The mechanism by which riluzole exerts its therapeutic effects in patients with ALS is unknown.
The clinical pharmacodynamics of riluzole has not been determined in humans.
Table 2 displays the pharmacokinetic parameters of riluzole.
Linear over a dose range of 25 mg to 100 mg every 12 hours (1/2 to 2 times the recommended dosage)
AUC ↓ 20% and Cmax ↓ 45% (high fat meal)
Plasma Protein Binding
96% (Mainly to albumin and lipoproteins)
Fraction metabolized (% dose)
At least 88%
Primary metabolic pathway(s) [in vitro ]
Some metabolites appear pharmacologically active in vitro, but the clinical implications are not known.
Primary elimination pathways (% dose)
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)].
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)].
The mean AUC of riluzole was approximately 45% higher in female patients than male patients.
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.
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.
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.
The efficacy of RILUTEK was demonstrated in two studies (Study 1 and 2) that evaluated RILUTEK 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 RILUTEK 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 RILUTEK compared to placebo. There was an early increase in survival in patients receiving RILUTEK 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 RILUTEK. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between the RILUTEK 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)
Study 2 was a randomized, double-blind, placebo-controlled clinical study that enrolled 959 patients with ALS. Patients were randomized to RILUTEK 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 RILUTEK compared to placebo. Figure 2 displays the survival curves for time to death or tracheostomy for patients randomized to either RILUTEK 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 RILUTEK 50 mg per day (one-half of the recommended daily dose), which could not be statistically distinguished from placebo, or the results of RILUTEK 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 RILUTEK and placebo was approximately 60 days.
Although RILUTEK 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)
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