INDOMETHACIN — indomethacin injection, powder, lyophilized, for solution
Fresenius Kabi USA, LLC
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.
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.
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 supplied in single dose vials containing 1 mg of indomethacin as a sterile lyophilized powder or plug for reconstitution.
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 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.
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.
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.
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].
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.
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)].
Administer Indomethacin for Injection carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue.
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