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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: March 20, 2020.



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 Rofecoxib was withdrawn in 2004 because of an association with an increase in cardiovascular events with its long term use.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use of rofecoxib was associated with an increased rate of cardiovascular and cerebrovascular events, and the drug was withdrawn in September 2004.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. As with other NSAIDs, rofecoxib is generally well tolerated, but side effects can include headache, dizziness, somnolence, dyspepsia, abdominal discomfort, diarrhea, peripheral edema and hypersensitivity reactions. Rare but serious adverse events from NSAIDs include gastrointestinal ulceration and bleeding, increased risk for cardiovascular disease, renal dysfunction and hypersensitivity reactions including anaphylaxis, exfoliative dermatitis and Stevens Johnson syndrome.


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.

Drug Class: Nonsteroidal Antiinflammatory Drugs


Case 1. Acute hepatocellular injury with jaundice due to rofecoxib.(1).

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.

Key Points

Medication:Rofecoxib (25 mg daily)
Pattern:Mixed-cholestatic (R=2.4)
Severity:3+ (jaundice and hospitalization)
Latency:22 months
Recovery:Nearly complete within 3 months
Other medications:Levothyroxine, prednisone, multivitamins

Laboratory Values

Weeks After
Alk P
02393145.6Rofecoxib stopped
28921712.2ERCP normal
4Liver biopsy showing intrahepatic cholestasis
Normal <40 <125 <1.2


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.



Rofecoxib – Vioxx®

(Removed from Market Worldwide, 2004)


Nonsteroidal Antiinflammatory Drugs


Rofecoxib 162011-90-7 C17-H14-O4-S image 135021465 in the ncbi pubchem database


Papachristou GI, Demetris AJ, Rabinovitz M. Acute cholestatic hepatitis associated with long-term use of rofecoxib. Dig Dis Sci. 2004;49:459–61. [PubMed: 15139498]


References updated: 20 March 2020

Abbreviations: NSAID, nonsteroidal antiinflammatory drugs.

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    (Expert review of NSAID induced liver injury from 1999; rofecoxib was not discussed).
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  • Grossner T, Smyth EM, Fitzgerald GA. Pharmacotherapy of inflammation, fever, pain, and gout. In, Brunton LL, Hilal-Dandan R, Knollman BC. Goodman & Gilman’s The pharmacological basis of therapeutics, 13th ed. New York: McGraw-Hill, 2018. pp. 685-709.
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    (52 year old woman developed jaundice and itching 3 months after starting rofecoxib [bilirubin 24.6 mg/dL, ALT 228 U/L, Alk P 1314 U/L], with prolonged jaundice treated with an extracorporeal liver assist device and ultimately resolving 6 months later).
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  • Papachristou GI, Demetris AJ, Rabinovitz M. Acute cholestatic hepatitis associated with long-term use of rofecoxib. Dig Dis Sci. 2004;49:459–61. [PubMed: 15139498]
    (76 year old woman developed jaundice and pruritus 22 months after starting rofecoxib [bilirubin 5.6 rising to 12.2 mg/dL, ALT 239 U/L, Alk P 314 U/L], with resolution over next 2-3 months: Case 1).
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    (69 year old woman developed fatigue 3 days after starting rofecoxib and stopped it promptly, but developed jaundice 1 month later [bilirubin 18.1 mg/dL, ALT 42 times ULN, Alk P 4 times ULN], with severe course and slow recovery over 6 months).
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    (62 year old man developed jaundice and itching 5 months after starting rofecoxib [bilirubin 14.0 rising to 29.8 mg/dL, AST 21 U/L, Alk P 218 U/L], with acute interstitial nephritis, ultimately resolving over next 3 months).
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    (Two cases: 44 year old man developed jaundice 2 weeks after restarting rofecoxib [bilirubin 14.1 mg/dL, ALT 1826 U/L, Alk P 741 U/L], resolving in 2 months; 44 year old woman developed jaundice and itching 6 weeks after starting rofecoxib [bilirubin 12.1 mg/dL, ALT 995 U/L, Alk P 243 U/L], resolving in 1-2 months).
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    (Compared rates of spontaneous reporting of adverse effects of NSAIDs in Spain and France, found high rate of liver reports [compared to all types] for sulindac [14%] and nimesulide [17%], low for celecoxib [2% of 275 reports] and rofecoxib [0.6% of 499 reports]: 3 cases of liver injury attributed to rofecoxib from Spain and 6 from France 1982-2001).
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    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, NSAIDs were implicated as a sole agent in 8 cases and as one of several agents in 3 cases, but none were attributed to rofecoxib).
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    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, 62 of which were attributed to NSAIDs but mostly to nimesulide and a few to piroxicam, diclofenac and naproxen, but none to rofecoxib).
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