July 27, 2016
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Rilutek

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Rilutek




CLINICAL PHARMACOLOGY

Mechanism Of Action

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

Pharmacodynamics

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

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 (½ to 2 times the recommended dosage)
Food effect AUC I 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].

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].

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.

Clinical Studies

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-Meir Curves)

Time to Tracheostomy or Death in ALS Patients in Study 1 -  Illustration

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-Meir Curves)”

Time to Tracheostomy or Death in ALS Patients in Study 2 - Illustration

Last reviewed on RxList: 6/7/2016
This monograph has been modified to include the generic and brand name in many instances.

Rilutek - User Reviews

Rilutek User Reviews

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