Skip to Content

Rilutek

Generic Name: Riluzole
Class: Central Nervous System Agents, Miscellaneous
VA Class: CN900
Chemical Name: 6-(Trifluoromethoxy)-2-benzothiazolamine
Molecular Formula: C8H5F3N2OS
CAS Number: 1744-22-5

Medically reviewed on June 4, 2018

Introduction

Antiglutamate agent that acts in the CNS;2 3 4 5 6 7 10 11 12 13 27 a synthetic aryl-substituted benzothiazolamine.1 2 3 4 5 6 7 9 27

Uses for Rilutek

Amyotrophic Lateral Sclerosis

Management of amyotrophic lateral sclerosis (ALS, Lou Gehrig disease, Charcot sclerosis);1 7 11 15 22 24 27 designated an orphan drug by FDA for this use.26

Has been shown to slow disease progression and prolong survival to a modest degree (e.g., by about 2–3 months); because of this possible benefit, experts recommend that the drug should be offered to patients with ALS.1 24 27 34 35

Rilutek Dosage and Administration

General

  • Measure serum aminotransferases, including ALT levels, before and during riluzole therapy.1 (See Hepatic Effects under Cautions.)

Administration

Oral Administration

Administer orally twice daily, 1 hour before or 2 hours after meals.1 22 24 27 (See Food under Pharmacokinetics.)

Dosage

Adults

Amyotrophic Lateral Sclerosis
Oral

50 mg twice daily.1

Special Populations

Hepatic Impairment

No specific dosage recommendations; however, use not recommended in patients with aminotransferase concentrations >5 times ULN or evidence of liver dysfunction.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.1

Geriatric Patients

No specific dosage recommendations.1

Cautions for Rilutek

Contraindications

History of severe hypersensitivity reactions to riluzole or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis reported.1

Hepatic Effects

Liver injury, including fatalities, reported.1 Asymptomatic elevations of aminotransferase concentrations (e.g., ALT) also reported and have recurred following rechallenge with the drug.1 Maximum increases in ALT occurred within the first 3 months of therapy.1

Monitor serum aminotransferase concentrations prior to and during therapy;1 also monitor for signs and symptoms of hepatic injury (monthly for the first 3 months of treatment, then periodically thereafter).1 Use not recommended in patients with aminotransferase concentrations >5 times ULN.1 Discontinue therapy if there is evidence of liver dysfunction (e.g., elevated bilirubin concentrations).1

Neutropenia

Severe neutropenia (ANC <500/mm3) reported within first 2 months of therapy.1 Advise patients to report febrile illness.1

Interstitial Lung Disease

Interstitial lung disease, including hypersensitivity pneumonitis, reported.1 Discontinue immediately if interstitial lung disease develops.1

Specific Populations

Pregnancy

No adequate data on use of riluzole in pregnant women.1 In animal studies, adverse developmental effects (e.g., decreased embryofetal/offspring viability, growth, and functional development) observed at clinically relevant doses.1

If used during pregnancy, advise patient of potential risk to the fetus1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Advise patients that the potential for serious adverse effects in nursing infants from riluzole is not known.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in safety or efficacy between patients ≥65 years of age and younger adults.1 However, greater sensitivity in some older individuals cannot be ruled out.1

Hepatic Impairment

Increased exposure to riluzole observed in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment; such patients may be at increased risk of adverse effects.1 Pharmacokinetics not studied in patients with severe hepatic impairment.1

Use not recommended in patients with preexisting signs or symptoms of liver dysfunction.1 (See Hepatic Effects under Cautions.)

Renal Impairment

Clinically important pharmacokinetic changes not observed in patients with moderate or severe renal impairment.1 Pharmacokinetics not studied in patients undergoing hemodialysis.1

Race

Japanese patients more likely to have increased riluzole concentrations; risk of riluzole-associated adverse effects may be greater in such patients.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Asthenia,1 nausea,1 decreased lung function,1 hypertension,1 abdominal pain,1 vomiting,1 arthralgia,1 dizziness,1 dry mouth,1 insomnia,1 pruritus,1 tachycardia,1 flatulence,1 increased cough,1 peripheral edema,1 urinary tract infection,1 circumoral paresthesia,1 somnolence,1 vertigo,1 eczema.1

Interactions for Rilutek

Substrate of CYP1A2.1

Drugs Affecting Hepatic Microsomal Enzymes

Moderate or potent inhibitors of CYP1A2: In vitro findings suggest increased riluzole exposure likely; may increase risk of riluzole-associated adverse effects.1

Inducers of CYP1A2: In vitro findings suggest decreased riluzole exposure likely; may reduce efficacy of riluzole.1

Specific Drugs

Drug

Interaction

Allopurinol

Possible increased risk of hepatotoxicity1

Ciprofloxacin

Increased riluzole exposure likely; possible increased risk of riluzole-associated adverse effects1

Digoxin

No effect on riluzole protein binding in vitro1

Fluvoxamine

Increased riluzole exposure likely; possible increased risk of riluzole-associated adverse effects1

Imipramine

No effect on riluzole protein binding in vitro1

Methoxsalen

Increased riluzole exposure likely; possible increased risk of riluzole-associated adverse effects1

Methyldopa

Possible increased risk of hepatotoxicity1

Mexiletine

Increased riluzole exposure likely; possible increased risk of riluzole-associated adverse effects1

Oral contraceptives

Increased riluzole exposure likely; possible increased risk of riluzole-associated adverse effects1

Quinine

No effect on riluzole protein binding in vitro1

Sulfasalazine

Possible increased risk of hepatotoxicity1

Vemurafenib

Increased riluzole exposure likely; possible increased risk of riluzole-associated adverse effects1

Warfarin

No effect on riluzole or warfarin protein binding in vitro1

Zileuton

Increased riluzole exposure likely; possible increased risk of riluzole-associated adverse effects1

Rilutek Pharmacokinetics

Absorption

Bioavailability

Oral bioavailability approximately 60%.1

With multiple-dose administration, riluzole accumulates in plasma by about twofold.1

Food

Food reduces AUC by 20% and peak plasma concentrations by 45%.1

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): AUC increased by 1.7- or 3-fold, respectively.1

Severe hepatic impairment: Pharmacokinetics not studied.1

Moderate or severe renal impairment: No clinically important effect on pharmacokinetics.1

Patients undergoing hemodialysis: Pharmacokinetics not studied.1

Age ≥65 years: No clinically important effect on pharmacokinetics.1

Gender: Mean AUC approximately 45% higher in females compared with males.1

Race: Clearance 50% lower in Japanese patients compared with Caucasian patients after normalizing for body weight.1

Smokers: Clearance approximately 20% higher in smokers compared with nonsmokers.1

Distribution

Plasma Protein Binding

96% (mainly to albumin and lipoproteins).1

Elimination

Metabolism

Metabolized by CYP1A2 and by direct and sequential glucuronidation.1

Elimination Route

Excreted in urine (90%) mainly as metabolites and in feces (5%).1

Half-life

12 hours.1

Stability

Storage

Oral

Tablets

20°–25°C; protect from bright light.1

Actions and Spectrum

  • Precise mechanism of action has not been fully elucidated1 but appears to involve interference with the effects mediated by excitatory amino acids (EAAs) in the CNS, possibly through inhibition of glutamic acid release,2 3 4 5 6 9 11 12 15 17 18 27 blockade or inactivation of voltage-dependent sodium channels,4 5 6 7 15 17 18 19 27 and/or activation of a G-protein-dependent signal transduction pathway.6 17 27

  • May act via noncompetitive blockade of EAA receptors;5 14 however, does not appear to bind to any known glutamate receptor.2 4 6

  • Exhibits neuroprotective properties in vitro and in vivo in animals, including inhibition of neuronal toxicity associated with exposure to EAAs 7 or cerebrospinal fluid from ALS patients,6 7 and inhibits neuronal toxicity associated with anoxia4 7 9 or focal or global ischemia.2 3 4 6 7 9

  • Prolonged survival in a study in a transgenic mouse model of ALS but did not delay onset of the disease.21 22

Advice to Patients

  • Importance of patients informing clinician of any manifestations of possible liver injury (e.g., yellowing of the whites of the eyes).1

  • Importance of patients informing clinician of any febrile illness.1

  • Importance of patients informing clinician of any respiratory symptoms (e.g., dry cough, difficult or labored breathing).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Riluzole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg*

Rilutek

Covis

Riluzole Tablets

AHFS DI Essentials. © Copyright 2018, Selected Revisions June 4, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Covis. Rilutek (riluzole) tablets prescribing information. Cary, NC; 2016 Apr.

2. Mantz J, Chéramy A, Thierry AM et al. Anesthetic properties of riluzole (54274 RP), a new inhibitor of glutamate neurotransmission. Anesthesiology. 1992; 76:844-8. http://www.ncbi.nlm.nih.gov/pubmed/1349464?dopt=AbstractPlus

3. Mantz J, Laudenbach V, Lecharny JB et al. Riluzole, a novel antiglutamate, blocks GABA uptake by striatal synaptosomes. Eur J Pharmacol. 1994; 257:R7-8. http://www.ncbi.nlm.nih.gov/pubmed/8082687?dopt=AbstractPlus

4. Martin D, Thompson MA, Nadler JV. The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1. Eur J Pharmacol. 1993; 250:473-6. http://www.ncbi.nlm.nih.gov/pubmed/8112408?dopt=AbstractPlus

5. Hays SJ, Rice MJ, Ortwine DF et al. Substituted 2-benzothiazolamines as sodium flux inhibitors: quantitative structure–activity relationships and anticonvulsant activity. J Pharm Sci. 1994; 83:1425-32. http://www.ncbi.nlm.nih.gov/pubmed/7884664?dopt=AbstractPlus

6. Couratier P, Sindou P, Esclaire F et al. Neuroprotective effects of riluzole in ALS CSF toxicity. Neuroreport. 1994; 5:1012-4. http://www.ncbi.nlm.nih.gov/pubmed/8061281?dopt=AbstractPlus

7. Rabasseda X, Mealy N, Castaner J. Riluzole. Drugs Future. 1994; 19:920-2.

9. Dessi F, Ben-Ari Y, Charriaut-Marlangue C. Riluzole prevents anoxic injury in cultured cerebellar granule neurons. Eur J Pharmacol. 1993; 250:325-8. http://www.ncbi.nlm.nih.gov/pubmed/8112389?dopt=AbstractPlus

10. Rowland LP. Riluzole for the treatment of amyotrophic lateral sclerosis—too soon to tell? N Engl J Med. 1994; 330:636-7. Editorial. (IDIS 326266)

11. Orrell RW, Lane RJM, Guiloff RJ. Recent developments in the drug treatment of motor neurone disease. BMJ. 1994; 309:140-1. http://www.ncbi.nlm.nih.gov/pubmed/8044087?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2540678&blobtype=pdf

12. Rowland LP. Amyotrophic lateral sclerosis. Curr Opin Neurol. 1994; 7:310-5. http://www.ncbi.nlm.nih.gov/pubmed/7952238?dopt=AbstractPlus

13. Benavides J, Camelin JC, Mitrani N et al. 2-amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid neurotransmission—II. Neuropharmacology. 1985; 24:1085-92. http://www.ncbi.nlm.nih.gov/pubmed/3001571?dopt=AbstractPlus

14. Debono MW, Le Guern J, Canton T et al. Inhibition by riluzole of electrophysiological responses mediated by rat kainate and NMDA receptors expressed in Xenopus oocytes. Eur J Pharmacol. 1993; 235:283-9. http://www.ncbi.nlm.nih.gov/pubmed/7685290?dopt=AbstractPlus

15. Anon. Riluzole for amyotrophic lateral sclerosis. Med Lett Drugs Ther. 1995; 37:113-4. http://www.ncbi.nlm.nih.gov/pubmed/7500908?dopt=AbstractPlus

16. Meldrum B, Garthwaite J. Neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci. 1990; 11:379-87. http://www.ncbi.nlm.nih.gov/pubmed/2238094?dopt=AbstractPlus

17. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994; 330:613-22. http://www.ncbi.nlm.nih.gov/pubmed/7905600?dopt=AbstractPlus

18. Martin D, Thompson MA, Nadler JV. The neuroprotective agent riluzole inhibits release of glutamate and aspartate from slices of hippocampal area CA1. Eur J Pharmacol. 1993; 250:473-6. http://www.ncbi.nlm.nih.gov/pubmed/8112408?dopt=AbstractPlus

19. Hubert JP, Delumeau JC, Glowinski J et al. Antagonism by riluzole of entry of calcium evoked by NMDA and veratridine in rat cultured granule cells: evidence for a dual mechanism of action. Br J Pharmacol. 1994; 113:261-7. http://www.ncbi.nlm.nih.gov/pubmed/7812619?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=1510058&blobtype=pdf

20. McKee P, Fuller GN, Stevens DL. Riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994; 331:272. http://www.ncbi.nlm.nih.gov/pubmed/8068095?dopt=AbstractPlus

21. Gurney ME, Cutting FB, Zhai P et al. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol. 1996; 39:147- 57. http://www.ncbi.nlm.nih.gov/pubmed/8967745?dopt=AbstractPlus

22. Rhone-Poulenc Rorer, Collegeville, PA: Personal communication.

24. Lacomblez L, Bensimon G, Leigh PN et al. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet. 1996; 347:1425-31. http://www.ncbi.nlm.nih.gov/pubmed/8676624?dopt=AbstractPlus

25. MacRae KD. Riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994; 331:272-3.

26. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2018 Jan 30. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

27. Bensimon G, Lacomblez L, Meininger V et al. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994; 330:585-91. http://www.ncbi.nlm.nih.gov/pubmed/8302340?dopt=AbstractPlus

28. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 209176Orig1s000: Summary Review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209176Orig1s000SumR.pdf

29. Bonafede R, Mariotti R. ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles. Front Cell Neurosci. 2017; 11:80. http://www.ncbi.nlm.nih.gov/pubmed/28377696?dopt=AbstractPlus

30. Mathis S, Couratier P, Julian A et al. Current view and perspectives in amyotrophic lateral sclerosis. Neural Regen Res. 2017; 12:181-184. http://www.ncbi.nlm.nih.gov/pubmed/28400790?dopt=AbstractPlus

31. Hogden A, Foley G, Henderson RD et al. Amyotrophic lateral sclerosis: improving care with a multidisciplinary approach. J Multidiscip Healthc. 2017; 10:205-215. http://www.ncbi.nlm.nih.gov/pubmed/?dopt=AbstractPlus

33. Sawada H. Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis. Expert Opin Pharmacother. 2017; 18:735-738. http://www.ncbi.nlm.nih.gov/pubmed/28406335?dopt=AbstractPlus

34. Miller RG, Jackson CE, Kasarskis EJ et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009; 73:1218-26. http://www.ncbi.nlm.nih.gov/pubmed/19822872?dopt=AbstractPlus

35. . Practice advisory on the treatment of amyotrophic lateral sclerosis with riluzole: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1997; 49:657-9. http://www.ncbi.nlm.nih.gov/pubmed/9305318?dopt=AbstractPlus

Hide