Indometacin

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Adequacy of study:

other information

Data source

Reference

Reference 1

Reference Type:

other: FDA approved label document

Title:

Label for Indocin(R) -Indomethacin (Oral Suspension) by IROKO Pharmaceuticals, LLC

Year:

2009

Bibliographic source:

Pharmapendium(TM), Elsevier, Inc.

Reference 2

Reference Type:

other: FDA Approval Package

Title:

New Drug Application (NDA) 018332

Year:

1980

Bibliographic source:

Pharmapendium (TM) by Elsevier, Inc.

Reference 3

Reference Type:

other: FDA approval package

Title:

NDA 018858

Year:

1982

Bibliographic source:

Pharmapendium(TM) by Elsevier, Inc.

Reference 4

Reference Type:

other: FDA approval package

Title:

NDA 018878

Year:

1983

Bibliographic source:

Pharmapendium(TM) by Elsevier, Inc.

Reference 5

Reference Type:

other: FDA approval package

Title:

NDA 018730

Year:

1984

Bibliographic source:

Pharmapendium(TM) by Elsevier, Inc.

Reference 6

Reference Type:

other: FDA approval package

Title:

NDA 018185

Year:

1989

Bibliographic source:

Pharmapendium(TM) by Elsevier, Inc.

Results and discussion

Any other information on results incl. tables

A comprehensive evaluation of indomethacin is available from U.S. Food & Drug Administration (www.pharmapendium.com). Based on that the following informations are given:

Indocin(R) is a drug formulation containing indomethacin as the active ingredient. Total daily doses are between 150 - 200 mg/Patient, divided in 3 - 4 dosages/day.

Indomethacin belongs to the class of non-steroidal anti-inflammatory drugs (NSAIDs) with antipyretic, anti-inflammatory and analgesic properties. It is a potent prostaglandin synthesis inhibito in vitro and is therapeutically used in different formulations for different indications comprising long-term treatment of rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis as well as more acute indications like painful shoulder and acute gouty arthritis. In neonatal infants indomethacin is used for treatment of persistent ductus arteriosus.

Use of indomethacin is contraindicated in patients with known hypersensitivity, in patients who have experienced asthma, urticaria, or allergic-tpye reactions after taking aspirin or other NSAIDs and for treatment of peri-operative pain in patients with coronary artery bypass graft surgery. Warnings are given with respect to cardiovascular thrombotic events, onset or worsening of hypertension, congestive heart failure and edema, gastrointestinal effects (risk of ulceration, bleeding, perforation), renal effects and kidney disease (papillary necrosis, renal injury, decreased prostaglandin-mediated renal blood flow), hyperkalemia, anaphylaxis, anaphylactoid reactions, skin reactions (exfoliative dermatitis, Steven-Johnson-Syndrom, toxic epidermal necrolysis), ocular and central nervous effects. Anemia (in relation to fluid retention or gastrointestinal blood loss, effects on erythropoesis) and inhibition of platelet aggregation (reversible) may occur. Increase of liver enzymes (ALT/AST) and rare cases of jaundice, fatal fulminant hepatitis, liver necrosis and heptaic failure have been reported. In pregnancy Indomethacin should be avoided due to the risk of premature closure of the ductus arteriosus.

Unwanted effects during drug therapy affects with the highest incidence (> 1%) the gastrointestinal system (nausea, vomiting, dyspepsia, diarrhea, constipation, pain), the central nervous system (headache, dizziness, vertigo, somnolence, depression and fatigue) and tinnitus.

The toxicity studies of indomethacin comprised acute, subacute and chronic toxicity studies in mice, rats, guinea pigs, rabbits, cats, dogs, monkeys, domestic pigs and chickens. Chronic toxicity studies were performed in dogs (up to 129 weeks), rats (up to 52 weeks), monkeys (18 weeks), rabbits (22 weeks) and guinea pigs (27 weeks). Men tolerated indomethacin better than experimental animals (especially than dogs and rats). The most observed toxic effect of Indomethacin i.e. gastric ulceration occurred within 2 weeks when more than 5 mg/kg bw was administered. Besides the GI tract, kidney and liver toxicities were the most frequent effects. In the chronic toxicity studies, cellular infiltration of kidney and liver in rats, and renal amyloidosis and papillary necrosis in mice were observed at dose levels of 2 -5 mg/kg/day. The carcinogenicity study in rats and mice revealed no tumorigenic effect (dose levels: 0.5, 1.0 and 2.0 (later decreased 1.5 due to high mortality) mg/kg/day.

In reproductive toxicity studies in rats and mice (dosages of 0.5,1, 2 and 4 mg/kg/day) , teratogenicity was not observed up to 4 mg/kg/day. Retarded fetal ossification was secondary to reduced fetal weights. Maternal toxicity, increased prenatal loss (resorptions) and malformations were reported at higher doses (5 -15 mg/kg/day) in mice. Indomethacin delayed parturition in rats, and caused an increase of neuronal necrosis in the brain (diencephalon) of newborn rats when given at a dose of 4 mg/kg/day for the last 3 days before parturition. This effect was not evident when the identical dose was given to newborn rats on the first 3 days of life.

In rat studies with NSAIDs dystocias, delayed parturition, decreased pup survival occurred.

Effects of Indomethacin and other drugs of this class when given during the 3rd trimester on the human fetus include constriction of the ductus arteriosus prenatally, incompetence of tricuspidal incompetence, pulmonary hyertension, non-closure of the ductus arteriosus postnatally, myocardial degenerativ changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal disfunction of failure, renal injura/dysgenesis, oligohydramnios, gastrointestinal bleeding or perforation, increased risk of necrotizing enterocolitis.

The acute oral LD50 of Indomethacin base in female mice was 849 mg/kg based on 24 hour mortality and 50 mg/kg based on 14 -day mortality (GI toxicity), the oral LD50 for rats was 12 mg/kg; in newborn (24- 72 hours old) rats oral LD50 was 44 mg/kg ; LD50 after intravenous administration in Beagle pups appears to be > 81 mg/kg.

Indomethacin passes the placenta (Clinical Pharmacokin. 6, 245 -258, 1981) and is transfered into milk (Am J. Hosp. Pharm. 31, 844 -854, 1974). Intravasal administration of 0.1 ml/kg of an 25 mg/mL solution (1%) was not irritant to arteries and veins (of rats?).

Pharmacokinetic investigation in humans revealed 100% protein-binding (90% to albumin), entero-hepatic circulation, high bioavailability after oral and rectal administration (about 100%), elimination after oral administration via urine (~ as conjugated parent drug (23% of total) and non-conjugated metabolites) and bile/feces (~40%), half-life time of 5 -10 hours, and maximum plasma concentration after ~2 hours. Metabolites in adults are desmethyl-, desbenzoyl- and desmethyl-desbenzoyl- Indomethacin.