Riluzole (Page 3 of 3)

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/ m 2 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/m 2 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 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 compared to placebo. There was an early increase in survival in patients receiving riluzole 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. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between the riluzole 50 mg twice daily and placebo groups was approximately 90 days.

figure1
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Figure 1. Time to Tracheostomy or Death in ALS Patients in Study 1 (Kaplan-Meir Curves)

Study 2 was a randomized, double-blind, placebo-controlled clinical study that enrolled 959 patients with ALS. Patients were randomized to riluzole 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 compared to placebo. Figure 2 displays the survival curves for time to death or tracheostomy for patients randomized to either riluzole 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 50 mg per day (one-half of the recommended daily dose), which could not be statistically distinguished from placebo, or the results of riluzole 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 and placebo was approximately 60 days.

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

figure2
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Figure 2. Time to Tracheostomy or Death in ALS Patients in Study 2 (Kaplan-Meir Curves)”

16 HOW SUPPLIED/STORAGE AND HANDLING

Riluzole Tablets, USP 50 mg are white to off-white, film-coated, capsule-shaped and engraved with “795” on one side, plain on the other. Riluzole is supplied in bottles of 60 tablets, NDC 42291-775-60.

Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature]. Protect from bright light.

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 symptomsfor example, dry cough and difficult or labored breathing [see Warnings and Precautions ( 5.3)]

Manufactured for:

AvKARE

Pulaski, TN 38478

Mfg. Rev. 09/20

AV 09/20 (P)

50
(click image for full-size original)

RILUZOLE
riluzole tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42291-775(NDC:69076-200)
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
CALCIUM PHOSPHATE, DIBASIC, ANHYDROUS
CELLULOSE, MICROCRYSTALLINE
SILICON DIOXIDE
MAGNESIUM STEARATE
CROSCARMELLOSE SODIUM
HYPROMELLOSES
LACTOSE MONOHYDRATE
TITANIUM DIOXIDE
TRIACETIN
CITRIC ACID MONOHYDRATE
Product Characteristics
Color white (white to off-white) Score no score
Shape OVAL (capsule-shaped) Size 10mm
Flavor Imprint Code 795
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:42291-775-60 60 TABLET, FILM COATED in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA206045 10/07/2020
Labeler — AvKARE (796560394)

Revised: 01/2022 AvKARE

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