Ketoprofen is a nonsteroidal antiinflammatory drug (NSAID) used in treatment of acute pain and chronic arthritis. Ketoprofen has been linked to a low rate of serum enzyme elevations during therapy and to rare instances of clinically apparent acute liver injury.
Ketoprofen (kee” toe proe’ fen) belongs to the propionic derivative class of NSAIDs similar to naproxen and ibuprofen. Like other NSAIDs, ketoprofen is a cyclo-oxygenase (Cox-1 and -2) inhibitor that blocks the formation of prostaglandins that are important in pain and inflammatory pathways. Ketoprofen has analgesic as well as antipyretic and anti-inflammatory activities. Ketoprofen was approved in the United States in 1986 and is still widely used. Current indications include chronic joint pain due to osteoarthritis and rheumatoid arthritis as well as mild-to-moderate acute pain and dysmenorrhea. The recommended dose in adults with chronic arthritis is 50 to 75 mg 3 or 4 times per day with a maximum dose of 300 mg daily. Ketoprofen is available by prescription in the form of capsules or tablets of 25, 50 and 75 mg in both generic and trade formulations (Orudis, Oruvail, among others). Extended-release formulations of 100, 150 and 200 mg are also available for once-daily dosing. Ketoprofen is also available in over-the-counter formulations of 12.5 mg tablets for the treatment of mild-to-moderate pain and dysmenorrhea. As with other NSAIDs, ketoprofen is generally well tolerated, but side effects can include headache, dizziness, somnolence, gastrointestinal upset, nausea, abdominal discomfort, diarrhea, peripheral edema, and hypersensitivity reactions.
Prospective studies show that 1% to 2% of patients taking ketoprofen to experience at least transient serum aminotransferase elevations. These may resolve even with drug continuation. Marked aminotransferase elevations (>3 fold elevated) occur in <1% of patients. Clinically apparent liver injury with jaundice from ketoprofen is very rare and only individual case reports have been published. The latency to onset has been rapid, often within a few days of starting. The pattern of enzyme elevations has ranged from cholestatic to hepatocellular. Immunoallergic features are present in some cases (low-grade fever, rash), but are generally not prominent, and autoantibody formation is rare. Most cases resolve promptly on stopping therapy. Ketoprofen is not mentioned in large case series on drug-induced liver injury or acute liver failure.
Likelihood score: C (probable rare cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of ketoprofen hepatotoxicity is not known, but likely to be due to an idiosyncratic reaction to an intermediate of its metabolism. Ketoprofen is extensively metabolized by the liver.
Outcome and Management
Severity ranges from asymptomatic elevations in serum aminotransferase levels, to symptomatic hepatitis with or without jaundice. A single case of fulminant hepatitis possibly due to ketoprofen has been reported, but death appeared to be due to complications of pancreatitis and renal insufficiency. Patients with ketoprofen induced liver injury should avoid other propionic acid derivatives such as naproxen and ibuprofen.
Drug Class: Nonsteroidal Antiinflammatory Drug
Case 1. Acute hepatocellular injury and jaundice arising within a few days of starting ketoprofen.
[Modified from Bonaventure C, Nancey S, Pont E, Michalet V, Chevalier M, Vial T, Taieb S, et al. [Ketoprofen-induced acute hepatitis]. Gastroenterol Clin Biol 2001; 25: 716-7. French
A 23-year-old woman developed abdominal pain and nausea 2 days and jaundice 4 days after starting ketoprofen for low back pain. She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. Her only other medication was birth control pills. Physical examination was normal except for jaundice; there was no fever, rash or hepatomegaly. Laboratory tests showed serum bilirubin of 2.9 mg/dL with marked elevations in serum aminotransferase levels (ALT~30 times ULN, AST~14 times ULN) and normal alkaline phosphatase (Table). There was no eosinophilia. Tests for hepatitis A, B, C, and E were negative as were autoantibodies. A liver biopsy showed hepatic necrosis and inflammation, mild cholestasis and prominence of eosinophils in portal areas. Stopping ketoprofen was followed by rapid improvement. She remained on birth control pills.
|Medication:||Ketoprofen (200 mg extended release once daily for 4 days)|
|Severity:||3+ (jaundice, hospitalization)|
|Latency:||2 days to symptoms, 4 days to jaundice|
|Recovery:||Complete recovery 2 months after stopping|
|Other medications:||Combination estrogen and progesterone birth control pill|
|Time After Starting||Time After Stopping||ALT* (U/L)||Alk P (U/L)||Bilirubin* (mg/dL)||Other|
|0||Ketoprofen given for low back pain|
|4 days||0||1260||Normal||3.2||Ketoprofen stopped|
|8 days||4 days||1218||5.6|
|12 days||8 days||1134||7.7||Liver biopsy|
|24 days||3 weeks||378||5.4||Discharged|
|10 weeks||10 weeks||40||Normal||0.5|
|Normal Values||< 42||< 1.2|