FDA label d1c1c754-782c-4abb-8e82-9cd139ca49a0

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 Indomethacin Capsules] 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 ).

ADVERSE REACTIONS In a double-blind, placebo-controlled trial of 405 premature infants weighing less than or equal to 1750 g with evidence of large ductal shunting, in those neonates treated with indomethacin (n=206), there was a statistically significantly greater incidence of bleeding problems, including gross or microscopic bleeding into the gastrointestinal tract, oozing from the skin after needle stick, pulmonary hemorrhage, and disseminated intravascular coagulopathy. There was no statistically significant difference between treatment groups with reference to intracranial hemorrhage. The neonates treated with indomethacin for injection also had a significantly higher incidence of transient oliguria and elevations of serum creatinine (greater than or equal to 1.8 mg/dL) than did the neonates treated with placebo. The incidences of retrolental fibroplasia (grades III and IV) and pneumothorax in neonates treated with indomethacin for injection were no greater than in placebo controls and were statistically significantly lower than in surgically-treated neonates. The following additional adverse reactions in neonates have been reported from the collaborative study, anecdotal case reports, from other studies using rectal, oral, or intravenous indomethacin for treatment of patent ductus arteriosus or in marketed use. The rates are calculated from a database which contains experience of 849 indomethacin-treated neonates reported in the medical literature, regardless of the route of administration. One year follow-up is available on 175 neonates and shows no long-term sequelae which could be attributed to indomethacin. In controlled clinical studies, only electrolyte imbalance and renal dysfunction (of the reactions listed below) occurred statistically significantly more frequently after indomethacin for injection than after placebo. Reactions marked with a single asterisk (*) occurred in 3-9 percent of indomethacin-treated neonates; those marked with a double asterisk (**) occurred in 3-9 percent of both indomethacin- and placebo-treated neonates. Unmarked reactions occurred in less than 3 percent of neonates. Renal : renal failure, renal dysfunction in 41 percent of neonates, including one or more of the following: reduced urinary output; reduced urine sodium, chloride, or potassium, urine osmolality, free water clearance, or glomerular filtration rate; elevated serum creatinine or BUN; uremia. Cardiovascular : intracranial bleeding**, pulmonary hypertension. Gastrointestinal : gastrointestinal bleeding*, vomiting, abdominal distention, transient ileus, gastric perforation, localized perforation(s) of the small and/or large intestine, necrotizing enterocolitis. Metabolic : hyponatremia*, elevated serum potassium*, reduction in blood sugar, including hypoglycemia, increased weight gain (fluid retention). Coagulation : decreased platelet aggregation (see PRECAUTIONS ). The following adverse reactions have also been reported in neonates treated with indomethacin, however, a causal relationship to therapy with indomethacin for injection has not been established: Cardiovascular : bradycardia. Respiratory : apnea, exacerbation of pre-existing pulmonary infection. Metabolic : acidosis/alkalosis. Hematologic : disseminated intravascular coagulation, thrombocytopenia. Ophthalmic : retrolental fibroplasia.** Dermatologic : drug reaction with eosinophilia and systemic symptoms (DRESS). To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals USA Inc, Pennington, NJ 08534 at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.