knee = £23.64  Uses varices of medium severity, ulcer treatment and prophy-  laxis, mild oedema, varicosis during pregnancy   Hosiery, compression at ankle 25-35 mmHg, thigh length or  below knee with open or knitted in heel. 1 pair, circular knit  (standard), thigh length = £13.40, below knee = £11.52,  (made-to-measure) thigh length = £37.79, below knee =  £23.64; flat bed (made-to-measure, only with open heel and  open toe), thigh length = £37.79, below knee = £23.64  Uses gross varices, post thrombotic venous insufficiency, gross  oedema, ulcer treatment and prophylaxis    merits (usually made-to-measure) with a seam, provide  greater rigidity and stiffness to maintain reduction of  lymphoedema following treatment with compression  bandages.   A standard range of light, medium, or high compression  garments are available, as well as low compression (12-  16 mm Hg) armsleeves, made-to-measure garments up  to compression 90 mmHg, and accessories — see Drug  Tariff for details.   Note There are different compression values for lymphoedema  garments and graduated compression hosiery, see table, p. 955.   In addition to the product listed below, accessories  such as application aids for hosiery are available, see  Drug Tariff for details   Anklets, compression 18-24 mmHg, circular knit (standard  and made-to-measure), 1 pair = £6.66; flat bed (standard and  made-to-measure) =£13.84; net (made-to-measure) =£13.09   Anklets, compression 25-35 mmHg, circular knit (standard  and made-to-measure), 1 pair = £9.09; flat bed (standard) =  £9.29, (made-to-measure) = £13.84   Kneecaps, compression 18-24 mmHg, circular knit (stan-  dard and made-to-measure), 1 pair = £6.66; flat bed (stan-  dard and made-to-measure) = £13.84; net (made-to-mea-  sure) = £10.87   Kneecaps, compression 25-35 mmHg, circular knit (stan-  dard and made-to-measure), 1 pair = £8.88; flat bed (stan-  dard) = £8.88, (made-to-measure) = £13.84   Lymphoedema compression garments are used to  maintain limb shape and prevent additional fluid reten-  tion. Either flat-bed or circular knitting methods are  used in the manufacture of elasticated compression  garments. Seamless, circular-knitted garments (in stan-  dard sizes) can be used to prevent swelling if the  lymphoedema is well controlled and if the limb is in  good shape and without skin folds. Flat-knitted gar-    Numbers following the preparation entries in the BNF  correspond to the code numbers of the cautionary  labels that pharmacists are recommended to add  when dispensing. It is also expected that pharmacists  will counsel patients when necessary.   Counselling needs to be related to the age, experi-  ence, background, and understanding of the indivi-  dual patient. The pharmacist should ensure that the  patient understands how to take or use the medicine  and how to follow the correct dosage schedule. Any  effects of the medicine on driving or work, any foods  or medicines to be avoided, and what to do if a dose is  missed should also be explained. Other matters, such  as the possibility of staining of the clothes or skin by a  medicine should also be mentioned.   For some preparations there is a special need for  counselling, such as an unusual method or time of  administration or a potential interaction with a com-  mon food or domestic remedy, and this is indicated  where necessary.   Original packs Most preparations are dispensed in  unbroken original packs that include further advice for  the patient in the form of patient information leaflets.  Label 10 may be of value where appropriate. More  general leaflets advising on the administration of pre-  parations such as eye drops, eye ointments, inhalers,  and suppositories are also available.   Scope of labels In general no label recommendations  have been made for injections on the assumption that  they will be administered by a healthcare professional or  a well-instructed patient. The labelling is not exhaustive  and pharmacists are recommended to use their profes-  sional discretion in labelling new preparations and those  for which no labels are shown.   Individual labelling advice is not given on the adminis-  tration of the large variety of antacids. In the absence of  instructions from the prescriber, and if on enquiry the  patient has had no verbal instructions, the directions  given under ‘Dose’ should be used on the label.   It is recognised that there may be occasions when  pharmacists will use their knowledge and professional  discretion and decide to omit one or more of the  recommended labels for a particular patient. In this  case counselling is of the utmost importance. There  may also be an occasion when a prescriber does not  wish additional cautionary labels to be used, in which  case the prescription should be endorsed ‘NCL’ (no  cautionary labels). The exact wording that is required  instead should then be specified on the prescription.  Pharmacists label medicines with various wordings in  addition to those directions specified on the prescrip-  tion. Such labels include ‘Shake the bottle’, ‘For external  use only’, and ‘Store in a cool place’, as well as ‘Discard .   apply particularly to antibiotic mixtures, diluted liquid  and topical preparations, and to eye-drops. Although  not listed in the BNF these labels should continue to be  used when appropriate; indeed, ‘For external use only’ is  a legal requirement on external liquid preparations,  while ‘Keep out of the reach of children’ is a legal  requirement on all dispensed medicines. Care should  be taken not to obscure other relevant information with  adhesive labelling.   It is the usual practice for patients to take standard  tablets with water or other liquid and for this reason no  separate label has been recommended.   The label wordings recommended by the BNF apply to  medicines dispensed against a prescription. Patients  should be aware that a dispensed medicine should  never be taken by, or shared with, anyone other than  for whom the prescriber intended it. Therefore, the BNF  does not include warnings against the use of a dispensed  medicine by persons other than for whom it was speci-  fically prescribed.    The label or labels for each preparation are recom-  mended after careful consideration of the information  available. However, it is recognised that in some cases  this information may be either incomplete or open to a  different interpretation. The BNF will therefore be grate-  ful to receive any constructive comments on the label-  ling suggested for any preparation.   For BNF 61 (March 2011) a revised set of advisory  and cautionary labels has been introduced. All of the  existing labels have been user-tested, and the  revised wording selected reflects terminology that  is better understood by patients.    Wordings which can be given as separate warnings are  labels 1-19, 29-30, and 32. Wordings which can be  incorporated in an appropriate position in the directions  for dosage or administration are labels 21-28. A label  has been omitted for number 20; labels 31 and 33 no  longer apply to any medicines in the BNF and have  therefore been deleted.   If separate labels are used it is recommended that the  wordings be used without modification. If changes are  made to suit computer requirements, care should be  taken to retain the sense of the original.   To be used on preparations for children containing  antihistamines, or other preparations given to chil-  dren where the warnings of label 2 on driving or  alcohol would not be appropriate.    958 Appendix 9: Cautionary and advisory labels for dispensed medicines BNF 61    Warning: This medicine may make you sleepy. If this 8  happens, do not drive or use tools or machines. Do  not drink alcohol   To be used on preparations for adults that can cause  drowsiness, thereby affecting the ability to drive and  operate hazardous machinery; label 1 is more appro-  priate for children. It is an offence to drive while under  the influence of drink or drugs.   Some of these preparations only cause drowsiness in  the first few days of treatment and some only cause  drowsiness in higher doses.   In such cases the patient should be told that the  advice applies until the effects have worn off. However  many of these preparations can produce a slowing of  reaction time and a loss of mental concentration that  can have the same effects as drowsiness.   Avoidance of alcoholic drink is recommended because  the effects of CNS depressants are enhanced by  alcohol. Strict prohibition however could lead to some  patients not taking the medicine. Pharmacists should  therefore explain the risk and encourage compliance,  particularly in patients who may think they already  tolerate the effects of alcohol (see also label 3).   Queries from patients with epilepsy regarding fitness  to drive should be referred back to the patient’s  doctor.   Side-effects unrelated to drowsiness that may affect a  patient’s ability to drive or operate machinery safely  include blurred vision, dizziness, or nausea. In gen-  eral, no label has been recommended to cover these  cases, but the patient should be suitably counselled.  Warning: This medicine may make you sleepy. If this  happens, do not drive or use tools or machines  To be used on preparations containing monoamine-  oxidase inhibitors ; the warning to avoid alcohol and  dealcoholised (low alcohol) drink is covered by the  patient information leaflet.   Also to be used as for label 2 but where alcohol is not  an issue.   To be used on preparations where a reaction such as  flushing may occur if alcohol is taken (e.g. metronid-  azole). Alcohol may also enhance the hypoglycaemia  produced by some oral antidiabetic drugs but routine  application of a warning label is not considered  necessary.   Do not take indigestion remedies 2 hours before or  after you take this medicine   To be used with label 25 on preparations coated to  resist gastric acid (e.g. enteric-coated tablets). This is  to avoid the possibility of premature dissolution of the  coating in the presence of an alkaline pH.   Label 5 also applies to drugs such as ketoconazole  where the absorption is significantly affected by  antacids-, the usual period of avoidance recom-  mended is 2 hours.   Do not take indigestion remedies, or medicines con-  taining iron or zinc, 2 hours before or after you take  this medicine   To be used on preparations containing ofloxacin and  some other quinolones, doxycycline, lymecycline,  minocycline, and penicillamine. These drugs chelate  calcium, iron and zinc and are less well absorbed  when taken with calcium-containing antacids or pre-  parations containing iron or zinc. These incompatible  preparations should be taken 2 hours apart.   Do not take milk, indigestion remedies, or medicines  containing iron or zinc, 2 hours before or after you  take this medicine   To be used on preparations containing ciprofloxacin,  norfloxacin or tetracyclines that chelate calcium, iron,  magnesium, and zinc and are thus less available for  absorption; these incompatible preparations should  be taken 2 hours apart. Doxycycline, lymecycline and  minocycline are less liable to form chelates and  therefore only require label 6 (see above).    Warning: Do not stop taking this medicine unless  your doctor tells you to stop   To be used on preparations that contain a drug which  is required to be taken over long periods without the  patient necessarily perceiving any benefit (e.g. anti-  tuberculous drugs).   Also to be used on preparations that contain a drug  whose withdrawal is likely to be a particular hazard  (e.g. clonidine for hypertension). Label 10 (see below)  is more appropriate for corticosteroids.   9 Space the doses evenly throughout the day. Keep  taking this medicine until the course is finished,  unless you are told to stop   To be used on preparations where a course of treat-  ment should be completed to reduce the incidence of  relapse or failure of treatment.   The preparations are antimicrobial drugs given by  mouth. Very occasionally, some may have severe side-  effects (e.g. diarrhoea in patients receiving clinda-  mycin) and in such cases the patient may need to be  advised of reasons for stopping treatment quickly and  returning to the doctor.   To be used particularly on preparations containing  anticoagulants, lithium and oral corticosteroids. The  appropriate treatment card should be given to the  patient and any necessary explanations given.   This label may also be used on other preparations to  remind the patient of the instructions that have been  given.   To be used on preparations that may cause phototoxic  or photoallergic reactions if the patient is exposed to  ultraviolet radiation. Many drugs other than those  listed in Appendix 9 (e.g. phenothiazines and  sulphonamides) may, on rare occasions, cause reac-  tions in susceptible patients. Exposure to high inten-  sity ultraviolet radiation from sunray lamps and sun-  beds is particularly likely to cause reactions.   12 Do not take anything containing aspirin while taking  this medicine   To be used on preparations containing probenecid  and sulfinpyrazone whose activity is reduced by  aspirin.   Label 12 should not be used for anticoagulants since  label 10 is more appropriate.   To be used on preparations that are intended to be  dissolved in water (e.g. soluble tablets) or mixed with  water (e.g. powders, granules) before use. In a few  cases other liquids such as fruit juice or milk may be  used.   To be used on preparations that may cause the  patient’s urine to turn an unusual colour. These  include triamterene (blue under some lights), levo-  dopa (dark reddish), and rifampicin (red).   15 Caution: flammable. Keep your body away from fire or  flames after you have put on the medicine   To be used on preparations containing sufficient  flammable solvent to render them flammable if  exposed to a naked flame.   To be used on glyceryl trinitrate tablets to remind the  patient not to transfer the tablets to plastic or less  suitable containers.   To be used on preparations for the treatment of acute  migraine except those containing ergotamine, for  which label 18 is used. The dose form should be   It may also be used on preparations for which no dose  has been specified by the prescriber.   18 Do not take more than ... in 24 hours. Also, do not  take more than ... in any one week   To be used on preparations containing ergotamine.  The dose form should be specified, e.g. tablets or  suppositories.   19 Warning: This medicine makes you sleepy. If you still  feel sleepy the next day, do not drive or use tools or  machines. Do not drink alcohol   To be used on preparations containing hypnotics (or  some other drugs with sedative effects) prescribed to  be taken at night. On the rare occasions (e.g. nitraze-  pam in epilepsy) when hypnotics are prescribed for  daytime administration this label would clearly not be  appropriate. Also to be used as an alternative to the  label 2 wording (the choice being at the discretion of  the pharmacist) for anxiolytics prescribed to be taken  at night.   To be used on preparations that are liable to cause  gastric irritation, or those that are better absorbed  with food.   Patients should be advised that a small amount of  food is sufficient.   To be used on some preparations whose absorption is  thereby improved.   23 Take this medicine when your stomach is empty. This  means an hour before food or 2 hours after food   To be used on oral preparations whose absorption  may be reduced by the presence of food and acid in  the stomach.   To be used on preparations that should be sucked or  chewed.   The pharmacist should use discretion as to which of  these words is appropriate.   To be used on preparations that are enteric-coated or  designed for modified-release.   To be used on preparations designed for sublingual  use. Patients should be advised to hold under the  tongue and avoid swallowing until dissolved. The  buccal mucosa between the gum and cheek is occa-  sionally specified by the prescriber.   To be used on preparations that should be well diluted  (e.g. chloral hydrate), where a high fluid intake is  required (e.g. sulphonamides), or where water is  required to aid the action (e.g. methylcellulose). The  patient should be advised that ‘a full glass’ means at  least 150 mL. In most cases fruit juice, tea, or coffee  may be used.   To be used on external preparations that should be  applied sparingly (e.g. corticosteroids, dithranol).   Do not take more than 2 at any one time. Do not take  more than 8 in 24 hours   To be used on containers of dispensed solid dose  preparations containing paracetamol for adults when  the instruction on the label indicates that the dose can  be taken on an ‘as required’ basis. The dose form  should be specified, e.g. tablets or capsules.   This label has been introduced because of the serious  consequences of overdosage with paracetamol.  Contains paracetamol. Do not take anything else  containing paracetamol while taking this medicine  To be used on all containers of dispensed prepara-  tions containing paracetamol.   Contains aspirin. Do not take anything else contain-  ing aspirin while taking this medicine  To be used on containers of dispensed preparations  containing aspirin when the name on the label does  not include the word ‘aspirin’.   Abilify orodispersible tabs, 2, C,  administration, see BNF  Abstral, 2, 26  Acamprosate, 21, 25  Acarbose, C, administration, see  BNF   Accolate, 23  Acebutolol, 8  Aceclofenac, 21  Acemetacin, 21, C, driving  Acenocoumarol, 10, anti-  coagulant card  Acetazolamide, 3  Acetazolamide m/r, 3, 25  Aciclovir susp and tabs, 9  Acipimox, 21    Acitretin, 10, patient information  leaflet, 11, 21  Acrivastine, C, driving  Actiq, 2   Actonel, C, administration, food  and calcium, see BNF  Acupan, 2, 14, (urine pink)  Adalat LA, 25  Adalat Retard, 25  Adalimumab, C, tuberculosis  Adapalene, 11    960 Appendix 9: Cautionary and advisory labels for dispensed medicines BNF 61   Alitretinoin, 10, patient informa-  tion leaflet, 11, 21  Allegron, 2  Allopurinol, 8, 21, 27  Almogran, 3  Almotriptan, 3  Alphosyl HC, 28  Alphaderm, 28, C, application,  see BNF  Alprazolam, 2  Altargo, 28  Alvedon, 30   Alvesco, 8, C, administration  Amantadine, C, driving  Amifampridine, 3, 21  Aminophylline m/r, see preps  Amiodarone, 11  Amisulpride, 2  Amitriptyline, 2   Amoxil dispersible sachets, 9, 13  Amoxil paed susp, 9, C, use of  pipette   Ampicillin, 9, 23  Anafranil, 2  Anafranil m/r, 2,25  Anagrelide, C, driving  Anakinra, C, blood disorder  symptoms  Androcur, 21   APO-go, 10, C, driving, see BNF  Apomorphine, 10, C, driving, see  BNF   Aptivus caps, 5, 21  Aptivus oral solution, 5, 21, C,  crystallisation  Arava, 4   Aripiprazole orodispersible tabs,  2, C, administration, see BNF  Arlevert, 2  Aromasin, 21  Arpicolin, C, driving  Artemether with lumefantrine,  21, C, driving    Asacol MR tabs, 5, 25, C, blood  disorder symptoms, see BNF  Asacol enema and supps, C,  blood disorder symptoms, see  BNF   Asasantin Retard, 21, 25  Ascorbic acid tabs (500 mg), 24  Asmabec preps, 8, C, adminis-  tration; with high doses, 10,  steroid card   Asmanex, 8, 10, steroid card, C,  administration  Asmasal, C, administration  Aspirin dispersible tabs, 13, 21,  also 32 (if ‘aspirin’ not on label)  Aspirin e/c, 5, 25, also 32 (if  ‘aspirin’ not on label)   Atorvastatin, C, muscle effects,  see BNF  Atovaquone, 21  Atripla, 23, 25   Augmentin susp and tabs, 9  Augmentin Duo, 9  Aureocort, 28, C, application, see  BNF   Avandamet, 21  Avelox, 6, 9, C, driving  Avloclor, 5, C, malaria prophy-  laxis, see BNF  Avodart, 25  Avomine, 2  Axorid, 21, 25  Azathioprine, 21  Azithromycin caps, 5, 9, 23  Azithromycin susp and tabs, 5, 9   Baclofen, 2, 8, 21  Balsalazide, 21, 25  Baraclude, C, administration  Baratol, 2  Baxan, 9   Beclometasone inhalations, 8, C,  administration; with high  doses, 10, steroid card  Becodisks, 8, C, administration;  with high doses, 10, steroid  card   Benzoin tincture, compound, 15  Besavar XL, 21, 25, C, initial  dose, driving, see BNF  Beta-Adalat, 8, 25   Betamethasone soluble tab, 10,  steroid card, 13, 21, (when  used as a mouthwash, Label:  10, 13, C, administration)  Betamethasone tab, 10, steroid  card, 21   Betamethasone external preps,  28, C, application, see BNF  Betamethasone plaster, C, appli-  cation, see BNF  Betamethasone scalp applica-  tion, 15, 28, C, application, see  BNF   Betnesol tabs, 10, steroid card,  13, 21, (when used as a  mouthwash, Label: 10, 13, C,  administration)   Betnovate external preps, 28, C,  application, see BNF  Betnovate scalp application, 15,  28, C, application, see BNF  Betnovate-RD, 28, C, application,  see BNF   Bettamousse, 28, C, application,  see BNF  Bezafibrate, 21  Bezafibrate m/r, 21, 25  Bezalip, 21  Bezalip-Mono, 21, 25  Biorphen, C, driving  Bisacodyl tabs, 5, 25  Bisoprolol, 8   Broflex, C, driving, see BNF  Bromocriptine, 10, 21, C, driving,  see BNF  Brufen, 21  Brufen gran, 13, 21  Brufen Retard, 25, 27  Buccastem, 2, C, administration,  see BNF    Budesonide inhalations, 8, C,  administration; with high  doses, 10, steroid card  Budesonide caps, 5, 10, steroid  card, 22, 25   Budesonide m/r caps, 5, 10,  steroid card, 25  Buprenorphine, 2, 26  Bupropion, 25, C, driving  Buserelin nasal spray, C, nasal  decongestants, see BNF  Buspirone, C, driving  BuTrans, 2   Cabergoline, 10, 21, C, driving,  see BNF  Cacit, 13  Cacit D3, 13  Cafergot, 18, C, dosage  Calceos, 24  Calcicard CR, 25   Calcichew-D 3 tabs, chewable, 24  Calcichew tabs, chewable, 24  Calcium-500, 25  Calcium acetate caps, C, with  meals   Calcium acetate tabs, C, do not  chew, with meals  Calcium carbonate tabs, chew-  able, 24   Calcium carbonate tabs and gran  effervescent, 13  Calcium gluconate effervescent  tabs, 13   Calcium phosphate sachets, 13  Calcium Resonium, 13  Calcium and ergocalciferol tabs,  C, administration, see BNF  Calcort, 5, 10, steroid card  Calfovit D3, 13, 21  Calmurid HC , 28, C, application,  see BNF  Calpol susp, 30  Camcolit 250 tabs, 10, lithium  card, C, fluid and salt intake,  see BNF   Camcolit 400 tabs, 10, lithium  card, 25, C, fluid and salt  intake, see BNF  Campral EC, 21, 25  Canesten HC, 28, C, application,  see BNF   Caprin, 5, 25, 32  Caramet CR, 10, 14, 25, C, driv-  ing, see BNF  Carbaglu, 13    Carbamazepine chewable, 3, 8,  21, 24, C, blood, hepatic or  skin disorder symptoms, driv-  ing, see BNF   Carbamazepine liq, supps and  tabs, 3, 8, C, blood, hepatic or  skin disorder symptoms, driv-  ing, see BNF   Carbamazepine m/r, 3, 8, 25, C,  blood, hepatic or skin disorder  symptoms, driving, see BNF  Carbimazole, C, blood disorder  symptoms, see BNF  Cardene SR, 25   Cardura, C, initial dose, driving  Cardura XL, 25, C, initial dose,  driving   Cefaclor m/r, 9, 21, 25  Cefadroxil, 9  Cefalexin, 9  Cefixime, 9  Cefpodoxime, 5, 9, 21  Cefradine, 9  Cefuroxime susp, 9, 21  Cefuroxime tab, 9, 21, 25  Celance, 10, C, driving, see BNF  Celectol, 8,22   Cetirizine, C, driving  Champix, 3  Chemydur 60XL, 25  Chloral hydrate, 19, 27  Chloral paed elixir, 1, 27  Chloral mixt, 19, 27  Chlordiazepoxide, 2  Chloroquine, 5, C, malaria  prophylaxis, see BNF  Chlorphenamine, 2  Chlorpromazine solution, supps  and tabs, 2, 11   Cholestagel, 21, C, avoid other  drugs at same time, see BNF  Ciclesonide, 8, C, administration  Ciclosporin, C, administration,  see BNF   Cimzia, 10, Alert card, C, tuber-  culosis, blood disorders  Cinacalcet, 21  Cinnarizine, 2  Cipralex drops, C, driving,  administration  Cipralex tabs, C, driving  Cipramil drops, C, driving,  administration  Cipramil tabs, C, driving  Ciprofloxacin, 7, 9, 25, C, driving    Ciproxin susp and tabs, 7, 9, 25,  C, driving  Circadin, 2,21,25  Citalopram drops, C, driving,  administration  Citalopram tabs, C, driving  CitraFleet, 10, patient informa-  tion leaflet, 13, C, administra-  tion   Citramag, 10, patient information  leaflet, 13, C, administration  Clarelux, 15, 28, C, application,  see BNF   Clarithromycin, 9  Clarithromycin m/r, 9, 21, 25  Clarithromycin sachets, 9, 13  Clasteon, C, food and calcium,  see BNF  Clemastine, 2   Clobetasol external preps, 28, C,  application, see BNF  Clobetasol scalp application, 15,  28, C, application, see BNF  Clobetasone butyrate, 28, C,  application, see BNF  Clofazimine, 8, 14, (urine red), 21  Clomethiazole, 19  Clomipramine, 2  Clomipramine m/r, 2, 25  Clonazepam, 2, 8, C, driving, see  BNF   Clonidine, see Catapres  Clopixol, 2  Clotam Rapid, 21  Clotrimazole spray, 15  Clozapine tabs, 2, 10, patient  information leaflet  Clozapine susp, 2, 10, patient  information leaflet, C, adminis-  tration   Clozaril, 2, 10, patient informa-  tion leaflet  Coal tar paint, 15  Coal tar solution, 15  Co-amoxiclav, 9  Co-beneldopa, 10, 14, (urine  reddish), C, driving, see BNF  Co-beneldopa dispersible tabs,  10, 14, (urine reddish), C,  administration, driving, see  BNF   Co-careldopa, 10, 14, (urine red-  dish), C, driving, see BNF  Co-careldopa intestinal gel, 10,  14, (urine reddish), C, driving,  see BNF    962 Appendix 9: Cautionary and advisory labels for dispensed medicines BNF 61   Codalax, 14, (urine red)  Co-danthramer, 14, (urine red)  Co-danthrusate, 14, (urine red)  Codeine phosphate syr and tabs,  2   Codipar, 2, 29, 30  Co-dydramol, 29, 30  Co-fluampicil, 9, 22  Colazide, 21, 25  Colesevelam, 21, C, avoid other  drugs at same time, see BNF  Colestid, 13, C, avoid other drugs  at same time, see BNF  Colestipol preps, 13, C, avoid  other drugs at same time, see  BNF   Colestyramine, 13, C, avoid other  drugs at same time, see BNF  Collodion, flexible, 15  Colofac, C, administration, see  BNF   Colofac MR, 25, C, administra-  tion, see BNF  Colpermin, 5, 22, 25  Combodart, 25, C, driving, see  BNF   Convulex, 8, 21, 25, C, blood or  hepatic disorder symptoms,  driving, see BNF  Copeg us, 21  Co-prenozide, 8, 25  Coracten preps, 25  Cordarone X, 11  Corgard, 8   Co-triamterzide, 14, (urine blue  in some lights), 21  Co-trimoxazole susp and tabs, 9  Coversyl, 22  Coversyl Arginine, 22  Coversyl Plus, 22  Coversyl Arginine Plus, 22  Creon preps, C, administration,  see BNF    Cycloserine caps, 2, 8  Cymbalta, 2  Cymevene, 21  Cyproheptadine, 2  Cyprostat, 21  Cyproterone, 21  Cystrin, 3  Cytotec, 21   Daktarin oral gel, 9, C, hold in  mouth, after food  Dalacin C, 9, 27, C, diarrhoea, see  BNF   Dantrium, 2, C, driving, hepato-  toxicity, see BNF  Dantrolene, 2, C, driving,  hepatotoxicity, see BNF  Dapsone, 8  Darifenacin m/r, 3, 25  Darunavir, 21, C, missed dose,  see BNF  Dasatinib, 25  Daxas, C, patient card  DDAVP Melt, 26, C, fluid intake,  see BNF   DDAVP tabs and intranasal, C,  fluid intake, see BNF  Deferasirox, 13, 22  Deferiprone, 14, C, blood disor-  ders   Deflazacort, 5, 10, steroid card  Deltacortril e/c, 5, 10, steroid  card, 25   Deltastab inj, 10, steroid card  Demeclocycline, 7, 9, 11, 23  De-Noltab, C, administration, see  BNF   Denzapine tabs, 2, 10, patient  information leaflet  Denzapine susp, 2, 10, patient  information leaflet, C, adminis-  tration   Dermovate cream and oint, 28, C,  application, see BNF  Dermovate-NN cream and oint,  28, C, application, see BNF  Dermovate scalp application, 15,  28, C, application, see BNF  Deseril, 2, 21  Desloratadine, C, driving  DesmoMelt, 26, C, fluid intake,  see BNF   Desmopressin sublingual tabs,  26, C, fluid intake, see BNF  Desmopressin tabs and intrana-  sal, C, fluid intake, see BNF  Desmospray, C, fluid intake, see  BNF    Destolit, 21  Detrunorm, 3  Detrunorm XL, 3,25  Detrusitol, 3  Detrusitol XL, 3, 25  Dexamethasone inj, 10, steroid  card   Dexketoprofen, 22  DF 118 Forte, 2  DHC Continus, 2,25  Dia micron MR, 25  Diamorphine preps, 2  Diamox tabs, 3  Diamox SR, 3, 25  Diazepam, 2 or 19  Diclofenac potassium, 21  Diclofenac sodium dispersible  tabs, 13, 21   Diclofenac sodium e/c, 5, 25  Diclofenac sodium m/r, 21, 25  Diclo flex Retard, 21,25  Diclomax 75 mg SR and Retard,  21, 25  Diconal, 2   Diflucan 50 and 200 mg, 9  Diflucan susp, 9  Diflucortolone external preps,   28, C, application, see BNF  Digoxin elixir, C, use of pipette  Dihydrocodeine, 2  Dihydrocodeine m/r, 2, 25  Dilcardia SR, 25  Diloxanide, 9  Diltiazem, 25  Dilzem preps, 25  Dioderm, 28, C, application, see  BNF   Dipentum, 21, C, blood disorder  symptoms, see BNF  Diprosalic, 28, C, application, see  BNF   Dipyridamole, 22  Dipyridamole m/r, 21, 25  Disipal, C, driving  Disodium etidronate, C, food and  calcium, see BNF  Disopyramide m/r, 25  Disprol, 30  Distaclor, 9    BNF 61 Appendix 9: Cautionary and advisory labels for dispensed medicines 963   Doxazosin, C, initial dose, driving  Doxazosin m/r, 25, C, initial  dose, driving  Doxepin, 2   Doxepin topical, 2, 10, patient  information leaflet  Doxycycline caps, 6, 9, 11, 27, C,  posture, see BNF  Doxycycline caps m/r, 6, 11, 27,  C, posture, see BNF  Doxycycline dispersible tabs, 6,  9, 11, 13   Doxycycline tabs, 6, 11, 27, C,  posture, see BNF  Dozic, 2  Driclor, 15  Dronedarone, 21  Dukoral, C, administration  Duloxetine, 2   Edronax, C, driving  Efavirenz caps and tabs, 23  Efcortesol, 10, steroid card  Efexor XL, 3, 25, C, driving  Effentora, 2, C, administration,  see BNF   Emcor preps, 8  Emeside, 8, C, blood disorder  symptoms, driving, see BNF  Emflex, 21, C, driving  Emselex, 3, 25   En-De-Kay mouthwash, C, food  and drink, see BNF  Enfuvirtide, C, hypersensitivity  reactions, see BNF  Entacapone, 14, (urine reddish-  brown), C, driving, avoid iron-  containing preparations at the  same time of day  Entecavir, C, administration  Entocort CR, 5, 10, steroid card,  25   Epanutin caps, 8, C, administra-  tion, blood or skin disorder  symptoms, driving, see BNF  Epanutin Infatabs, 8, 24, C, blood  or skin disorder symptoms,  driving, see BNF  Epanutin susp, 8, C, administra-  tion, blood or skin disorder  symptoms, driving, see BNF  Epiduo, 11   Epilim Chrono, 8, 21, 25, C, blood  or hepatic disorder symptoms,  driving, see BNF  Epilim Chronosphere, 8, 21, 25,  C, administration, blood or  hepatic disorder symptoms,  driving, see BNF   Epilim crushable tabs, liquid and  syrup, 8, 21, C, blood or  hepatic disorder symptoms,  driving, see BNF   Epilim e/c tabs, 5, 8, 25, C, blood  or hepatic disorder symptoms,  driving, see BNF  Episenta, 8, 21, 25, C, adminis-  tration, blood or hepatic disor-  der symptoms, driving, see BNF  Eprosartan, 21  Equasym XL, 25  Ergotamine, 18, C, dosage  Erlotinib, 23  Erymax, 5, 9, 25  Erythrocin, 9   Erythromycin caps, 5, 9, 25  Erythromycin ethyl succinate, 9  Erythromycin stearate tabs, 9  Erythromycin tabs, 5, 9, 25  Erythroped, 9  Erythroped A tabs, 9  Escitalopram drops, C, driving,  administration  Escitalopram tabs, C, driving  Eslicarbazepine, 8, C, driving  Esomeprazole granules, 25, C,  administration   Ethosuximide, 8, C, blood disor-  der symptoms, driving, see BNF  Etidronate, C, food and calcium,  see BNF   Etodolac m/r, 25  Etonogestrel implant, C, see  patient information leaflet  Etoposide caps, 23  Etravirine, 21, C, rash and  hypersensitivity reactions  Etrivex, 28, C, application, see  BNF   Eumovate external preps, 28, C,  application, see BNF  Eurax-Hydrocortisone, 28, C,  application, see BNF  Everolimus, 25, C, pneumonitis,  see BNF   Fasigyn, 4, 9, 21, 25  Faverin, C, driving, see BNF  Fefol, 25   Felbinac foam, 15  Feldene caps, 21  Feldene Melt, 10, patient infor-  mation leaflet, 21  Felodipine m/r, 25  Fematrix, C, administration, see  BNF    Fen bid, 25  Fenbufen, 21  Fenofibrate, 21  Fenoprofen, 21  Fenopron, 21   Fentanyl buccal tablets, 2, C,  administration, see BNF  Fentanyl lozenges, 2  Fentanyl nasal spray, 2, C,  administration, see BNF  Fentanyl patches, 2, C, adminis-  tration    964 Appendix 9: Cautionary and advisory labels for dispensed medicines BNF 61   Ferriprox, 14, C, blood disorders  Ferro grad, 25  Ferro grad C, 25  Ferro grad Folic, 25  Ferrous salts m/r, see preps  Fesoterodine, 3, 25  Fexofenadine, 5, C, driving  Fibrelief, 13, C, administration,  see BNF  Firdapse, 3, 21  Flagyl S, 4, 9  Flagyl supps, 4, 9  Flagyl tabs, 4, 9, 21, 25, 27  Flamasacard, 25, 32  Flavoxate, 3  Flecainide m/r, 25  Fleet Phospho-soda, 10, patient  information leaflet, C, adminis-  tration   Florinef, 10, steroid card  Flotros, 23  Floxapen, 9, 23  Fluanxol, 2, C, administration,  driving, see BNF  Flucloxacillin, 9, 23  Fluconazole 50 and 200 mg, 9  Fluconazole susp, 9  Fludrocortisone, 10, steroid card  Fludroxycortide external preps,  28, C, application, see BNF  Fluocinolone external preps, 28,  C, application, see BNF  Fluocinonide external preps, 28,  C, application, see BNF  Fluocortolone external preps, 28,  C, application, see BNF  Fluorigard mouthwash, C, food  and drink, see BNF  Fluoxetine, C, driving, see BNF  Flupentixol, see preps  Flurazepam, 19  Flurbiprofen, 21  Flurbiprofen m/r, 21, 25  Fluticasone external preps, 28, C,  application, see BNF  Fluticasone inhalations, 8, C,  administration; with high  doses, 10, steroid card  Fluvastatin, C, muscle effects,  see BNF   Fluvoxamine, C, driving, see BNF  Foradil, C, administration  Forceval caps, 25  Formoterol fumarate, C, adminis-  tration   Fosrenol, 21, C, to be chewed  Fostair, 8, C, administration; with  high doses, 10, steroid card  Frisium, 2 or 19, 8, C, driving, see  BNF   Fulsovin susp, 9, 21, C, driving  Furadantin, 9, 14, (urine yellow  or brown), 21   Gabapentin, 3, 5, 8, C, driving,  see BNF  Gabitril, 21  Galantamine, 3, 21  Galantamine m/r, 3, 21, 25  Ganciclovir, 21  Gemfibrozil, 22  Gliclazide m/r, 25  Glivec, 21,2 7   Glucophage powder, 13, 21, C,  administration, see BNF  Glucophage SR, 21, 25  Glucophage tabs, 21  Glucosamine oral powder, 13  Glusartel, 13   Glyceryl trinitrate m/r, 25  Glyceryl trinitrate tabs, 16  Golimumab, 10, Alert card, C,  tuberculosis, blood disorders  Griseofulvin spray, 15  Griseofulvin susp, 9, 21, C, driv-  ing   Hydromorphone caps, 2, C,  administration, see BNF  Hydromorphone m/r, 2, C,  administration, see BNF  Hydroxychloroquine, 5, 21  Hydroxyzine, 2   Hyoscine hydrobromide patches,  19, C, application, see BNF  Hypolar Retard, 25  Hypovase, C, initial dose, driving,  see BNF   Ibandronic acid tabs, C, admin-  istration, see BNF  Ibuprofen, 21  Ibuprofen gran, 13, 21  Ibuprofen m/r, 25, 27  Idarubicin caps, 25  Imatinib, 21, 27  Imdur, 25   Imiquimod, 10, patient informa-  tion leaflet  Imodium Plus, 24  Implanon, C, see patient infor-  mation leaflet  Imunovir, 9  Imuran, 21   Indacaterol, C, administration  Indapamide m/r, 25  Inderal-LA, 8, 25  Indinavir, 27, C, administration,  see BNF   Indolar SR, 21, 25, C, driving  Indometacin caps and mixt, 21,  C, driving    BNF 61 Appendix 9: Cautionary and advisory labels for dispensed medicines 965   Industrial methylated spirit, 15  Inegy, C, muscle effects, see BNF  Infacol, C, use of dropper  Infliximab, 10, Alert card, C,  tuberculosis and hypersensi-  tivity reactions  Inosine pranobex, 9  Inovelon, 21, C, driving, see BNF  Instanyl, 2, C, administration, see  BNF   Insulin, C, see BNF  Intal, 8, C, administration  Intelence, 21, C, rash, and  hypersensitivity reactions  Invega, 2, 25   Invirase, 21, C, arrhythmias  Iodine Solution, Aqueous, 27  Ipocol, 5, 25, C, blood disorder  symptoms, see BNF  Ipratropium inhalations, C,  administration  Isentress, 25  Isib 6oXL, 25  Ismo Retard, 25  Ismo tabs, 25   Isoket Retard, 25  Isoniazid elixir and tabs, 8, 22  Isosorbide dinitrate m/r, 25  Isosorbide mononitrate, 25  Isosorbide mononitrate m/r, 25  Isotard XL, 25   Isotretinoin, 10, patient informa-  tion leaflet, 11, 21  Isotretinoin gel, 11  Isotrex, 11  Isotrexin, 11   Itraconazole caps, 5, 9, 21, 25, C,  hepatotoxicity  Itraconazole liq, 9, 23, C,  hepatotoxicity   Kapake caps and tabs, 2, 29, 30  Kay-Cee-L, 21  Keflex, 9   Ketoconazole tabs, 5, 9, 21, C,  hepatotoxicity  Ketoprofen caps, 21  Ketoprofen m/r caps, 21, 25  Ketotifen, 2, 21  Ketorolac tabs, 17, 21  Ketovail, 21, 25   Klaricid sachets, 9, 13  Klaricid XL, 9, 21, 25  Klean-Prep, 10, patient informa-  tion leaflet, 13, C, administra-  tion   Lacosamide tabs and syrup, 8, C,  driving, see BNF  Lamictal dispersible tabs, 8, 13,  C, driving, skin reactions, see  BNF   Lansoprazole caps, 5, 22, 25  Lansoprazole oro-dispersible  tabs, 5, 22, C, administration,  see BNF   Lariam, 21, 25, 27, C, driving,  malaria prophylaxis, see BNF  Laxido, 13   Lenalidomide, 25, C, symptoms  of thromboembolism, neutro-  penia, or thrombocytopenia,  patient information leaflet  Lercanidipine, 22  Lescol, C, muscle effects, see BNF  LescolXL, 25, C, muscle effects,  see BNF   Levetiracetam, 8  Levocetirizine, C, driving  Levofloxacin, 6, 9, 25, C, driving  Levomepromazine, 2    Li-Liquid, 10, lithium card, C,  fluid and salt intake, see BNF  Linezolid susp and tabs, 9, 10,  patient information leaflet  Lioresal, 2, 8, 21  Lipantil, 21   Liraglutide, C, administration  Liskonum, 10, lithium card, 25, C,  fluid and salt intake, see BNF  Lithium carbonate, 10, lithium  card, C, fluid and salt intake,  see BNF   Lithium carbonate m/r, 10, lith-  ium card, 25, C, fluid and salt  intake, see BNF  Lithium citrate liq, 10, lithium  card, C, fluid and salt intake,  see BNF   Locoid scalp lotion, 15, 28, C,  application, see BNF  Lodotra, 10, steroid card, 21, 25  Lofepramine, 2  Lofexidine, 2  Lopid, 22  Loprazolam, 19  Lopresor, 8  Lopresor SR, 8, 25  Loramyc C, 10, C, administration,  see BNF   Loratadine, C, driving  Lorazepam, 2 or 19  Lormetazepam, 19  Loron tabs, 10, patient informa-  tion leaflet, C, food and cal-  cium, see BNF   Losec, C, administration, see BNF  Lotriderm, 28, C, application, see  BNF   Lugol’s solution, 27  Lustral, C, driving, see BNF  Lyclear Dermal cream, 10, patient  information leaflet  Lymecycline, 6, 9  Lyrica, 3, 8, C, driving  Lysodren, 2, 10, 21, C, driving,  adrenal suppression  Lysovir, C, driving    966 Appendix 9: Cautionary and advisory labels for dispensed medicines BNF 61    Madopar, 10, 14, (urine reddish),  C, driving, see BNF  Madopar dispersible tabs, 10,  14, (urine reddish), C, admin-  istration, driving, see BNF  Madopar CR, 5, 10, 14, (urine  reddish), 25, C, driving, see  BNF   Magnapen, 9, 22  Magnesium citrate effervescent  pdr, 10, patient information  leaflet, 13, C, administration  Magnesium sulphate, 13, 23  Malarivon, 5, C, malaria prophy-  laxis   Manerix, 10, patient information  leaflet, 21  Manevac, 25, 27  Marevan, 10, anticoagulant card  Marol, 2, 25  Maxalt, 3   Mecysteine, 5, 22, 25  Medikinet XL, 25  Medrone tabs, 10, steroid card,  21   Mefloquine, 21, 25, 27, C, driv-  ing, malaria prophylaxis, see  BNF    Melatonin, 2, 21, 25  Meloxicam tabs, 21  Mepacrine, 4, 9, 14, 21  Meprobamate, 2  Meptazinol, 2  Meptid, 2   Mesalazine e/c, see preps  Mesalazine m/r, see preps  Mesalazine enema and supps, C,  blood disorder symptoms, see  BNF    Mesalazine gran, see preps  Mesren MR, 5, 25, C, blood dis-  order symptoms, see BNF  Metformin m/r, 21, 25  Metformin powder, 13, 21, C,  administration, see BNF  Metformin solution and tabs, 21  Methadone, 2  Methadose, 2  Methenamine, 9  Methocarbamol, 2  Methotrexate tabs, C, NSAIDs,  see BNF   Methylprednisolone tabs, 10,  steroid card, 21  Methysergide, 2, 21  Metirosine, 2   Metoclopramide oral solution, C,  use of pipette  Metoclopramide m/r, 25  Metopirone, 21, C, driving  Metoprolol, 8  Metoprolol m/r, 8, 25  Metosyn cream and oint, 28, C,  application, see BNF  Metrolyl supps, 4, 9  Metronidazole mixt, 4, 9  Metronidazole supps, 4, 9  Metronidazole tabs, 4, 9, 21, 25,  27   Metyrapone, 21, C, driving  Mezavant XL, 21, 25, C, blood  disorder symptoms, see BNF  Mianserin, 2, 25  Micanol, 28   Miconazole buccal tabs, 10, C,  administration, see BNF  Miconazole oral gel, 9, C, hold in  mouth, after food  Midrid, 30, C, dosage  Mifegyne, 10, patient informa-  tion leaflet   Migril, 2, 18, C, dosage  Mildison, 28, C, application, see  BNF   Minocycline m/r, 6, 25  Mintec, 5, 22, 25  Mirapexin, 10, C, driving, see BNF  Mirapexin Prolonged Release,   10, 25, C, driving, see BNF  Mirtazapine oral solution, 2  Mirtazapine orodispersible  tablets, 2, C, administration,  see BNF   Mirtazapine tabs, 2, 25  Misoprostol, 21  Mitotane, 2, 10, 21, C, driving,  adrenal suppression  Mizolastine, 25, C, driving  Mizollen, 25, C, driving  Mobic tabs, 21  Mobiflex, 21   Moclobemide, 10, patient infor-  mation leaflet, 21  Modigraf, 13, 23, C, driving, see  BNF   Mometasone external preps, 28,  C, application, see BNF  Mometasone inhaler, 8, 10, ster-  oid card, C, administration  Monomax SR, 25  Monomax XL, 25  Monomil XL, 25  Monosorb XL, 25  Montelukast chewable tabs, 23,  24   Morphine preps, 2  Morphine m/r susp, 2, 13  Morphine m/r caps and tabs, see  preps   Motifene, 25  Movicol preps, 13  Moviprep, 10, patient informa-  tion leaflet, 13, C, administra-  tion   Moxifloxacin, 6, 9, C, driving  Moxisylyte, 21  Moxonidine, 3  MST Continus susp, 2, 13  MST Continus tabs, 2, 25  Multaq, 21   Mycobutin, 8, 14, (urine orange-  red), C, soft lenses  Mycophenolic acid, 25  Myfortic, 25   Myocrisin inj, 11, C, blood disor-  der symptoms, see BNF  Myotonine Chloride, 22  Mysoline, 2, 8, C, driving, see  BNF    Nabilone, 2, C, behavioural  effects, see BNF  Nabumetone, 21  Nabumetone susp, 21  Nadolol, 8   Nafarelin spray, 10, patient  information leaflet, C, nasal  decongestants, see BNF  Naftidrofuryl, 25, 27  Nalcrom, 22, C, administration,  see BNF   Nalidixic acid, 9, 11  Napratec, 21  Naprosyn EC, 5, 25  Naprosyn tabs, 21  Naproxen e/c, 5, 25  Naproxen tabs, 21  Naramig, 3  Naratriptan, 3   Natecal D3, 24  Natrilix SR, 25  Navelbine caps, 21, 25  Nebilet, 8  Nebivolol, 8    BNF 61 Appendix 9: Cautionary and advisory labels for dispensed medicines 967    Nedocromil sodium inhalation, 8,  C, administration  Nefopam, 2, 14, (urine pink)  Nelfinavir tabs, 21  Neoclarityn, C, driving  Neo-Mercazole, C, blood disorder  symptoms, see BNF  Neo-NaClex-K, 25, 27, C, posture,  see BNF   Neotigason, 10, patient informa-  tion leaflet, 11, 21  Nerisone, 28, C, application, see  BNF   Nerisone Forte, 28, application,  see BNF  Neulactil, 2  Neupro, 10, C, driving  Neurontin, 3, 5, 8, C, driving, see  BNF   Nexium tabs, C, administration  Nias pan, 21, 25  Nicardipine m/r, 25  Nicorette Inhalator, C, adminis-  tration, see BNF  Nicorette Microtab, 26  Nicotine (inhaled), C, adminis-  tration, see BNF  Nicotine (sublingual), 26  Nicotinell lozenges, 24  Nicotinic acid m/r, see preps  Nifedipine m/r, see preps  Nifedi press MR, 25  Niferex elixir, C, infants, use of  dropper   Nilotinib, 23, 25, 27  NiQuitin lozenges, 24  Nitrazepam, 19, (infantile  spasms 1, 8)   Nitrofurantoin, 9, 14, (urine yel-  low or brown), 21  Nitrofurantoin m/r, 9, 14, (urine  yellow or brown), 21, 25  Nivaquine, 5, C, malaria prophy-  laxis, see BNF   Norfloxacin, 7, 9, 23, C, driving  Normacol preps, 25, 27, C,  administration, see BNF  Normax, 14, (urine red)  Norprolac, 10, 21, C, driving, see  BNF   Nortriptyline, 2  Norvir oral solution, 21, C,  administration, see BNF  Norvir tabs, 21, 25  Noxafil, 3, 9, 21  Nozinan, 2  Nplate, C, driving  Nuelin SA preps, 21, 25  Nurofen for children, 21   Nystatin susp (mouth), 9, C, use  of pipette, hold in mouth, after  food   Octim, C, fluid intake, see BNF  Oestrogel, C, administration, see  BNF   Ofloxacin, 6, 9, 11, C, driving  Olanzapine tabs, 2  Olanzapine orodispersible tabs,  2, C, administration, see BNF  Olbetam, 21   Omega-3-acid ethyl esters, 21  Omeprazole caps, C, administra-  tion, see BNF  Omeprazole tabs, 25  Onbrez Breezhaler, C, adminis-  tration   Ondansetron oral lyophilisates,  C, administration, see BNF  Onsenal, 21  Opilon, 21  Optimax, 3  Oramorph preps, 2  Ora morph SR, 2, 25  Orap, 2   Orelox, 5, 9, 21  Orphenadrine, C, driving  Orudis caps, 21  Oruvail, 21, 25  Oseltamivir, 9   OsmoPrep, 10, patient informa-  tion leaflet, C, administration  Osvaren, C, do not crush or chew,  with meals, avoid other drugs  at the same time, see BNF  Oxazepam, 2   Oxcarbazepine, 3, 8, C, see BNF  Oxis, C, administration  Oxprenolol, 8  Oxprenolol m/r, 8, 25  Oxybutynin tabs and elixir, 3  Oxybutynin patch, 3, C, adminis-  tration, see BNF  Oxycodone caps and liq, 2  Oxycodone m/r, 2, 25  OxyContin, 2,25  OxyNorm, 2   Palladone SR, 2, C, administra-  tion, see BNF  Paludrine, 21, C, malaria  prophylaxis, see BNF  Panadol caps, 29, 30    Panadol tabs, 29, 30  Panadol OA tabs, 30  Panadol Soluble, 13, 29, 30  Panadol susp, 30  Pancrease preps, C, administra-  tion, see BNF   Pancrex V caps, 125 caps and pdr,  C, administration, see BNF  Pancrex V tabs, 5, 25, C, dose,  see BNF   Pantoprazole, 25  Paracetamol liq and supps, 30  Paracetamol tabs and caps, 29,  30   Paradote, 29, 30  Paramax sachets, 13, 17, 30  Paramax tabs, 17, 30  Pariet, 25   Paroxetine tabs, 21, C, driving  Paroxetine susp, 5, 21, C, driving  Pazopanib, 23, 25  PecFent, 2, C, administration, see  BNF    Penbritin, 9,23  Penicillamine, 6, 22, C, blood  disorder symptoms, see BNF  Pentasa tabs and gran, C,  administration, blood disorder  symptoms, see BNF  Pentasa enema and supps, C,  blood disorder symptoms, see  BNF   Pentazocine caps and tabs, 2, 21  Pentoxifylline m/r, 21, 25  Peppermint oil caps, 5, 22, 25  Percutol, C, administration, see  BNF   Permethrin dermal cream, 10,  patient information leaflet  Perphenazine, 2  Persantin, 22  Person tin Retard, 21, 25  Pethidine, 2   Phenindione, 10, anticoagulant  card, 14, (urine pink or orange)  Phenobarbital elixir and tabs, 2,  8, C, driving, see BNF    968 Appendix 9: Cautionary and advisory labels for dispensed medicines BNF 61    Phenoxymethylpenicillin, 9, 23  Phenytoin caps and tabs, 8, C,  administration, blood or skin  disorder symptoms, driving,  see BNF   Phenytoin chewable tabs, 8, 24,  C, blood or skin disorder  symptoms, driving, see BNF  Phenytoin susp, 8, C, adminis-  tration, blood or skin disorder  symptoms, driving, see BNF  Phosex, C, do not chew, with  meals   PhosLo , C, with meals  Phosphate-Sandoz, 13  Phyllocontin Continus, 25  Physeptone, 2  Physiotens, 3   Picolax, 10, patient information  leaflet, 13, C, solution, see BNF  Pilocarpine tabs, 21, 27, C, driv-  ing   Pivmecillinam, 9, 21, 27, C, pos-  ture, see BNF  Pizotifen, 2  Plaquenil, 5, 21  Plendil, 25   Podophyllin paint cpd, 15, C,  application, see BNF  Ponstan, 21  Posaconazole, 3, 9, 21  Potaba caps, 21  Potaba Envules, 13, 21  Potassium chloride m/r, see  preps   Prednisolone inj, 10, steroid card  Prednisolone tabs, 10, steroid  card, 21    Priadel liq, 10, lithium card, C,  fluid and salt intake, see BNF  Priadel tabs, 10, lithium card, 25,  C, fluid and salt intake, see BNF  Primidone, 2, 8, C, driving, see  BNF   Pripsen, 13  Pro-Banthine, 23  Probenecid, 12, 21, 27  Procarbazine, 4  Prochlorperazine, 2  Prochlorperazine buccal tabs, 2,  C, administration, see BNF  Procyclidine, C, driving  Progesterone (micronised), C,  administration, see BNF  Prograf, 23, C, driving, see BNF  Proguanil, 21, C, malaria  prophylaxis, see BNF  Progynova TS preps, C, adminis-  tration, see BNF  Promazine, 2  Promethazine, 2  Propafenone, 21, 25, C, driving  Propantheline, 23  Propiverine hydrochloride, 3  Propiverine hydrochloride m/r, 3,  25   Propranolol m/r, 8, 25  Protelos, 5, 13, C, administra-  tion, see BNF  Prothiaden, 2  Protopic, 4, 11, 28  Prozac, C, driving, see BNF  Psorin, 28   Pulmicort Respules, 8, 10, ster-  oid card, C, dose  Pyrazinamide, 8   Questran preps, 13, C, avoid  other drugs at same time, see  BNF   Quetiapine, 2  Quetiapine m/r, 2, 23, 25  Quinagolide, 10, 21, C, driving,  see BNF   Ranexa, 25, patient alert card  Ranitidine effervescent tabs, 13  Ranolazine, 25, patient alert card  Rapamune, C, administration  Rasilez, 21  Rebetol, 21  Reboxetine, C, driving  Regulan, 13, C, administration,  see BNF  Regurin, 23  Regurin XL, 23, 25   Remedeine, 2, 29, 30  Remicade, 10, Alert card, C,  tuberculosis and hypersensi-  tivity reactions  Reminyl, 3, 21  ReminylXL, 3, 21, 25  Renagel, 25, C, with meals  Renvela sachets, 13, C, with  meals   Resonium A, 13  Restandol, 21, 25  Retapamulin, 28  Retin A, 11   Revlimid, 25, C, symptoms of  thromboembolism, neutrope-  nia, or thrombocytopenia,  patient information leaflet  Revolade, C, other drugs, see BNF  Reyataz, 5, 21  Rhumalgan, 5, 25  Riamet, 21, C, driving  Ribavirin caps, tabs, and solu-  tion, 21   Rifabutin, 8, 14, (urine orange-  red), C, soft lenses  Rifadin, 8, 14, (urine orange-red),  22, C, soft lenses  Rifampicin caps and syrup, 8, 14,  (urine orange-red), 22, C, soft  lenses   Rifater, 8, 14, (urine orange-red),  22, C, soft lenses  Rifinah, 8, 14, (urine orange-red),  22, C, soft lenses  Rilutek, C, blood disorders, driv-  ing   Rimactane, 8, 14, (urine orange-  red), 22, C, soft lenses  Risedronate sodium, C, adminis-  tration, food and calcium, see  BNF   Risperdal orodispersible tabs, 2,  C, administration, see BNF  Risperdal tabs, 2  Risperidone liquid, 2, C, use of  dose syringe   Risperidone orodispersible tabs,  2, C, administration, see BNF  Risperidone tabs, 2  Ritonavir oral solution, 21, C,  administration, see BNF  Ritonavir tabs, 21, 25  Rivastigmine, 21, 25  Rivotril, 2, 8, C, driving, see BNF  Rizatriptan tabs, 3  Rizatriptan wafers, 3, C, admin-  istration    BNF 61 Appendix 9: Cautionary and advisory labels for dispensed medicines 969    Roaccutane, 10, patient informa-  tion leaflet, 11, 21  RoActemra, alert card, C, diverti-  cular perforation, infection, see  BNF   Roflumilast, C, patient card  Romiplostim, C, driving  Ropinirole, 10, 21, C, driving, see  BNF   Rotigotine, 10, C, driving  Rowachol, 22  Rowatinex caps, 25  Rufinamide, 21, C, driving, see  BNF   Salazopyrin EN-tabs, 5, 14, (urine  orange-yellow), 25, C, blood  disorder symptoms and soft  lenses, see BNF  Salbulin Novolizer, C, adminis-  tration   Salbutamol inhalations, C,  administration  Salbutamol m/r, 25  Salicylic acid collodion, 15  Salmeterol, C, administration  Salofalk enema and supps, C,  blood disorder symptoms, see  BNF   Salofalk tabs, 5, 25, C, blood  disorder symptoms, see BNF  Sandrena, C, administration, see  BNF   Sando-K, 13, 21  Sandocal, 13  Sandocal +D preps, 13  Sanomigran, 2   Sapropterin, 13, 21, C, adminis-  tration, see BNF  Saquinavir, 21, C, arrythmias  Sativex, C, driving, see BNF  Scopoderm TTS, 19, C, adminis-  tration, see BNF  Sebivo, C, muscle effects   Selegiline (freeze-dried tablets),  C, administration, see BNF  Selexid, 9, 21, 27, C, posture, see  BNF   Septrin susp and tabs, 9  Seractil, 21  Sere, 21  Serenace, 2   Seretide, 8, 10, steroid card  (250- and 500-Accuhaler only),  C, administration  Seretide Evohaler, 8, C, adminis-  tration, 10, steroid card (125-  and 250-Evohaler only)  Serevent, C, administration  Seroquel, 2  SeroquelXL, 2, 23, 25  Seroxat tabs, 21, C, driving  Seroxat susp, 5, 21, C, driving  Sertraline, C, driving, see BNF  Sevelamer carbonate sachets,   13, C, with meals  Sevelamer carbonate tabs, 25, C,  with meals   Sinemet CR, 10, 14, (urine red-  dish), 25, C, driving, see BNF  Sinemet, 10, 14, (urine reddish),  C, driving, see BNF  Sinepin, 2   Sirolimus, C, administration  Skelid, C, food and calcium  Slo-Phyllin, 25 or C, administra-  tion, see BNF  Sloprolol, 8, 25  Slow Sodium, 25  Slow-Fe, 25  Slow-Fe Folic, 25  Slow-K, 25, 27, C, posture, see  BNF   Sodium chloride m/r, 25  Sodium chloride and glucose oral  pdr, cpd, 13   Sodium clodronate, C, food and  calcium, see BNF  Sodium cromoglicate (oral), 22,  C, administration, see BNF  Sodium cromoglicate inhalation,  8, C, administration  Sodium fusidate susp, 9, 21  Sodium fusidate tabs, 9    Sodium picosulfate pdr, 10,  patient information leaflet, 13,  C, see BNF   Sodium valproate e/c, 5, 8, 25, C,  blood or hepatic disorder  symptoms, driving, see BNF  Sodium valproate m/r and gran-  ules, 8, 21, 25, C, blood or  hepatic disorder symptoms,  driving, see BNF  Sodium valproate crushable  tabs, liquid and syrup, 8, 21, C,  blood or hepatic disorder  symptoms, driving, see BNF  Solian, 2  Solifenacin, 3   Sporanox liq, 9, 23, C, adminis-  tration, hepatotoxicity  Spry cel, 25   Stalevo, 10, 14, (urine reddish-  brown), C, driving, see BNF  Stavudine, 23   Strontium, 5, 13, C, administra-  tion, see BNF  Stugeron, 2  Suboxone, 2, 26  Subutex, 2, 26  Sucralfate, 5  Sulfadiazine, 9, 27  Sulfasalazine, 14, (urine orange-  yellow), C, blood disorder  symptoms and soft lenses, see  BNF   Sulfasalazine e/c, 5, 14, (urine  orange-yellow), 25, C, blood  disorder symptoms and soft  lenses, see BNF  Sulfinpyrazone, 12, 21  Sulindac, 21  Sulpiride, 2    970 Appendix 9: Cautionary and advisory labels for dispensed medicines BNF 61   Sumatriptan, 3, 10, patient  information leaflet  Sunitinib, 14  Suprax, 9  Supra lip, 21   Suprefact nasal spray, C, nasal  decongestants, see BNF  Surgam tabs, 21  Surgical spirit, 15  Surmontil, 2   Symmetrel, C, driving  Synalar external preps, 28, C,  application, see BNF  Synarel, 10, patient information  leaflet, C, nasal decongestants,  see BNF  Synflex, 21   Tacrolimus granules, 13, 23, C,  driving, see BNF  Tacrolimus topical, 4, 11, 28  Tambocor XL, 25  Tamiflu, 9   Tamsulosin m/r, 25, C, driving,  see BNF  Tarceva, 23  Targinact, 2, 25  Tarivid, 6, 9, 11, C, driving  Tarka, 25   Tasigna, 23, 25, 27  Tasmar, 14, 25  Tavanic, 6, 9, 25, C, driving  Tavegil, 2   Tegretol Chewtabs, 3, 8, 21, 24,  C, blood, hepatic or skin disor-  der symptoms, driving, see BNF  Tegretol liq, supps and tabs, 3, 8,  C, blood, hepatic or skin disor-  der symptoms, driving, see BNF  Tegretol Retard, 3, 8, 25, C,  blood, hepatic or skin disorder  symptoms, driving, see BNF  Telbivudine, C, muscle effects  Tel fast, 5, C, driving  Telithromycin, 9, C, driving,  hepatic disorders  Telzir susp, C, administration,  see BNF  Temazepam, 19  Temgesic, 2, 26  Temodal, 23, 25  Temozolomide, 23, 25  Tenif, 8, 25    Tenoretic, 8  Tenormin, 8  Tenoxicam tabs, 21  Tensipine MR, 21, 25  Terazosin, C, initial dose, driving,  see BNF  Terbinafine, 9  Terbutaline inhalations, C,  administration  Terbutaline m/r, 25  Testim, C, administration, see  BNF   Testosterone buccal tablets, C,  administration, see BNF  Testosterone gel, C, administra-  tion, see BNF   Tetrabenazine, 2  Tetracycline, 7, 9, 23, C, posture  Tetralysal preps, 6, 9  Teveten, 21   Thalidomide, 2, C, symptoms of  peripheral neuropathy and  thromboembolism, see BNF  Thalidomide Pharmion, 2, C,  symptoms of peripheral neuro-  pathy and thromboembolism,  see BNF   Theophylline m/r, see preps  Tiagabine, 21  Tiaprofenic acid tabs, 21  Tilade, 8, C, administration  Tildiem preps, 25  Tiludronic acid, C, food and cal-  cium   Tinidazole tabs, 4, 9, 21, 25  Tiotropium inhalations, C,  administration  Tipranavir caps, 5, 21  Tipranavir oral solution, 5, 21, C,  crystallisation  Tizanidine, 2, 8  Tocilizumab, alert card, C,  diverticular perforation, infec-  tion, see BNF   Toctino, 10, patient information  leaflet, 11, 21  Tolcapone, 14, 25  Tolfenamic acid, 21  Tolterodine, 3  Tolterodine m/r, 3, 25  To pa max Sprinkle, 3, 8, C,  administration, driving, see  BNF    Topiramate tabs, 3, 8, C, driving,  see BNF  Topotecan, 25  Toradol tabs, 17, 21  Tostran, C, administration  Toviaz, 3, 25  TradorecXL, 2, 25  Tramacet, 2, 25, 29, 30  Tramacet effervescent tabs, 2, 13,  29, 30  Tramadol, 2  Tramadol m/r, 2, 25  Tramadol soluble, 2, 13  Tramake, 2   Tramquel SR, 2, C, administra-  tion, see BNF  Tran date, 8, 21  Trasicor, 8  Trasidrex, 8, 25  Traxam foam, 15  Trazodone, 2, 21  Tredaptive, 21, 25  Trental m/r, 21, 25  Treosulfan, 25  Tretinoin caps, 21, 25  Tretinoin external preps, 11  Triamcinolone inj, 10, steroid  card   Triamterene, 14, (urine blue in  some lights), 21  Triapin preps, 25  Trientine, 6, 22  Trifluoperazine, 2  Trihexyphenidyl syrup, C, driving,  see BNF   Trihexyphenidyl tabs, C, with or  after food, driving, see BNF  Trileptal, 3, 8, C, see BNF  Trilostane, 21   Trizivir, C, hypersensitivity reac-  tions, see BNF  Trospium chloride, 23  Trospium chloride m/r, 23, 25  Truvada, 21, C, administration,  see BNF  Tryptophan, 3  Tylex caps, 2, 29, 30  Tylex effervescent tabs, 2, 13, 29,  30   Typhoid vaccine, oral, 23, 25, C,  administration, see BNF  Tyverb, C, see BNF    BNF 61 Appendix 9: Cautionary and advisory labels for dispensed medicines 971   Ustekinumab, 10, C, tuber-  culosis, see BNF  Utinor, 7, 9, 23, C, driving  Utrogestan, C, administration,  see BNF    Valaciclovir, 9  Valcyte, 21  Valganciclovir, 21  Vallergan, 2  Valoid, 2  Valni XL, 25   Valproic acid, see individual pre-  parations  Valtrex, 9  Vancocin caps, 9  Vancomycin caps, 9  Varenicline, 3   Vasran XL, 21, 25, C, initial dose,  driving, see BNF  Venlafaxine, 3, C, driving  Venlafaxine m/r, 3, 25, C, driving  Ventmax SR, 25   Vepesid caps, 23  Verapamil m/r, 25  Vera press, 25  Vertab SR, 25  Vesanoid, 21, 25  Vesicare, 3  Vfend, 9, 11, 23  Viazem XL, 25  Vibramycin-D, 6, 9, 11, 13  Victoza, C, administration  Videx e/c caps, 25, C, adminis-  tration, see BNF   Vigabatrin sachets, 3, 8, 13, C,  driving, see BNF  Vigabatrin tabs, 3, 8, C, driving,  see BNF  Vimovo, 22, 25  Vimpat tabs and syrup, 8, C,  driving, see BNF  Vinorelbine caps, 21, 25  Viracept tabs, 21    Viramune, C, hypersensitivity  reactions, see BNF  Viread, 21, C, administration, see  BNF   Volta rol dispersible tabs, 13, 21  Voltarol Rapid, 21  Volta rol 75 mg SR and Retard, 21,  25    Zaditen, 2, 21  Zafirlukast, 23  Zaleplon, 2  Zamadol, 2  Zamadol 24 hr, 2,25  Zamadol SR, 2, C, administration,  see BNF  Zanaflex, 2, 8  Zanidip, 22    Zarontin, 8, C, blood disorder  symptoms, driving, see BNF  Zavedos caps, 25  Zebinix, 8, C, driving  Zelapar, C, administration, see  BNF    Zemon XL, 25  Zemtard XL, 25  Zeridame SR, 2, 25  Zerit, 23   Zidovudine oral solution, C, use  of oral syringe  Zimbacol XL, 21, 25  Zimovane, 19  Zinc acetate, 23  Zinc sulphate, see preps  Zinnat susp, 9, 21  Zinnat tabs, 9, 21, 25  Zispin SolTab, 2  Zithromax caps, 5, 9, 23  Zithromax susp, 5, 9  Zocor, C, muscle effects, see BNF  Zofran Melt, C, administration,  see BNF   Zomorph, 2, C, administration,  see BNF  Zonegran, 3  Zonisamide, 3  Zopiclone, 19   Zoton FasTab, 5, 22, C, adminis-  tration, see BNF  Zovirax susp and tabs, 9  Zuclopenthixol, 2  Zyban, 25, C, driving  Zydol, 2   Zydol soluble tabs, 2, 13  Zydol SR, 2,25  Zydol XL, 2, 25  Zyloric, 8, 21, 27  Zyprexa tabs, 2   Zyprexa Velotab, 2, C, adminis-  tration, see BNF  Zyvox susp and tabs, 9, 10,  patient information leaflet   The following list has been approved by the appropriate  Secretaries of State, and the preparations therein may  be prescribed by dental practitioners on form FP10D  (GP14 in Scotland, WP10D in Wales).   Aciclovir Oral Suspension, BP, 200 mg/5 mL  Aciclovir Tablets, BP, 200 mg  Aciclovir Tablets, BP, 800 mg  Amoxicillin Capsules, BP  Amoxicillin Oral Powder, DPF  Amoxicillin Oral Suspension, BP  Ampicillin Capsules, BP  Ampicillin Oral Suspension, BP  Artificial Saliva Oral Spray, DPF  1 Artificial Saliva Substitutes as listed below (to be pre-  scribed only for indications approved by ACBS):   2 Aspirin Tablets, Dispersible, BP  Azithromycin Oral Suspension, 200 mg/5 mL, DPF  Beclometasone Pressurised Inhalation, BP, 50 micr-  ograms/metered inhalation, CFC-free, as:   Benzydamine Oromucosal Spray, BP 0.15%  Betamethasone Soluble Tablets, 500 micrograms, DPF  Carbamazepine Tablets, BP  Carmellose Gelatin Paste, DPF  Cefalexin Capsules, BP  Cefalexin Oral Suspension, BP  Cefalexin Tablets, BP  Cefradine Capsules, BP  Cetirizine Hydrochloride Tablets, 10 mg, DPF  Chlorhexidine Gluconate Gel, BP  Chlorhexidine Mouthwash, BP  Chlorhexidine Oral Spray, DPF  Chlorhexidine Oromucosal Solution, Alcohol-free, 0.2%,  DPF   Chlorphenamine Oral Solution, BP  Chlorphenamine Tablets, BP  Choline Salicylate Dental Gel, BP  Clarithromycin Oral Suspension, 125 mg/5 mL, DPF  Clarithromycin Oral Suspension, 250 mg/5 mL, DPF  Clarithromycin Tablets, BP  Clindamycin Capsules, BP    Co-amoxiclav Tablets, BP, 250/125 (amoxicillin 250 mg  as trihydrate, clavulanic acid 125 mg as potassium  salt)   Co-amoxiclav Oral Suspension, BP, 125/31 (amoxicillin  125 mg as trihydrate, clavulanic acid 31.25 mg as  potassium salt)/ 5 mL   Co-amoxiclav Oral Suspension, BP, 250/62 (amoxicillin  250 mg as trihydrate, clavulanic acid 62.5 mg as  potassium salt)/ 5 mL  Diazepam Oral Solution, BP, 2mg/5mL  Diazepam Tablets, BP  Diclofenac Sodium Tablets, BP  Dihydrocodeine Tablets, BP, 30 mg  Dispersible Doxycycline Tablets, BP  Doxycycline Capsules, BP, 100 mg  Doxycycline Tablets, 20 mg, DPF  Ephedrine Nasal Drops, BP  Erythromycin Ethyl Succinate Oral Suspension, BP  Erythromycin Ethyl Succinate Tablets, BP  Erythromycin Stearate Tablets, BP  Erythromycin Tablets, BP  Fluconazole Capsules, 50 mg, DPF  Fluconazole Oral Suspension, 50 mg/5 mL, DPF  Hydrocortisone Cream, BP, 1%   Hydrocortisone Oromucosal Tablets, BP  Hydrogen Peroxide Mouthwash, BP  Ibuprofen Oral Suspension, BP, sugar-free  Ibuprofen Tablets, BP  Lansoprazole Capsules, DPF  Lidocaine 5% Ointment, DPF  Lidocaine Spray 10%, DPF  Loratadine Tablets, 10 mg, DPF   3 Menthol and Eucalyptus Inhalation, BP 1980  Metronidazole Oral Suspension, BP  Metronidazole Tablets, BP   Miconazole Cream, BP  Miconazole Oromucosal Gel, BP  Miconazole and Hydrocortisone Cream, BP  Miconazole and Hydrocortisone Ointment, BP  Mouthwash Solution-tablets, DPF  Nitrazepam Tablets, BP  Nystatin Oral Suspension, BP  Gastro-resistant Omeprazole Capsules, BP  Oxytetracycline Tablets, BP   4 Paracetamol Oral Suspension, BP  Paracetamol Tablets, BP  Paracetamol Tablets, Soluble, BP  Penciclovir Cream, DPF  Phenoxymethylpenicillin Oral Solution, BP  Phenoxymethylpenicillin Tablets, BP  Promethazine Hydrochloride Tablets, BP  Promethazine Oral Solution, BP   prescribed, dispersible aspirin tablets should be dispensed sion 120 mg/ 5 mL should be dispensed    Sodium Chloride Mouthwash, Compound, BP  Sodium Fluoride Mouthwash, BP  Sodium Fluoride Oral Drops, BP  Sodium Fluoride Tablets, BP  Sodium Fluoride Toothpaste 0.619%, DPF  Sodium Fluoride Toothpaste 1.1%, DPF  Sodium Fusidate Ointment, BP  Temazepam Oral Solution, BP  Temazepam Tablets, BP  Tetracycline Tablets, BP   Preparations in this list which are not included in the  BP or BPC are described under Details of DPF  preparations, below   Preparations on the List of Dental Preparations which  are specified as DPF are described as follows in the DPF.   Although brand names have sometimes been included  for identification purposes preparations on the list  should be prescribed by non-proprietary name.   (proprietary product: Xerotin) consists of water,  sorbitol, carmellose (carboxymethylcellulose), potas-  sium chloride, sodium chloride, potassium phosphate,  magnesium chloride, calcium chloride and other  ingredients, pH neutral   (proprietary product: Betnesol Soluble Tablets ),  betamethasone (as sodium phosphate) 500 micr-  ograms   (proprietary product: Orabase Oral Paste), gelatin,  pectin, carmellose sodium, 16.58% of each in a sui-  table basis   consist of tablets which may contain antimicrobial,  colouring and flavouring agents in a suitable soluble  effervescent basis to make a mouthwash suitable for  dental purposes   (proprietary product: SST), citric acid, malic acid and  other ingredients in a sorbitol base   Co-amoxiclav Oral Suspen- Co-amoxiclav Oral Suspen-  sion, 125/31 (amoxicillin sion, BP, 125/31 (amoxicil-  125 mg as trihydrate, clavu- lin 125 mg as trihydrate,  lanic acid 31.25 mg as clavulanic acid 31.25 mg as  potassium salt)/5mL, DPF potassium salt)/5mL   Co-amoxiclav Oral Suspen- Co-amoxiclav Oral Suspen-  sion, 250/62 (amoxicillin sion, BP, 250/62 (amoxicil-  250 mg as trihydrate, clavu- lin 250 mg as trihydrate,  lanic acid 62.5 mg as clavulanic acid 62.5 mg as  potassium salt)/5mL, DPF potassium salt)/5mL   Nurse Prescribers’ Formulary Appendix (Appendix  NPF). List of preparations approved by the Secretary of  State which may be prescribed on form FP10P (form  HS21(N) in Northern Ireland, form GP10(N) in Scotland,  forms WP10CN and WP10PN in Wales) by Nurses for  National Health Service patients.   Community practitioners who have completed the  necessary training may only prescribe items appearing  in the nurse prescribers’ list set out below. Community  Practitioner Nurse Prescribers are recommended to  prescribe generically, except where this would not be  clinically appropriate or where there is no approved  generic name.    Preparations on this list which are not included in  the BP or BPC are described on p. 975    Almond Oil Ear Drops, BP  Arachis Oil Enema, NPF  1 Aspirin Tablets, Dispersible, 300 mg, BP  Bisacodyl Suppositories, BP (includes 5-mg and 10-mg  strengths)   Catheter Maintenance Solution, Chlorhexidine, NPF  Catheter Maintenance Solution, Sodium Chloride, NPF  Catheter Maintenance Solution, ‘Solution G’, NPF  Catheter Maintenance Solution, ‘Solution R’, NPF  Chlorhexidine Gluconate Alcoholic Solutions containing  at least 0.05%   Choline Salicylate Dental Gel, BP  Clotrimazole Cream 1%, BP  Co-danthramer Capsules, NPF  Co-danthramer Capsules, Strong, NPF  Co-danthramer Oral Suspension, NPF  Co-danthramer Oral Suspension, Strong, NPF  Co-danthrusate Capsules, BP  Co-danthrusate Oral Suspension, NPF  Crotamiton Cream, BP  Crotamiton Lotion, BP   Aquadrate® 10% w/w Cream  Aqueous Cream, BP  Arachis Oil, BP  Balneum® Plus Cream  Cetraben® Emollient Cream  Dermamist®   E45® Cream  E45® Itch Relief Cream  Emulsifying Ointment, BP  Eucerin® Intensive 10% w/w Urea Treatment  Cream   Liquid and White Soft Paraffin Ointment, NPF  Neutrogena® Norwegian Formula Dermatological  Cream   Nutraplus® Cream  Oilatum® Cream  Oilatum® Junior Cream  Paraffin, White Soft, BP  Paraffin, Yellow Soft, BP  2 QV® Cream  2 QV® Lotion  QV® Wash  Ultrabase®   3 Balneum Plus® Bath Oil  Cetraben® Emollient Bath Additive  Dermalo® Bath Emollient  Diprobath®   Doublebase® Emollient Bath Additive  Doublebase® Emollient Shower Gel  Doublebase® Emollient Wash Gel  Hydromol® Bath and Shower Emollient  Oilatum® Emollient  Oilatum® Junior Bath Additive  Oilatum® Gel  2 QV® Bath Oil   Zerolatum® Emollient Medicinal Bath Oil  2 Zeroneum® Bath Oil  Zerozole® Bath Oil   3. Except pack sizes that are not to be prescribed under the  NHS (see Part XVIIIA of the Drug Tariff, Part XI of the  Northern Ireland Drug Tariff)   5 mL and 250 mg/ 5 mL strengths — both of which are  available as sugar-free formulations)   Gygel® Contraceptive Jelly  Sterculia Granules, NPF  Sterculia and Frangula Granules, NPF  Titanium Ointment, BP  Water for Injections, BP  Zinc and Castor Oil Ointment, BP  Zinc Cream, BP  Zinc Ointment, BP   Community Practitioner Nurse Prescribers in England,  Wales and Northern Ireland can prescribe any appliance  or reagent in the relevant Drug Tariff. In the Scottish  Drug Tariff, Appliances and Reagents which may not be  prescribed by Nurses are annotated Nx.   Appliances (including Contraceptive Devices 3 ) as listed  in Part IXA of the Drug Tariff (Part III of the Northern  Ireland Drug Tariff, Part 3 (Appliances) and Part 2  (Dressings) of the Scottish Drug Tariff)   Incontinence Appliances as listed in Part IXB of the  Drug Tariff (Part III of the Northern Ireland Drug Tariff,  Part 5 of the Scottish Drug Tariff)   Stoma Appliances and Associated Products as listed  in Part IXC of the Drug Tariff (Part III of the Northern  Ireland Drug Tariff, Part 6 of the Scottish Drug Tariff)  Chemical Reagents as listed in Part IXR of the Drug  Tariff (Part II of the Northern Ireland Drug Tariff, Part 9  of the Scottish Drug Tariff)   National Health Service Drug Tariff for England and  Wales: www.ppa.org.uk/ppa/edt_intro.htm  Health and Personal Social Services for Northern  Ireland Drug Tariff:    Preparations on the Nurse Prescribers’ Formulary which  are not included in the BP or BPC are described as  follows in the Nurse Prescribers’ Formulary.   Although brand names have sometimes been included  for identification purposes, it is recommended that non-  proprietary names should be used for prescribing med-  icinal preparations in the NPF except where a non-  proprietary name is not available.   (proprietary products: OptiFlo S', Uro-Tainer Sodium  Chloride ; Uriflex-S), sodium chloride 0.9%   (proprietary products: OptiFlo G; Uro-Tainer Suby G;  Uriflex G), citric acid 3.23%, magnesium oxide 0.38%,  sodium bicarbonate 0.7%, disodium edetate 0.01%    3. Nurse Prescribers in Family Planning Clinics — where it is  not appropriate for nurse prescribers in family planning  clinics to prescribe contraceptive devices using form  FP10(P) (forms WP10CN and WP10PN in Wales), they   1. Except for indications and doses that are may prescribe using the same system as doctors in the   (proprietary products: OptiFlo R\ JJro-Tainer Solu-  tion R; UriflexR), citric acid 6%, gluconolactone 0.6%,  magnesium carbonate 2.8%, disodium edetate 0.01%   (proprietary products: ChloraPrep\ Hydrex Solution ;  Hydrex spray), chlorhexidine gluconate in alcoholic  solution   (proprietary product: Codalax), co-danthramer 25/  200 in 5 mL (dantron 25 mg, poloxamer ‘188’ 200 mg/  5mL)   (proprietary product: Codalax Forte), co-danthramer  75/1000 in 5mL (dantron 75 mg, poloxamer ‘188’   (proprietary product: Normax), co-danthrusate 50/60  (dantron 50 mg, docusate sodium 60mg/5mL)   (proprietary products: Conotrane Cream, dimeticone  ‘350’ 22%; Siopel Barrier Cream, dimeticone ‘1000’  10%; Vasogen Barrier Cream, dimeticone 20%),  dimeticone 10-22%   (proprietary product: Norgalax Micro-enema) docu-  sate sodium 120 mg in 10 g   macrogol ‘3350’ (polyethylene glycol ‘3350’) 13.125 g,  sodium bicarbonate 178.5 mg, sodium chloride  350.7 mg, potassium chloride 46.6 mg/sachet (pro-  prietary products: Movicol, Laxido)   Note Amount of potassium chloride varies according to  flavour of Movicol ® as follows: plain-flavour (sugar-free) =  50.2 mg/sachet; lime and lemon flavour = 46.6mg/sachet;  chocolate flavour = 31.7mg/sachet. 1 sachet when recon-  stituted with 125 mL water provides K + 5.4 mmol/litre   (proprietary product: Movicol-Halj), macrogol ‘3350’  (polyethylene glycol ‘3350’) 6.563 g, sodium bicarb-  onate 89.3 g, sodium chloride 175.4 mg, potassium  chloride 23.3 mg/sachet   consist of tablets which may contain antimicrobial,  colouring and flavouring agents in a suitable soluble  effervescent basis to make a mouthwash   nicotine (as bitartrate) 1 mg or 2 mg (proprietary  product: Nicotinell Mint Lozenge) or nicotine (as  polacrilex) 2 mg or 4 mg (proprietary product:  NiQuitin Lozenges), or nicotine (as resinate complex)   (proprietary products: Nicorette Gum, Nicotinell  Gum, NiQuitin Gum), nicotine 2 mg or 4 mg   (proprietary product: Nicorette Microtab), nicotine  (as a cyclodextrin complex) 2 mg   10 mg, or 15 mg (proprietary product: Boots NicAssist  Patch, Nicorette Patch) or releasing in each 24 hours  nicotine approx. 7 mg, 14 mg, or 21 mg (proprietary  products: Nicopatch, Nicotinell TTS, NiQuitin)   (proprietary product: Carbalax), sodium acid phos-  phate (anhydrous) 1.3 g, sodium bicarbonate 1.08 g   (proprietary product: Pripsen Oral Powder), piper-  azine phosphate 4g, sennosides 15.3 mg/sachet   2. For use with inhalation mouthpiece; to be prescribed as  either a starter pack (6 cartridges with inhalator device and  holder) or refill pack (42 cartridges with inhalator device)   3. To be prescribed as either a starter pack (2 x 15-tablet discs  with dispenser) or refill pack (7 x 15-tablet discs)   (proprietary products: Micolette Micro-enema,  Micralax Micro-enema, Relaxit Micro-enema), sod-  ium citrate 450 mg with glycerol, sorbitol and an  anionic surfactant   (proprietary product: Sprilon), dimeticone 1.04%, zinc  oxide 12.5% in a pressurised aerosol unit   (proprietary product: Steripaste), sterile cotton ban-  dage impregnated with paste containing zinc oxide  15%   (proprietary product: Zipzoc), sterile rayon stocking  impregnated with ointment containing zinc oxide 20%   Nurse Independent Prescribers (formerly known as  Extended Formulary Nurse Prescribers) are able to  prescribe any medicine for any medical condition,  including some Controlled Drugs (see below).   Nurse Independent Prescribers must work within their  own level of professional competence and expertise.  They are recommended to prescribe generically, except  where this would not be clinically appropriate or where  there is no approved non-proprietary name.   Nurse Independent Prescribers are also able to pre-  scribe independently the Controlled Drugs in the table  below, solely for the medical conditions indicated.   For information on the mixing of medicines by Nurse  Independent Prescribers, see Mixing of medicines prior  to administration in clinical practice — responding to  legislative changes. National Prescribing Centre, May  2010 (available at www.npc.co.uk/policy/mixing/  mixing_medicines.htm).   Up-to-date information and guidance on nurse indepen-  dent prescribing is available on the Department of  Health website at    Controlled drugs prescribable by Nurse Independent Prescribers solely for the medical  conditions indicated   Treatment of initial or acute withdrawal symptoms caused  by the withdrawal of alcohol from persons habituated to it   Use in palliative care, pain relief in respect of suspected  myocardial infarction or for relief of acute or severe pain  after trauma, including in either case postoperative pain  relief   Use in palliative care, treatment of initial or acute with-  drawal symptoms caused by the withdrawal of alcohol  from persons habituated to it, tonic-clonic seizures   Use in palliative care, pain relief in respect of suspected  myocardial infarction or for relief of acute or severe pain  after trauma, including in either case postoperative pain  relief   Use in palliative care, pain relief in respect of suspected  myocardial infarction or for relief of acute or severe pain  after trauma, including in either case postoperative pain  relief   independent prescribing, palliative care means the care of patients with advanced,    A range of non-medical healthcare professionals can  prescribe medicines for patients as either Indepen-  dent or Supplementary Prescribes.    Independent prescribes are practitioners responsible  and accountable for the assessment of patients with  previously undiagnosed or diagnosed conditions and  for decisions about the clinical management required,  including prescribing. They are recommended to pre-  scribe generically, except where this would not be  clinically appropriate or where there is no approved  non-proprietary name.   Supplementary prescribing is a partnership between  an independent prescriber (a doctor or a dentist) and a  supplementary prescriber to implement an agreed  Clinical Management Plan for an individual patient  with that patient’s agreement.   Independent and Supplementary Prescribes are iden-  tified by an annotation next to their name in the  relevant professional register.   Up-to-date information and guidance on non-medical  prescribing is available on the Department of Health  website at www.dh.gov.uk/nonmedicalprescribing.    For information on the mixing of medicines by Inde-  pendent and Supplementary Prescribes, see Mixing  of medicines prior to administration in clinical prac-  tice — responding to legislative changes, National  Prescribing Centre, May 2010 (available at  www.npc.co.uk/ policy/ mixing/  mixing_medicines.htm).   For information on the supply and administration of  medicines to groups of patients using Patient Group  Directions, see p. 4.   Optometrist Independent Prescribes can prescribe any  licensed medicine for ocular conditions affecting the eye  and the tissues surrounding the eye, except Controlled  Drugs or medicines for parenteral administration. Opto-  metrist Independent Prescribes must work within their  own level of professional competence and expertise.   Pharmacist Independent Prescribes can prescribe any  medicine, except Controlled Drugs, for any medical  condition. Pharmacist Independent Prescribes must  work within their own level of professional competence  and expertise.    The following is an alphabetical  list of manufacturers and other  companies referenced in the  BNF, with their medicines infor-  mation or general contact details.  For information on ‘special-order’  manufacturers and specialist  importing companies see p. 988.   H. J. Heinz Company Ltd  tel: (020) 8573 7757  farleys_heinz@heinz. co.uk    Unlicensed medicines are avail-  able from ‘special-order’ manu-  facturers and specialist-importing  companies; the MHRA maintains  a register of these companies at  http://tinyurl.com/cdslke   Licensed hospital manufactur-  ing units also manufacture ‘spe-  cial-order’ products as unlicensed  medicines, the principal NHS  units are listed below. A database  [Pro-File, www.pro-file.nhs.uk)  provides information on medi-  cines manufactured in the NHS;  access is restricted to NHS phar-  macy staff.   The Association of Commercial  Specials Manufacturers may also  be able to provide further infor-  mation about commercial compa-  nies (www.acsm.uk.com).   The MHRA recommends that  an unlicensed medicine should  only be used when a patient has  special requirements that can-  not be met by use of a licensed  medicine   Pharmacy Department  Guy’s Hospital  Great Maze Pond  London, SE1 9RT.  tel: (020) 7188 4992 (order)  tel: (020) 7188 5003 (enquiry)  fax: (020) 7188 5013  paul.forsey@gstt.nhs.uk   London, NW3 2QG.  tel: (020) 7830 2424 (order)  tel: (020) 7830 2282 (enquiry)  fax: (020) 7794 1875  christine.trehane@nhs.net   London, SW17 0QT.  tel: (020) 8725 1770/1768  fax: (020) 8725 3947  vinodh.kumar@stgeorges.nhs.uk   Mr T. Murphy  Production Manager  University College Hospital  235 Euston Rd  London, NW1 2BU.  tel: (020) 7380 9723 (order)  tel: (020) 7380 9472 (enquiry)  fax: (020) 7380 9726  tony.murphy@uclh.nhs.uk   Colchester, C04 5JL.  tel: (01206) 745 962 (order)  tel: (01206) 742 949 (enquiry)  fax: (01206) 841 249  nicola.rhodes@colchester.nhs.uk   Assistant Head of Pharmacy, Technical  and Logistical Services  Pharmacy Production Units  Nottingham University Hospitals NHS  Trust   Queens Medical Centre Campus  Nottingham, NG7 2UH.  tel: (0115) 875 4521 (order)  tel: (0115) 924 9924 ext: 64177  (enquiry)   Ms K. Ferguson  Chief Technician  Pharmacy Technical Services  University Hospital of North Stafford-  shire NHS Trust  City General Site  Stoke-on-Trent, ST4 6QG.  tel: (01782) 552 289 (order)  tel: (01782) 552 290 (enquiry)  fax: (01782) 552 916  caroline.ferguson@uhns.nhs.uk   Mr Y. Hunter-Blair  Production Manager  Newcastle Specials  Pharmacy Production Unit  Royal Victoria Infirmary  Queen Victoria Rd  Newcastle-upon-Tyne, NE1 4LP.  tel: (0191) 282 0395 (order)  tel: (0191) 282 0389 (enquiry)  fax: (0191) 282 0469  yan.hunter-blair@nuth.nhs.uk   Preston, PR2 9HT.  tel: (01772) 523 617 (order)  tel: (01772) 522 593 (enquiry)  fax: (01772) 523 645  angela.nutman@lthtr.nhs.uk   Stockport Pharmaceuticals  Pharmacy Department  Stepping Hill Hospital  Stockport  Cheshire, SK2 7JE.  tel: (0161) 419 5666 (order)  tel: (0161) 419 5657 (enquiry)  fax: (0161) 419 5426  mike.booth@stockport.nhs.uk   Product Development Manager  Pharmacy Manufacturing Unit  Portsmouth Hospitals NHS Trust  Unit D2, Railway Triangle Industrial  Estate   Devon, TQ4 7TW.  tel: (01803) 664 707  fax: (01803) 664 354  phil.bendell@nhs.net   Pharmacy Production Director  Pharmacy Manufacturing Unit  Huddersfield Royal Infirmary  Gate 2-Acre Mills, School St  Lindley   Huddersfield, HD3 3ET.  tel: (01484) 355 388 (order)  tel: (01484) 355 371 (enquiry)  fax: (01484) 355 377  stephen.langford@cht.nhs.uk   Mr G. Conkie  Production Manager  Western Infirmary  Dumbarton Rd  Glasgow, Gil 6NT.  tel: (0141) 211 2754 (order)  tel: (0141) 211 2882 (enquiry)  fax: (0141) 211 1967  graham.conkie@ggc.scot.nhs.uk   Dr B. W. Millar  General Manager  Tayside Pharmaceuticals  Ninewells Hospital  Dundee, DD1 9SY.  tel: (01382) 632 052 (order)  tel: (01382) 632 183 (enquiry)  fax: (01382) 632 060  baxter.millar@nhs.net   20 Fieldway  Cardiff, CF14 4HY.  tel: (029) 2074 8120  fax: (029) 2074 8130  paul.spark@wales.nhs.uk    Principal page references are  printed in bold type. Proprietary  (trade) names and names of organ-  isms are printed in italic type;  where the BNF does not include a  full entry for a branded product, the  non-proprietary name is shown in  brackets   Abciximab, 150, 151 , 152  infusion table, 894  Abdominal surgery, antibacterial  prophylaxis, 330  Abelcet, 378  Abidec, 621   habitual see Miscarriage,  recurrent, 456  haemorrhage, 486  induction, 485  Abrasive agents, acne, 726  Abraxane, 550  Abscess, dental, 328  Absence seizures, 281  atypical, 281   Absorbent cotton, bandages,  dressings, gauze, 948, 950  Abstral, 266  Acamprosate, 310  Acanthamoeba keratitis, 667,  684   Flixotide, 188  Seretide, 189  Serevent, 179  Ventolin, 178  Accupro, 120  Accuretic, 120  ACE inhibitors   heart failure, 114, 115  hypertension, 115  myocardial infarction, 156  renal function, 115  Acea, 736   postoperative pain, 785  Acenocoumarol, 146, 147  Acetaminophen see Paracetamol  Acetazolamide  diuretic, 90  epilepsy, 294, 677  glaucoma, 674, 677  Acetic acid, otitis externa, 685  Acetylcholine, 681, 682  Acetylcysteine  eye, 680   infusion table, 894  paracetamol poisoning, 34, 36  Acetylsalicylic acid see Aspirin  Aciclovir, 392, 393  herpes simplex, 392  buccal, 696  eye, 392, 669  genital, 392, 739  labialis, 739  skin, 739  herpes zoster, 392  infusion table, 894  Acid aspiration, 5 1  surgery, 776  Acidex, 46   Acidosis, metabolic, 596, 599  Acipimox, 168  Acitretin, 716, 720  Acknowledgements, iv  Aclasta, 476  Acnamino MR, 349  Acne, 724   Acromegaly, 465, 477, 574  ACTH see Corticotropin, 462  Actiban, 954  Actico, 954   Acticoat products, 945, 946  Actidose-Aqua Advance, 33  Acti-Fast, 952  ActiFormCool, 938  Actilite, 944  Actilyse, 158  Actinac — discontinued  Actinic keratosis, 731  Actinomycin D see Dactinomycin,  527    ActivHeal products  alginate, 943  film dressing, 938  foam, 942  hydrocolloid, 940  hydrogel, 938  Activon products, 944  Acti-Wrap, 951  Actonel preparations, 474  Actos, 433   Crohn’s disease, 60, 66  psoriasis, 721, 723  rheumatic diseases, 647, 650  Adapalene, 725, 726   Addicts, notification of, 10  Add-Ins, 931  Addiphos, 607  Addison’s disease, 442  Additives see Excipients  Additrace, 607  Adefovir, 397, 398  Adenocor, 93  Adenoscan (adenosine), 93  Adenosine, 92, 93  Adenuric, 656   Adult advanced life support  algorithm, inside back cover  Adva-Co, 954  Advadraw products, 943  Advagraf, 559  Advantage Plus, 438  Advasil, 947  Advasoft, 954   Advate (factor VIII fraction), 160  Advazorb products, 942  Adverse reactions, reporting, 12  Advisory Committee on Border-  line Substances see ACBS  Advisory labels see Cautionary  and advisory labels  AeroChamber, 183  Afinitor, 546  Agalsidase  alfa, 623  beta, 623   infusion tables, 894  Agammaglobulinaemia, congeni-  tal, replacement therapy, 769  Age-related macular  degeneration, 683  Aggrastat, 154  Agomelatine, 243  Agrippal, 758  AIDS, 381   hookworm infections, 416  hydatid disease, 416  strongyloidiasis, 417  Albumin solution, 600  Albunorm (albumin)  preparations, 600  Albustix, 437  Albuterol see Salbutamol  Alclometasone dipropionate, 710  Alcohol    Aldactide preparations (co-  flumactone), 89  Aldactone, 88  Aldara, 730  Aldesleukin, 563  Aldioxa, 745  Aldomet, 111   Aldosterone antagonists, 88  Aldurazyme, 625  Alemtuzumab, 560  Alendronate sodium see Alendro-  nic acid   Alendronic acid, 469, 472  colecalciferol with, 472  Alfacalcidol, 618  Alfentanil, 263, 786 , 787  infusion table, 894  Alfuzosin, 506 , 507  Alginates   antacids, 45, 46  dressings, 942, 943  honey with, 944  silver with, 946  Algisite products, 943  silver with, 946  Algivon, 944  Alglucosidase alfa, 625  infusion table, 894  Algosteril products, 943  Alicalm, 916  Alimemazine   premedication, 193  Alimta, 534  Alione, 941  Aliskiren, 124  Alitretinoin, 714, 715  Alkalinisation of urine, 512  Alkeran, 526  Alkylating drugs, 523  Alldress, 939  Allegron, 236   anaphylaxis, 197  angioedema, 199  conjunctivitis, 671  corticosteroids in, 443  food, 66  rhinitis, 688  Allevyn products  foam, 942   silver with, 946  soft polymer, 940  silver with, 946  Allopurinol, 655 , 656, 657  Almogran, 274  Almond oil, ear, 688  Almotriptan, 274  Alomide, 672  Alopecia   Alphosyl 2 in 1, Til  AlphosylHC, 719  Alprazolam, 213, 214  Alprostadil, 514 , 515  Altacite Plus, 46  Altargo, 735  Alteplase, 157 , 158  infusion table, 894  Alternative medicine, 1  Alu-Cap   hyperphosphataemia, 612  Aluminium acetate, ear, 685, 686  Aluminium chloride, 745  Aluminium hydroxide  antacid, 45 , 46   magnesium with, 45  hyperphosphataemia, 612  Aluminium oxide, 726  Alvedon (paracetamol), 260  Alverine, 48  Alvesco, 188  Alzheimer’s disease, 317  Amantadine   parkinsonism, 306  viral infections, 399 , 400  Amaryl, 429  Ambirix, 755  AmBisome, 378  Ambrisentan, 107  Amethocaine see Tetracaine  Ametop, 799   Amfetamines  abuse, 9  poisoning by, 38  Amias, 122  Amifampridine, 659  Amifostine, 522 , 523  infusion table, 894  Amikacin, 350, 351  infusion table, 894  tuberculosis, 363  Amikin, 351   bumetanide with, 89  cyclop enthiazide with, 89  furosemide with, 89  hydrochlorothiazide with, 89  timolol and hydrochloro-  thiazide with, 104   ACBS, 929, 930, 931, 933  intravenous nutrition, 602  Aminobenzoic acid, 616, 617  Aminoglycosides  ear, 685, 688  eye, 667  skin, 734  systemic, 349  Aminophylline, 181 , 182  infusion table, 894  see also Theophylline  Aminoplasmal preparations, 603  Aminosalicylates, 59, 61  Aminoven preparations, 603  Amiodarone, 93, 94 , 95   perphenazine with, 235  diabetic neuropathy, 436  migraine prophylaxis, 235  neuropathic pain, 235 , 272  nocturnal enuresis, 235  Amix (amoxicillin), 336  Amlodipine, 128 , 129  olmesartan with, 123  see also Calcium-channel  blockers   abscess, 411  dysentery, 411  Amoebicides, 411  Amoram (amoxicillin), 336  Amorolfine, 736, 737  Amoxicillin, 336 , 337  infusion table, 894  urinary tract infection, 371  Amoxident (amoxicillin), 336  Amoxil preparations, 337  Amoxycillin see Amoxicillin  Amphetamine see Amfetamines  Amphotericin, 373, 374, 378  bladder infections, 513  eye infection, 679  infusion, 378   chronic renal failure, 582  haemolytic, 582, 589  hypoplastic, 582  iron-deficiency, 576  megaloblastic, 580  pernicious, 580  sideroblastic, 582  Anaesthesia   analgesics, 785  antimuscarinics, 781  corticosteroids, 444, 775  dental practice, 776  driving, 776  general   dental practice, 794  eye, 679  mouth, 693  rectal, 75  skin, 706   muscle relaxants, 788  status epilepticus, 294  Anafranil preparations, 235  Anagrelide, 590 , 591  Anakinra, 650, 651  Anal fissure, 77  Analeptics, 199   Analgesics, 257  compound, 258  non-opioid, 257  NSAIDs, 257, 630  anaesthesia, 785  dental pain, 63 1  elderly, 25  orofacial pain, 63 1  palliative care, 20  poisoning by, 34  rheumatic diseases, 630  topical, 664  opioid, 262   anaesthesia, 786  cough suppressants, 204  dependence on, 9  diabetic neuropathy, 436  diarrhoea, 58  equivalent doses, 20  neuropathic pain, 273  obstetric pain, 263  palliative care, 20  poisoning by, 36  Anapen preparations, 198, 199  Anaphylactic shock, 197  Anaphylaxis, 197  Anastrozole, 568, 569  Ancotil, 380  Ancylostomiasis, 416  Androcur, 460  Androgens, 458   dental practice, 27, 29  management  aspirin, 155  beta-blockers, 98, 155  calcium-channel blockers,  128   clopidogrel, 155  heparins, 155  nitrates, 125  potassium-channel  activators, 134  statins, 156  stable, 154  unstable, 155  Angioedema, 199  hereditary, 199   C 1-esterase inhibitor, 199  danazol, 479  icatibant, 199  tranexamic acid, 159  Angiotensin-converting enzyme  inhibitors see ACE inhibitors  Angiotensin-II receptor  antagonists, 121  Angiox, 144  Angitak, 127  Angitil preparations, 129  Angular cheilitis, 695   bacterial infection, 735  fungal infection, 737  inflammation, 707  Anhydrol Forte , 745  Anidulafungin, 378 , 379  infusion table, 895  Anistreplase, 157  Ankylosing spondylitis, 648  Anogenital warts, 730  Anorectics, 248  Anorexia   alginates and, 45  aluminium, 44  bismuth, 44  calcium, 44  magnesium, 44  palliative care, 21, 22  simeticone and, 45  sodium content, 45  Antazoline, 671  Antepsin, 54  Anterior uveitis, 673  Anthelmintics, 415  Anthracyclines, 526  Anthralin see Dithranol  Anthraquinones, 68  Anthrax   antibacterial treatment, 368  vaccine, 749, 750  Anti-androgens, 460  Anti-arrhythmic drugs, 90    Antibacterials  acne, 725, 727  diarrhoea, 57  eczema, 714  infections  ear, 685  eye, 667  oral, 321  skin, 734  vaginal, 492  policies, 321   principles for selecting, 321  prophylaxis, 330  summary of therapy, 322  Antibiotic-associated colitis see  Clostridium difficile  Antibiotics see Antibacterials  Anticholinergic drugs see Anti-  muscarinics   Anticholinergic syndrome, 781  Anticholinesterases, 658  anaesthesia, 791  Anticoagulant treatment  booklets, 147  Anticoagulants  oral, 146   772, 773  Antidepressants  anxiety, 233  choice, 232, 234  obsessive-compulsive disorder,  233   MAOIs with, 238  migraine, 277  neuropathic pain, 272  urinary incontinence, 509  withdrawal, 233  Antidiabetic drugs  insulin, 419  oral, 427   Antidiarrhoeal drugs see Diarr-  hoea, 57, 596  Antidiuretic hormone, 466  antagonist, 468  inappropriate secretion, 468  Antiemetics, 249   Antifibrinolytic drugs, 159  Antifungal drugs, 373  anogenital, 492  oropharyngeal, 695  skin, 736   allergic emergencies, 197  allergy, 191  eye, 671  nose, 689  skin, 707   cough preparations, 204  eczema, 714  nasal decongestants, 205  nausea and vertigo, 249, 250  Antihypertensives  ACE inhibitors, 115  adrenergic neurone blockers,  111   alpha-blockers, 112  angiotensin-II receptor  antagonists, 121  beta-blockers, 98  calcium-channel blockers, 128  centrally-acting, 110  renin inhibitors, 124  vasodilator, 107   Anti-inflammatory analgesics see  Analgesics, NSAIDs  Antileprotic drugs, 366  Antilymphocyte immunoglobulin,  582   rheumatic diseases, 644  Antimanic drugs, 229  Antimetabolites, 529  Antimicrobial dressings, 944  Antimigraine drugs, 273  Antimotility drugs, 58  Antimuscarinics   gastro-intestinal, 47  parkinsonism, 306  premedication, 781  quaternary ammonium, 47  urinary tract, 508  Antineoplastic drugs, 518  see also Cytotoxic drugs  Anti-oestrogens, 461  Antiperspirants, 745  Antiplatelet drugs, 149  coronary stenting, 150  Antiprotozoal drugs, 402  Antipruritics, topical, 707    Antipsychotics, 216  depot injections, 227  equivalent doses  depot, 227  oral, 218  high doses, 215  withdrawal, 216  Antipyretics, 257  Antirabies immunoglobulin, 771,  772   Antiretrovirals, 381, 391  Antiseptics, 742  ACBS, 934  lozenges, 697  mouthwashes, 697  sprays, oropharynx, 697  Antiserum, 749  Antispasmodics, 47  Antitetanus immunoglobulin, 772  Antithymocyte immunoglobulin,  555 , 556   infusion table, 895  Antithyroid drugs, 440  Antituberculous drugs, 361  Antitussives, 204  Antivaricella-zoster  immunoglobulin, 772  Antivenoms, 41  Antiviral drugs, 381  eye, 669  mouth, 696  skin, 739  Anugesic-HC, 76  Anusol preparations, 76  Anxiety, 213   APD see Disodium pamidronate  Aphthous ulcers, 693  Apidra, 423  Aplastic anaemia, 582  APO-go, 299  Apomorphine, 298 , 299  Appetite   stimulants, 622  suppressants, 248  Applications, definition, 700  Apraclonidine, 676, 681, 682  Aprepitant, 249, 255 , 520  Apresoline, 108   Aprovel, 122  Aptivus, 389  Aquacel products, 941  silver with, 946  Aquadrate, 703  Aquaflo, 938  Aquaform, 938  Aquamol, 702  Aqueous cream, 702  menthol with, 707  Aqueous iodine oral solution, 441  Arachis oil    Aranesp preparations, 583  Arava, 647  Arcoxia, 635  Aredia Dry Powder, 473  Arginine supplement, 933  Argipressin (Pitressin), 468  Aricept preparations, 318  Arimidex, 569  Aripiprazole   psychosis, 222, 223  resistant depression, 233  Arixtra, 146  Arlevert, 250  Aromasin, 569  Aromatase inhibitors, 568  Arpicolin, 307  Arrhythmias, 90  beta-blockers, 98  dental practice, 29  poisoning and, 32  supraventricular, 91  ventricular, 92  Arsenic trioxide, 537  Artelac (hypromellose), 680  Artelac SDU, 680  Artemether   Arthrofen (ibuprofen), 636  Arthrotec preparations, 635  Arthroxen (naproxen), 639  Articaine, 794  Artificial saliva, 698  palliative care, 22  Arythmol, 96  Arzerra, 560  Arzip, 555   Ascensia products, 426, 438  Ascorbic acid, 617  iron excretion, 587  Asilone preparations, 46  Askina products  charcoal, 944  film dressing, 937, 938  foam, 942  hydrocolloid, 941  hydrogel, 938   Haemophilus influenzae type b,  prophylaxis, 330  influenza vaccine, 757  malaria, 404   acute (table), 173  beta 2 agonists, 175  chronic (table), 172  emergency treatment, 171  dental practice, 27  exercise-induced, 175  nocturnal, 175, 176  pregnancy, 170  prophylaxis, 189  Astringents  ear, 685  skin, 742  AT-10, 620  Atarax, 194  Atazanavir, 382, 386  Atenolol, 100   cardiovascular disease  chlortalidone with, 100  co-amilozide with, 100  nifedipine with, 100  infusion table, 895  migraine, 277  see also Beta-adrenoceptor  blocking drugs  Athlete’s foot, 736  Atimos Modulite, 177  Ativan (lorazepam), 214  Atomoxetine, 245 , 246  Atonic seizures, 281  Atorvastatin, 162, 163  Atosiban, 489 , 490  infusion table, 895  Atovaquone   proguanil with, 410  Atracurium, 788, 789  infusion table, 895  Atrauman products, 937  silver with, 945  Atrial fibrillation, 81, 90 , 146  Atrial flutter, 81,91  Atriance, 534  Atripla, 385   anaesthesia, 781 , 782  bradycardia, 781  anticholinesterases and, 791  antispasmodic, 47  beta-blocker poisoning, 37  bradycardia, 91   Atypical antipsychotics, 222  poisoning by, 38  prolactin elevation, 222  Augmentin preparations, 338  Aureocort, 714  Aurothiomalate, 642  Autopen, 426  Avamys, 691  Avandamet, 431  Avandia, 431  Avastin, 538  Avaxim, 754   Azamune (azathioprine), 554  Azarga, 678  Azathioprine, 553  eczema, 721  immunosuppression, 554  inflammatory bowel disease,  60, 65   infusion table, 895  myasthenia gravis, 659  rheumatic disease, 645  thiopurine methyltransferase  testing, 553   Azidothymidine see Zidovudine  Azilect, 304  Azithromycin, 352  trachoma, 667  Azopt, 677  AZT see Zidovudine  Aztreonam, 346   Babyhaler, 183  Bacillus Calmette-Guerin  bladder instillation, 563  vaccines, 750 , 751  Bacitracin  eye, 669   clindamycin, in, 354  metronidazole, in, 367  Bactigras, 946  Bactroban, 735  Nasal, 693   androgenetic alopecia, 733  cytotoxic drugs, 520  Balneum preparations, 703, 704  Balsalazide, 59, 61  Bambec, 176  Bambuterol, 176  Bandages   adhesive, 953  cohesive, 953  compression, 954  multi-layer, 954  conforming, light-weight, 951  medicated, 955  non-extensible, 951  support, 953  tubular, 951  Baraclude, 398  Baratol, 113  Barbiturates, 215  anaesthesia, 777  Barkat products, 925, 926, 927  Barrier preparations, 705  Basal cell carcinoma, 730, 731  Basiliximab, 555, 556  infusion table, 895  Bath additives   BD Safe-clip, 427  Becaplermin, 745  Beclometasone dipropionate  asthma, 184, 186, 187  chronic, 172  formoterol with, 187  nasal allergy, 689, 690  oral ulceration, 693  ulcerative colitis, 59, 64  Beclomethasone dipropionate see  Beclometasone dipropionate   Begrivac, 758  Belladonna, 47  Bemiparin, 141, 142  Benadryl Allergy Relief, 192  Bendamustine, 524  Bendrofluazide see Bendroflu-  methiazide   Bendroflumethiazide, 84  hypercalciuria, 610  potassium with, 90  timolol with, 104  BeneFIX (factor IX fraction), 160  Benerva (thiamine), 616  Benign fibrocystic breast disease,  479   Benperidol, 218  Benquil, 218  Benzalkonium, 733  cetrimide with, 706  chlorhexidine with, 704  dimeticone with, 706  Benzathine benzylpenicillin, 326,  333   alcohol withdrawal, 310  anaesthesia, 783  antagonist, 792  anxiolytics, 213  epilepsy, 293  hypnotics, 208   palliative care, 22  mania, 229  muscle spasm, 660  poisoning by, 37  withdrawal, 207  Benzoic acid ointment,  compound, 736, 737  Benzoin tincture, compound, 204  Benzoyl peroxide, 724  adapalene with, 726  clindamycin with, 725  hydroxyquinoline with, 725  Benzthiazide, 84  Benzydamine, 693, 694  Benzyl alcohol, presence of, 2  Benzyl benzoate, 740 , 741  Benzylpenicillin sodium, 333, 334  infusion table, 895  Beractant, 200  Berinert, 199   Beriplex P/N (dried prothrombin  complex), 160  Besavar XL, 507  Beta 2 agonists, 175  Beta-Adalat, 100   angina, 98, 155  anxiety, 213  arrhythmias, 93, 94, 98  eye, 674   premature labour, 489, 490  Beta-blockers see Beta-adreno-  ceptor blocking drugs  Betacap, 710  Beta-Cardone, 104  Betadine preparations, 744  Betaferon, 562  Betagan, 674  Betahistine, 250, 256  Betaine, 626 , 627  Betaject Light (interferon beta-  lb), 562   Beta-lactamases, 333  Betaloc preparations, 102  Betamethasone, 443, 446 , 447  skin, 710   calcipotriol with, 717  clotrimazole with, 711  salicylic acid with, 711  Betamethasone sodium  phosphate, 447  ear, 686  eye, 670   infusion table, 895  nose, 690, 692  oral ulceration, 694  rheumatic disease, 641  Betamethasone valerate  skin, 710, 711   clioquinol with, 711  fusidic acid with, 711  neomycin with, 711  B eta-Pro grane, 99  Betaxolol, 674  Betesil, 710  Bethanechol  laxative, 69  urinary retention, 508  Betim, 104  Betnelan, 447  Betnesol, 447  ear, 686  eye, 670  mouth, 694  nose, 690  parenteral, 641  Betnesol-N  ear, 686  eye, 670  nose, 692   Bevacizumab, 537, 538  Bexarotene, 538  Bezafibrate, 166 , 167  Bezalip preparations, 166, 167  BiAlimenta products, 927  Biatain products, 942  silver with, 946  Bicalutamide, 573  Bicarbonate   see also Sodium bicarbonate  Biguanides, 429  Bile acid sequestrants, 164  Bilharziasis, 416  Biliary-tract infection, 323  Bimatoprost, 675  timolol with, 675  Binocrit, 584  BiNovum, 499  Bioclusive, 938  Biorphen, 307  Biosimilar medicines, 1  Biotene Oralbalance, 698  Biotin, 15, 616  Biotrol products, 948  BioXtra, 698   Bipolar disorder, 229  Birthmarks, ACBS, 934  Bisacodyl, 68, 69  Bismuth chelate, 53  Bismuth subgallate, 75  Bisoprolol, 101   see also Beta-adrenoceptor  blocking drugs  Bisphosphonates  breast cancer, 569  hypercalcaemia, 609  osteoporosis, 469, 471  Bites   Bleo-Kyowa (bleomycin), 527  Bleomycin, 527  Blepharitis, 667  Blood incompatibilities, 892  Blood products, 160, 161  BM-Accutest, 438  Bocouture, 309  Body-surface, dosage and, 16  Body-weight, dosage and, 15  Boils, 742  Bolamyn SR, 430  Bondronat, 474  Bone metabolism, drugs  affecting, 469    Bone-marrow suppression, cyto-  toxic drugs, 520  Bonilux XL (venlafaxine), 245  Bonjela (choline salicylate), 695  Bonviva preparations, 474  Borderline substances see ACBS  Bortezomib, 538 , 539  Bosentan, 107 , 108  Botox, 309  Botulinum   antitoxin, 751  hyperhidrosis, 745  toxin type A, 309  migraine, 277  toxin type B, 309  Botulism antitoxin, 751  Bowel   milk, drugs in, 19  prescribing during, 19  Breeze products, 438  Brevibloc, 102  Brevinor, 498  Brevoxyl, 724  Br exidol, 639  Bricanyl preparations, 179  Bridion, 792  Brimonidine, 676 , 677  timolol with, 677  Brinzolamide, 677  timolol with, 678  BritLofex, 317  Broflex, 307  Brolene, 669  Bromocriptine, 477, 478  acromegaly, 477  galactorrhoea, 477  hypogonadism, 478  lactation suppression, 478  neuroleptic malignant  syndrome, 217  Parkinson’s disease, 298, 299  prolactinoma, 478  Bronchiectasis, 202  Bronchitis, 202, 324  bronchodilators, 171  Bronchodilators   adrenoceptor agonist, 175  antimuscarinic, 179  surgery, 776  sympathomimetic, 175  theophylline, 181  Bronchospasm, 175  Brucellosis, 346, 365  Brufen preparations, 636   Brymont (brimonidine), 677  BSA, 16  Buccastem, 252  Buclizine, 261  Budelin Novolizer, 187  Budenofalk, 64  Budesonide   asthma, 184, 187  chronic, 172  formoterol with, 188  autoimmune hepatitis, 64  chronic obstructive airways  disease, formoterol with, 188  Crohn’s, 59, 64  croup, 174 
PharmacologyByLipincott BNF_djvu.txt