Indomethacin (injection)

# Dosing Information
- 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
- 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.
- 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.  .  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.  .
- 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.
- Administer Indomethacin for Injection carefully to avoid extravascular injection or leakage as the solution may be irritating to tissue.
- 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 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 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.
- Intracranial bleeding, pulmonary hypertension.
- Gastrointestinal bleeding*, vomiting, abdominal distention, transient ileus, gastric perforation, localized perforation(s) of the small and/or large intestine, necrotizing enterocolitis.
- Hyponatremia*, elevated serum potassium*, reduction in blood sugar, including hypoglycemia, increased weight gain (fluid retention).
- Decreased platelet aggregation .
- 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:
- Bradycardia.
- Apnea, exacerbation of pre-existing pulmonary infection.
- Acidosis/alkalosis.
- Disseminated intravascular coagulation, thrombocytopenia.
- 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 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.

# =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.
- 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.
- 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.
- 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.
- 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.
- 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 ].
- Indomethacin is designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid.  The structural formula is:
- Pregnant rats, given 2 mg/kg/day and 4 mg/kg/day during the last trimester of gestation, delivered offspring whose pulmonary blood vessels were both reduced in number and excessively muscularized.  These findings are similar to those observed in the syndrome of persistent pulmonary hypertension of the neonate.
This container closure is not made with natural rubber latex.
- Protect from light.
- Store container in carton until contents have been used.
NDC 63323-659-03
INDOMETHACIN FOR INJECTION
1 mg per vial
FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS
Sterile     Rx only
Single Dose Vial - Discard unused portion
NDC 63323-659-03
INDOMETHACIN FOR INJECTION
1 mg per vial
For Intravenous Use Only
FOR THE PREPARATION OF INTRAVENOUS SOLUTIONS
Rx only
One vial
Single Dose Vial - Discard any unused portion immediately.