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DRUG RECORD

 

MEFENAMIC ACID

OVERVIEW
Mefenamic Acid

 

Introduction
Mefenamic acid is a nonsteroidal antiinflammatory drug (NSAID) used largely for acute treatment of pain.  Mefanamic acid has been linked to rare instances of clinically apparent, acute liver injury.

Background
Mefenamic (mef" e nam' ik) acid belongs to the anthranilic acid derivative class of NSAIDs (fenamates).  Like other NSAIDs, mefenamic acid is a cyclo-oxygenase (Cox-1 and -2) inhibitor and blocks the production of intracellular prostaglandins that are important in pain and inflammatory pathways.  Mefenamic acid has analgesic as well as antipyretic and antiinflammatory activities, but is used largely for treatment of pain.  Mefenamic acid was approved in the United States in 1967, but is not a commonly used agent.  Mefenamic acid is indicated for the treatment of mild-to-moderate acute pain or dysmenorrhea.  It is available by prescription only in capsules of 250 and 500 mg in generic forms and under the brand name Ponstel. The recommended dose is 250 to 500 mg 3 to 4 times daily for periods of less than 7 days.  Like most NSAIDs, mefenamic acid is generally well tolerated, but side effects can include headache, dizziness, somnolence, nausea, diarrhea, abdominal discomfort, heartburn, peripheral edema and hypersensitivity reactions.

Hepatotoxicity
Prospective studies show that less than 5% of patients taking mefenamic acid experience transient serum aminotransferase elevations.  These may resolve even with drug continuation.  Marked aminotransferase elevations (>3 fold elevated) occur in <1% of patients.  There have been very rare cases of mefenamic acid induced liver injury published, and mefenamic acid is not mentioned as an etiologic agent in large case series on drug induced liver injury or acute liver failure.  In one case report, the latency to onset of symptoms was short and associated with Stevens-Johnson syndrome and cholestatic liver injury.  The paucity of published cases makes it impossible to characterize a typical clinical pattern of liver injury.

Mechanism of Injury
The mechanism of mefenamic acid hepatotoxicity is not known, but is likely to be idiosyncratic hypersensitivity.  The absence of reports of liver injury from mefenamic acid may be due, in part, to the infrequency of its use and limited duration of treatment.

Outcome and Management
The asymptomatic elevations in serum aminotransferase levels are usually self-limited and resolve even with continuing mefenamic acid.  Severe cases of mefenamic acid hepatotoxicity, but not chronic hepatitis, have been described.  Cross reactivity to hepatic injury among various classes of NSAIDs has not been well characterized; however, after clinically apparent injury attributable to mefenamic acid, it would be prudent to avoid other anthranilic acid derivatives (fenamates generally not available in the United States, such as tolfenamic acid and flufenamic acid), and patients who are switched to other NSAIDs should be monitored carefully.

 

Drug Class:  Nonsteroidal Antiinflammatory Drugs

 

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PRODUCT INFORMATION
Mefenamic Acid

 

REPRESENTATIVE TRADE NAMES
Mefenamic Acid – Ponstel®

 

DRUG CLASS
Nonsteroidal Antiinflammatory Drugs

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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

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ANNOTATED BIBLIOGRAPHY
Mefenamic Acid

 

References updated: 11 February 2014

 

  1. 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).

  2. 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).

  3. 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).

  4. Imoto S, Matsumoto H, Fujii M. Drug-related hepatitis. Ann Intern Med 1979; 91: 129. PubMed Citation  (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).

  5. 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 Citation  (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]).

  6. 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. PubMed Citation  (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).

  7. 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. PubMed Citation  (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).

  8. 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. PubMed Citation  (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).

  9. 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. PubMed Citation  (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).

  10. 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. PubMed Citation  (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).

  11. 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. PubMed Citation  (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).

  12. 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. PubMed Citation  (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).

  13. 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 for mefenamic acid).

  14. Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol 2010; 16: 5651-61. PubMed Citation  (Review of estimated frequency of drug induced liver injury due to NSAIDs from large published epidemiological studies; no mention of mefenamic acid).

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OTHER REFERENCE LINKS
Mefenamic Acid

 

  1. PubMed logoRecent References on Mefenamic Acid

  2. Clinical Trials logoTrials on Mefenamic Acid

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