Tolmetin is a nonsteroidal antiinflammatory drug (NSAID) that is available by prescription only and used for therapy of chronic arthritis. Tolmetin is associated with low rates of serum aminotransferase elevations during therapy and has been linked to rare instances of clinically apparent drug induced liver injury.
Tolmetin (tol' met in) belongs to the acetic acid derivative class of NSAIDs similar to diclofenac, sulindac and indomethacin. Like other NSAIDs, tolmetin is a cyclo-oxygenase (Cox-1 and Cox-2) inhibitor which blocks the formation of prostaglandins that are important in pain and inflammatory pathways. Tolmetin has analgesic as well as antipyretic and antiinflammatory activities. Tolmetin is one of the oldest NSAIDs in clinical use having been approved in the United States in 1976. It is currently not commonly used, having been replaced by NSAIDs with longer half-lives and better tolerance. The current indications for tolmetin include osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and juvenile rheumatoid arthritis. Tolmetin is available only by prescription and in several generic forms of 200, 400 and 600 mg tablets or capsules and formerly under the brand name Tolectin. The usual dose in adults is 1 to 2 g per day in divided doses. As with other NSAIDs, tolmetin is generally well tolerated, but side effects can include headache, dizziness, somnolence, dyspepsia, abdominal discomfort, diarrhea, peripheral edema and hypersensitivity reactions.
Up to 5% of patients taking tolmetin chronically experience at least 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 no convincing cases of tolmetin induced liver injury published in the literature and tolmetin is not mentioned as an etiologic agent in large case series on drug induced liver injury or acute liver failure. Reports of liver injury including acute liver failure attributed to tolmetin have been received by the Food and Drug Administration. Thus, liver injury from tolmetin may occur, but is rare. The latency, clinical features and outcome of tolmetin induced liver injury have not been described.
Mechanism of Injury
Tolmetin has a short half-life and is extensively metabolized by the liver. The mechanism of tolmetin hepatotoxicity is not known.
Outcome and Management
The asymptomatic elevations in serum aminotransferase levels are usually self-limited and resolve even with continuing tolmetin. Convincing instances of fatal and chronic cases have not been described in the literature.
REPRESENTATIVE TRADE NAMES
Tolmetin – Generic, Tolectin®
Nonsteroidal Antiinflammatory Drugs
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 16 December 2013
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; although there are no case reports in the literature, several instances of heptocellular injury attributed to tolmetin have been reported to the FDA).
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 about 5% of recipients develop minor elevations in aminotransferase levels, but that clinically apparent liver injury from tolmetin is very rare).
Grosser T, Smyth
E, FitzGerald GA. Anti-inflammatory, antipyretic, and analgesic agents;
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O'Brien WM. Long-term efficacy and safety of tolmetin sodium in treatment of geriatric patients with rheumatoid arthritis and osteoarthritis: a retrospective study. J Clin Pharmacol 1983; 23: 309-23. PubMed Citation (Retrospective review of 847 geriatric patients with rheumatoid arthritis or osteoarthritis treated with tolmetin, AST levels usually decreased on treatment, but minor elevations found in 19 patients [2%]; no mention of hepatitis or jaundice).
Jick H, Jick SS, Hunter JR, Walker AM. Follow-up study of tolmetin users. Pharmacotherapy 1989; 9: 91-4. PubMed Citation (Follow up of 7 years of 8370 tolmetin users for reports of hospitalization possibly caused by drug: 692 hospitalized within 90 days of prescription, but only 17 were possibly related, 11 for peptic ulcer, 1 for hepatitis, but arose >30 days after stopping and was considered unlikely to be related).
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; tolmetin mentioned as having led to little or no liver injury).
Shaw GW, Anderson R. Multisystem failure and hepatic microvesicular fatty metamorphosis associated with tolmetin ingestion. Arch Pathol Lab Med 1991; 115: 818-21. PubMed Citation (15 year old girl with juvenile rheumatoid arthritis developed fatigue within 10 days of starting tolmetin and was admitted with seizures, acidosis and progressive renal and pulmonary failure; ALT 440 U/L, AST 4378 U/L, LDH 7073 U/L, Alk P 212 U/L and bilirubin 1.2 mg/dL dying after 3 days; microvesicular fat on autopsy. High tolmetin levels detected suggestive of an overdose leading to shock and lactic acidosis).
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 trials 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 on tolmetin).
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 tolmetin).
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; tolmetin was not listed among more than 29,000 NSAID related 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. 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]).
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 or discussion of tolmetin).
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:
Citation (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]; tolmetin 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 PubMed Citation (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 tolmetin).
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