Indocid_PDA

INDOCID® P.D.A.

MSD

Indomethacin Sodium

Nonsteroidal Anti-inflammatory Agent for Closure of Patent Ductus Arteriosus

Action And Clinical Pharmacology: Indomethacin is a nonsteroidal, anti-inflammatory agent which inhibits prostaglandin synthesis. The disposition of indomethacin following i.v. administration (0.2 mg/kg) in preterm neonates with patent ductus arteriosus has not been extensively evaluated. Even though the plasma half-life of indomethacin was variable among premature infants, it was shown to vary inversely with postnatal age and weight. In one study of 28 evaluable infants, the plasma half-life in those infants less than 7 days old averaged 20 hours (range: 3 to 60 hours, n=18). In infants older than 7 days, the mean plasma half-life of indomethacin was 12 hours (range 4 to 38 hours, n=10). Grouping the infants by weight, mean plasma half-life in those weighing less than 1 000 g was 21 hours (range: 9 to 60 hours, n=10); in those infants weighing more than 1 000 g, the mean plasma half-life was 15 hours (range: 3 to 52 hours, n=18).

Following i.v. administration in adults, indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean half-life of indomethacin is estimated to be about 4 to 5 hours. Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites, all in the unconjugated form. About 60% of an oral dosage is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations.

The percent bound in neonates has not been studied. In controlled trials in premature infants, however, no evidence of bilirubin displacement has been observed as evidenced by increased incidence of bilirubin encephalopathy (kernicterus).

Indications And Clinical Uses: To close hemodynamically significant patent ductus arteriosus in premature infants weighing between 500 and 1 750 g when after 48 hours usual medical management (e.g., fluid restriction, diuretics, digitalis, respiratory support) is ineffective. Clearcut clinical evidence of a hemodynamically significant patent ductus arteriosus should be present, such as respiratory distress, a continuous murmur, a hyperactive precordium, cardiomegaly and pulmonary plethora on chest x-ray.

Indomethacin is indicated to close patent ductus arteriosus in premature infants when usual medical management is ineffective.

Contra-Indications: Infants with proven or suspected infection that is untreated; infants who are bleeding, especially those with active intracranial hemorrhage or gastrointestinal bleeding; infants with thrombocytopenia; infants with coagulation defects; infants with or who are suspected of having necrotizing enterocolitis; infants with significant impairment of renal function; jaundiced infants with bilirubin ³10 mg/dL or those with known hepatic diseases; in infants 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).

Manufacturers’ Warnings In Clinical States: Renal: Indomethacin may cause significant reduction in urine output (50% or more) with concomitant elevations of BUN and creatinine (³1.8 mg/dL), and reductions in glomerular filtration rate and creatinine clearance (see Adverse Effects). Most of the renal abnormalities reported have been reversible but some fatalities occurred. However, because adequate renal function can depend upon renal prostaglandin synthesis, indomethacin, as a prostaglandin inhibitor, may precipitate renal insufficiency, including acute renal failure, especially in infants 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, no additional dose should be given until the urine output returns to normal levels (see Contraindications).

Indomethacin in preterm infants may suppress water excretion to a greater extent than sodium excretion. This may result in hyponatremia. Renal function and serum electrolytes should be monitored (see Dosage).

CNS: Prematurity per se, is associated with an increased incidence of spontaneous intracranial hemorrhage, however, because indomethacin inhibits platelet aggregation, the potential for intracranial bleeding may be increased. A number of intracranial hemorrhages have been reported in infants who received indomethacin. However, in one multi-center study involving 405 infants, the incidence of intracranial hemorrhage in babies treated with indomethacin was not significantly higher than in the control infants.

Gastrointestinal: Clinical results indicate that major gastrointestinal bleeding was no more common in those infants receiving indomethacin than in those infants on placebo. However, gastrointestinal bleeding (e.g., chemical detection of blood in stool) was more commonly noted in those infants treated with indomethacin. Severe gastrointestinal effects have been reported in adults with various arthritic disorders treated for a prolonged period with oral indomethacin.

The following have been reported with oral use of indomethacin in adults and could occur in infants on i.v. indomethacin: irritation of the gastrointestinal tract and single or multiple gastrointestinal ulcerations. Fatalities have been reported in some instances. Rarely, intestinal ulceration has been associated with stenosis and obstruction.

Because of the occurrence, and at times severity, of gastrointestinal reactions to indomethacin the prescribing physician must be continuously alert for any sign or symptom signaling a possible gastrointestinal reaction. The risks of continuing therapy with indomethacin in the face of such symptoms must be weighed against the possible benefits to the individual patient.

Precautions: 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 for a prolonged period with oral indomethacin for arthritic disorders. If clinical signs and symptoms consistent with liver disease develop in the neonate, or if systemic manifestations occur, indomethacin should be discontinued.

Indomethacin, like other nonsteroidal anti-inflammatory agents, can inhibit platelet aggregation. Premature infants should be observed for signs of bleeding. Indomethacin has been shown to prolong bleeding time (but within the normal range) in normal adult subjects. This effect may be exaggerated in patients with underlying hemostatic defects (see Contraindications).

The drug should be administered carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue.

Drug Interactions: Digitalis: Preterm infants with patent ductus arteriosus and associated cardiac failure are frequently treated with digitalis. The half-life of digitalis in preterm infants is generally prolonged, and renal function during therapy with indomethacin is often reduced. Where both drugs are used concomitantly, the infant should be observed closely; frequent ECGs and serum digitalis levels may be required to prevent or to detect digitalis toxicity early.

Furosemide: Therapy with indomethacin may decrease the natriuretic effect of furosemide.

Aminoglycosides: In one study of premature infants treated with indomethacin and also receiving either gentamicin or amikacin, both peak and trough levels were significantly elevated for both antibiotics.

Clinical studies in adults have shown that the administration of indomethacin can reduce the natriuretic and anti-hypertensive effects of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis by nonsteroidal anti-inflammatory drugs. Therefore, when Indocid P.D.A. is added to the treatment of an infant receiving furosemide or thiazides, or furosemide or thiazides are added to the treatment of an infant receiving Indocid P.D.A., the patient should be observed closely to determine if the desired effect of furosemide or thiazides is obtained.

Adverse Reactions: In a collaborative double-blind placebo-controlled trial of 405 premature infants weighing less than or equal to 1 750 g with evidence of large ductal shunting, there was a statistically significantly greater incidence of bleeding problems in those infants treated with indomethacin than in those treated with placebo. Specifically, these bleeding disorders included gross or microscopic bleeding into the gastrointestinal tract, oozing from the skin after needle puncture, pulmonary hemorrhage, microscopic hematuria and disseminated intravascular coagulopathy. There was no statistically significant difference between treatment groups with reference to intracranial (e.g., intraventricular) hemorrhage.

The infants treated with sterile indomethacin also had a significantly higher incidence of transient oliguria and hypercreatininemia (³1.8 mg/dL) than did the infants treated with placebo.

The incidence of retrolental fibroplasia (grades III and IV) and pneumothorax in infants treated with indomethacin were no greater than in placebo controls and were statistically significantly lower than in surgically-treated infants.

The following additional adverse reactions in infants have been reported from the collaborative study, anecdotal case reports, and from other studies using rectal, oral, or i.v. indomethacin for treatment of patent ductus arteriosus.

Cardiovascular: pulmonary hypertension, intracranial bleeding.

Gastrointestinal: gastrointestinal bleeding, abdominal distension, vomiting, melena, transient ileus and localized perforation(s) of the small and/or large intestine.

Laboratory Findings: hyponatremia, elevated serum creatinine, elevated serum potassium, elevated BUN, decreased platelet aggregation, and reduction in blood sugar including hypoglycemia.

General: increased weight gain (fluid retention); exacerbation of infection.

Renal: renal dysfunction 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; uremia.

The following adverse reactions have also been reported in infants treated with indomethacin, however, a causal relationship to therapy with indomethacin has not been established.

Cardiovascular: bradycardia. Respiratory: apnea, exacerbation of pre-existing pulmonary infection. Hematologic: disseminated intravascular coagulation. Metabolic: acidosis/alkalosis. Gastrointestinal: necrotizing enterocolitis. Ophthalmic: retrolental fibroplasia.

For adverse effects which have been reported in adults, please consult the monograph for Indocid.

Dosage And Administration: For i.v. administration only.

Dosage recommendations for closure of the ductus arteriosus depends on the age of the infant at the time of therapy. A course of therapy is defined as from 1 up to 3 i.v. doses of indomethacin given at 12 to 24 hours 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, no additional doses should be given until laboratory studies indicate that renal function has returned to normal.

If severe adverse reactions occur, stop the drug.

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, no further doses are necessary. If during continued medical management the ductus arteriosus re-opens, a second course of 1 to 3 doses may be given, each dose separated by a 12 to 24 hours interval as described above (in the U.S. collaborative study about 10% of the infants required a second course of therapy).

If the infant remains unresponsive to therapy with indomethacin after 2 courses, surgery may be necessary for closure of the ductus arteriosus.

Directions for Use: The solution may be prepared with 2 mL of preservative-free sterile sodium chloride injection 0.9% or sterile, preservative-free water for injection. Benzyl alcohol as a preservative has been associated with toxicity in newborns. Therefore, all diluents should be preservative-free. With 2 mL of diluent the concentration of the solution will equal approximately 0.05 mg/0.1 mL. Any unused portion of the solution should be discarded because there is no preservative contained in the vial. A fresh solution should be prepared just prior to each administration. Once reconstituted, the indomethacin solution may be injected i.v. over 5 to 10 seconds.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Further dilution with i.v. infusion solutions is not recommended. Indocid P.D.A. is not buffered, and reconstitution with solutions at pH values below 6.0 may result in precipitation of the insoluble indomethacin free acid moiety.

Availability And Storage: Each single-dose vial of sterile, lyophilized powder contains: indomethacin sodium trihydrate equivalent to 1 mg indomethacin. Boxes of 3 as a white to yellow lyophilized cake or plug. Store at room temperature (15 to 30°C). Protect from light. Store vials in carton until contents have been used.

INDOCID® P.D.A. MSD Indomethacin Sodium Nonsteroidal Anti-inflammatory Agent for Closure of Patent Ductus Arteriosus

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