OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

View in own window

DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Flurbiprofen	5104-49-4	C15-H13-F-O2

ANNOTATED BIBLIOGRAPHY

References updated: 25 January 2018

• Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-53.

  (Expert review of hepatotoxicity published in 1999; flurbiprofen is listed as having a very low incidence of hepatotoxicity which is typically hepatocellular).
• Lewis JH, Stine JG. Nonsteroidal anti-inflammatory drugs and leukotriene receptor antagonists: pathology and clinical presentation of hepatotoxicity. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd. Amsterdam: Elsevier, 2013, pp. 369-401.

  (Review of hepatotoxicity of NSAIDs mentions that only a single case of hepatotoxicity from flurbiprofen has been reported [Kotowski 1982]).
• Grosser T, Smyth E, FitzGerald GA. Anti-inflammatory, antipyretic, and analgesic agents; pharmacotherapy of gout. In, Brunton LL, Chabner B, Knollman B, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 959-1004.

  (Textbook of pharmacology and therapeutics).
• Kotowski KE, Grayson MF. Side effects of non-steroidal anti-inflammatory drugs. Br Med J (Clin Res Ed) 1982; 285 (6338): 377. [PMC free article: PMC1498992] [PubMed: 6807485]

  (56 year old woman with mixed connective tissue disease developed abdominal pain, fever, rash and jaundice 3 months after restarting flurbiprofen [bilirubin 1.3 mg/dL, AST >1200 U/L, Alk P 150 U/L], resolving within 7 weeks of stopping; authors mention two other cases reported by the manufacturer, one with jaundice and recurrence on rechallenge).
• Zimmerman HJ. Update of hepatotoxicity due to classes of drugs in common clinical use: non-steroid drugs, anti-inflammatory drugs, antibiotics, antihypertensives, and cardiac and psychotropic agents. Semin Liver Dis 1990; 10: 322-8. [PubMed: 2281340]

  (Extensive review of NSAID related liver injury states that flurbiprofen has only rarely been linked to liver injury).
• Ruiz-Rebollo ML, Delgado-Fontaneda E, Testillano-Tarrero M, Moretó-Canela M. [Cholestasis caused by hypersensitivity to flurbiprofen]. Rev Esp Enferm Dig 1992; 82: 130-1. Spanish. [PubMed: 1389551]

  (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).
• Walker AM. Quantitative studies of the risk of serious hepatic injury in persons using nonsteroidal antiinflammatory drugs. Arthritis Rheum 1997; 40: 201-8. [PubMed: 9041931]

  (Review of population based studies of NSAID use and hepatic injury; frequency of clinically apparent liver injury from NSAIDs overall was ~10 cases per 100,000 patient-years of use; flurbiprofen is not specifically discussed).
• Lacroix I, Lapeyre-Mestre M, Bagheri H, Pathak A, Montastruc JL; Club de Reflexion des cabinets de Groupe de Gastro-Enterologie (CREGG); General Practitioner Networks. Nonsteroidal anti-inflammatory drug-induced liver injury: a case-control study in primary care. Fundam Clin Pharmacol 2004; 18: 201-6. [PubMed: 15066135]

  (Case controlled study of patients presenting with suspected drug induced liver injury in a general practice context in Southern France found 88 cases which were matched with 178 controls; 22 cases vs 16 controls had been exposed to NSAIDs; 5 diclofenac, 4 ibuprofen, 4 ketoprofen, 2 niflumic acid, 1 flurbiprofen and 1 meloxicam, rest to salicylates which were as frequently used in controls as cases; there were no fatalities and cases were more common in women than men).
• Rubenstein JH, Laine L. Systematic review: the hepatotoxicity of non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther 2004; 20: 373-80. [PubMed: 15298630]

  (NSAIDs are the most commonly used drugs in the US and account for a large proportion of cases of hepatic injury, but the frequency is quite rare. Among 7 population based studies, hospitalization occurred in 22.4/100,000 patient-years of NSAID use [rate ratio=1.5] and deaths from liver injury occurred in ~1/100,000 patient-years; frequency of injury did not increase with age and was no more common in women than men; in case controlled studies, higher odds ratio for liver injury was found with sulindac, indomethacin, piroxicam and diclofenac; no mention of flurbiprofen).
• Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-1101. [PubMed: 16165719]

  (Survey of all cases of fatal drug induced liver injury from Swedish Adverse Drug Reporting system from 1966-2002; among 103 cases, none were attributed to flurbiprofen).
• 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: 16867024]

  (Analysis of reports of liver injury from NSAIDs from France and Spain from 1982-2001; flurbiprofen is not specifically mentioned).
• Arellano FM, Yood MU, Wentworth CE, Oliveria SA, Rivero E, Verman A, Rothman K. Use of cyclo-oxygenase 2 inhibitors (COX-2) and prescription non-steroidal anti-inflammatory drugs (NSAIDS) in UK and USA populations Implications for COX-2 cardiovascular profile. Pharmacoepidemiol Drug Saf 2006; 15: 861-72. [PubMed: 17086563]

  (Surveys from the UK and USA indicate that ibuprofen, naproxen and diclofenac were the most commonly used NSAIDs; flurbiprofen was not among the top 10 agents used).
• 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. [PMC free article: PMC3654244] [PubMed: 18955056]

  (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).
• Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol 2010; 16: 5651-61. [PMC free article: PMC2997980] [PubMed: 21128314]

  (Review of estimated frequency of drug induced liver injury due to NSAIDs from large published epidemiological studies; no discussion of flurbiprofen).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury and 7 to NSAIDs, including 4 to bromfenac, 2 diclofenac and 1 etodolac, but none to other NSAIDS including flurbiprofen, ibuprofen and naproxen).
• 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: 24381241]

  (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. [PMC free article: PMC3568201] [PubMed: 23325533]

  (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).
• Lapeyre-Mestre M, Grolleau S, Montastruc JL; Association 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: 21929527]

  (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).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, including 6 attributed to diclofenac (ranking 2nd), but none were due to flurbiprofen).
• Dağ MS, Aydınlı M, Oztürk ZA, Türkbeyler IH, Koruk I, Savaş MC, Koruk M, et al. Drug- and herb-induced liver injury: a case series from a single center. Turk J Gastroenterol 2014; 25: 41-5. [PubMed: 24918129]

  (Among 82 cases of drug or herbal product induced liver injury seen at a single referral center in Turkey between 2008 and 2012, NSAIDs were the most common class of agents implicated, accounting for 19 cases [23%] of which 7 were due to flubroprofen, one of which resulted in acute liver failure).
• 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. [PMC free article: PMC4446235] [PubMed: 25754159]

  (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).
• Schmeltzer PA, Kosinski AS, Kleiner DE, Hoofnagle JH, Stolz A, Fontana RJ, Russo MW; Drug-Induced Liver Injury Network (DILIN). Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int 2016; 36: 603-9. [PMC free article: PMC5035108] [PubMed: 26601797]

  (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 [3], meloxicam [3], etodolac [2], oxaprozin [2], ibuprofen [2] and sulindac [1], while none were attributed to flurbiprofen).