Riluzole

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

Introduction

An antiglutamate agent that acts in the CNS;^{1 2 3 4 5 6 7 10 11 12 13} a synthetic aryl-substituted benzothiazolamine.^{1 2 3 4 5 6 7 8 9}

Uses for Riluzole

Amyotrophic Lateral Sclerosis

Used in the management of amyotrophic lateral sclerosis (ALS, Lou Gehrig disease, Dejerine-type Charcot syndrome) to extend survival and/or time to tracheostomy;^{1 7 8 11 15 22 24} designated an orphan drug by FDA for this use.²⁶

Riluzole Dosage and Administration

General

• 
  

  Measure serum aminotransferases, including ALT levels, before and during riluzole therapy.⁸ (See Hepatic Effects under Cautions.)

  
  

Administration

Oral Administration

Administer orally, usually in 2 equally divided doses daily, 1 hour before or 2 hours after meals.^{1 8 22 24} (See Food under Pharmacokinetics.)

Dosage

Adults

Amyotrophic Lateral Sclerosis

Oral

50 mg every 12 hours.⁸

Prescribing Limits

Adults

Amyotrophic Lateral Sclerosis

Oral

Maximum 50 mg every 12 hours; higher daily dosages provide no additional benefit but may increase the risk of adverse effects.^{8 22 24}

Special Populations

Hepatic Impairment

Use with caution; however, no specific dosage recommendations.^a

Discontinue therapy if ALT is >10 times ULN or if jaundice develops.^a

Manufacturer states that there is no experience with reinitiating therapy in patients whose therapy was discontinued for ALT >5 times ULN.^a

Renal Impairment

Use with caution; however, no specific dosage recommendations.^a

Geriatric Patients

Use with caution; however, no specific dosage recommendations.^a

Cautions for Riluzole

Contraindications

History of severe hypersensitivity reactions to riluzole or any ingredient in the formulation.⁸

Warnings/Precautions

Warnings

Hepatic Effects

Associated with increases in serum aminotransferase (ALT) concentrations.^a Maximum increases usually occur within 3 months of initiating therapy and are usually transient when <5 times ULN.⁸

Rarely, jaundice has been reported.^a

Use not recommended in patients with baseline elevations of liver function tests (especially increased bilirubin).^a Use with caution in patients with current or a history of abnormal liver function (i.e., significant abnormalities in serum transaminase [ALT; AST], bilirubin, and/or gamma-glutamate transferase [GGT] levels).^a

Determine serum aminotransferase (ALT) concentrations prior to initiating therapy, once monthly during the first 3 months, every 3 months during the first year, and periodically thereafter; determine more frequently if increases in ALT concentrations develop.^a

Manufacturer states there is no experience of continuing treatment in patients whose ALT is >5 times ULN and if a decision is made to continue therapy, at least weekly monitoring of liver function tests is recommended.^a

Hematologic Effects

Neutropenia (ANC <500/mm³) reported rarely within the first 2 months of therapy.⁸ Monitor WBC counts if febrile illness occurs.⁸

Specific Populations

Pregnancy

Category C. ⁸

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^a Discontinue nursing because of potential risk to nursing infants.⁸

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{8 22}

Geriatric Use

Possible increased incidence of hepatic dysfunction compared with younger adults.⁸ Use with caution due to greater frequency of decreased hepatic and/or renal function observed in the elderly.⁸ Adverse effects similar to those in younger adults.⁸

Hepatic Impairment

Use with caution;⁸ increased AUC in patients with mild or moderate hepatic impairment.⁸ Pharmacokinetics not studied in patients with severe hepatic impairment.⁸

Manufacturer states there is no experience with continuing treatment in patients once ALT >5 times ULN and if a decision is made to continue therapy, frequent monitoring (at least weekly) of liver function tests is recommended.^a

Renal Impairment

Use with caution.⁸ There is no significant difference in pharmacokinetic parameters between patients with moderate or severe renal insufficiency and healthy volunteers. ⁸ Pharmacokinetics not studied in patients undergoing hemodialysis.⁸

Common Adverse Effects

Asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting, vertigo, circumoral paresthesia, anorexia, somnolence.⁸

Interactions for Riluzole

Appears to be metabolized principally by CYP1A2; pharmacokinetic interactions with substrates of CYP1A2 are likely.⁸ CYP2D6, 2C19, 3A4, and 2E1 not significantly involved in metabolism.^a

Not known whether riluzole has potential for enzyme induction in humans.⁸

Protein-bound Drugs

Potential pharmacokinetic interactions (displacement of riluzole or other protein-bound drugs).⁸

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP1A2: potential pharmacokinetic interaction (decreased rate of riluzole elimination).⁸

Inducers of CYP1A2: potential pharmacokinetic interaction (increased rate of riluzole elimination).⁸

Specific Drugs and Food

Drug	Interaction	Comments
Alcohol	Possible additive adverse hepatic effects8
Allopurinol	Possible additive adverse hepatic effects8	Safety of concomitant administration not established; use caution8
Amitriptyline	Possible decreased rate of riluzole eliminationa
Caffeine	Possible decreased rate of riluzole eliminationa
Charcoal-broiled food	Possible increased rate of riluzole eliminationa
Cigarette smoke	Possible increased rate of riluzole eliminationa
Digoxin	No effect on riluzole protein binding in vitroa
Imipramine	No effect on riluzole protein binding in vitroa
Methyldopa	Possible additive adverse hepatic effects8	Safety of concomitant administration not established; use caution8
Omeprazole	Possible increased rate of riluzole elimination
Phenacetin	Possible decreased rate of riluzole elimination
Quinine	No effect on riluzole protein binding in vitroa
Quinolones	Possible decreased rate of riluzole eliminationa
Rifampin	Possible increased rate of riluzole elimination
Sulfasalazine	Possible additive adverse hepatic effects8	Safety of concomitant administration not established; use caution8
Tacrine	Potential pharmacokinetic interaction (altered metabolism) with concurrent use of other drugs metabolized by CYP1A2a
Theophylline	Possible decreased rate of riluzole elimination
Warfarin	No effect on riluzole or warfarin protein binding in vitroa

Riluzole Pharmacokinetics

Absorption

Bioavailability

Well-absorbed (approximately 90%); average absolute oral bioavailability approximately 60%.⁸

With multiple-dose administration, riluzole accumulates in plasma by about twofold; steady-state is reached in <5 days.⁸

Food

High fat meal decreases absorption, reducing AUC by about 20% and peak blood levels by about 45%.⁸

Special Populations

Increased AUC in patients with mild or moderate hepatic impairment.⁸ Pharmacokinetics not studied in patients with severe hepatic impairment.⁸

Distribution

Plasma Protein Binding

96% (mainly to albumin and lipoproteins).⁸

Elimination

Metabolism

Extensively metabolized in the liver to 6 major and a number of minor metabolites, principally via CYP1A2-dependent hydroxylation and glucuronidation.

Elimination Route

Excreted in urine (90%) mainly as metabolites and in feces (5%).⁸

Half-life

Averages 12 hours after repeated doses.⁸

Stability

Storage

Oral

Tablets

20°–25°C; protect from bright light.⁸

Actions and SpectrumActions

• 
  

  Precise mechanism of action has not been fully elucidated but appears to involve interference with the effects mediated by excitatory amino acids (EAAs) in the CNS, possibly through inhibition of glutamic acid release,^{1 2 3 4 5 6 8 9 11 12 15 17 18} blockade or inactivation of voltage-dependent sodium channels,^{1 4 5 6 7 8 15 17 18 19} and/or activation of a G-protein-dependent signal transduction pathway.^{1 6 17}

  
  


• 
  

  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 8} or cerebrospinal fluid from ALS patients,^{6 7} and inhibits neuronal toxicity associated with anoxia^{4 7 8 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.^{8 21 22}

  
  

Advice to Patients

• 
  

  Importance of patients informing clinician of any febrile illness.⁸

  
  


• 
  

  Importance of taking riluzole on a regular basis and at the same time of the day (e.g., in the morning and evening) each day.⁸ Importance of taking every 12 hours on an empty stomach, 1 hour before or 2 hours after meals.^{1 8 22 24}

  
  


• 
  

  If a dose is missed, importance of patient taking only the next scheduled dose.⁸

  
  


• 
  

  Risk of dizziness, vertigo, or somnolence: avoid driving or operating machinery until effects on individual are known.⁸

  
  


• 
  

  Alcohol may increase the risk of serious hepatotoxicity; drinking excessive amounts of alcohol should be discouraged.⁸

  
  


• 
  

  Importance of keeping riluzole out of the reach of children.⁸

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.⁸

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.⁸

  
  


• 
  

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

  
  

Preparations

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

Riluzole

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	50 mg	Rilutek	Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Rilutek 50MG Tablets (SANOFI-AVENTIS U.S.): 60/$999.99 or 180/$2950.97

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. 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. [IDIS 326262] [PubMed 8302340]

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. [PubMed 1349464]

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. [PubMed 8082687]

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. [PubMed 8112408]

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. [PubMed 7884664]

6. Couratier P, Sindou P, Esclaire F et al. Neuroprotective effects of riluzole in ALS CSF toxicity. Neuroreport. 1994; 5:1012-4. [PubMed 8061281]

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

8. Aventis. Rilutek (riluzole) tablets prescribing information. Bridgewater, NJ; 2003 May.

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. [PubMed 8112389]

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. [IDIS 332937] [PubMed 8044087]

12. Rowland LP. Amyotrophic lateral sclerosis. Curr Opin Neurol. 1994; 7:310-5. [PubMed 7952238]

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. [PubMed 3001571]

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. [PubMed 7685290]

15. Anon. Riluzole for amyotrophic lateral sclerosis. Med Lett Drugs Ther. 1995; 37:113-4. [PubMed 7500908]

16. Meldrum B , Garthwaite J. Neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci. 1990; 11:379-87. [PubMed 2238094]

17. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med. 1994; 330:613-22. [IDIS 326265] [PubMed 7905600]

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. [PubMed 8112408]

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. [PubMed 7812619]

20. McKee P, Fuller GN, Stevens DL. Riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994; 331:272. [IDIS 332877] [PubMed 8068095]

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. [PubMed 8967745]

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. [IDIS 365047] [PubMed 8676624]

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

26. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

a. Aventis. Rilutek (riluzole) tablets prescribing information. Bridgewater, NJ; 2004 September.

More Riluzole resources

• Riluzole Side Effects (in more detail)
• Riluzole Dosage
• Riluzole Use in Pregnancy & Breastfeeding
• Riluzole Drug Interactions
• Riluzole Support Group
• 1 Review for Riluzole - Add your own review/rating

• Riluzole Professional Patient Advice (Wolters Kluwer)


• Riluzole MedFacts Consumer Leaflet (Wolters Kluwer)


• riluzole Concise Consumer Information (Cerner Multum)


• riluzole Advanced Consumer (Micromedex) - Includes Dosage Information


• Rilutek Prescribing Information (FDA)

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