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Indomethacin (Systemic)



INN:

Indometacin

VA CLASSIFICATION
Oral
Primary: MS102
Secondary: MS400; CN850; CN105 ; CV900

Parenteral
Primary: CV900



Note: For information pertaining to use of indomethacin for other indications, see Anti-inflammatory Drugs, Nonsteroidal (Systemic).

Commonly used brand name(s): Apo-Indomethacin; Indameth; Indocid; Indocid PDA; Indocin; Indocin I.V; Novomethacin.

Another commonly used name is
indometacin .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Ductus arteriosus, patent, closure adjunct—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Ductus arteriosus, patent (treatment)—Intravenous indomethacin sodium is indicated to induce pharmacologic closure of a hemodynamically significant patent ductus arteriosus (PDA) in premature infants weighing 500 to 1750 grams. Evidence of a hemodynamically significant PDA (such as respiratory distress, continuous murmur, hyperactive precordium, enlarged heart, congestion in the lungs, and associated constitutional symptoms) should be present prior to therapy. In the U.S., indomethacin is FDA-approved for administration only if these signs and symptoms persist after 48 hours of conservative treatment, such as fluid restriction, diuretics, {05} and respiratory support. [However, some neonatologists recommend that indomethacin therapy be instituted as soon as possible after identification of the PDA, especially if echocardiography shows the presence of a significant left-to-right shunt and/or the infant is being mechanically ventilated.]1 {05}
—Some investigators have not found successful closure to be associated with birth weight or postnatal age. However, others have reported the medication"s efficacy to be decreased in infants >2 weeks of age (possibly because metabolism and/or clearance of indomethacin increases with neonatal age) and in infants weighing < 1000 grams (possibly because of insufficient muscular development in the ductal wall). Reopening of the ductus may occur following initial closure; although reclosure may occur spontaneously or in response to additional indomethacin, some infants may require surgery to achieve permanent closure.
—[Indomethacin has also been administered orally (via a nasogastric tube) or rectally, as a suspension prepared from capsule contents, for this purpose.]1 However, intravenous administration is preferred because it produces more predictable indomethacin serum concentrations, leading to a higher closure rate (> 80%), than oral or rectal administration. Also, intravenous administration produces fewer gastrointestinal adverse effects than oral indomethacin.
—[Indomethacin is not specifically approved by U.S. or Canadian regulatory agencies for administration to premature neonates without substantial evidence of a hemodynamically significant PDA. However, preliminary evidence suggests that administration at the first sign of a murmur (but no other symptoms) may prevent development of a symptomatic PDA in infants weighing < 1000 grams. These infants may be at greater risk of developing a symptomatic PDA than those with a murmur (but no other symptoms) weighing > 1000 grams.]1

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    1–(4–chlorobenzoyl)–5–methoxy–2–methyl–1H–indole–3–acetic acid, sodium salt, trihydrate{01}.
Molecular weight—
    Indomethacin: 357.79
    Indomethacin sodium (trihydrate): 433.82 {06}

pKa—
    4.5

Mechanism of action/Effect:

Indomethacin inhibits the activity of the enzyme cyclooxygenase to decrease the formation of precursors of prostaglandins and thromboxanes from arachidonic acid. Inhibition of prostaglandin synthesis (and the consequent reduction of prostaglandin activity) permits constriction of the patent ductus arteriosus, which may be due to excessive production, and/or increased sensitivity of the premature ductus to the dilating effects, of prostaglandins of the E series.


Other actions/effects:

Indomethacin reversibly inhibits platelet aggregation.

Absorption:

When administered via nasogastric tube—Poor and incomplete, possibly because of indomethacin"s insolubility and/or abnormalities in gastric function (gastric acid secretion, gastric motility, etc.) or pH in premature neonates with a patent ductus arteriosus.

Protein binding:

Has not been determined in the premature neonate. {01} {04} Very high (99%), to albumin, in adults.

Biotransformation:

Hepatic; the rate of metabolism increases with neonatal age.

Half-life:

Greatly prolonged as compared with that reported in adults; varies inversely with postnatal age and weight. The prolonged half-life may reflect extensive and/or repeated enterohepatic circulation and re-entry into plasma.

Infants <7 days of age—3 to 60 hours; average 20 hours. {04}

Infants >7 days of age—4 to 38 hours; average 12 hours. {04}

Infants <1000 grams—9 to 60 hours; average 21 hours. {04}

Infants >1000 grams—3 to 52 hours; average 15 hours. {06}

Peak serum concentration:

Subject to wide individual variation when administered by any route but especially following oral administration.

Elimination:
    Renal and biliary excretion of metabolites and of unchanged indomethacin. In adults, 10 to 20% of a dose is excreted in the urine as unchanged indomethacin; the quantity excreted unchanged in the premature neonate has not been determined.
    In dialysis—Indomethacin is not dialyzable.


Precautions to Consider

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: In addition to the interactions listed below, the possibility should be considered that additive or multiple effects leading to impaired blood clotting and/or increased risk of bleeding may occur if indomethacin is used concurrently with any medication having a significant potential for causing hypoprothrombinemia, thrombocytopenia, or gastrointestinal ulceration or hemorrhage.

» Aminoglycosides {04} or
» Digitalis glycosides {04}    (indomethacin may decrease renal clearance of aminoglycosides or digitalis glycosides, leading to increased plasma concentrations, elimination half-lives, and risk of aminoglycoside or digitalis toxicity; careful observation is required when indomethacin is given concomitantly with digitalis; frequent electrocardiograms (ECG) and serum digitalis levels may be necessary{06}; dosage adjustment of aminoglycosides may also be required, based on evidence of toxicity and/or measurement of plasma concentration)


Nephrotoxic medications, other (See Appendix II ) {04}    (concurrent use with indomethacin may increase the risk and/or severity of adverse renal effects)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Urinary 5-hydroxyindoleacetic acid (5-HIAA) determinations    (false 5-HIAA concentration values may be measured via the Goldenberg modification of Undenfriend's method because indomethacin metabolites are structurally similar to 5-HIAA)

With physiology/laboratory test values
Bleeding time    (may be prolonged because of suppressed platelet aggregation; effects in the premature neonate may persist for several days after the medication is discontinued)


Blood glucose concentration    (may be decreased or, less frequently, increased)


Blood urea nitrogen (BUN) concentration and
Creatinine concentration, serum and
Glucose concentration, urine and
Potassium concentration, serum and
Protein (including albumin) concentrations, urine    (may be increased because indomethacin decreases glomerular filtration rate )


Chloride concentration, urine and
Creatinine clearance and
Free water clearance and
Glomerular filtration rate and
Osmolality, urine and
Potassium concentration, urine and
Sodium concentration, urine and
Sodium concentration, serum and
Urine volume    (may be decreased)


Note: Indomethacin may decrease both sodium and water excretion; however, water retention may exceed that of sodium so that the net effect is a reduction of serum sodium concentration (dilutional hyponatremia).


Leukocyte count and
Platelet count    (may be decreased)


Liver function tests, especially transaminase (AST [SGOT]; ALT [SGPT]) activity    (values may be increased; if significant abnormalities occur, clinical signs and symptoms consistent with liver disease develop, or systemic manifestations such as eosinophilia or rash occur, indomethacin should be discontinued)


Plasma renin activity (PRA)    (may be decreased; also, indomethacin may block the increase in PRA usually produced by bumetanide, furosemide, or indapamide)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Bleeding, active, especially intracranial or gastrointestinal {04} or
» Coagulation defects {04}    (increased risk of severe hemorrhage because indomethacin inhibits platelet aggregation and may cause gastrointestinal bleeding)


» Enterocolitis, necrotizing, proven or suspected {04}    (may be exacerbated)


» Heart disease, congenital, such as: {04}
Coarctation of the aorta, severe
Pulmonary atresia
Tetralogy of Fallot, severe or
» Lesions, severely obstructive, left-sided, other {05}    (patency of the ductus arteriosus may be required to provide satisfactory pulmonary or systemic blood flow; {01} indomethacin should not be administered until the safety of inducing closure has been determined )


» Infection, untreated, confirmed or suspected {04}    (symptoms of progression may be masked; also, sepsis may predispose the patient to renal insufficiency and increase the risk of renal impairment or failure; in addition, an unexpectedly high rate of treatment failure has been reported following indomethacin administration to infants with sepsis {05})


Jaundice, severe    (although no evidence of bilirubin displacement has been seen in controlled trials,{06} indomethacin may cause displacement of bilirubin, thus increasing the risk of kernicterus in patients with severe jaundice, and should be used with caution{05} )


» Renal function impairment, severe,{06}    (may be exacerbated)


» Thrombocytopenia{06}    (increased risk of severe hemorrhage because indomethacin inhibits platelet aggregation and may cause gastrointestinal bleeding; although platelets may be administered if necessary, indomethacin should be used only when the risk of surgery outweighs the risk of administering blood products {05})


Risk-benefit should be considered when the following medical problems exist
Conditions predisposing to renal insufficiency, such as:
Congestive heart failure
Extracellular volume depletion
Hepatic function impairment    (increased risk of renal function impairment, including acute renal failure )



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Electrolyte concentrations, serum and
Renal function tests    (monitoring recommended during and following indomethacin administration; if renal function impairment occurs, [as shown by: concomitant elevations of blood urea nitrogen and creatinine, and reductions in glomerular filtration rate and creatinine clearance; anuria or marked oliguria, with urinary output < 0.6 mL/kg per hour]{06} therapy should be suspended until adequate renal function has been restored)

{06}


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Gastrointestinal problems (abdominal distention; bleeding [incidence 3% to 9%]; gastric perforation [incidence < 3%]; transient ileus; vomiting)
    
renal function impairment —incidence >40%

Note: Renal function impairment is characterized by decreases in urine volume; free water clearance; urine osmolality; glomerular filtration rate; creatinine clearance; and excretion of sodium, potassium, and chloride. Corresponding increases in blood urea nitrogen (BUN), blood creatinine, and serum potassium occur. Water retention may be greater than sodium retention, leading to dilutional hyponatremia.
Gastrointestinal problems have been reported more frequently with oral (via a nasogastric tube) than with intravenous administration.


Incidence less frequent
    
Bleeding problems
    
hypoglycemia

Note: Bleeding problems reported (in addition to gastrointestinal bleeding) include pulmonary hemorrhage, disseminated intravascular coagulopathy, microscopic hematuria, and oozing at needle puncture sites.
Intracranial hemorrhage, necrotizing enterocolitis, and retrolental fibroplasia have also been reported; however, the incidence in indomethacin-treated infants is not greater than that reported in other premature infants, who are known to be at risk for these complications.


Incidence rare
    
Acidosis
    
alkalosis
    
apnea
    
bradycardia
    
exacerbation of preexisting pulmonary infection





General Dosing Information
Sterile indomethacin sodium is to be administered intravenously only, over a 5- to 10-second period. Extravasation must be avoided because the solution is irritating to tissues.

Restriction of fluid intake (recommended for treatment of premature neonates with a patent ductus arteriosus) should be continued during indomethacin treatment.

Administration of 1 mg per kg of body weight (mg/kg) of furosemide immediately following indomethacin has been reported to prevent or reduce indomethacin-induced adverse renal effects without interfering with ductus arteriosus closure. However, furosemide administration is not a generally accepted measure for achieving this purpose. If a significant decrease in renal function occurs following a dose of indomethacin as indicated by a serum creatinine concentration greater than 1.2 to 1.4 mg per dL (106-124 micromols/L) or other appropriate tests, additional doses should be withheld until urine volume increases to normal levels (i.e., > 1 mL per kg of body weight per hour) and/or laboratory studies indicate return of normal renal function.

The medication should be discontinued if any severe adverse reaction, especially hepatic function impairment or disease, occurs.

If significant constriction or closure of the ductus arteriosus does not occur following 2 courses (3 doses per course) of indomethacin therapy, surgery may be required.

Reopening of the ductus arteriosus may occur following initial closure. Although spontaneous reclosure has occurred in many patients, additional indomethacin or surgery may be required.

For treatment of adverse effects or overdose
Recommended treatment may include:

   • Discontinuing or temporarily suspending administration.
   • Monitoring the patient and treating observed symptoms. The possibility must be considered that gastrointestinal ulceration or hemorrhage may not occur until several days after administration.
Hemodialysis is not effective in removing indomethacin from the circulation.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

INDOMETHACIN CAPSULES USP

Usual pediatric dose
[Patent ductus arteriosus closure adjunct]1


Infants up to 48 hours of age at time of first dose:
Oral, via nasogastric tube, 200 mcg (0.2 mg) of indomethacin per kg of body weight initially. If necessary, one or two additional doses of 100 mcg (0.1 mg) of indomethacin per kg of body weight may be given at twelve- to twenty-four-hour intervals.



Infants 2 to 7 days of age at time of first dose:
Oral, via nasogastric tube, 200 mcg (0.2 mg) of indomethacin per kg of body weight initially. If necessary, one or two additional doses of 200 mcg (0.2 mg) of indomethacin per kg of body weight may be given at twelve- to twenty-four-hour intervals.



Infants over 7 days of age at time of first dose:
Oral, via nasogastric tube, 200 mcg (0.2 mg) of indomethacin per kg of body weight initially. If necessary, one or two additional doses of 250 mcg (0.25 mg) of indomethacin per kg of body weight may be given at twelve- to twenty-four-hour intervals.



Note: Some investigators have used initial doses of 300 mcg (0.3 mg) per kg of body weight.
The recommended dose may also be administered rectally (as a suspension prepared from capsule contents); however, intravenous administration is preferred if available.


Strength(s) usually available
U.S.—


25 mg (Rx) [Indameth] [Indocin][Generic]


50 mg (Rx) [Indameth] [Indocin][Generic]

Canada—


25 mg (Rx) [Apo-Indomethacin] [Indocid] [Novomethacin]


50 mg (Rx) [Apo-Indomethacin] [Indocid] [Novomethacin]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a well-closed container.



Parenteral Dosage Forms

INDOMETHACIN FOR INJECTION

Usual pediatric dose
Patent ductus arteriosus closure adjunct


Infants up to 48 hours of age at time of first dose:
Intravenous, 200 mcg (0.2 mg) of indomethacin per kg of body weight initially. If necessary, one or two additional doses of 100 mcg (0.1 mg) of indomethacin per kg of body weight may be given at twelve- to twenty-four-hour intervals.



Infants 2 to 7 days of age at time of first dose:
Intravenous, 200 mcg (0.2 mg) of indomethacin per kg of body weight initially. If necessary, one or two additional doses of 200 mcg (0.2 mg) of indomethacin per kg of body weight may be given at twelve- to twenty-four-hour intervals.



Infants over 7 days of age at time of first dose:
Intravenous, 200 mcg (0.2 mg) of indomethacin per kg of body weight initially. If necessary, one or two additional doses of 250 mcg (0.25 mg) of indomethacin per kg of body weight may be given at twelve- to twenty-four-hour intervals.



Note: Some investigators have used initial doses of 300 mcg (0.3 mg) of anhydrous indomethacin per kg of body weight.


Size(s) usually available:
U.S.—


1 mg (Rx) [Indocin I.V{06}]

Canada—


1 mg (Rx) [Indocid PDA]

Note: Each vial contains indomethacin sodium trihydrate, equivalent to 1 mg indomethacin, as a lyophilized powder or plug.{06}


Packaging and storage:
Store below 30 °C (86 °F), unless otherwise directed by manufacturer. Protect from light.

Preparation of dosage form:
Add 1 or 2 mL of preservative-free 0.9% sodium chloride injection or preservative-free sterile water for injection to the contents of the vial. A solution prepared using 1 mL of diluent contains 100 mcg (0.1 mg) of anhydrous indomethacin per 0.1 mL; a solution prepared using 2 mL of diluent contains 50 mcg (0.05 mg) of anhydrous indomethacin per 0.1 mL.

Stability:
Sterile indomethacin sodium contains no preservatives. Therefore, the medication should be reconstituted immediately prior to use and any unused solution should be discarded.

Incompatibilities:
Sterile indomethacin sodium contains no buffering agents. Further dilution of the reconstituted solution with intravenous infusion solutions is not recommended because free indomethacin may be precipitated if the pH of the solution is < 6.



Revised: 12/21/1999



References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. Indocin PDA package insert, MSD, 8/31/86, in PDR 41, 1987, pp 1308-10.
  1. Indocin PDA package insert, MSD, 12/86, Rec 6/87.
  1. Salzer HR, Salzer-Muhar U, Pollak A, Weninger M. Sepsis and indomethacin failure in premature infants with symptomatic patent ductus arteriosus. Lancet 1987; 1(8539): 977.
  1. Indocin I.V. package insert, (MSD—US), Rev 11/91, Rec 4/92.
  1. Reviewer comment.
  1. Product Information: Indocin I.V., indomethacin sodium trihydrate. Merck & Co., West Point, PA, USA, 06/1998.
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