Indomethacin

INDOMETHACIN- indomethacin sodium injection, powder, lyophilized, for solution
Hospira, Inc.

DESCRIPTION

Sterile Indomethacin for Injection, USP for intravenous administration is lyophilized indomethacin for injection. Each vial of indomethacin for injection contains indomethacin sodium, USP equivalent to 1 mg indomethacin; 3 mg sodium citrate dihydrate, USP and 0.13 mg citric acid anhydrous, USP 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-1H -indole-3-acetic acid, sodium salt, trihydrate. Its molecular weight is 433.82. Its empirical formula is C19 H15 CINNaO4 •3H2 O and its structural formula is:

indomethacin-structureindomethacin-structure

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 indomethacin for injection 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 indomethacin for injection had a 75 to 80 percent closure rate. In one of these studies, a multicenter study, involving 405 pre-term infants, later reopening of the ductus arteriosus occurred in 26 percent of neonates treated with indomethacin for injection, 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 to 60 hours, n=18). In neonates older than 7 days, the mean plasma half-life of indomethacin was 12 hours (range: 4 to 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 to 60 hours, n=10); in those neonates weighing more than 1000 g, the mean plasma half-life was 15 hours (range: 3 to 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).

INDICATIONS AND USAGE

Indomethacin for injection is indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1750 g when after 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support, etc.) is ineffective. Clear-cut clinical evidence of a hemodynamically significant patent ductus arteriosus should be present, such as respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly and pulmonary plethora on chest x-ray.

CONTRAINDICATIONS

Indomethacin for injection is contraindicated in: neonates with proven or suspected infection that is untreated; neonates who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding; neonates with thrombocytopenia; neonates with coagulation defects; neonates with or who are suspected of having necrotizing enterocolitis; neonates with significant impairment of renal function; neonates with congenital heart disease in whom patency of the ductus arteriosus is necessary for satisfactory pulmonary or systemic blood flow (e.g., pulmonary atresia, severe tetralogy of Fallot, severe coarctation of the aorta).

WARNINGS

Gastrointestinal Effects

In the collaborative study, major gastrointestinal bleeding was no more common in those neonates receiving indomethacin than in those neonates on placebo. However, minor gastrointestinal bleeding (i.e., chemical detection of blood in the stool) was more commonly noted in those neonates treated with indomethacin. Severe gastrointestinal effects have been reported in adults with various arthritic disorders treated chronically with oral indomethacin. [For further information, see package insert for oral capsule indomethacin.]

Central Nervous System Effects

Prematurity per se, is associated with an increased incidence of spontaneous intraventricular hemorrhage. Because indomethacin may inhibit platelet aggregation, the potential for intraventricular bleeding may be increased. However, in the large multicenter study of indomethacin for injection (see CLINICAL PHARMACOLOGY), the incidence of intraventricular hemorrhage in neonates treated with indomethacin for injection was not significantly higher than in the control neonates.

Renal Effects

Indomethacin for injection may cause significant reduction in urine output (50 percent or more) with concomitant elevations of blood urea nitrogen and creatinine, and reductions in glomerular filtration rate and creatinine clearance. These effects in most neonates are transient, disappearing with cessation of therapy with indomethacin for injection. However, because adequate renal function can depend upon renal prostaglandin synthesis, indomethacin for injection may precipitate renal insufficiency, including acute renal failure, especially in neonates with other conditions that may adversely affect renal function (e.g., extracellular volume depletion from any cause, congestive heart failure, sepsis, concomitant use of any nephrotoxic drug, hepatic dysfunction). When significant suppression of urine volume occurs after a dose of indomethacin for injection, no additional dose should be given until the urine output returns to normal levels.

Indomethacin for injection in pre-term infants may suppress water excretion to a greater extent than sodium excretion. When this occurs, a significant reduction in serum sodium values (i.e., hyponatremia) may result. Neonates should have serum electrolyte determinations done during therapy with indomethacin for injection. Renal function and serum electrolytes should be monitored (see PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION).

PRECAUTIONS

General

Indomethacin for injection may mask the usual signs and symptoms of infection. Therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing controlled infection.

Severe hepatic reactions have been reported in adults treated chronically with oral indomethacin for arthritic disorders. [For further information, see package insert for oral indomethacin.] If clinical signs and symptoms consistent with liver disease develop in the neonate, or if systemic manifestations occur, indomethacin for injection should be discontinued.

Indomethacin for injection may inhibit platelet aggregation. In one small study, platelet aggregation was grossly abnormal after indomethacin therapy (given orally to premature infants to close the ductus arteriosus). Platelet aggregation returned to normal by the tenth day. Premature infants should be observed for signs of bleeding.

The drug should be administered carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue.

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