Riluzole is a neuroprotective agent used for therapy of amyotrophic lateral sclerosis. Riluzole is associated with a low rate of serum aminotransferase elevations during therapy and has been linked to rare instances of clinically apparent, acute liver injury.
Riluzole (ril' ue zole) is a benzothiazole that is neuroprotective in vitro and in vivo. The mechanism by which it protects neurons from toxic injury is unknown, but it appears to inhibit glutamate release, to block post-synaptic glutamate receptors and to inactivate voltage dependent sodium channels. Studies in patients with amyotrophic lateral sclerosis suggest that riluzole may slow disease progression and neurologic deterioration. Riluzole was approved for use in the United States in 1995 and is commonly used in management of amyotrophic lateral sclerosis. Riluzole is available in tablets of 50 mg under the brand name Rilutek. The typical maintenance dosage is 50 mg every 12 hours. Common side effects include fatigue, weakness, dizziness, nausea, diarrhea, and cough.
Serum aminotransferase elevations occur in approximately up to 12% of patients on long term riluzole therapy, but elevations above 3 times the upper limit of normal (ULN) occur in less than 3% of patients. These elevations are usually mild-to-moderate in severity and are rarely associated with symptoms. Most elevations resolve spontaneously, but persistent or marked elevations require drug discontinuation or dose modification. Routine monitoring of serum aminotransferase levels is recommended for the first 6 months of therapy. Clinically apparent liver injury due to riluzole is rare, but several cases have been reported, arising after 1 to 12 months of therapy and characterized by a hepatocellular or mixed pattern of serum enzyme elevations. Immunoallergic and autoimmune features were uncommon. Most cases were mild to moderate in severity and recovery was rapid upon drug discontinuation, but evidently fatal cases have been reported to the sponsor.
Mechanism of Injury
Riluzole is extensively metabolized by the liver by the cytochrome P450 system into multiple intermediates, not all of which have been characterized. The hepatotoxicity of riluzole may be related to production of a toxic or immunogenic intermediate.
Outcome and Management
The severity of liver injury from riluzole ranges from minor, transient elevations in serum aminotransferase levels to acute hepatic injury with jaundice and possible to acute liver failure. Routine monitoring of serum aminotransferase levels is recommended during the first 6 months of riluzole therapy and therapy discontinued for elevations greater than 5 times ULN. Riluzole has not been linked to cases of chronic hepatitis or vanishing bile duct syndrome. Restarting riluzole can result in recurrence of liver injury and should be avoided.
References regarding the safety and potential hepatotoxicity of the drugs used
for Alzheimer disease are provided together after the Overview section of
Alzheimer Disease Agents.
REPRESENTATIVE TRADE NAMES
Riluzole – Rilutek®
Alzheimer Disease Agents
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 10 January 2014
Zimmerman HJ. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 709-42. (Expert review of hepatotoxicity published in 1999; riluzole is mentioned for its potential to cause ALT elevations [~6%]).
Larrey D. Hepatotoxicity of psychotropic drugs and drugs of abuse. In,
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apparent liver injury is rare, only 5 cases having been reported in the
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Castells LI, Gamez J, Cervera C, Guardia J. Icteric toxic hepatitis associated with riluzole. Lancet 1998; 351: 648. PubMed Citation (71 year old woman developed jaundice 6 months after starting riluzole for amyotrophic lateral sclerosis [bilirubin 15.4 mg/dL, ALT 1026 U/L, Alk P 356 U/L], with rapid resolution and normal values within 2 months of stopping).
Remy A-J, Camu W, Ramos J, Blanc P, Larrey D. Acute hepatitis after riluzole administration. J Hepatol 1999; 30: 527-30. PubMed Citation (Two women with amylotrophic lateral sclerosis, ages 56 and 71, developed evidence of liver injury 7 and 4 weeks after starting riluzole [bilirubin normal and 4.5 mg/dL, ALT 22 and 3 times ULN, Alk P normal], with resolution in 4-12 weeks, one patient had positive rechallenge).
Barbare JC, Imbert A, Benkirane A. [Recent developments concerning drug- induced liver toxicity]. Presse Med 2001; 30: 673-6. French. PubMed Citation (Review of importance of central reporting of drug induced liver injury, providing examples of recently described hepatotoxic reactions, including 3 recent cases of hepatocellular injury due to riluzole).
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study of riluzole in early Parkinson's disease. Parkinsonism Relat Disord 2002; 8: 271-6. PubMed Citation (Among 20 patients with early Parkinson disease treated with riluzole or placebo for 12 months, none developed any abnormality in liver tests and their were no discontinuations or serious adverse events due to liver injury).
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Bensimon G, Doble A. The tolerability of riluzole in the treatment of patients with amyotrophic lateral sclerosis. Expert Opin Drug Saf 2004; 3: 525-34. PubMed Citation (Review of pharmacology, efficacy and safety of riluzole in amyotrophic lateral sclerosis; ALT elevations >3 times ULN occurred in 35 [9%] of 395 patients on riluzole vs 12 of 406 [3%] on placebo; all resolved either despite continuing or with stopping: recommended monthly monitoring of aminotransferase levels for first 3 months of treatment).
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Wokke J. Riluzole. Lancet 1996; 348 (9030): 795-9. PubMed Citation (Review of structure, mechanisms of action, pharmacokinetics, efficacy and safety of riluzole; mentions that ALT and AST elevations occur not infrequently, but are usually less than 3 times ULN and that no case of jaundice has been reported).
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disease: an early Australian experience (1996-2002). J Clin Neurosci 2006;13:78-83. PubMed Citation (Among 25 patients with motor neurone disease treated with riluzole for up to 12 months, "there was no significant alteration" in ALT or AST).
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Initiative Study Group. Riluzole in Huntington's disease: a 3-year, randomized
controlled study. Ann Neurol 2007; 62: 262-72. PubMed Citation (Among 537 adults with Huntington disease treated with riluzole or placebo for up to 3 years, 7 [2%] on riluzole and 1 [0.5%] on placebo had ALT elevations and 5 patients on riluzole stopped therapy because of liver enzyme elevations; no mention of clinically apparent liver injury or serious hepatic adverse events).
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 between 2004 and 2008, none were attributed to riluzole).
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. PubMed Citation (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, but none were attributed to riluzole).
Grossman RG, Fehlings MG, Frankowski RF, Burau KD, Chow DS, Tator C, Teng A,
et al. A Prospective, Multicenter, Phase I Matched-Comparison Group
Trial of Safety, Pharmacokinetics, and Preliminary Efficacy of Riluzole in
Patients with Traumatic Spinal Cord Injury. J Neurotrauma 2013 Oct 11. [Epub
ahead of print] PubMed Citation (Among 36 patients with acute spinal cord injury treated with riluzole twice daily for 14 days, ALT elevaitons occurred in 70%, but elevations were usually mild-to-moderate and resolved once therapy was stopped, no patient developing jaundice or progressive increase in values).
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