10. Anderson GD . A mechanistic approach to antiepileptic drug interactions . Ann Pharmacother 1998 ; 32 : 554 \200\223 63 . 11. Perucca E , Hedges A , Makki KA , Ruprah M , Wilson JF , Richens A . A neurotoxicity associated with concomitant use of sodium channel- blocking antiepileptic dru gs: A pharmacodynamic interaction? Epilepsy Behav 2011 ; 20 : 20 \200\223 3 . comparative study of the enzyme inducing properties of anticonvulsant drugs in epileptic pa tients . Br J Clin Pharmacol 1984 ; 18 : 401 \200\223 10 . 12. Patsalos PN , Bourgeois BFD . The epilepsy prescribers guide to 34. Reutens DC , Duncan JS , Patsalos PN . Disabling tremor after lamotrigine with sodium v alproate . Lancet 1993 ; 342 : 185 \200\223 6 . antiepileptic drugs . Cambridge: Cambridge University Press , 2010 . 13. Johannessen Landma rk C , Patsalos PN . Drug interactions involving the 35. Babany G , Larrey D , Pessayre D . Macrolide antibiotics as inducers and inhibitors of cytochrome P450 in experimental animals and man . Prog Drug Metab 1988 ; 11 : 61 \200\223 98 . new second- and third-generation antiepileptic drugs . Exp Rev Neurotherapeut 2010 ; 10 : 1 19 \200\223 40 . 14. Patsalos PN , Ghattaura S , Ratnaraj N , Sander JW . In situ metabolism of levetiraceta m in blood of patients with epilepsy . Epilepsia 2006 ; 47 : 1818 \200\223 21 . 36. Frigo GM , Lecchini S , Caravaggi M , Gatti G , Tonini M , S \200\231Angelo L , et al. Reduction in phenytoin clearance caused by cimetidine . Eu r J Clin Pharmacol 1983 ; 25 : 1 35 \200\223 7 . 15. Perucca E . Clinical implications of hepatic microsomal enzyme 37. Levine M , Jones MW , Sheppard I . Differential effect of cimetidine on serum concentra tions of carbamazepine and phenytoin . Neurology 1985 ; 35 : 562 \200\223 5 . induction by antiepileptic drugs . Pharmacol Ther 1987 ; 33 : 139 \200\223 44 . 16. Patsalos PN , Duncan JS , Shorvon SD . Effect of the removal of antiepileptic drugs on antipyrine kinetics in patients taking polytherapy . Br J Clin Pharmacol 1988 ; 26 : 253 \200\223 9 . 38. Zielinski JJ , Lichten EM , Haidukewych D . Clinically signi \201 cant danazol-carbamazepine interaction . Ther Drug Monit 1987 ; 9 : 24 \200\223 7 . CHAPTER 25 drug interactions 277 47. Hugen PW , Burger DM , Brinkman K. Ter Hofstede HJ , Schuurman R , Koopmans PP , et al. Carbamazepine-indinavir interaction causes antiretroviral therapy failure . Ann Pharmacoth er 2000 ; 34 : 465 \200\223 70 . 48. Michelucci R , Cipolla G , Passarelli D , Gatti G , O chan M , Heinig R , 39. Spina E , Perucca E . Clinical signi \201 cance of pharmacokinetic interactions between antiepileptic and psychotropic drugs . Epilepsia 2002 ; 43 ( Suppl. 2 ): 37 \200\223 44 . 40. Garcia AB , Ibara AL , Etessam JP , Salio AM , Martinez DP , Diaz RS , et al . Protease inhibitor-induced carbamazepine toxicity . Clin Neuropharmacol 2000 ; 23 : 216 \200\223 8 . et al . Reduced plasma nisoldipine concentrations in phenytoin-treated patients with epilep sy . Epilepsia 1996 ; 37 : 1107 \200\223 10 . 49. Murphy M , Dominiczak M . Ef \201 cacy of statin therapy: possible effect of 41. Sabers A , Ohman I , Christensen J , Tomson T . Oral contraceptives reduce lamotrigine plasma levels . Neur ology 2003 ; 61 : 570 \200\223 1 . phenytoin . Postgrad Med 1999 ; 75 : 359 \200\223 60 . 50. Freedman MD , Olatidoye AG . Clinically signi \201 cant drug interactions 42. Reimers A , Helde G , Brodtkorb E . Ethinyl estradiol, not progesterone, reduces lamotr igine serum concentrations . Epilepsia 2005 ; 46 : 1414 \200\2231 7 . with the oral anticoagulants . Drug Saf 1994 ; 10 : 381 \200\223 94 . 51. Levine M , Sheppard I . Biphasic interaction of phenytoin and warfarin . 43. Galimberti CA , Mazzucchelli I , Arbasino C , Canevini MP , Fattore C , Perucca E . Inc reased apparent oral clearance of valproic acid during intake of combined contraceptive ste roids in women with epilepsy . Epilepsia 2006 ; 47 : 1569 \200\223 72 . Clin Pharm 1984 ; 3 : 200 \200\223 3 . 52. Campana C , Regazi MB , Buggia I , Molinaro M . Clinically signi \201 cant drug interactions with cyclosporin . An update. Clin Pharmacokin 1996 ; 30 : 141 \200\223 79 . 44. Haroutiunian S , Ratz Y , Rabinovich B , Adam M , Hoffman A . Valproic acid plasma conc entration decreases in a dose-independent manner following administration of meropenem: A r etrospective study . J Clin Pharmavol 2009 ; 49 : 1363 \200\223 9 . 53. Mula M . Anticonvulsants \200\224 antidepressants pharmacokinetic drug interactions: the role of CYP450 system in psychopharmacology . Curr Drug Metab 2008 ; 9 : 730 \200\223 7 . 45. Doose DR , Kohl KA , Desai-Krieger D . No clinically signi \201 cant effect of 54. Crawford P . Interactions between antiepileptic drugs and hormonal topiramate on haloperidol plasma concentration . Eu r Neuropsychopharmacol 1999 ; 9 : S357 . contraception . CNS Drugs 2002 ; 16 : 263 \200\223 72 . 55. Sabers A . Pharmacokinetic interactions between contraceptives and 46. Bittencourt PRM , Gracia CM , Martins R , Fernandes AG , Diekmann antiepileptic drugs . Seizure 2008 ; 17 : 141 \200\223 4 . HW , Jung W . Phenytoin and carbamazepine decrease oral bioavailability or praziquentel . N eurology 1992 ; 42 : 492 \200\223 6 . This page intentionally left blank CHAPTER 26 The Pharmacokinetics and Clinical Therapeutics of the Antiepileptic Drugs Mark Cook and Sim on Shorvon Pharmacokinetics of antiepileptic drugs Pharmacokinetics is the study of drug absorption, d istribution, metabolism, and elimination. A working knowledge of the pharmacology, pharmaco kinetics, indications, and common and serious side effects are important for appropriate us e of the anti- convulsant medications, which are summarized in this chapter. when unexpected toxicities may result paradoxically through reduction of the enzyme-inducin g agent. Other drugs are more rarely given including acetazolamide, piracetam, and adrenocorticotrop ic hormone (ACTH), and these agents are not discussed here. Basic pharmacokinetic parameters are shown in Tables 26. 1 and 26. 2 . Between 1989 \200\2232011, 15 new antiepileptic drugs (AEDs) were licensed ( 1 , 2 ). These are eslicarbazepine felbamate, gabapentin, lacosamide lamotrigine, levetiracetam, oxcarbaz epine, pregabalin, retigabine, ru \201 namide, stiripentol, tiagabine, topiramate, viga- b atrin, and zonisamide ( 3 ). Generally these new AEDs are licensed as \200\230add-on \200 \231 therapies, at least for initial use, after which there may be scope for conversion to monotherapy. Because they are used in combination, pharmacokinetic interactions can be of i mpor- tance. Such interactions include those relating to protein-binding displacement from albumin in blood, and metabolic inhibitory and induction interactions occurring in the live r. Overall, the newer AEDs are less prone to be involved in interactions because their phar macokinetics are more favorable and many are mini- mally or not bound to blood albumin (esl icarbazepine, felbamate, gabapentin, lacosamide levetiracetam, ru \201 namide, topiramate, and vigabatrin) and are primarily renally excreted or metabolized by non-cytochrome P450 o r uridine glucoronyl transferases (e.g. gabapentin, lacosamide levetiracetam, ru \201 nami de, topiramate, and vigabatrin). Gabapentin, lacosamide, levetiracetam, pregaba- lin, retig abine, and vigabatrin have few clinically significant pharmacokinetic interactions. Of the new AEDs, lamotrigine and topiramate have the greatest range of signi \201 cant interactio ns ( 4 \200\2236 ). The pharmacokinetics of the various agents may be signi \201 cantly altered by metabolic d ysfunction, age, and pregnancy. The reader is directed to the relevant chapters of this boo k for the speci \201 c details of these situations. Pharmacology and clinical therapeutics of antiepileptic drugs Carbamazepine This is an impo rtant and very well-established drug (it has been used in clinical practice since the late 1960s) and is widely recom- mended as \201 rst-line therapy for partial and secondarily g eneralized epilepsy. It has for many years been amongst the most widely pre- scribed drugs worldwide. It acts by inhibiting voltage-dependent sodium conductance, with other less sign ificant actions on monoamine, acetylcholine, and N-methyl-D-aspartate (NMDA) receptors. The pharmacokinetics of the drug are not optimal. It is variably and poorly absorbed. Altho ugh it has linear kinetics, there is an active metabolite (carbamazepine 10,11 epoxide). Ca rbamazepine is metabolized in the liver by the CYP3A4 isoform of the P450 enzyme system. Dr ugs that induce or inhibit CYP3A4 can have marked effects on carbamazepine levels and as ca rbamazepine is a potent inducer of drug metabolizing enzymes, and so is involved in many dr ug inter actions. Amongst these are decrease of car- bamazepine levels by concomitant thera py with phenytoin and barbiturates. Increase in carbamazepine-10,11-epoxide levels by valpr oate. Carbamazepine levels can be increased by verapamil, erythromycin, dextropropoxyphene, and many other drugs. Carbamazepine signi \201 cantly lowers levels of many other antiepi - leptic drugs and other medications. It also autoinduces its own Metabolism of retigabine, topiramate, tiagabine, zonisamide, and felbamate can be induced b y enzyme-inducing AEDs. These agents are less susceptible to the enzyme inhibition induced by valproate, however. Of the newer agents, only \201 ve may signi \201 cantly impair the efficacy of oral cont raceptives: eslicarbazepine, felbamate, oxcarbazepine, ru \201 namide, and topiramate. The most clinically signi \201 cant pharmacodynamic interaction relates to the synergism o f valproate and lamotrigine. This interac- tion can be quite complex when these together ar e used in conjunction with enzyme inducing agents, such as carbamazepine, oxford textbook of epilepsy and epileptic seizures 280 Table 26.1 Pharmacokinetic parameters of commonly used antiepileptics Table 26.2 Pharmacokinetic parameters of commonly used antiepileptics Metabolism Half -life (h) Drug Oral bio- availability ( % ) Time to peak level (h) Drug Protein binding ( % ) Active metabolite Drug interactions Carbamazepine 75 CBZ-epoxide Carbamazepine 75 \200\22385 4 \200\2238 Hepatic 5 \200\22326 Clobazam 83 N-desmethyl clobazam Clobazam 90 1 \200\2234 Hepatic 10 \200\22377 (50 ) Clonazepam 86 None Clonazepam 80 \210 90 \210 100 \210 65 \210 100 \210 100 \210 100 1 \200\2234 Hepatic 20 \200\22380 Ethosuximide <10 None Elsicarbazepine 2 Hepatic 13 \200\22320 Gabapentin None None None Ethosuximide <4 Hepatic 30 \200\22360 Lacosamide <15 None Gabapentin 2 \200\2233 None 5 \200\2237 Lamotrigine 55 None Lacosamide 1 \200\2234 Hepatic 13 Levetiracetam None None Lamotrigine 1 \200\2233 Hepatic 12 \200\22360 Oxcarbazepine 60 MHD Levetiracetam 1 \200\2232 Non-hepatic 6 \200\2238 Phenobarbital 45 \200\22360 None Oxcarbazepine <100 4 \200\2236 Hepatic 8 \200\22310 Phenytoin 85 \200\22395 None Phenobarbital 80 \200\223100 1 \200\2233 Hepatic 75 \200\223120 Pregabalin None None None Phenytoin 95 4 \200\22312 Hepatic 7 \200\22342 Primidone 25 Phenobarbital Pregabalin 90 \210 100 1 None 6 Retigabine 80 None Primidone 3 Hepatic 5 \200\22318 (75 \200\223120) Tiagabine 96 None Retigabine 60 % \210 96 \210 100 \210 100 \210 100 \210 100 1 \200\2232 Hepatic 6 \200\22310 Topiramate 15 None Tiagabine 1 \200\2232 Hepatic 5 \200\2239 Valproate 85 \200\22395 None Topiramate 2 \200\2234 Hepatic 19 \200\22325 Vigabatrin None None None Valproate 0.5 \200\2238 Hepatic 12 \200\22317 Zonisamide 30 \200\22360 None Vigabatrin 0.5 \200\2232 None 4 \200\2237 = Many interactions, frequently of clinical relevance and many require dose modi \201 ca tion. * = Minor interactions which can be common, but are not usually of much clinical rele vance. Zonisamide 2 \200\2234 Hepatic 50 \200\22370 metabolism. Its interactions with the oral contraceptive and warfa- rin are particularly no teworthy. of therapy, and this is why the initial dose should be low and then slowly incremented. Common or important side effects include drowsiness, fatigue, dizziness, ataxia, diplopia, blurring of vision, sedation, headache, insomnia, nausea, loss of appetite, gastrointestina l disturbance, tremor, weight gain, impotence, effects on behavior and mood, other psychiat ric and psychological effects, hepatic disturbance, rash and other skin reactions, bone mar row dyscrasia, changes in blood parameters especially leucopenia, hyponatraemia, water rete ntion, hepatic, renal and endocrine effects, cardiorespiratory effects. It is a highly effective drug, and indeed is the gold standard still against which other dr ugs are compared \200\224 and this after nearly 50 years of usage. The usual indication fo r use, in adults and children, is \201 rst-line therapy in partial and generalized tonic \200\223clonic seizures (not absence and myoclonus), and also in childhood epilepsy syndrom es. Preparations included tablets in a range of doses, slow-release preparations, liquid an d suppositories. The usual starting dosage for adults is 100 \200\223200 mg/day, and increa sed every 2 \200\2233 weeks by 100/200 mg. Maintenance dosages are usually in the range of 400 \200\2231600 mg/day. For slow-release formulations, a 30 % higher dosage should be give n as plasma levels are lower for these slightly less bioavailable compounds. About 5 % of patients develop a rash on initiation of therapy and all should be warned abou t this. Stevens \200\223Johnson syndrome and the related disease toxic epidermal necrolysis are serious and potentially life-threatening reactions to the use of carbamazepine, which have been shown in certain ethnic groups, particularly Han Chinese, to be associated with a genetic marker, HLA-B * 1502 ( 7 ). The FDA has recently recommended that patients with an cestry from areas in which HLA-B * 1502 is present (Asia and South East Asia) should be scr eened for the HLA-B * 1502 allele before starting treatment with carbamazepine. This is a r apidly evolving area of knowledge, and other HLA types have been associated with rash in Eu ropean populations ( 8 ). Therapy should be immediately stopped if rash develops. Other sid e effects are generally worse on initiation Usual dosage in children: less than 1 year, 100 \200\223200mg/day; 1 \200\2235 years, 200 \200\223400mg/day; 5 \200\22310 years, 400 \200\223600mg/day;10 \200\22315 years, 600 \200 \2231000mg. Again, for the slow-release formulations, higher dosages are required. Dosing interval is usually 2 times/day, but 2 \200\2234 times/day may be better tolerated at higher doses or in children. Blood level monitoring can be useful; the usually quoted target range is 17 \200\22351 m ol/L (4 \200\22312 micrograms/mL). Good effect may be achieved at lower levels however, and high levels may be very well tolerated. As with other AEDs, clinical parameters are genera lly CHAPTER 26 the pharmacokinetics and clinical therapeutics of the antiepileptic drugs 281 ataxia, personality and behavioral changes, hyperactivity (typically in children), restless ness, aggressiveness, psychotic reac- tion, seizure exacerbations, drooling and excessive s aliva production (especially in children), leucopenia, and withdrawal symptoms more useful when monitoring the effects and tolerability of the drug. Clobazam Clobazam is an interesting and valuable second-line therapy and has been in clinic al use since 1979. It acts as a gamma aminobutyric acid A (GABA A ) receptor agonist. Popul ar in Europe for many years, trials of clobazam in Lennox \200\223Gastaut syndrome have rek indled interest in this agent recently ( 9 ), and it has been approved in the US only since late 2011. It is the only commonly used 1,5-benzodiazepine and perhaps as a result of this has distinc- tive properties that set it apart from the others. Usual indications for use are as second-line therapy in partial and generalized seizures, i ncluding absence and myoclonus, in both adults and children. Clonazepam is also used in Len nox \200\223 Gastaut syndrome, neonatal seizures, infantile spasms, and status epilepticus. Available preparations include tablets and liquid formulations. Usual adult dosage is initi ally 0.25 mg at night, with maintenance doses of 0.5 \200\2234 mg/day. The usual dosage in children: under 1 year, 1mg/day; 1 \200\2235 years: 1 \200\2232mg/day; and above 5 years: 1 \200\2233mg/day. The dosing interval is 1 \200\2232 times/day. Blood level monitoring is n ot useful. Drug interactions are generally minor, but clobazam clearance is increased by enzyme-induci ng agents, and occasionally clobazam may result in an increase in the plasma levels of othe r antiepileptic drugs. Common or important side effects include sedation, dizziness, weakness, blurring of vision, restlessness, ataxia, hypotonia, behavioral disturbance, withdrawal symptoms and paradoxic al agitation, particularly in children. Eslicarbazepine acetate Eslicarbazepine acetate was licensed for clinical use in Europe in 2009. It is a derivative of carbamazepine and acts as a prodrug to the pharmacologically ac tive eslicarbazepine (S \200\223licarbazepine). Eslicarbazepine acetate is rapidly absorbed after oral ingestion. Its minor metabolites (R-licarbazepine and oxcarbazepine) are pharma cologically active. The bioavailability of eslicarbazepine is 90 % and it is 30 % protein b ound in serum. It is eliminated chie \202 y through glucuronic acid, as are its metabolite s, and excreted renally. As with carbamazepine and oxcarbazepine, it acts on the voltage-ga ted sodium channel. Clobazam is widely felt to be the most useful benzodiazepine in chronic treatment. It has a broad-spectrum activity; relatively high response rates in refractory epilepsy, and is gen erally very well tol- erated. It is also used as a one-off therapy for periods of seizure e xacerbation (or seizure clusters) and also taken on a single day as prophylaxis on days whe n the occurrence of a seizure needs to be particularly avoided (e.g. travel, exams, etc.). The development of tolerance is its main problem. It is easy to use, without the need for s tarting at a low dose or dosage incrementation. As with the other benzodiazepines, toleranc e is prone to develop with prolonged use, particularly with large doses. Accumulation of th e active metabo- lite desmethylclobazam, which has a half-life of about 50 hours can be an important factor. Phenytoin can decrease eslicarbazepine serum levels signi \201 cantly as may carbamazepine , phenobarbital, and primidone. Eslicarbazepine can decrease the clearance of phenytoin and increase phenytoin serum levels. Eslicarbazepine can increase the clearance of lamotrigine and topiramate. Eslicarbazepine can decrease the level of levonorgestrel and ethinyloestra dial and so impair the ef \201 cacy of the oral contraceptive. It can signi \201 cantly d ecrease warfarin blood levels. Co-administration with car- bamazepine can aggravate neuroto xic side effects such as diplopia, abnormal coordination, and dizziness. Indications are as second-line therapy for partial and generalized tonic \200\223clonic sei zures, for both adults and children. Clobazam is also used for intermittent therapy, and on e-off prophylactic therapy. A tablet is the only available preparation. The usual adult dosage is 10 \200\22320 mg/day (adults), but higher doses can be used depen ding on tolerability. The usual dosage in children 3 \200\22312 years is 5 \200\22310mg/dai ly 1 \200\2232 times/daily. Blood level monitoring is not generally useful. Side effects are as for carbamazepine and oxcarbazepine. The most common side effects obser ved are dizziness, somnolence, headache, nausea, vomiting, diarrhea, blurred vision and ver tigo. These side effects are dose-dependent. Hyponatraemia has been observed in 0.6 \200 \2231.3 % of patients treated with Eslicarbazepine during the pre-marketing clinical trials . Dose should be adjusted in patients with renal or hepatic impairment. Clonazepam Introduced into clinical practice in 1963, Clonazepam is now only occasionally u sed in routine therapy in adults. It has a greater place in severe childhood epilepsies. It can be useful as monotherapy occasionally, particularly when seizures occur at a predictab le time such as in sleep. Myoclonus is sometimes dramatically suppressed by clonazepam. It has a broad-spectrum action but tolerance and withdrawal seizures limit its value in routin e therapy in chronic epilepsy. It is widely used as an effective intravenous therapy in sta tus epilepticus. Like the other benzodiazepine drugs, its main action is as an agonist at t he GABA A receptor. Its licensed indication is as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization. The preparations available are as liquid suspension or tablet form of 400, 600, and 800 mg sizes. The drugs should be started at a dose of 400 mg/day for 1 \200\2232 weeks before rea ching the mainte- nance dose of 800 \200\2231200 mg/day. Plasma levels are of uncertain value as yet, and a therapeutic range has not been established. Clonazepam levels can be lowered by co-medication with enzyme Ethosuximide Ethosuximide was introduced into practice in 1958, and was \201 rst-line the rapy of generalized absence seizures for many years. inducing drugs. Important or common side effects include sedation, which is common and may be severe, cogni tive impairment, drowsiness, oxford textbook of epilepsy and epileptic seizures 282 Of these 30 % of cases are fatal. The risk of hepatic failure is between 1:24,000 to 1:34,0 00, and 40 % of cases are fatal. It has been only occasionally used in recent years, but demonstra- tion of superiority to l amotrigine in the therapy of absence has recently been demonstrated and rekindled interest in the use of this agent ( 10 ). It acts by blocking conduction in low voltage (LVA) T type calcium channels. Indications for use are as monotherapy or adjunctive therapy in the treatment of partial se izures, with and without generalization in adults, and in children as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox \200\223Gastaut s yndrome. Ethosuximide is well absorbed, has linear kinetics, and is metab- olized in the liver (cyto chrome CYP3A4), and is only 10 % protein bound. Its clearance is reduced by co-medication w ith valproate. Ethosuximide has a number of important interactions, levels are reduced by c o-administration of carbamazepine, phenytoin, phe- nobarbital, and other drugs such as rifa mpicin. Serum valproic acid levels may be decreased by ethosuximide. Ethosuximide levels ar e increased by some drugs (e.g. isoniazid). Co-medication with ethosuximide does not genera lly interfere with levels of other AEDs. Felbamate is available in tablets of 400 and 600 mg size, and as a oral suspension (600 mg/ 5 mL). The dosage in adults is 1200 mg daily, and in children 2 \200\22314 years 15 \200 \22345 mg/kg/day. Dosing interval is 3 \200\2234 times daily. Gabapentin Gabapentin was designed to be an analog of GABA, but in fact its antiepileptic e ffects are probably due to its binding to the 2 subunit of the neuronal voltage-depen dent calcium channel. It has been used mainly in neurogenic pain, and its epilepsy usage is con- \201 ned to adjunctive therapy in refractory partial epilepsy. Its place in the the rapy of both pain and epilepsy has been to some extent superseded by the newer drug pregaba lin, which has the same mechanism of action but is more potent. Side effects can be problematic and serious, and include idiosyncratic blood reactions and the induction of behavioral and psychiatric symptoms. Headache, drowsiness and sedation are common effects. Gastrointestinal symptoms are common, and can be prominent. Other effects include lethargy, ataxia, diplopia, dizziness, hiccups, behavioral disturbances including a ggression and irritability, hyperexcitibility in children, acute psychotic reactions and ot her psychiatric side effects especially depression. Extrapyramidal symptoms, insomnia, bloo d dyscra- sias of various sorts that can be severe, rash, lupus-like syndrome, and other se vere idiosyncratic reactions can be occasionally seen. It has variable absorption, and is poorly absorbed at high doses, but has otherwise excelle nt pharmacokinetics and is excreted unchanged. Gabapentin has no important drug interaction s. Signi \201 cant side effects include drowsiness, dizziness, weight gain, seizure exacerbat ion, ataxia, headache, tremor, psychiatric disturbance especially depression and anxiety, c ognitive blunting, concentration and memory difficulties, impotence, diplopia, nausea, vomi ting, \202 atulence and other gastrointestinal effects, rhinitis, peripheral oedema (whic h can be painful), joint and muscle pains, cough, dyspnoea, itching, pancreatic and hepatic disturbance. However, generally gabapentin is a well-tolerated drug, but has a reputation of having rather modest ef \201 cacy. It has a role particularly in the treatment of mild epilepsy, in children or in the elderly where the excellent pharmacokinetics and lack of in teractions are a useful feature. The usual indication is generalized absence seizures, in adults and children. Ethosuximide is available as either capsules or syrup. The starting dose is 250 mg daily. Maintenance doses are 750 \200\223 2000 mg/day. The usua l dosage in children initially is 10 \200\22315 mg/ kg/day, and maintenance 20 \200\22340 m g/kg/day. Dosing is 2 \200\2233 times daily. Blood level monitoring is of limited practical value, and is increasingly dif \201 cult to obtain in many countries. The stated thera- peutic range is 40 \200\223100 mg/L. The usual indications for use are partial or secondarily general- ized epilepsy, in adults and children. It is available in tablet and capsule preparations of 100, 300, 400, 600, and 800 mg. The usual adult dosage initially is 300 mg/day, aiming for a maintenance dose of 9 00 \200\2233600 mg/day. In children, the initial dose is 10 \200\22315 mg/kg/ day, and main tenance 40 mg/kg/day in children aged 3 \200\2234 years, and 25 \200\22335 mg/kg/day in chi ldren 5 \200\22312 years of age. Dosing inter- vals are typically 2 \200\2233 times/day. Bl ood level monitoring is not useful. Felbamate Felbamate was licensed in 1993, but its use now is very limited due to the risk o f serious idiosyncratic liver failure and bone marrow toxicity. Felbamate is recommended on ly in patients who have not responded to other AED treatments. Felbamate has a bioavailability of 90 \200\22395 % , and is minimally protein bound. Metabo lism is hepatic with renal excretion of metabolites. Felbamate is an inhibitor of hepatic e nzymes and can increase concentrations of phenobarbital, phenytoin, valproic acid, carbamaz epine and clobazam. The metabolism of felbamate is increased by enzyme-inducing agents such as carbamazepine, phe- nobarbital, phenytoin, and primidone, resulting in reduced serum ha lf-life. A novel mode of interaction is with gabapentin, which can reduce the elimination h alf-life of felbamate and clearance sig- ni \201 cantly due to an interaction at the level of renal excretion. Felbamate inhibits the metabolism of warfarin and may reduce the effec tiveness of oral contraceptives. Lacosamide This agent has a relatively novel action on the slow inactivation current of the neuronal sodium channel, an action which differs in a minor way from that of other convent ional AEDs acting on the sodium channel such as carbamazepine, phenytoin, or lamotrigine. I t also has unique binding site to the CMRP-2 protein, though the signi \201 cance of this is uncertain. It shows ef \201 cacy in a broad range of experimental epilepsy models. Lacosamide has excellent pharmacokinetics \200\224 complete absorp- tion, linear kinetics, a plasma half-life of about 13 hours, dose-level proportionality, low protein bindings, an d 95 % of the dose is excreted in the urine as drug and metabolites. There are no clinical important drug interactions. It has no effect on the plasma levels of Adverse reactions include decreased appetite, vomiting, insom- nia, nausea, dizziness, somn olence, and headache. Aplastic anae- mia and hepatic (liver) failure are rare but serious e ffects. The risk of aplastic anemia has been estimated between 1:3600 and 1:5000. CHAPTER 26 the pharmacokinetics and clinical therapeutics of the antiepileptic drugs 283 relatively good tolerability. There is some uncertainty as to whether lamotrigine aggravate s myoclonus in all idiopathic generalized syndromes, but it is recognized to aggravate seve re myoclonic epilepsy of infancy ( 12 ), and there are case reports aggravation of other se izure types. Lamotrigine is nevertheless a useful agent in most patients with idiopathic ge neralized epilepsies, and concerns over myoclonus aggravation are perhaps overemphasized. other drugs. Co-medication with other enzyme-inducing drugs may reduce the lacosamide level slightly. Reported side effects include: dizziness, headache, nausea, fatigue and blurring of vision. Angioneurotic oedema has been reported. Aggravation of side effects of the common neurotox ic side effects of other sodium channel blockers, particularly carbamazepine and phenytoin is well recognized, and reduction in the doses of these agents may signi \201 cantly impro ve tolerability. It is a generally well-tolerated medication. The usual indications for use are therapy of partial and general- ized epilepsy, Lennox \200\223Gastaut syndrome, and other generalized epilepsy syndromes, in both adults and chil dren. Clinical trials show the drug to have good ef \201 cacy and the long-term retention rate i n the open extension of the trials was also very good. It is newly licensed for use as add- on therapy for partial onset seizures in adults, and its place in routine therapy has not y et been established. It is available as tablets in 5, 25, 50, 100, 150, and 200 mg size, and in dispersible form s. The usual adult dose is initially 12.5 \200\223 25 mg/day, the lower dose being appropri ate when co-administered with valproate. The usual maintenance dose in combination therapy without valproic acid and without enzyme- inducing agents is 200 \200\223400 mg/day. As initial monotherapy the dose is typically 100 \200\223400 mg/ day. When given as combination therapy with valproic acid, without enzyme inducing agents, 100 \200\223400 mg/day. As combina- tion therapy with enzyme inducing agen ts without valproic acid: 300 \200\223500 mg/day. The usual indication for use is therapy of partial-onset seizures with or without secondary generalization in adults. Preparations include tablets of 50, 100, 150, 200 mg strengths; IV solution (10 mg/mL), and oral syrup (15 mg/mL). The usual initial adult dosage is 50 mg/day, aiming for a mainte- nance dose of 200 \200 \223400 mg/day. The dosing interval is 2 times/day. Blood level monitoring is not useful. The usual dosage in children when used as part of combination therapy without valproic acid , and without enzyme inducing agents, children 2 \200\22312 years of age: 2.5 \200\2237.5 m g/kg/day. As combina- tion therapy with valproic acid without enzyme inducing agents in chi ldren 2 \200\22312 years of age: 1 \200\2233 mg/kg/day. As combination therapy with enzyme inducing agents without valproic acid for children 2 \200\22312 years of age: 5 \200\22315 mg/kg/day. Lamotrigine This drug was \201 rst licensed for use in 1991. It has since established a p lace as a useful \201 rst- and second-line therapy in a broad spec- trum of epilepsies. I t acts by a variety of mechanisms, most impor- tant being sodium channel conduction blockad e, like phenytoin and carbamazepine. Given the very long serum half-life, particularly with co- It has complex pharmacokinetics, is metabolized in the liver, and has drug interactions, wh ich complicate its use. The most important interaction is with valproate, co-medication wit h which can result in a very marked elevation of lamotrigine levels. Serum lamotrigine leve ls are reduced by many drugs including enzyme inducing antiepileptic drugs (e.g. carbamazep ine, phenytoin, phenobarbital), rifampicin, combined steroid contraceptives. Lamotrigine ma y reduce the serum levels of levonorgestrel. In the later stages of pregnancy, the levels o f lamotrigine can fall greatly. administration of valproate, the dosing interval is 1 \200\2232 times/day. Blood level monitoring is of limited usefulness, it may have particular utility in establis hing an effective target range prior to pregnancy, when the dose may need to be increased 5 0 \200\223100 % in the last trimester through increased clearance ( 13 ). The usual target range is generally considered 2.5 \200\22315 mg/L, but much higher levels are often tolerat ed very well. Levetiracetam The drug was licensed in 1999/2000 in the USA/Europe and is a powerful antiep ileptic compound, which has rapidly gained an important place in clinical practice both in monotherapy and poly- therapy. It acts by binding to the synaptic vesicle (SV2A) protein an d this is a unique mode of action not shared by other widely used antiepileptics ( 14 ). Important or common side effects include rash and hypersensi- tivity reaction involving fev er, hepatic dysfunction, blood dyscra- sias, disseminated intravascular coagulation, and mu ltiorgan failure. A troublesome side effect is an allergic rash which can be occasionally s evere or progress to a Stevens \200\223Johnson syndrome. The frequency of skin rash is high er in children than in adults. Early reports suggested that 1 in 50 children developed a po ten- tially life-threatening rash, but the incidence has fallen since the recognition that slow incrementation \200\224 particularly in patients co- medicated with valproate \200 \224 greatly reduces the risk. Headache can be marked, and aseptic meningitis is recognized ( 11 ). Ataxia, asthe- nia, fatigue, diplopia, nausea, vomiting, dizziness, somnolence, in somnia, depression, psychosis, tremor, movement disorder, other neurological and psychiatri c effects, arthralgia, lupus-like syndrome, and photosensitivity have all been reported. It has excellent pharmacokinetics and is metabolized largely by hydrolysis and only 24 % of the drug is metabolized in the liver. Co-medication with levetiracetam does not affect lev els of other drugs. Levetiracetam levels can fall by up to 20 \200\22330 % on co-medi- cati on with enzyme-inducing AEDs. It is generally very well tolerated without the usual sedative effects of other AEDs or the typical central nervous system side effects of the sodium channel-blocking antiepileptics. Its main drawback is its tendency in susceptible individuals to cause marked irritability and occasionally aggressive or psychotic behavior ( 15 , 16 ). It can paradoxically increas e seizure frequency in occasional patients especially at high doses. Other important or com mon side effects include behavioral change, irritability, aggression, mood change, depressi on, anxiety, and psychosis. Other side effects include headache, unsteadiness, tremor and h yperkinesis, memory In spite of all this, the impact of side effects in routine practice is generally low and t he drug is generally well tolerated, although some side effects such as insomnia can limit its use. Its main disadvantages relate to the need to individualize dose according to co-medication and the need for a slow introduc- tion of therapy. Its main advantages are its broad spectr um and oxford textbook of epilepsy and epileptic seizures 284 headache, fatigue, nausea, and gastrointestinal disturbances. Other side effects include an orexia, alopecia, pancreatic disturbance, lupus-like syndrome, cardiorespiratory disturbanc e, and other cognitive and neurological symptoms. and attention disturbance, somnolence, asthenia, visual distur- bance, gastrointestinal dis turbance, infection, itching, rash, alopecia, blood dyscrasia, myalgia, pancreatic and hepa tic distur- bance, and cough. Its usual indication is as a \201 rst- or second-line treatment in partial and secondaril y generalized seizures, in both adults and children. It is easy to use in clinical practice and has a broad-spectrum activity in epilepsy, controlling generalized and partial seizures. Its current licensing is as adjunctive therapy for partial seizures in adults and children from 4 years of age; adjunctive therapy for myoclonic seizures in adults and adolescents wi th juvenile myoclonic epilepsy from 12 years of age; as adjunctive therapy for primary gene ralized tonic \200\223clonic seizures in adults and adolescents with idiopathic generalized epilepsy from 12 years of age in Europe and from 6 years of age in the US; initial monothe rapy for partial seizures in adults, in Europe but not the US. Available preparations are tablets of 150, 300, 600 mg size, and oral suspension. The usual adult dosage initially is 600 mg/day, with maintenance doses of 900 \200\2232400 mg/day. I n children the usual dosage is initially 4 \200\2235 mg/kg/day, increased by increments of 5 mg/ kg/day weekly, with a maintenance dose of 20 \200\22345 mg/kg/day. Dosing intervals are 2 times/day. Serum level monitoring may be useful in some cases. The t arget range 3 \200\22335 mg/L. The usual indication for use is as \201 rst line and adjunctive therapy of partial-onset seizures and of generalized tonic \200\223clonic seizures and myoclonic seizures in IGE. Le vetiracetam may also be useful for other generalized seizure types. Phenobarbital Phenobarbital is a remarkable compound, introduced into practice in 1912, and still, in volume terms, the most commonly prescribed AED in the world. It is by far the ch eapest of the AEDs commonly available. It is highly effective with an ef \201 cacy that ge nerally speak- ing has not been bettered by any subsequent drug. It is extensively metaboli zed in the liver and is involved in a number of drug inter- actions, although these are usu ally minor. It has a very long half- life and a tendency to accumulate. Its main disadvanta ges relate to its cerebral side effects and its tendency to cause sedation, but this is sel dom a problem at low doses. In children, there is a strong ten- dency to cause hyperexcitib ility and behavioral change, which often limits its use. Its main mechanism of action is en hancement of GABA A receptor activity, but it also depresses glutamate excita- bility and a ffects sodium, potassium, and calcium conductance. Usual preparations include tablets of 250, 500, 750, 1000 mg size, oral solution (100 mg/mL ), and an IV preparation (500 mg/5mL) The usual adult dosage is initially 125 \200\223250 m g/day, with increments of 125 \200\223250 mg every 2 weeks. Maintenance doses are typically 750 \200\2233000 mg/day. Dosage needs to be reduced in renal disease. In children the initial dosage is 10 \200\22320 mg/kg/day with incre- ments of 10 \200\2232 0 mg/kg/day every 2 weeks, and maintenance of 20 \200\22360 mg/kg/day. The dosing interval is 2 times/day Serum level monitoring is not routinely available in mos t centers, and only occasionally useful. The target range is 12 \200\22346 mg/L.