1 INDICATIONS AND USAGE 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 ) 2 DOSAGE AND ADMINISTRATION 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.

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 ) 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.

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.