Riluzole

Riluzole
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Overview

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Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• Riluzole tablets, USP are indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS).
• Riluzole extends survival and/or time to tracheostomy.

Dosage

• The recommended dose for riluzole tablets is 50 mg every 12 hours. No increased benefit can be expected from higher daily doses, but adverse events are increased.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

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Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

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Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

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Contraindications

• Riluzole tablets are contraindicated in patients who have a history of severe hypersensitivity reactions to riluzole or any of the tablet components.

Warnings

Liver Injury / Monitoring Liver Chemistries

• Riluzole tablets should be prescribed with care in patients with current evidence or history of abnormal liver function indicated by significant abnormalities in serum transaminase (ALT/SGPT; AST/SGOT), bilirubin, and/or gamma-glutamate transferase (GGT) levels. Baseline elevations of several LFTs (especially elevated bilirubin) should preclude the use of riluzole.

• Riluzole, even in patients without a prior history of liver disease, causes serum aminotransferase elevations. Treatment should be discontinued if ALT levels are ≥ 5 X ULN or if clinical jaundice develops.

• Experience in almost 800 ALS patients indicates that about 50% of riluzole-treated patients will experience at least one ALT/SGPT level above the upper limit of normal, about 8% will have elevations > 3 × ULN, and about 2% of patients will have elevations > 5 × ULN. A single non-ALS patient with epilepsy treated with concomitant carbamazepine and phenobarbital experienced marked, rapid elevations of liver enzymes with jaundice (ALT 26 × ULN, AST 17 × ULN, and bilirubin 11 × ULN) four months after starting riluzole; these returned to normal 7 weeks after treatment discontinuation.

• Maximum increases in serum ALT usually occurred within 3 months after the start of riluzole therapy and were usually transient when < 5 times ULN. In trials, if ALT levels were < 5 times ULN, treatment continued and ALT levels usually returned to below 2 times ULN within 2 to 6 months. Treatment in studies was discontinued, however, if ALT levels exceeded 5 × ULN, so that there is no experience with continued treatment of ALS patients once ALT values exceed 5 times ULN. There were rare instances of jaundice. There is limited experience with rechallenge of patients who have had riluzole discontinued for ALT > 5 X ULN, but there is the possibility of increased ALT values reoccurring (see PRECAUTIONS: Laboratory Tests). Therefore, rechallenge is not recommended.

• In postmarketing experience, cases of clinical hepatitis associated with riluzole have been reported, including with fatal outcome.

Neutropenia

Among approximately 4000 patients given riluzole for ALS, there were three cases of marked neutropenia (absolute neutrophil count less than 500/mm3), all seen within the first 2 months of riluzole treatment. In one case, neutrophil counts rose on continued treatment. In a second case, counts rose after therapy was stopped. A third case was more complex, with marked anemia as well as neutropenia and the etiology of both is uncertain. Patients should be warned to report any febrile illness to their physicians. The report of a febrile illness should prompt treating physicians to check white blood cell counts.

Interstitial Lung Disease

• Cases of interstitial lung disease have been reported in patients treated with riluzole, some of them severe; upon further investigation, many of these cases were hypersensitivity pneumonitis. If respiratory symptoms develop such as dry cough and/or dyspnea, chest radiography should be performed, and in case of findings suggestive of interstitial lung disease or hypersensitivity pneumonitis (e.g., bilateral diffuse lung opacities), riluzole should be discontinued immediately. In the majority of the reported cases, symptoms resolved after drug discontinuation and symptomatic treatment.

PRECAUTIONS

Use in Patients with Concomitant Disease Riluzole should be used with caution in patients with concomitant liver insufficiency (see WARNINGS, CLINICAL PHARMACOLOGY). In particular, in cases of riluzole-induced hepatic injury manifested by elevated liver enzymes, the effect of the hepatic injury on riluzole metabolism is unknown.

Special Populations Riluzole should be used with caution in elderly patients whose hepatic function may be compromised due to age. Also, female patients may possess a lower metabolic capacity to eliminate riluzole compared to males (see CLINICAL PHARMACOLOGY: Special Populations).

Information for the Patients Patients should be advised to report any febrile illness to their physicians (see WARNINGS: Neutropenia).

Patients should be advised to report any cough or difficulties in breathing to their physicians (see WARNINGS: Interstitial Lung Disease).

Patients and caregivers should be advised that riluzole tablets should be taken on a regular basis and at the same time of the day (e.g., in the morning and evening) each day. If a dose is missed, take the next tablet as originally planned.

Patients should be warned about the potential for dizziness, vertigo, or somnolence and advised not to drive or operate machinery until they have gained sufficient experience on riluzole to gauge whether or not it affects their mental and/or motor performance adversely.

Whether alcohol increases the risk of serious hepatotoxicity with riluzole is unknown; therefore, patients being treated with riluzole should be discouraged from drinking excessive amounts of alcohol.

Patients should also be made aware that riluzole tablets should be stored at temperatures 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) and protected from bright light.

Riluzole tablets must be kept out of the reach of children.

Adverse Reactions

Clinical Trials Experience

• The most commonly observed AEs associated with the use of riluzole more frequently than placebo treated patients were: asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting, vertigo, circumoral paresthesia, anorexia, and somnolence. Asthenia, nausea, dizziness, diarrhea, anorexia, vertigo, somnolence, and circumoral paresthesia were dose related.

• Approximately 14% (n = 141) of the 982 individuals with ALS who received riluzole in pre-marketing clinical trials discontinued treatment because of an adverse experience. Of those patients who discontinued due to adverse events, the most commonly reported were: nausea, abdominal pain, constipation, and ALT elevations. In a dose response study in ALS patients, the rates of discontinuation of riluzole for asthenia, nausea, abdominal pain, and ALT elevation were dose related.

Incidence in Controlled ALS Clinical Studies

• Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients with ALS treated with riluzole (n=794) participating in placebo-controlled trials and were numerically greater in the patients treated with riluzole 100 mg/day than with placebo or for which a dose response relationship is suggested.

• The prescriber should be aware that these figures cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the AE incidences in the population studied.

Postmarketing Experience

(Description)

Drug Interactions

• There have been no clinical studies designed to evaluate the interaction of riluzole with other drugs.

• As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Hepatotoxic Drugs The clinical trials in ALS excluded patients on concomitant medications which were potentially hepatotoxic, (e.g., allopurinol, methyldopa, sulfasalazine). Accordingly, there is no information about the safety of administering riluzole in conjunction with such medications. If the practitioner chooses to prescribe such a combination, caution should be exercised.

Drugs Highly Bound To Plasma Proteins Riluzole is highly bound (96%) to plasma proteins, binding mainly to serum albumin and to lipoproteins. The effect of riluzole (up to 5 mcg/mL) on warfarin (5 mcg/mL) binding did not show any displacement of warfarin. Conversely, riluzole binding was unaffected by the addition of warfarin, digoxin, imipramine and quinine at high therapeutic concentrations.

Effect of Other Drugs On Riluzole Metabolism In vitro studies using human liver microsomal preparations suggest that CYP 1A2 is the principal isozyme involved in the initial oxidative metabolism of riluzole and, therefore, potential interactions may occur when riluzole is given concurrently with agents that affect CYP 1A2 activity. Potential inhibitors of CYP 1A2 (e.g., caffeine, phenacetin, theophylline, amitriptyline, and quinolones) could decrease the rate of riluzole elimination, while inducers of CYP 1A2 (e.g., cigarette smoke, charcoal-broiled food, rifampicin, and omeprazole) could increase the rate of riluzole elimination.

Effect of Riluzole On the Metabolism of Other Drugs CYP 1A2 is the principal isoenzyme involved in the initial oxidative metabolism of riluzole; potential interactions may occur when riluzole is given concurrently with other agents which are also metabolized primarily by CYP 1A2 (e.g., theophylline, caffeine, and tacrine). Currently, it is not known whether riluzole has any potential for enzyme induction in humans.

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Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Pregnancy category C

• Oral administration of riluzole to pregnant animals during the period of organogenesis caused embryotoxicity in rats and rabbits at doses of 27 mg/kg and 60 mg/kg, respectively, or 2.6 and 11.5 times, respectively, the recommended maximum human daily dose on a mg/m2 basis. Evidence of maternal toxicity was also observed at these doses.

• When administered to rats prior to and during mating (males and females) and throughout gestation and lactation (females), riluzole produced adverse effects on pregnancy (decreased implantations, increased intrauterine death) and offspring viability and growth at an oral dose of 15 mg/kg or 1.5 times the maximum daily dose on a mg/m2 basis.

• There are no adequate and well-controlled studies in pregnant women. Riluzole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy Category (AUS): (Description)

Labor and Delivery

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Nursing Mothers

• In rat studies, 14C-riluzole was detected in maternal milk. It is not known whether riluzole is excreted in human breast milk. Because many drugs are excreted in human milk, and because the potential for serious adverse reactions in nursing infants from riluzole is unknown, women should be advised not to breast-feed during treatment with riluzole.

Pediatric Use

• The safety and the effectiveness of riluzole in pediatric patients have not been established.

Geriatic Use

• Age-related compromised renal and hepatic function may cause a decrease in clearance of riluzole. In controlled clinical trials, about 30% of patients were over 65. There were no differences in adverse effects between younger and older patients.

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Renal Impairment

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Hepatic Impairment

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Females of Reproductive Potential and Males

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Immunocompromised Patients

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Others

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Administration and Monitoring

Administration

• Oral

• Riluzole tablets should be taken at least an hour before, or two hours after, a meal to avoid a food-related decrease in bioavailability.

Monitoring

Condition 1

(Description regarding monitoring, from Warnings section)

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(Description regarding monitoring, from Warnings section)

Condition 3

(Description regarding monitoring, from Warnings section)

IV Compatibility

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Y-Site

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Admixture

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Syringe

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TPN/TNA

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Overdosage

Acute Overdose

Signs and Symptoms

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Management

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Chronic Overdose

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Management

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Pharmacology

Riluzole
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Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

• Riluzole was not carcinogenic in mice or rats when administered for 2 years at daily oral doses up to 20 mg/kg and 10 mg/kg, respectively, which are approximately equivalent to the maximum human dose on a mg/m2 basis.

• The genotoxic potential of riluzole was evaluated in the bacterial mutagenicity (Ames) test, the mouse lymphoma mutation assay in L5178Y cells, the in vitro chromosomal aberration assay in human lymphocytes and the in vivo rat cytogenetic assay and in vivo mouse micronucleus assay in bone marrow. There was no evidence of mutagenic or clastogenic potential in the Ames test, the mouse lymphoma assay, or the in vivo assays in the mouse and rat. There was an equivocal clastogenic response in the in vitro human lymphocyte chromosomal aberration assay, which was not reproduced in a second assay performed at equal or higher concentrations; riluzole was therefore considered non-clastogenic in the human lymphocyte assay.

• N-hydroxyriluzole, the major active metabolite of riluzole, caused chromosomal damage in the in vitro mammalian mouse lymphoma assay and in the in vitro micronucleus assay that used the same mouse lymphoma cell line, L5178Y. N-hydroxyriluzole was not mutagenic in this cell line when tested in the HPRT gene mutation assay, and was negative in the Ames bacterial gene mutation assay (with and without rat or hamster S9), the in vitro UDS assay in rat hepatocytes, the chromosomal aberration test in human lymphocytes, and the in vivo mouse bone marrow micronucleus test.

• Riluzole impaired fertility when administered to male and female rats prior to and during mating at an oral dose of 15 mg/kg or 1.5 times the maximum daily dose on a mg/m2 basis.

Clinical Studies

There is limited information regarding Riluzole Clinical Studies in the drug label.

How Supplied

• Riluzole tablets, USP 50 mg are white to off white colored, round-shaped, biconvex film-coated tablets and debossed with “538” on one side and plain on other side.

They are supplied as follows:

• Unit Dose Box of 30’s ………………...NDC 0179-0150-70

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F)and protect from bright light.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• Patients should be advised to report any febrile illness to their physicians.

• Patients should be advised to report any cough or difficulties in breathing to their physicians.

• Patients and caregivers should be advised that riluzole tablets should be taken on a regular basis and at the same time of the day (e.g., in the morning and evening) each day. If a dose is missed, take the next tablet as originally planned.

• Patients should be warned about the potential for dizziness, vertigo, or somnolence and advised not to drive or operate machinery until they have gained sufficient experience on riluzole to gauge whether or not it affects their mental and/or motor performance adversely.

• Whether alcohol increases the risk of serious hepatotoxicity with riluzole is unknown; therefore, patients being treated with riluzole should be discouraged from drinking excessive amounts of alcohol.

• Patients should also be made aware that riluzole tablets should be stored at temperatures 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) and protected from bright light.

• Riluzole tablets must be kept out of the reach of children.

Precautions with Alcohol

Alcohol-Riluzole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Riluzole Brand Names in the drug label.

Look-Alike Drug Names

• (Paired Confused Name 1a) — (Paired Confused Name 1b)
• (Paired Confused Name 2a) — (Paired Confused Name 2b)
• (Paired Confused Name 3a) — (Paired Confused Name 3b)

Drug Shortage Status

Drug Shortage

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References

The contents of this FDA label are provided by the National Library of Medicine.