title: Indomethacin - Neonatal Intensive Care Drug Manual
text: |
  Neonatal Intensive Care Drug Manual
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  bet | 307/654 | Sana | 03.01.2022 | Hajmi | 1,5 Mb. | | #14803 |
  Indomethacin
  Revision Date : 20-7-202027/04/2021
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  Approved: TC, KOH
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  Alert
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  From April 2016, the international spelling for Indomethacin has been changed to Indometacin.
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  Indication
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  Closure of patent ductus arteriosus (PDA)
  Prevention of severe intra-ventricular haemorrhage.
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  Action
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  Prostaglandin inhibitor. Prostaglandins are important in maintaining ductal patency in utero.
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  Drug type
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  Non-steroidal anti-inflammatory drug (NSAID).
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  Trade name
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  Indocid PDA, Indomethacin Agila
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  Presentation
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  1 mg powder for reconstitution.
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  Dose
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  IV
  Single daily dose as follows:
  Post-natal Age
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  Day 1
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  Day 2
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  Day 3
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  ≤ 48 hours
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  0.2 mg/kg/dose
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  0.1 mg/kg/dose
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  0.1 mg/kg/dose
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  ˃ 48 hours
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  0.2 mg/kg/dose
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  0.2 mg/kg/dose
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  0.2 mg/kg/dose
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  Dose adjustment
  Therapeutic hypothermia
  ECMO
  Renal impairment
  Hepatic impairment
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  Not applicable
  Insufficient data to suggest dose adjustments.
  Refer to contraindications section.
  Insufficient data to suggest dose adjustments.
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  Maximum dose
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  0.2 mg/kg
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  Total cumulative dose
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  0.6 mg/kg
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  Route
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  IV
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  Preparation
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  Add 1 mL of WFI to the 1 mg powder for reconstitution. Then draw up 1 mL (1 mg) and add 9 mL WFI to make a final volume of 10 mL with a concentration of 0.1 mg/mL.
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  Administration
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  IV: Over 20−-30 minutes.
  Inspect visually for particulate matter and discolouration prior to administration.
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  Monitoring
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  Monitor urine output, cardiovascular status, serum biochemistry, renal function and for signs of bleeding.
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  Contraindications
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  Serious infection, active bleeding, thrombocytopenia or coagulopathy, necrotising enterocolitis (NEC) or intestinal perforation, significant renal dysfunction, ductal dependent congenital heart disease and pulmonary hypertension.
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  Precautions
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  Indomethacin is associated with transient renal impairment. Late and prolonged treatment of the ductus arteriosus with indomethacin may increase the incidence of NEC.
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  Drug interactions
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  Aminoglycosides: Dose may need to be modified if indomethacin affects renal function.
  Digoxin: Reduces indomethacin volume of distribution – increased dose may be required.
  Diuretics: Use of frusemide in combination with indomethacin may increase the incidence of renal impairment.
  Systemic corticosteroids: Intestinal perforation has been described in infants treated with early dexamethasone and indomethacin.
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  Adverse reactions
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  Prophylactic indomethacin is associated with oliguria/anuria.
  Treatment of the ductus arteriosus with indomethacin and prolonged courses of indomethacin are associated with NEC.
  Gastrointestinal perforation and possibly bleeding.
  Extravasation.
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  Compatibility
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  Fluids: Sodium chloride 0.9%, water for injection.
  Y site: Atropine, Cephazolin, cefotaxime, ceftazidime, clindamycin, dexamethasone, digoxin, fentanyl, fluconazole, frusemide, heparin, hydrocortisone, benzylpenicillin, potassium chloride, sodium bicarbonate.
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  Incompatibility
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  Fluids: Glucose 7.5%, Glucose 10%
  Y-site: Amino acid solutions, adrenaline, amikacin, atracurium, aztreonam, benztropine, buprenorphine, calcium chloride, calcium gluconate, chlorpromazine, dobutamine, dopamine, erythromycin, esmolol, gentamicin, glycopyrrolate, haloperidol lactate, hydralazine, labetalol, magnesium sulfate, metaraminol, midazolam, morphine sulfate, noradrenaline, ondansetron, pentamidine, pethidine, phenylephrine, promethazine, protamine, suxamethonium, tobramycin, vancomycin, vasopressin, verapamil.
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  Stability
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  Discard unused portion. Diluted solution is stable for 6 hours at room temperature.
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  Storage
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  Store unopened vials at room temperature (20−25°C)
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  Excipients
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  Evidence
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  Effectiveness:
  Prophylactic intravenous indomethacin in preterm infants has short-term benefits including a reduction in the incidence of symptomatic PDA, PDA surgical ligation and severe intraventricular haemorrhage (IVH). However, there is no evidence of effect on mortality or neurodevelopment5 (LOE I GOR C). Safety: Prophylactic indomethacin is associated with oliguria but not an increased creatinine or gastrointestinal side effects.
  Indomethacin for asymptomatic patent ductus arteriosus: Treatment of an asymptomatic PDA with indomethacin reduced the incidence of symptomatic PDA, duration of supplemental oxygen, with no effect on mortality, IVH, retinopathy of prematurity, length of ventilation, or NEC. Safety: Renal and gastrointestinal toxicities and long term neurodevelopment were not reported10 (LOE I, GOR C).
  Indomethacin versus ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight infants: Indomethacin is as effective as ibuprofen in closing a PDA6. Safety: Indomethacin increases the risk of NEC and transient renal insufficiency compared to ibuprofen.
  Summary recommendation: Ibuprofen is as effective as indomethacin in closing a PDA and currently appears to be the drug of choice. Ibuprofen reduces the risk of NEC and transient renal insufficiency compared to indomethacin6 (LOE I GOR B).
  Dose: Indomethacin given in total amounts for the prolonged course (6−8 doses) of 0.6−1.6 mg/kg compared with the short course 0.3−0.6 mg/kg (2–3 doses): There was no difference in efficacy between a short or prolonged course of indomethacin (LOE 1, GOR C). Safety: A prolonged course is associated with an increased risk of NEC but a decreased incidence of renal function impairment (oliguria and increased serum creatinine) 7 (LOE I, GOR B). Pharmacokinetic studies reported substantial interpatient variability11, 12 in clearance related to postnatal age2, 12. Bolus infusions of indomethacin are associated with alterations in renal, mesenteric and cerebral blood flow13. Ductus arteriosus closure rates are related to dose and indomethacin concentrations 11,14.
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  Practice points
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  References
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  1. Allegaert K. The impact of ibuprofen or indomethacin on renal drug clearance in neonates. The journal of maternal-fetal & neonatal medicine. 2009;22;88–91.
  2. Smyth JM, Collier PS, Darwish M, Millership JS, Halliday HL, Petersen S, McElnay JC. Intravenous indomethacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study. British journal of clinical pharmacology. 2004;58:249–58.
  3. Lee BS, Byun SY, Chung ML, Chang JY, Kim HY, Kim EA, Kim KS, Pi SY. Effect of furosemide on ductal closure and renal function in indomethacin-treated preterm infants during the early neonatal period. Neonatology. 2010;98:191–9.
  4. Brion LP, Campbell DE. Furosemide for symptomatic patent ductus arteriosus in indomethacin-treated infants. The Cochrane database of systematic reviews. 2001:CD001148.
  5. Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. The Cochrane database of systematic reviews. 2010:CD000174.
  6. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. The Cochrane database of systematic reviews. 2015;2:CD003481.
  7. Herrera C, Holberton J, Davis P. Prolonged versus short course of indomethacin for the treatment of patent ductus arteriosus in preterm infants. The Cochrane database of systematic reviews. 2007:CD003480.
  8. Stark AR, Carlo WA, Tyson JE, Papile LA, Wright LL, Shankaran S, Donovan EF, Oh W, Bauer CR, Saha S, Poole WK, Stoll BJ, National Institute of Child H, Human Development Neonatal Research N. Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. The New England journal of medicine. 2001;344:95–101.
  9. Walker SE, Gray S, Schmidt B. Stability of reconstituted indomethacin sodium trihydrate in original vials and polypropylene syringes. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 1998; 55:154–8.
  10. Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus arteriosus in preterm infants. The Cochrane database of systematic reviews. 2003:CD003745.
  11. Brash AR, Hickey DE, Graham TP, Stahlman MT, Oates JA, Cotton RB. Pharmacokinetics of indomethacin in the neonate. Relation of plasma indomethacin levels to response of the ductus arteriosus. The New England journal of medicine. 1981; 305:67–72.
  12. Yaffe SJ, Friedman WF, Rogers D, Lang P, Ragni M, Saccar C. The disposition of indomethacin in preterm babies. The Journal of pediatrics. 1980;97:1001–6.
  13. Gork AS, Ehrenkranz RA, Bracken MB. Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants. The Cochrane database of systematic reviews. 2008:CD006071.
  14. Shaffer CL, Gal P, Ransom JL, Carlos RQ, Smith MS, Davey AM, Dimaguila MA, Brown YL, Schall SA. Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus. Critical care medicine. 2002;30:343–8.
  15. Indomethacin. In: IV index. Trissel's 2 clinical pharmaceutics database (parenteral compatibility). Greenwood Village, Colorado: Truven Health Analytics. Accessed 9/9/15.
  16. Australian Injectable Drugs Handbook, 6th Edition, Society of Hospital Pharmacists of Australia 2014.
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  Original version Date: 29/09/2015
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  Author: NeoMed Consensus Group
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  Current Version number: 3
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  Current Version Date: 20-7-2020
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  Risk Rating: Low
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  Due for Review: 20-7-2025
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  Approval by: DTC
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  Approval Date: TBA
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