Indomethacin is a potent nonsteroidal anti-inflammatory drug (NSAID) typically used for chronic inflammatory arthritis. Indomethacin has been associated with rare cases of idiosyncratic drug-induced liver disease.
Indomethacin (in" doe meth' a sin) is a methylated indole and belongs to the acetic acid derivative class of NSAIDs. Like other NSAIDs, indomethacin has anti-pyretic, analgesic and anti-inflammatory activities. The NSAIDs owe their therapeutic effects to the inhibition of intracellular cyclooxygenases (Cox-1 and Cox-2) resulting in decrease in synthesis of prostaglandins which are potent mediators of pain and inflammation. Indomethacin was approved for use in the United States in 1965 and it continues to be widely used, with more than 2.5 million prescriptions filled yearly. Indomethacin is indicated for management of various forms of chronic arthritis, including osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and gouty arthritis, as well as acute shoulder pain and dysmenorrhea. Intravenous formulations of indomethacin are approved for the special indication of closure of patent ductus arteriosis in premature infants. Indomethacin is available by prescription as capsules of 25, 50 and 75 mg, in sustained release forms, as suppositories and as suspensions for oral use, in multiple generic forms as well as under several commercial names, including Indocin, Indochron, Indolar, Indo-Lemmon and Zendole. The recommended dosage in adults with chronic arthritis is 25 to 50 mg taken orally two to three times daily, increasing the dose until the symptoms are controlled or a maximum dose of 200 mg is reached. Injectible formulations of indomethacin are available in single dose 1 mg vials for intravenous use in premature infants with patent ducutus arteriosis. Non-hepatic side effects of indomethacin include headache, dizziness, somnolence, dyspepsia, abdominal discomfort, diarrhea, peripheral edema and hypersensitivity reactions.
Mild and transient elevations in serum aminotransferase levels are found in up to 15% of patients taking indomethacin chronically. Moderate ALT elevations (>3 times ULN) occur in less than 1% of patients. Frank liver injury with jaundice from indomethacin is rare (estimated at 1.1 per 100,000 prescriptions), and fewer than a dozen cases have been reported in the literature. The latency to onset of symptoms or jaundice is variable, but is usually within 1 to 8 weeks of starting, although instances of latency of 4 to 6 months have been reported. Patients present with anorexia, nausea and vomiting followed by jaundice. Hepatocellular patterns of enzyme elevations are most common, but cholestatic and mixed patterns have been reported. Allergic manifestations and autoimmune features are not common. The injury is usually self-limited, resolving in 1 to 3 months, but several fatal cases have been reported (Case 1), particularly after use of high doses in patients with juvenile rheumatoid arthritis or Still disease. Many of the reported cases of severe indomethacin associated hepatotoxicity have occurred in patients with a pre-existing, underlying chronic liver disease.
Mechanism of Injury
The mechanism by which indomethacin induces liver injury is not known, but is likely to be mediated by a toxic intermediate of its metabolism.
Severity and Recovery
Drug-induced liver injury from indomethacin is usually mild-to-moderate in severity and transient, but can progress to acute liver failure and death. In large case series, indomethacin is rarely mentioned as a cause of acute liver failure. Rechallenge may lead to recurrence and should be avoided. Cross-sensitivity to hepatic injury among the various NSAIDs has not been well defined. After clinically apparent hepatic injury from indomethacin, acetic acid related NSAIDs (sulindac, diclofenac, etodolac, tolmetin among others) might best be avoided, and those belonging to other classes administered with caution.
Case 1. Acute liver failure attributed to indomethacin therapy.
[Modified from: de Kraker-Sangster M, Bronkhorst FB, Brandt KH, Boersma JW. [Massive liver cell necrosis following administration of indomethacin in combination with aminophenzone] Ned Tijdschr Geneeskd 1981; 125: 1828-31. Dutch. PubMed Citation
A 40 year old man developed jaundice and dark urine two months after starting indomethacin for adult Still disease. The patient was known to have splenomegaly and alkaline phosphatase and GGT elevations with minimal elevations in aminotransferase levels and normal direct and total bilirubin before therapy (Table). A liver biopsy showed non-specific changes and activation of macrophages, findings that were attributed to his adult Still disease. He was initially treated with aminopyrine (1.5 g/day) and 6 weeks later indomethacin (100 mg/day) was added. On admission, 8 weeks after starting indomethacin, he had jaundice and prominent hepatomegaly. Serum aminotransferase levels and bilirubin were markedly elevated while alkaline phosphatase and GGT were less than pre-treatment values. He had no fever or rash and eosinophil counts were normal. Despite stopping both indomethacin and aminopyrine promptly, jaundice deepened, and he developed hepatic encephalopathy, gastrointestinal bleeding and multi-organ failure, and died two weeks after admission. Autopsy showed hepatosplenomegaly and portal hypertension with superimposed massive hepatic necrosis. The biliary tree was normal without obstruction.
|Medication:|| Indomethacin (100 mg daily)|
|Pattern:|| Hepatocellular (R=9.5)|
|| 5+ (Death from acute liver failure)
|| 2 Months
|| Aminopyrine (aminophenazone) 1.5 g/day for 3.5 months.
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Indomethacin started (100 mg/day)
||Death from multi-organ failure
A striking instance of acute liver failure arising two months after initiation of indomethacin therapy. An important feature was that the patient had an underlying liver disease before starting indomethacin, which was attributed to non-specific effects of Still disease. Thus, the clinical phenotype is more similar to "acute-on-chronic" hepatic injury. In retrospect, the patient may have had nodular regenerative hyperplasia which would account for the hepatosplenomegaly and minor aminotransferase and more marked alkaline phosphatase elevations. As such, the patient would be more susceptible to a poor outcome from acute hepatocellular injury due to a medication. Another factor complicating the interpretation was use of aminopyrine (also called aminophenazone), another anti-inflammatory NSAID which has been abandoned because of toxicity (renal and gastric). Causality assessment would probably designate this case as "possible" or at most "probable" indomethacin-induced hepatic injury.
Case 2. Acute hepatitis due to indomethacin therapy.
[Modified from: López Navidad A, Cadafalch Arpa J, Vehi Gasol C, Espinos Pérez J. [Acute hepatitis caused by indomethacin] Rev Esp Enferm Apar Dig 1987; 71: 358-9. Spanish. PubMed Citation]
A 55 year old man developed weakness, anorexia and abdominal pain followed by dark urine and jaundice and dark urine 3 weeks after starting indomethacin (125 mg daily) for painful heel spurs. A week after initial symptoms, blood tests showed an acute hepatitis and indomethacin was stopped. He had no history of liver disease, adverse drug reactions, alcohol abuse or risk factors for viral hepatitis. He was taking no other medications. He continued to worsen over the next several weeks and has admitted for evaluation. On examination he was deeply jaundiced with generalized pruritus and tender hepatomegaly but no rash, fever, or other signs of chronic liver disease or hepatic failure. Laboratory testing showed marked elevation in serum bilirubin and a hepatocellular pattern of serum enzyme elevations with prolongation of the prothrombin time (Table). Tests for hepatitis A and B were negative as was serology of Ebstein-Barr virus and cytomegalovirus infection. Abdominal ultrasound showed no evidence of biliary obstruction. Liver biopsy was refused. With routine medical management, he improved rapidly. When seen in follow up 4 months later he was asymptomatic and liver tests were normal.
|Medication:||Indomethacin (125 mg daily)|
|Severity: ||4+ (Jaundice, hospitalization, coagulopathy)|
|Latency: || 3 weeks|
|Recovery:|| 4 months|
|Other medications:|| None|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
|| Bilirubin (mg/dL)
This patient developed a moderately-severe acute hepatitis starting 3 weeks after initiation of indomethacin therapy. Other causes of liver injury were adequately excluded, although tests for hepatitis C and E were not available at the time (1985). The pattern of enzyme elevations was distinctly hepatocellular even though cholestasis was present with deep jaundice and pruritus.
REPRESENTATIVE TRADE NAMES
Indocin®, Various Generic
Anti-Inflammatory Agents, Non-Steroidal
FDA product labeling at DailyMed, National Library of Medicine, NIH
Indocin® (indomethacin) Product Labeling, Merck & Co.
||CAS REGISTRY NO
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