INDOMETHACIN

Sterile Indomethacin for Injection for intravenous administration is lyophilized indomethacin for injection. Each vial of indomethacin for injection contains 1 mg indomethacin; 0.29 mg monobasic sodium phosphate, 0.41 mg dibasic sodium phosphate and not more than 0.24 mg of sodium hydroxide (used for converting indomethacin base to the sodium salt) 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. If necessary, hydrochloric acid (q.s.) and sodium hydroxide (q.s.) are added as pH adjusters. The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. The pH of the product does not meet the USP monograph [FD&C Act Chapter V, SEC. 501. [21USC §351](b)]. Indomethacin is designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. The structural formula is: Structural Formula

Indomethacin for Injection is indicated to close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g when 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, or pulmonary plethora on chest x-ray. Indomethacin for Injection is a cardiovascular drug indicated: To close a hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1,750 g. ( 1 )

Dosage is dependent on the age of the infant at time of therapy. A course of therapy requires intravenous doses of Indomethacin for Injection given at 12 to 24 hour intervals. AGE at 1st dose DOSAGE (mg/kg) Less than 48 hours 1st 0.2 2nd 0.1 3rd 0.1 2 to 7 days 0.2 0.2 0.2 Over 7 days 0.2 0.25 0.25 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 Indomethacin for Injection, do not give additional doses until laboratory studies indicate that renal function has returned to normal 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 of Indomethacin for Injection, no further doses are necessary If the neonate remains unresponsive to therapy with Indomethacin for Injection after 2 courses, surgery may be necessary for closure of the ductus arteriosus. ( 2.1 ) For intravenous administration only . Dosage recommendations for closure of the ductus arteriosus depend on the age of the infant at the time of therapy. A course of therapy is defined as three intravenous doses of Indomethacin for Injection given at 12 to 24 hour intervals, with careful attention to urinary output. 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 Indomethacin for Injection, do not give additional doses until laboratory studies indicate that renal function has returned to normal [see Warnings and Precautions ( 5.7 )] . Dosage according to age is as follows: AGE at 1st dose DOSAGE (mg/kg) Less than 48 hours 1st 0.2 2nd 0.1 3rd 0.1 2 to 7 days 0.2 0.2 0.2 Over 7 days 0.2 0.25 0.25 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 of Indomethacin for Injection, 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. If the neonate remains unresponsive to therapy with Indomethacin for Injection after 2 courses, surgery may be necessary for closure of the ductus arteriosus. 2.1 Directions for Use Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. Prepare the solution with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection. Benzyl alcohol as a preservative has been associated with toxicity in neonates. Therefore, do not use diluents that contain preservatives. If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL. Discard any unused portion of the solution as it does not contain a preservative. Prepare a fresh solution just prior to each administration. Once reconstituted, the indomethacin solution may be injected intravenously. While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20 to 30 minutes. Further dilution with intravenous infusion solutions is not recommended.

Indomethacin for Injection is contraindicated in neonates: With proven or suspected infection that is untreated Who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding With thrombocytopenia or coagulation defects With or who are suspected of having necrotizing enterocolitis With significant impairment of renal function 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). Indomethacin for Injection is contraindicated in neonates: With proven or suspected infection that is untreated Who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding With thrombocytopenia or coagulation defects Suspected of having necrotizing enterocolitis With significant impairment of renal function With congenital heart disease in whom patency of the ductus arteriosus is necessary for satisfactory pulmonary or systemic blood flow. ( 4 )

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.

As renal function may be reduced by Indomethacin for Injection, consider reducing the dosage of those medications that rely on adequate renal function for their elimination. When used concomitantly with digoxin, monitor neonates for the development of digoxin toxicity. ( 7.1 ) Monitor prothrombin time when indomethacin is added to anticoagulants. ( 7.2 ) 7.1 Digoxin Because the half-life of digoxin (given frequently to pre-term infants with patent ductus arteriosus and associated cardiac failure) may be prolonged when given concomitantly with indomethacin, observe neonates receiving concomitant digoxin closely; frequent ECGs and serum digoxin levels may be required to prevent or detect digoxin toxicity early. 7.2 Anticoagulants Indomethacin usually does not influence the hypoprothrombinemia produced by anticoagulants. When indomethacin is added to anticoagulants, monitor prothrombin time closely. In post-marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and Indomethacin for Injection. 7.3 Furosemide Therapy with indomethacin may blunt the natriuretic effect of furosemide. This response has been attributed to inhibition of prostaglandin synthesis by non-steroidal anti-inflammatory drugs. In a study of 19 premature infants with patent ductus arteriosus treated with either Indomethacin for Injection alone or a combination of Indomethacin for Injection and furosemide, results showed that neonates receiving both Indomethacin for Injection and furosemide had significantly higher urinary output, higher levels of sodium and chloride excretion, and higher glomerular filtration rates than did those receiving Indomethacin for Injection alone. In this study, therapy with furosemide helped to maintain renal function in the premature infant when Indomethacin for Injection was added. 7.4 Aminoglycosides In one study of premature infants treated with Indomethacin for Injection and also receiving either gentamicin or amikacin, both peak and trough levels of these aminoglycosides were significantly elevated. 7.5 Drugs that Act on the Renin-Angiotensin System In some patients with compromised renal function, the co-administration of an NSAID and an ACE inhibitor or angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.

16.2 Storage Store at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F). Protect from light. Store container in carton until contents have been used. www.fresenius-kabi.com/us 451150C Fresenius Kabi Logo