Indomethacin

5 WARNINGS AND PRECAUTIONS Indomethacin may mask the usual signs of infection. ( 5.1 ) Monitor for signs of hepatic reactions. Indomethacin for Injection may need to be discontinued. ( 5.2 ) Indomethacin for Injection may inhibit platelet aggregation. ( 5.3 ) Gastrointestinal Effects: Monitor neonates for blood in stool. ( 5.4 ) Central Nervous System Effects: Monitor neonates for intraventricular hemorrhage. ( 5.5 ) Renal Effects: Monitor renal function and serum electrolytes. ( 5.6 ) 5.1 Infection Indomethacin 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. 5.2 Hepatic Reactions 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, discontinue Indomethacin for Injection. 5.3 Platelet Aggregation 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. Observe premature infants for signs of bleeding. 5.4 Gastrointestinal Effects In the collaborative study, major gastrointestinal bleeding was no more common in neonates receiving indomethacin than in neonates on placebo. However, minor gastrointestinal bleeding (i.e., chemical detection of blood in the stool) was more commonly noted in 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 indomethacin]. 5.5 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, the incidence of intraventricular hemorrhage in neonates treated with Indomethacin for Injection was not significantly higher than in the control neonates. 5.6 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, do not give additional doses until 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. Monitor renal function and serum electrolyte levels during therapy with Indomethacin for Injection [see Dosage and Administration ( 2 )] . 5.7 Administration Administer Indomethacin for Injection carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue.

6 ADVERSE REACTIONS Most common adverse reactions are bleeding problems, higher incidence of transient oliguria and elevations of serum creatinine. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience In a double-blind, placebo-controlled trial of 405 premature infants weighing less than or equal to 1,750 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 in intracranial hemorrhage. The neonates treated with Indomethacin for Injection 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 that 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 that 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 to 9 percent of indomethacin-treated neonates; those marked with a double asterisk (**) occurred in 3 to 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 Warnings and Precautions ( 5.3 )] . 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) A variety of additional adverse experiences have been reported in adults treated with oral indomethacin for moderate to severe rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute painful shoulder and acute gouty arthritis (see package insert for oral indomethacin for additional information concerning adverse reactions and other cautionary statements). Their relevance to the pre-term infant receiving indomethacin for patent ductus arteriosus is unknown, however, the possibility exists that these experiences may be associated with the use of Indomethacin for Injection in pre-term infants.