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Indocin I.V. (Indomethacin) - Description and Clinical Pharmacology

 
 



STERILE INDOCIN® I.V.
(Indomethacin for Injection)

DESCRIPTION

Sterile INDOCINRegistered trademark of Merck & Co., Inc., Whitehouse Station, NJ, U.S.A. I.V. (Indomethacin for Injection) for intravenous administration is lyophilized indomethacin for injection. Each vial contains indomethacin for injection equivalent to 1 mg indomethacin as a white to yellow lyophilized powder or plug. Variations in the size of the lyophilized plug and the intensity of color have no relationship to the quality or amount of indomethacin present in the vial.

Indomethacin for injection is designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 H -indole-3-acetic acid, sodium salt, trihydrate. Its molecular weight is 433.82. Its empirical formula is C19H15ClNNaO4•3H2O and its structural formula is:

CLINICAL PHARMACOLOGY

Although the exact mechanism of action through which indomethacin causes closure of a patent ductus arteriosus is not known, it is believed to be through inhibition of prostaglandin synthesis. Indomethacin has been shown to be a potent inhibitor of prostaglandin synthesis, both in vitro and in vivo. In human newborns with certain congenital heart malformations, PGE 1 dilates the ductus arteriosus. In fetal and newborn lambs, E type prostaglandins have also been shown to maintain the patency of the ductus, and as in human newborns, indomethacin causes its constriction.

Studies in healthy young animals and in premature infants with patent ductus arteriosus indicated that, after the first dose of intravenous indomethacin, there was a transient reduction in cerebral blood flow velocity and cerebral blood flow. Similar decreases in mesenteric blood flow and velocity have been observed. The clinical significance of these effects has not been established. In double-blind, placebo-controlled studies of INDOCIN I.V. in 460 small pre-term infants, weighing 1750 g or less, the neonates treated with placebo had a ductus closure rate after 48 hours of 25 to 30 percent, whereas those treated with INDOCIN I.V. had a 75 to 80 percent closure rate. In one of these studies, a multicenter study, involving 405 pre-term infants, later re-opening of the ductus arteriosus occurred in 26 percent of neonates treated with INDOCIN I.V., however, 70 percent of these closed subsequently without the need for surgery or additional indomethacin.

Pharmacokinetics and Metabolism

The disposition of indomethacin following intravenous administration (0.2 mg/kg) in pre-term neonates with patent ductus arteriosus has not been extensively evaluated. Even though the plasma half-life of indomethacin was variable among premature infants, it was shown to vary inversely with postnatal age and weight. In one study, of 28 neonates who could be evaluated, the plasma half-life in those less than 7 days old averaged 20 hours (range: 3-60 hours, n=18). In neonates older than 7 days, the mean plasma half-life of indomethacin was 12 hours (range: 4-38 hours, n=10). Grouping the neonates by weight, mean plasma half-life in those weighing less than 1000 g was 21 hours (range: 9-60 hours, n=10); in those neonates weighing more than 1000 g, the mean plasma half-life was 15 hours (range: 3-52 hours, n=18).

Following intravenous administration in adults, indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean plasma half-life of indomethacin is 4.5 hours. In the absence of enterohepatic circulation, it is 90 minutes. Indomethacin has been found to cross the blood-brain barrier and the placenta.

In adults, about 99 percent of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. The percent bound in neonates has not been studied. In controlled trials in premature infants, however, no evidence of bilirubin displacement has been observed as evidenced by increased incidence of bilirubin encephalopathy (kernicterus).

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