Indomethacin

Dose & administration
Closure of Ductus Arteriosus: Dose is dependent on age of infant at time of therapy and course includes three doses given IV with 12 to 24 hour intervals between doses (ref 1).

Post-natal age at first dose:

• Less than 48 hours: 1st dose 0.2 mg/kg, followed by 2nd and 3rd doses of 0.1 mg/kg/dose
• 2-7 days: 0.2 mg/kg/dose
• >7 days: 1st dose: 0.2 mg/kg, followed by 2nd and 3rd doses of 0.25 mg/kg/dose

If the ductus arteriosus closes or is significantly reduced in size after an interval of 48 hours or more from completion of the first course, no further doses are necessary.  If the ductus arteriosus re-opens, a second course of 1 to 3 doses may be given, each dose separated by a 12 to 24 hour interval as described above.

Prevention of intraventricular hemorrhage: Although dosing regimes of 0.1-0.2 mg/kg/dose have been studied, the largest RCT (ref 2) used the following schedule: 0.1mg/kg/dose IV over 20 minutes and every 24 hours, beginning the first day of life and for a total of 3 doses.

Indications
To close a hemodynamically significant patent ductus arteriosus in preterm infants.
To prevent intraventricular hemorrhage in preterm infants, weighing less than 1250g.

Contraindications and special considerations (incl incompatibilities)
Contraindications include active bleeding, significant thrombocytopenia or coagulation defects, necrotizing enterocolitis, untreated proven or suspected infection, and significantly impaired renal function.

Incompatibilities:

• Solution: 7.5% dextrose in water and 10% dextrose in water
• Injection site: calcium gluconate, cimetidine, dobutamine, dopamine, gentamicin, and tobramycin

Adverse effects
Bleeding problems, higher incidence of transient oliguria and elevations of serum creatinine, decreased platelet aggregation, and hypoglycemia. Further, gastrointestinal perforations may occur if used concurrently with corticosteroids. For this reason, concomitant administration of indomethacin and glucocorticoids should be avoided.

If anuria or marked oliguria (urinary output <0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose of, do not give additional doses until laboratory studies indicate that renal function has returned to normal.

Pharmacological  aspects
The exact mechanism of action through which indomethacin causes closure of a patent ductus arteriosus is not known, but inhibition of prostaglandin synthesis is the suggested mechanism of action.

The plasma half-life of indomethacin is variable among premature infants and has shown to vary inversely with postnatal age and weight:

• Postnatal age less than 7 days old averaged 20 hours
• Postnatal age more than 7 days old averaged 12 hours
• Weighing less than 1000 g  averaged 21 hours
• Weighing more than 1000 g averaged 15 hours

Monitor urine output, serum electrolytes, glucose, creatinine and blood urea nitrogen levels, platelet counts, and signs of bleeding should be monitored during treatment.

References

1. Product Information: indomethacin IV injection. APP Pharmaceuticals, LLC (per Manufacturer), Schaumburg, IL, Mar, 2010. (URL)
2. Long-Term Effects of Indomethacin Prophylaxis in Extremely-Low-Birth-Weight Infants. N Engl J Med 2001; 344:1966-1972. PMID: 11430325
3. Indomethacin Prophylaxis to Prevent Intraventricular Hemorrhage: Association between Incidence and Timing of Drug Administration. The Journal of pediatrics. 2013;163(3):706-10.e1. PMID: 23522865
4. Effects of Indomethacin Prophylaxis Timing on IVH and PDA in Extremely Low Birth Weight (ELBW) Infants. Archives of disease in childhood Fetal and neonatal edition. 2016;101(5):F418-F422. PMID: 18661761
5. Managing the patent ductus arteriosus in the premature neonate: a new look at what we thought we knew. Semin Perinatol Apr, 2012; 36(2): 130-138. PMID: 22414884
6. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2010, Issue 7. Art. No.: CD000174. PMID: 20614421