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 INDOCIN I.V. 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 INDOCIN I.V. 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 INDOCIN I.V. has not been established:
Respiratory: apnea, exacerbation of pre-existing pulmonary infection.
Hematologic: disseminated intravascular coagulation, thrombocytopenia.
Ophthalmic: retrolental fibroplasia.**
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 Capsules INDOCIN (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 INDOCIN I.V. in pre-term infants.
To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck Inc. at 1-800-455-1141
or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.