OVERVIEW

CASE REPORTS

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Ketoprofen	22071-15-4	C16-H14-O3

ANNOTATED BIBLIOGRAPHY

References updated: 25 April 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; ketoprofen is listed as having a very low rate of hepatic injury).
• 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.

  a few cases of hepatotoxicity from ketoprofen have been reported).
• 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).
• Wollheim FA, Lindroth Y, Sjoblom KG. A comparison of ketoprofen and naproxen in rheumatoid arthritis. Rheumatol Rehabil 1978; Suppl: 78-83. [PubMed: 364615]

  (Double-blind, cross over study of 4 week courses using different doses of ketoprofen vs naproxen in 30 patients with rheumatoid arthritis; common side effects were abdominal pain, dyspepsia, nausea, headache and pruritus; but "no abnormalities were found in... liver function tests").
• Gross W. Long-term studies on therapy and tolerance of ketoprofen. Rheumatol Rehabil 1978: Suppl: 112-3. [PubMed: 441625]

  (Among 33 patients given ketoprofen and 32 given indomethacin for 5 months, analgesic effect was good with both and there were "no significant differences... on the parameters of liver or renal function").
• Llorca G, Larbre JP, Collet Ph, Ravault A, Lejeune E. Changing the class of NSAID in cases of hepatotoxicity. Ann Rheum Dis 1988; 47: 791. [PMC free article: PMC1003601] [PubMed: 3178321]

  (44 year old man with ankylosing spondylitis developed mild Alk P elevations [144 U/L] and eosinophilia [9%] 2 months after starting diclofenac with normal ALT [9 U/L] and bilirubin [0.4 mg/dL]; abnormalities resolved rapidly on stopping diclofenac and did not reappear after switching to ketoprofen).
• 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 ketoprofen appears "not to have been incriminated in hepatic disease").
• Rambaud S, Nores JM, Rémy JM. [Jaundice related to the ingestion of ketoprofen] Ann Med Interne (Paris) 1990; 141: 278. French. [PubMed: 2369020]

  (49 year old man developed symptoms after 2 and jaundice after 4 days of ketoprofen therapy [bilirubin 3.6 mg/dL, ALT 82 U/L, Alk P 186 U/L], resolving within 5 weeks of stopping: Case 2).
• Nores JM, Rambaud S, Remy JM. Acute hepatitis due to ketoprofen. Clin Rheumatol 1991; 10: 215-6. [PubMed: 1914425]

  (Same case as in Rambaud [1990], but in English).
• Dutertre J-P, Bastides F, Jonville A-P, De Muret A, Sonneville A, Larrey D, Autret E. Microvesicular steatosis after ketoprofen administration. Eur J Gastroenterol Hepatol 1991; 3: 953-4. Not in PubMed.

  (47 year old man with rheumatoid arthritis developed abnormal Alk P [159 U/L] and GGT [145 U/L] without symptoms 2 weeks after starting ketoprofen that persisted and rose until ketoprofen was stopped 1 month later, resolving in 2 months; liver biopsy showed microvesicular steatosis).
• 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; ketoprofen reported in one study as 17 per 100,000 [2 cases among 14,457 person-years of risk]).
• Flamenbaum M, Abergel A, Marcato N, Zénut M, Kémény JL, Cassan P. [Regressive fulminant hepatitis, acute pancreatitis and renal insufficiency after taking ketoprofen]. Gastroenterol Clin Biol 1998; 22: 975-6. [PubMed: 9881281]

  (73 year old man developed vomiting and abdominal pain after 2 days and jaundice after 5 days of starting rectal ketoprofen [bilirubin 29.4 mg/dL, ALT 148 U/L, Alk P 1430 U/L], resolving upon stopping; patient also had pancreatitis and renal insufficiency; mental confusion was attributed to hepatic encephalopathy).
• 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. [PubMed: 11673741]

  (23 year old woman developed nausea after 2 days and jaundice after 4 days of ketoprofen therapy [bilirubin 2.9 mg/dL, ALT 30 times ULN, Alk P normal], resolving within 2 months of stopping: Case 1).
• Mété D, Milon A, Belon G, Gatina JH. [Acute pancreatitis and ketoprofen] Gastroenterol Clin Biol 2001; 25: 721-2. French. [PubMed: 11673744]

  (35 year old man developed pancreatitis without jaundice or liver tests abnormalities 2 months after starting ketoprofen [lipase 1255 U/L], with no other cause identified and normal endoscopic retrograde cholangiopancreatography).
• 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 ketoprofen).
• 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 ketoprofen).
• 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; ketoprofen listed as associated with 4 of 2114 [0.2%] hepatic reactions from Spain and 429 of 27,372 [1.5%] from France; details of injury not given).
• 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; ketoprofen not in top 10 agents used).
• Zabala S, Calpe MJ, Pérez G, Lerín FJ, Mouronval L. Neutropenia, thrombocytopenia and hepatic injury associated with dexketoprofen trometamol therapy in a previously healthy 35-year-old woman. J Clin Pharm Ther 2008; 33: 79-81. [PubMed: 18211621]

  (35 year old woman developed fever 5 days after starting dexketoprofen [active enantiomer of racemic ketoprofen, available in UK] and stopped at ten days [bilirubin 0.5 mg/dL, ALT 216 U/L, Alk P 105 U/L], with low platelet [94,000/μL] and white cell counts [1,600/μL] and resolution within 2 weeks of stopping).
• 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 ketoprofen).
• 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 ketoprofen).
• 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 ketoprofen, ibuprofen or naproxen).
• Famularo G, Gasbarrone L, Minisola G. Probable ketoprofen-associated nonalcoholic fatty liver disease and steatohepatitis. Ann Pharmacother 2011; 45: 423. [PubMed: 21364038]

  (45 year old woman developed abdominal pain and fever 5 days after starting ketoprofen [bilirubin 2.8 mg/dL, ALT 612 U/L, Alk P 810 U/L, without eosinophilia], resolving within 1 week of stopping; she had tolerated diclofenac and ketorolac in the past).
• 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, including ketoprofen in 3 for a rate of 1.55 per million-treatment years).
• 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/noncase analyses for nimesulide, diclofenac and piroxicam only).
• 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 due to ketoprofen).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common class of implicated agents being NSAIDS [n=62, 32%], but specific agents were nimesulide [n=53], piroxicam [5], diclofenac [2], gold salts [1], and naproxen [1]; ketoprofen was not listed]).
• 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 were attributed to NSAIDs, but none to ketoprofen [Schmeltzer 2016]).
• 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 1221 cases of drug induced liver injury enrolled in a prospective, US database between 2004 and 2014, 30 cases [2.5%] were attributed to NSAIDs, most commonly diclofenac; none were attributed to ketoprofen).
• Donati M, Conforti A, Lenti MC, Capuano A, Bortolami O, Motola D, Moretti U, et al; DILI-IT Study Group. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy. Br J Clin Pharmacol 2016; 82: 238-48. [PMC free article: PMC4917796] [PubMed: 26991794]

  (Among 179 cases of acute liver injury and 1770 controls admitted to 9 Italian hospitals between 2010 and 2014, NSAIDs used more frequently in cases compared to controls included nimesulide [17% vs 10%: odds ratio 1.88] and ibuprofen [14% vs 10%: odds ratio 1.59] whereas ketoprofen was being taken at a similar rate by cases [11%] as controls [10%]).
• Zoubek ME, González-Jimenez A, Medina-Cáliz I, Robles-Díaz M, Hernandez N, Romero-Gómez M, Bessone F, et al. High Prevalence of ibuprofen drug-induced Liver injury in Spanish and Latin-American registries. Clin Gastroenterol Hepatol 2018; 16: 292-294. [PubMed: 28782674]

  (Analysis of a Spanish and Latin-American registries identified 73 cases of NSAID induced liver injury, the most common agents being nimesulide [38%], diclofenac [34%] and ibuprofen [17%]; ketoprofen was not mentioned).