Rofecoxib is a nonsteroidal antiinflammatory drug (NSAID) that selectively inhibits cyclooxgenase-2 (Cox-2), which was used in the therapy of chronic arthritis and mild-to-moderate musculoskeletal pain. Rofecoxib was withdrawn in 2004 because of an association with an increase in cardiovascular events with its long term use. Rofecoxib had also been linked transient serum aminotransferase elevations during therapy and to rare instances of idiosyncratic drug induced liver disease.
Rofecoxib (roe" fe kox' ib) is a nonsteroidal antiinflammatory drug that acts through selective inhibition of cyclooxgenase-2 resulting in decreased prostaglandin synthesis and thereby decreasing inflammation, fever and pain. The specificity for Cox-2 is believed to make rofecoxib less likely to cause gastrointestinal mucosal injury compared to standard NSAIDs that inhibit both Cox-1 and Cox-2 enzymes. Rofecoxib was approved for use as therapy of chronic arthritis due to osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, as well as for acute pain from musculoskeletal conditions and trauma and for primary dysmenorrheal in 1998. Subsequently, large scale prospective studies suggested that use of rofecoxib was associated with an increased rate of cardiovascular and cerebrovascular events, and the drug was withdrawn in September 2004. Rofecoxib was previously available by prescription as capsules of 12.5 and 25 mg under the commercial name Vioxx and was given in several week courses for acute pain or trauma and long term for chronic arthritis. The typically recommended dose was 12.5 to 25 mg once daily.
In clinical studies involving several thousand patients treated for at least 3 months, the rate of serum aminotransferase enzyme elevations above three times the upper limit of the normal range was 1.8% in rofecoxib treated compared to 0.3% in placebo treated patients and 0.1-0.4% in patients receiving other common NSAIDs. Thus, ALT elevations due to rofecoxib were uncommon and usually of minimal clinical significance, resolving even with drug continuation.
In rare instances, rofecoxib can cause clinically apparent, symptomatic drug induced liver injury with jaundice. The pattern of liver enzyme elevations has usually been cholestatic or mixed (Case 1), although hepatocellular patterns of injury have also been described. The latency to onset of liver injury was extremely variable, ranging from a few weeks to several years, but was typically within 1 to 12 weeks of starting. Autoimmune and immunoallergic features were uncommon.
Likelihood score: C (probable rare cause of clinically apparent liver injury).
Mechanism of Injury
The cause of acute hepatic injury from rofecoxib is unknown. The clinical pattern of injury resembles that of other NSAID induced liver injury.
Outcome and Management
The idiosyncratic liver injury due to rofecoxib can lead to prolonged jaundice, but has not been associated with acute liver failure or vanishing bile duct syndrome. In the few cases that have been described, the time to recovery has varied greatly, but is usually 1 to 3 months. Rechallenge should be avoided, but there is little information to suggest that there is cross reactivity with other NSAIDs.
Case 1. Acute hepatocellular injury with jaundice due to rofecoxib.
[Modified from: Papachristou GI, Demetris AJ, Rabinovitz M. Acute cholestatic hepatitis associated with long-term use of rofecoxib. Dig Dis Sci 2004; 49: 459-61. PubMed Citation]
A 76 year old woman developed jaundice and pruritus 22 months after starting rofecoxib (25 mg daily) for osteoarthritis. She had no history of liver disease, alcohol abuse, drug allergies or risk factors for viral hepatitis. Her other medical condition included polymyalgia rheumatica for which she took prednisone (3 mg daily) and hypothyroidism for which she took levothyroxine (72 mcg daily). She took multivitamins, but no other over-the-counter or herbal medications. On examination, she was jaundiced and had mild hepatic tenderness, but no fever, rash, lymphadenopathy or signs of chronic liver disease. She was admitted for evaluation and rofecoxib was discontinued. Laboratory tests showed a total bilirubin of 5.6 mg/dL with a direct fraction of 5.2 mg/dL and modest elevations in aminotransferase and alkaline phosphatase levels (Table). Tests for viral hepatitis and autoimmune liver disease were negative. Imaging of the abdomen and liver were normal without evidence of biliary obstruction. Her jaundice and pruritus worsened. Magnetic resonance and endoscopic retrograde cholangiopancreatography (ERCP) were done and were normal. A liver biopsy showed intrahepatic cholestasis and mild bile duct damage with mild portal inflammation compatible with a drug induced cholestatic hepatitis. Subsequently, she improved and she was asymptomatic and liver tests were near normal when she was seen approximately 3 months after presentation.
|Medication:||Rofecoxib (25 mg daily)|
|| Mixed-cholestatic (R=2.4)|
||3+ (jaundice and hospitalization)
|Recovery:||Nearly complete within 3 months|
|Other medications:||Levothyroxine, prednisone, multivitamins|
|Weeks After Stopping
||Liver biopsy showing intrahepatic cholestasis
The history and presentation of this case were very typical of a drug induced cholestatic hepatitis and the only medication that could be implicated was rofecoxib which had been taken for 22 months. The latency to onset is atypical, however, but careful evaluation for other causes of obstructive jaundice was unrevealing, and she recovered with stopping the medication. Information of cross sensitivity to other NSAIDs would have been helpful.
REPRESENTATIVE TRADE NAMES
Rofecoxib – Vioxx®
(Removed from Market Worldwide, 2004)
Nonsteroidal Antiinflammatory Drugs
Product labeling at DailyMed, National Library of Medicine, NIH
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||CAS REGISTRY NUMBER
References updated: 06 June 2018
Abbreviations: NSAID, nonsteroidal antinflammatory drugs.
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