Riluzole: Package Insert and Label Information (Page 2 of 2)

8.6 Hepatic Impairment

Patients with mild [Child-Pugh’s (CP) score A] or moderate (CP score B) hepatic impairment had increases in AUC compared to patients with normal hepatic function. Thus, patients with mild or moderate hepatic impairment may be at increased risk of adverse reactions. The impact of severe hepatic impairment on riluzole exposure is unknown.

Use of riluzole tablets is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal or evidence of liver dysfunction (e.g., elevated bilirubin) [see Clinical Pharmacology (12.3)].

8.7 Japanese Patients

Japanese patients are more likely to have higher riluzole concentrations. Consequently, the risk of adverse reactions may be greater in Japanese patients [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Reported symptoms of overdose following ingestion of riluzole tablets ranging from 1.5 to 3 grams (30 to 60 times the recommended dose) included acute toxic encephalopathy, coma, drowsiness, memory loss, and methemoglobinemia.

No specific antidote for the treatment of riluzole tablet overdose is available. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.

11 DESCRIPTION

Riluzole tablets, USP are a member of the benzothiazole class. The chemical designation for riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole. Its molecular formula is C8 H5 F3 N2 OS, and its molecular weight is 234.20. The chemical structure is:

Riluzole Structural Formula
(click image for full-size original)

Riluzole, USP is a white to slightly yellow powder or crystalline powder that is very soluble in dimethylformamide, dimethylsulfoxide, and methanol; freely soluble in dichloromethane; sparingly soluble in 0.1 N HCl; and very slightly soluble in water and in 0.1 N NaOH.

Each film-coated tablet for oral use contains 50 mg of riluzole and the following inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism by which riluzole exerts its therapeutic effects in patients with ALS is unknown.

12.2 Pharmacodynamics

The clinical pharmacodynamics of riluzole has not been determined in humans.

12.3 Pharmacokinetics

Table 2 displays the pharmacokinetic parameters of riluzole.

Table 2. Pharmacokinetic Parameters of Riluzole

Absorption

Bioavailability (oral)

Approximately 60%

Dose Proportionality

Linear over a dose range of 25 mg to 100 mg every 12 hours (1/2 to 2 times the recommended dosage)

Food effect

AUC ↓ 20% and Cmax ↓ 45% (high fat meal)

Distribution

Plasma Protein Binding

96% (Mainly to albumin and lipoproteins)

Elimination

Elimination half-life

12 hours (CV = 35%)
The high interindividual variability in the clearance of riluzole is potentially attributable to variability of CYP1A2. The clinical implications are not known.

Accumulation

Approximately 2-fold

Metabolism

Fraction metabolized (% dose)

At least 88%

Primary metabolic pathway(s) [in vitro]

Oxidation: CYP1A2
Direct and sequential glucoronidation: UGT-HP4

Active Metabolites

Some metabolites appear pharmacologically active in vitro , but the clinical implications are not known.

Excretion

Primary elimination pathways (% dose)

Feces: 5%
Urine: 90% (2% unchanged riluzole)

Specific Populations

Hepatic Impairment

Compared with healthy volunteers, the AUC of riluzole was approximately 1.7-fold greater in patients with mild chronic hepatic impairment (CP score A) and approximately 3-fold greater in patients with moderate chronic hepatic impairment (CP score B). The pharmacokinetics of riluzole have not been studied in patients with severe hepatic impairment (CP score C) [see Use in Specific Populations (8.6)].

Race

The clearance of riluzole was 50% lower in male Japanese subjects than in Caucasian subjects, after normalizing for body weight [see Use in Specific Populations (8.7)].

Gender

The mean AUC of riluzole was approximately 45% higher in female patients than male patients.

Smokers

The clearance of riluzole in tobacco smokers was 20% greater than in nonsmokers.

Geriatric Patients and Patients with Moderate to Severe Renal Impairment

Age 65 years or older, and moderate to severe renal impairment do not have a meaningful effect on the pharmacokinetics of riluzole. The pharmacokinetics of riluzole in patients undergoing hemodialysis are unknown.

Drug Interaction Studies

Drugs Highly Bound To Plasma Proteins

Riluzole and warfarin are highly bound to plasma proteins. In vitro , riluzole did not show any displacement of warfarin from plasma proteins. Riluzole binding to plasma proteins was unaffected by warfarin, digoxin, imipramine and quinine at high therapeutic concentrations in vitro.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Riluzole was not carcinogenic in mice or rats when administered for 2 years at daily oral doses up to 20 and 10 mg/kg/day, respectively, which are approximately equal to the recommended human daily dose (RHDD, 100 mg) on a mg/m2 basis.

Mutagenesis

Riluzole was negative in in vitro (bacterial reverse mutation (Ames), mouse lymphoma tk,chromosomal aberration assay in human lymphocytes), and in vivo (rat cytogenetic and mouse micronucleus) assays.

N-hydroxyriluzole, the major active metabolite of riluzole, was positive for clastogenicity in the in vitro mouse lymphoma tk assay and in the in vitro micronucleus assay using the same mouse lymphoma cell line. N-hydroxyriluzole was negative in the HPRT gene mutation assay, the Ames assay (with and without rat or hamster S9), the in vitro chromosomal aberration assay in human lymphocytes, and the in vivo mouse micronucleus assay.

Impairment of Fertility

When riluzole (3, 8, or 15 mg/kg) was administered orally to male and female rats prior to and during mating and continuing in females throughout gestation and lactation, fertility indices were decreased and embryolethality was increased at the high dose. This dose was also associated with maternal toxicity. The mid dose, a no-effect dose for effects on fertility and early embryonic development, is approximately equal to the RHDD on a mg/m2 basis.

14 CLINICAL STUDIES

The efficacy of riluzole tablets was demonstrated in two studies (Study 1 and 2) that evaluated riluzole tablets 50 mg twice daily in patients with amyotrophic lateral sclerosis (ALS). Both studies included patients with either familial or sporadic ALS, a disease duration of less than 5 years, and a baseline forced vital capacity greater than or equal to 60% of normal.

Study 1 was a randomized, double-blind, placebo-controlled clinical study that enrolled 155 patients with ALS. Patients were randomized to receive riluzole tablets 50 mg twice daily (n = 77) or placebo (n = 78) and were followed for at least 13 months (up to a maximum duration of 18 months). The clinical outcome measure was time to tracheostomy or death.

The time to tracheostomy or death was longer for patients receiving riluzole tablets compared to placebo. There was an early increase in survival in patients receiving riluzole tablets compared to placebo. Figure 1 displays the survival curves for time to death or tracheostomy. The vertical axis represents the proportion of individuals alive without tracheostomy at various times following treatment initiation (horizontal axis). Although these survival curves were not statistically significantly different when evaluated by the analysis specified in the study protocol (Logrank test p = 0.12), the difference was found to be significant by another appropriate analysis (Wilcoxon test p = 0.05). As seen in Figure 1, the study showed an early increase in survival in patients given riluzole tablets. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between the riluzole tablets 50 mg twice daily and placebo groups was approximately 90 days.

Figure 1. Time to Tracheostomy or Death in ALS Patients in Study 1 (Kaplan-Meier Curves)
(click image for full-size original)

Figure 1. Time to Tracheostomy or Death in ALS Patients in Study 1 (Kaplan-Meier Curves)

Study 2 was a randomized, double-blind, placebo-controlled clinical study that enrolled 959 patients with ALS. Patients were randomized to riluzole tablets 50 mg twice daily (n = 236) or placebo (n = 242) and were followed for at least 12 months (up to a maximum duration of 18 months). The clinical outcome measure was time to tracheostomy or death.

The time to tracheostomy or death was longer for patients receiving riluzole tablets compared to placebo. Figure 2 displays the survival curves for time to death or tracheostomy for patients randomized to either riluzole tablets 100 mg per day or placebo. Although these survival curves were not statistically significantly different when evaluated by the analysis specified in the study protocol (Logrank test p = 0.076), the difference was found to be significant by another appropriate analysis (Wilcoxon test p = 0.05). Not displayed in Figure 2 are the results of riluzole tablets 50 mg per day (one-half of the recommended daily dose), which could not be statistically distinguished from placebo, or the results of riluzole tablets 200 mg per day (two times the recommended daily dose), which were not distinguishable from the 100 mg per day results. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between riluzole tablets and placebo was approximately 60 days.

Although riluzole tablets improved survival in both studies, measures of muscle strength and neurological function did not show a benefit.

Figure 2. Time to Tracheostomy or Death in ALS Patients in Study 2 (Kaplan-Meier Curves)
(click image for full-size original)

Figure 2. Time to Tracheostomy or Death in ALS Patients in Study 2 (Kaplan-Meier Curves)

16 HOW SUPPLIED/STORAGE AND HANDLING

Riluzole Tablets, USP are available containing 50 mg of riluzole, USP.

The 50 mg tablets are white, film-coated, capsule shaped, unscored tablets debossed with M on one side of the tablet and RE 50 on the other side. They are available as follows:

NDC 0378-4145-91
bottles of 60 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from bright light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

17 PATIENT COUNSELING INFORMATION

Advise patients to inform their healthcare provider if they experience:

Yellowing of the whites of the eyes [see Warnings and Precautions (5.1)]
Fever [see Warnings and Precautions (5.2)]
Respiratory symptoms—for example, dry cough and difficult or labored breathing [see Warnings and Precautions (5.3)]

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Manufactured by:
Mylan Laboratories Limited
Hyderabad — 500 096, India

75076602

Revised: 8/2020
MX:RILU:R3

PRINCIPAL DISPLAY PANEL – 50 mg

NDC 0378-4145-91

Riluzole
Tablets, USP
50 mg

Rx only 60 Tablets

Each film-coated tablet contains:
Riluzole, USP 50 mg

Usual Dosage: One tablet every 12 hours
by oral route. See accompanying
prescribing information.

Keep this and all medication out of the
reach of children.

Store at 20° to 25°C (68° to 77°F). [See
USP Controlled Room Temperature.]

Protect from bright light.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Made in India

Mylan.com

RMX4145D1

Dispense in a tight, light-resistant
container as defined in the USPusing a child-resistant closure.

Keep container tightly closed.

Code No.: MH/DRUGS/25/NKD/89

Riluzole Tablets, USP 50 mg Bottle Label
(click image for full-size original)
RILUZOLE riluzole tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0378-4145
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
RILUZOLE (RILUZOLE) RILUZOLE 50 mg
Inactive Ingredients
Ingredient Name Strength
ANHYDROUS DIBASIC CALCIUM PHOSPHATE
SILICON DIOXIDE
CROSCARMELLOSE SODIUM
HYPROMELLOSE, UNSPECIFIED
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
POLYETHYLENE GLYCOL, UNSPECIFIED
TITANIUM DIOXIDE
Product Characteristics
Color WHITE Score no score
Shape OVAL (capsule shaped) Size 10mm
Flavor Imprint Code M;RE;50
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0378-4145-91 60 TABLET, FILM COATED in 1 BOTTLE, PLASTIC None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA203042 07/22/2013
Labeler — Mylan Pharmaceuticals Inc. (059295980)

Revised: 08/2020 Mylan Pharmaceuticals Inc.

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