Flurbiprofen is a nonsteroidal antiinflammatory drug (NSAID) used in treatment of mild-to-moderate pain and symptoms of chronic arthritis. Flurbiprofen has been linked to a low rate of serum enzyme elevations during therapy and to rare instances of clinically apparent acute liver injury.
Flurbiprofen (flur" bi proe' fen) belongs to the propionic acid derivative class of NSAIDs, similar to fenoprofen, naproxen and ibuprofen. Like other NSAIDs, flurbiprofen is a cyclo-oxygenase (Cox-1 and -2) inhibitor that blocks the formation of prostaglandins that are important in pain and inflammatory pathways. Flurbiprofen has analgesic as well as antipyretic and antiinflammatory activities. Flurbiprofen was approved in the United States in 1988. Current indications include chronic joint pain due to osteoarthritis and rheumatoid arthritis, as well as mild-to-moderate acute pain. The recommended dose in adults with chronic arthritis is 50 to 100 mg two to four times daily, with a maximum dose of 300 mg daily. Flurbiprofen is available by prescription in the form of capsules or tablets of 50 and 100 mg in both generic and trade formulations (Ansaid). As with other NSAIDs, flurbiprofen is generally well tolerated, but side effects can include headache, dizziness, somnolence, gastrointestinal upset, nausea, abdominal discomfort, diarrhea, edema and hypersensitivity reactions.
Prospective studies show that mild elevations in serum aminotransferase levels can occur in up to 15% of patients taking flurbiprofen, but these are generally transient, mild and asymptomatic, often resolving even with drug continuation. Marked aminotransferase elevations (>3 fold elevated) occur in <1% of patients. Clinically apparent liver injury with jaundice from flurbiprofen is rare and only individual case descriptions have been published. The latency to onset is within 1 to 4 weeks of starting. The pattern of enzyme elevations is typically cholestatic, but hepatocellular cases have been described. 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. Flurbiprofen is not mentioned in large case series on drug induced liver injury or acute liver failure from the United States, but was listed as the second most common agent implicated in drug-induced liver injury in a case series from Turkey, one of which was fatal.
Likelihood score: C (probable rare cause of clinically apparent liver injury).
Mechanism of Injury
The mechanism of flurbiprofen hepatotoxicity is not known, but likely to be due to an idiosyncratic hypersensitivity reaction to an intermediate of its metabolism. Flurbiprofen is extensively metabolized by the liver, largely through the cytochrome P450 pathway (CYP 2C9).
Outcome and Management
Severity ranges from asymptomatic elevations in serum aminotransferase levels, to symptomatic hepatitis with or without jaundice, to acute liver failure and death. There are no convincing cases of chronic hepatitis or vanishing bile duct syndrome attributable to flurbiprofen use in the published literature. Patients with clinically apparent flurbiprofen induced liver injury should avoid other propionic acid derivatives such as fenoprofen, ibuprofen, ketoprofen and naproxen.
Case 1. Cholestatic hepatitis due to flurbiprofen.
[Modified from: Dogan S, Celikbilek M, Demirkan K, Yilmaz S, Deniz K, Gursoy S, Yucesoy M. Prolonged Cholestatic Jaundice Associated With Flurbiprofen. J Pharm Pract 2013; 27: 396-398. PubMed Citation]
A 28 year old man developed pruritus and jaundice 3 to 4 weeks after starting flurbiprofen (100 mg twice daily) for posttraumatic muscle and joint pains. He denied rash, fever and abdominal pain. He had no previous history of liver disease, alcohol abuse or risk factors for viral hepatitis. He took no other medications or herbal supplements and had no history of drug allergies. On presentation, he was jaundiced, but had no hepatic tenderness, organomegaly or signs of chronic liver disease. Laboratory testing showed a total bilirubin of 18.4 mg/dL (direct 10.0 mg/dL), ALT 75 U/L, AST 68 U/L, GGT 480 U/L and alkaline phosphatase 574 U/L (Table). A complete blood count, INR and albumin levels were normal. Tests for hepatitis A, B, C and E were negative as were autoantibodies. Abdominal ultrasound was normal and without evidence of biliary obstruction, which was verified by magnetic resonance cholangiopancreatography (MRCP). Flurbiprofen was stopped, but his liver tests worsened over the following week. A liver biopsy showed intrahepatic cholestasis without fibrosis, steatosis or features of extrahepatic obstruction. He was treated with prednisolone, ursodiol and cholestyramine and began to improve. These agents were tapered and eventually stopped, but his liver tests remained abnormal until 6 months after stopping flurbiprofen.
||Flurbiprofen (200 mg daily for ~1 month)
|| Cholestatic (R=0.5)
|| 3+ (jaundice, hospitalization)
|| 3 to 4 weeks
|| Complete recovery 6 months after stopping
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Flurbiprofen (200 mg daily) started for joint pain
| 7 months
| Normal Values
This was a convincing case of cholestatic hepatitis arising a month after starting flurbiprofen. No other medications were being taken, and clinical evaluation including MRCP identified no other cause of acute cholestatic jaundice. The course was moderately severe and protracted, but recovery was eventually complete. Clinically apparent liver injury from NSAIDs varies greatly in clinical features and outcomes. Some agents are associated with hepatocellular injury that can be severe (diclofenac, etodolac) and others with cholestatic hepatitis (meloxicam, celecoxib), and some agents with a long latency and autoimmune features (diclofenac, etodolac) and others with a short latency and immunoallergic features (oxaprozin, celecoxib). The NSAIDs are some of the most frequently taken medications worldwide, and hepatotoxicity from their use is clearly quite rare and generally only mild-to-moderate in severity and self-limited in course.
REPRESENTATIVE TRADE NAMES
Flurbiprofen – Generic, Ansaid®
Nonsteroidal Antiinflammatory Drugs
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 25 January 2018
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Moretó-Canela M. [Cholestasis caused by hypersensitivity to flurbiprofen]. Rev Esp Enferm Dig 1992; 82: 130-1. Spanish. PubMed Citation (63 year old woman developed fatigue, fever and rash within a day of starting flurbiprofen and subsequently developed jaundice 20 days later [bilirubin 14.6 mg/dL, ALT 86 U/L, Alk P 478 U/L], resolving rapidly upon stopping).
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Lapeyre-Mestre M, de Castro AM, Bareille MP, Garcia del Pozo J, Requejo AA, Arias LM, Montastruc J-L, et al. Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems. Fundam Clin Pharmacol 2006; 20: 391-5. PubMed Citation (Analysis of reports of liver injury from NSAIDs from France and Spain from 1982-2001; flurbiprofen is not specifically mentioned).
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Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (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 [4 diclofenac, 2 celecoxib, 1 meloxicam and 1 oxaprozin] and as one of several agents in 3 cases [1 diclofenac, 1 celecoxib, 1 ibuprofen]; none were attributed to flurbiprofen).
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Dogan S, Celikbilek M, Demirkan K, Yilmaz S, Deniz K, Gursoy S, Yucesoy M. Prolonged Cholestatic Jaundice Associated With Flurbiprofen. J Pharm Pract 2013; 27: 396-8. PubMed Citation (28 year old man developed pruritus and jaundice 1 month after starting flurbiprofen [bilirubin 18.4 mg/dL, ALT 75 U/L, Alk P 574 U/L], resolving slowly over the 6 months after stopping: Case 1).
Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R,
Jové J, Gatta A, et al. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study. Drug Saf 2013; 36: 135-44. PubMed Citation (Among 600 patients undergoing liver transplantation for acute liver failure at 52 European liver transplant centers between 2005 and 2007, 301 were considered idiopathic and had received a medication within 30 days of onset, including acetaminophen in 192 and NSAIDs in 40, but no specific mention of flurbiprofen).
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Française des Centres Régionaux de Pharmacovigilance (CRPV). Adverse drug reactions associated with the use of NSAIDs: a case/noncase analysis of spontaneous reports from the French pharmacovigilance database 2002-2006. Fundam Clin Pharmacol 2013; 27: 223-30. PubMed Citation (Analysis of serious adverse events reporting to a French pharmacovigilance database found highest cumulative rates for liver related reports for nimesulide [0.15 per million defined daily doses], followed by diclofenac [0.09], ketoprofen [0.09], piroxicam [0.06], naproxen [0.04] and meloxicam [0.03] being significant in case/non-case analyses for nimesulide, diclofenac and piroxicam only; no mention of flurbiprofen).
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implicated, accounting for 19 cases [23%] of which 7 were due to flubroprofen,
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Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 28 cases were attributed to an NSAID including 15 to diclofenac, 3 celecoxib, 3 meloxicam, 2 oxaprozin, 2 etodolac, and 1 each for ibuprofen, sulindac and valdecoxib, but none for flurbiprofen or fenoprofen).
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nonsteroidal anti-inflammatory drugs in the United States. Liver Int 2016; 36:
603-9. PubMed Citation (Among 1231 cases of suspected drug induced liver
injury enrolled in a prospective study in the US between 2004 and
2014, 30 [2%] were considered due to an NSAID, including diclofenac [n=16],
celecoxib , meloxicam , etodolac , oxaprozin , ibuprofen  and
sulindac , while none were attributed to flurbiprofen).
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