OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Mefenamic Acid – Ponstel®

DRUG CLASS

Nonsteroidal Antiinflammatory Drugs

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Mefenamic Acid	61-68-7	C15-H15-N-O2

ANNOTATED BIBLIOGRAPHY

References updated: 10 January 2020

• Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. The NSAIDS. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-41.

  (Review of hepatotoxicity of NSAIDs published in 1999: mentions that minor aminotransferase elevations occur in less than 5% of mefenamic acid recipients and was incriminated in an instance of “severe, but nonfatal, bridging necrosis”: Imoto).
• 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 mefenamic acid has been associated with only one published case of severe, but non-fatal hepatic necrosis: Imoto).
• Grosser T, Smyth E, FitzGerald GA. Anti-inflammatory, antipyretic, and analgesic agents; pharmacotherapy of gout. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 987-89. (Textbook of pharmacology and therapeutics).
• Imoto S, Matsumoto H, Fujii M. Drug-related hepatitis. Ann Intern Med 1979; 91: 129. 464433. [PubMed: 464433]

  (Letter to editor stating that 35 patients with drug induced liver disease were seen over 6 years at a single Japanese center; 9 had severe bridging necrosis on liver biopsy; one case being attributed to mefenamic acid; but no details given of latency, test results, clinical features, course or competing diagnoses).
• 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. 2281340. [PubMed: 2281340]

  (Extensive and excellent review article on liver injury due to NSAIDs; mefenamic acid is mentioned as being associated with a single case report of hepatocellular injury [Imoto]).
• Chan JCN, Lai FM, Critchley JAJH. A case of Stevens-Johnson syndrome, cholestatic hepatitis and haemolytic anaemia associated with use of mefenamic acid. Drug Saf 1991; 6: 230-4. 2064763. [PubMed: 2064763]

  (44 year old woman developed rash after 2 weeks of mefenamic acid [with acetaminophen and furosemide] presenting with Stevens-Johnson syndrome, hemolytic anemia and bilirubin 18.0 mg/dL, ALT 427 U/L, Alk P 1220 U/L and renal failure progressing to multiorgan failure and death in 4 days, autopsy showed intrahepatic cholestasis and acute tubular necrosis).
• Schwartz D, Gremmel F, Kurz R, Tragl KH, Gellner B, Pausch V. Case report: acute renal failure, thrombocytopenia and nonhemolytic icterus probably caused by mefenamic acid(Parkemed)-dependent antibodies. Beitr Infusionsther 1992; 30: 413-5. 1284748. [PubMed: 1284748]

  (65 year old man developed acute renal failure and thrombocytopenia shortly after a 3 day course of mefenamic acid followed by jaundice [bilirubin 20.7 mg/dL] which was attributed to "an isolated defect in glucuronization"; patient recovered and no other details given).
• de Mello NR, Baracat EC, Tomaz G, Bedone AJ, Camargos A, Barbosa IC, de Souza RN, et al. Double-blind study to evaluate efficacy and safety of meloxicam 7.5 mg and 15 mg versus mefenamic acid 1500 mg in the treatment of primary dysmenorrhea. Acta Obstet Gynecol Scand 2004; 83: 667-73. 15225193. [PubMed: 15225193]

  (Controlled trial of 2 doses of meloxicam vs mefenamic acid for 3 to 5 days in 337 women with dysmenorrhea, aminotransferase elevations occurred in 2 of 227 meloxicam-, but in none of 110 mefenamic acid treated subjects).
• Somchit N, Sanat F, Gan EH, Shahrin IA, Zuraini A. Liver injury induced by the non-steroidal anti-inflammatory drug mefenamic acid. Singapore Med J 2004; 45: 530-2. 15510325. [PubMed: 15510325]

  (Study in mice: dose dependent hepatotoxicity found with single intraperitoneally injection of 100-200 mg/kg as well as 14 day course at 50-100 mg/kg of mefenamic acid).
• Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: a systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol 2005; 3: 489-98. 15880319. [PubMed: 15880319]

  (Review of randomized clinical trial of NSAIDS for frequency of adverse events; ALT >3 fold ULN in 0.43% of ibuprofen, 0.43% naproxen, 0.42% celecoxib, 1.8% rofecoxib, 3.55% diclofenac and 0.29% of placebo recipients, rare liver related severe adverse events or deaths with any; no mention of mefenamic acid).
• 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: 1095-101. 16165719. [PubMed: 16165719]

  (Survey of all cases of drug induced liver injury with fatal outcome from Swedish Adverse Drug Reporting system from 1966-2002: among 103 cases, 3 attributed to naproxen, but none to mefenamic acid).
• Lapeyre-Mestre M, de Castro AM, Bareille MP, Del Pozo JG, Requejo AA, Arias LM, 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. 16867024. [PubMed: 16867024]

  (Analysis of reports of liver injury from NSAIDs from France and Spain from 1982-2001; mefenamic acid was not listed among more than 29,000 liver adverse event reports).
• 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. 18955056. [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 for mefenamic acid).
• Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol 2010; 16: 5651-61. 21128314. [PMC free article: PMC2997980] [PubMed: 21128314]

  (Review of estimated frequency of drug induced liver injury due to NSAIDs from large published epidemiological studies; no mention of mefenamic acid).
• Couto M, Duarte C, Geraldes L, Inês L, Malcata A. Anaphylaxis to mefenamic acid in a patient with new onset of systemic lupus erythematosus. Allergol Immunopathol (Madr) 2010; 38: 224-6. 20153574. [PubMed: 20153574]

  (32 year old woman with lupus developed rash, followed by angioedema and anaphylactic shock a week after starting mefenamic acid for suspected lupus with accompanying hemolytic anemia, thrombocytopenia and liver test abnormalities [bilirubin 0.8 mg/dL, ALT 219 U/L, prothrombin time 22 sec], which rapidly improved with medical support and high dose corticosteroid therapy).
• 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. 20949552. [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, of which 7 were due to NSAIDs, including 4 to bromfenac, 2 to diclofenac and 1 to etodolac, but none to mefenamic acid).
• Lapeyre-Mestre M, Grolleau S, Montastruc JL; Adsociation 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. 21929527. [PubMed: 21929527]

  (Analysis of 42,389 spontaneous serious adverse event reports to the French Pharmacovigilance database on 8 NSAIDs between 2002 and 2006; liver adverse events were most frequent with nimesulide [0.15 per million daily doses] compared to diclofenac [0.09], ketoprofen [0.09] piroxicam [0.06], naproxen [0.04], meloxicam [0.03], and tenoxicam [0.03]; mefenamic acid not discussed).
• 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. 23419359. [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 for mefenamic acid or other NSAIDs).
• 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. 24552865. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996-2012 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]; mefenamic acid 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. 25754159. [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 mefenamic acid [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. 26601797. [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, including 16 to diclofenac, 3 celecoxib, 3 meloxicam, 2 etodolac, 2 oxaprozin, 2 ibuprofen, 1 sulindac, and 1 valdecoxib, but none to mefenamic acid).
• 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. 26991794. [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], and risk was higher in those taking higher doses; mefenamic acid is not listed).
• Sriuttha P, Sirichanchuen B, Permsuwan U. Hepatotoxicity of Nonsteroidal anti-inflammatory drugs: a systematic review of randomized controlled trials. Int J Hepatol 2018; 2018: 5253623. 29568654. [PMC free article: PMC5820561] [PubMed: 29568654]

  (Systematic review of published randomized controlled trials for evidence of hepatotoxicity, found 18 studies that fit the stringent criteria, but none of them dealt with mefenamic acid).
• Ben-Nasr H, Ksouda K, Harrabi B, Hammami ST, Zeghal K, Affes H. Pediatric liver failure following mefenamic acid associated to herbal auto-medication: A case report. Therapie 2019; 74: 677-80. 31635831. [PubMed: 31635831]

  (4 year old boy developed severe acute hepatocellular liver injury [ALT 1920 U/L, GGT 283 U/L, bilirubin 6.4 mg/dL, INR 1.52] 2 weeks after starting a mefenamic acid based cough medication and while intermittently receiving a home brewed herbal tea prepared from nutmeg [Mirystica fragrans], a flower [Hibiscus saabdariffa] and mint [Mentha aquatic], recovering within 3 weeks of presentation).