Inactive Ingredients

Core: anhydrous dibasic calcium phosphate, USP; microcrystalline cellulose, NF; anhydrous colloidal silica, NF; magnesium stearate, NF; croscarmellose sodium, NF.

Film coating: hypromellose, USP; polyethylene glycol 6000; titanium dioxide, USP.

Mechanism of Action

The etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS the enzyme superoxide dismutase has been found to be defective.

The mode of action of RILUTEK is unknown. Its pharmacological properties include the following, some of which may be related to its effect: 1) an inhibitory effect on glutamate release, 2) inactivation of voltage-dependent sodium channels, and 3) ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors.

Riluzole has also been shown, in a single study, to delay median time to death in a transgenic mouse model of ALS. These mice express human superoxide dismutase bearing one of the mutations found in one of the familial forms of human ALS.

It is also neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. In in vitro tests, riluzole protected cultured rat motor neurons from the excitotoxic effects of glutamic acid and prevented the death of cortical neurons induced by anoxia.

Due to its blockade of glutamatergic neurotransmission, riluzole also exhibits myorelaxant and sedative properties in animal models at doses of 30 mg/kg (about 20 times the recommended human daily dose) and anticonvulsant properties at a dose of 2.5 mg/kg (about 2 times the recommended human daily dose).

Pharmacokinetics

Riluzole is well-absorbed (approximately 90%), with average absolute oral bioavailability of about 60% (CV=30%). Pharmacokinetics are linear over a dose range of 25 to 100 mg given every 12 hours. A high fat meal decreases absorption, reducing AUC by about 20% and peak blood levels by about 45%. The mean elimination half-life of riluzole is 12 hours (CV=35%) after repeated doses. With multiple-dose administration, riluzole accumulates in plasma by about twofold and steady-state is reached in less than 5 days. Riluzole is 96% bound to plasma proteins, mainly to albumin and lipoproteins over the clinical concentration range.

The 50 mg market tablet was equivalent, with respect to AUC, to the tablet used in the dose ranging clinical trials, while the Cmax was approximately 30% higher. Both tablets have been used in clinical trials. However, if doses greater than those recommended are given, it is likely that higher plasma levels will be achieved, the safety of which has not been established (see DOSAGE AND ADMINISTRATION).

Metabolism and Elimination

Riluzole is extensively metabolized to six major and a number of minor metabolites, not all of which have been identified. Some metabolites appear pharmacologically active in in vitro assays. The metabolism of riluzole is mostly hepatic and consists of cytochrome P450-dependent hydroxylation and glucuronidation.

There is marked interindividual variability in the clearance of riluzole, probably attributable to variability of CYP 1A2 activity, the principal isozyme involved in N-hydroxylation.

In vitro studies using liver microsomes show that hydroxylation of the primary amine group producing N-hydroxyriluzole is the main metabolic pathway in human, monkey, dog and rabbit. In humans, cytochrome P450 1A2 is the principal isozyme involved in N-hydroxylation. In vitro studies predict that CYP 2D6, CYP 2C19, CYP 3A4 and CYP 2E1 are unlikely to contribute significantly to riluzole metabolism in humans. Whereas direct glucuroconjugation of riluzole (involving the glucurotransferase isoform UGT-HP4) is very slow in human liver microsomes, N-hydroxyriluzole is readily conjugated at the hydroxylamine group resulting in the formation of O- (>90%) and N-glucuronides.

Following a single 150 mg dose of 14C-riluzole to 6 healthy males, 90% and 5% of the radioactivity was recovered in the urine and feces respectively over a period of 7 days. Glucuronides accounted for more than 85% of the metabolites in urine. Only 2% of a riluzole dose was recovered in the urine as unchanged drug.

Special Populations

Clinical Trials

The efficacy of RILUTEK as a treatment of ALS was established in two adequate and well-controlled trials in which the time to tracheostomy or death was longer for patients randomized to RILUTEK than for those randomized to placebo.

These studies admitted 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%.

In one study, performed in France and Belgium, 155 ALS patients were followed for at least 13 months (maximum duration 18 months) after being randomized to either 100 mg/day (given 50 mg BID) of RILUTEK or placebo.

Figure 1, which follows, 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 eva luated 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, the study showed an early increase in survival in patients given riluzole. Among the patients in whom treatment failed during the study (tracheostomy or death) there was a difference between the treatment groups in median survival of approximately 90 days. There was no statistically significant difference in mortality at the end of the study.

In the second study, performed in both Europe and North America, 959 ALS patients were followed for at least 1 year (North American centers) and up to 18 months (European centers) after being randomized to either 50, 100, 200 mg/day of RILUTEK or placebo.

Figure 2, which follows, displays the survival curves for time to death or tracheostomy for patients randomized to either 100 mg/day of RILUTEK or placebo. Although these survival curves were not statistically significantly different when eva luated 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 50 mg/day of RILUTEK which could not be statistically distinguished from placebo and the results of 200 mg/day which are essentially identical to 100 mg/day. As seen, the study showed an early increase in survival in patients given riluzole. Among the patients in whom treatment failed during the study (tracheostomy or death) there was a difference between the treatment groups in median survival of approximately 60 days. There was no statistically significant difference in mortality at the end of the study.

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

Liver Injury / Monitoring Liver Chemistries

RILUTEK 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 (see PRECAUTIONS and DOSAGE AND ADMINISTRATION sections). Baseline elevations of several LFTs (especially elevated bilirubin) should preclude the use of RILUTEK.

RILUTEK, even in patients without a prior history of liver disease, causes serum aminotransferase elevations. Treatment should be discontinued if ALT levels are ≥ 5 × 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 RILUTEK; 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 RILUTEK discontinued for ALT > 5 × 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 (see ADVERSE REACTIONS) 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.