Pharmacology

Pharmacodynamics. The mode of action of riluzole is not known. The following pharmacologic properties may be related to its beneficial effect in amyotrophic lateral sclerosis:

Pharmacokinetics. Important points are as follows:

Formulations. An oral liquid formulation, 5 mg/mL suspension, is now available and provides an important therapeutic option for patients with amyotrophic lateral sclerosis, as most of them are unable to swallow solid tablets due to disease-related dysphagia (06).

Delivery of riluzole to the brain. Entry of riluzole into the brain across the blood-brain barrier is restricted because it is a substrate of P-glycoprotein. A formulation of riluzole with lipid nanoparticles has been shown to improve delivery to the brain with greater efficacy than free riluzole in rats (03). Results of another animal experimental study indicate that nanoemulsion of riluzole for intranasal administration improves delivery to the brain and has the potential to reduce the dose of riluzole and avoid dose-related adverse events during treatment of amyotrophic lateral sclerosis (19).

Clinical trials

Main evidence for the approval of riluzole was based on a prospective, randomized, double-blind, placebo-controlled trial (02). Riluzole appeared to slow the progression of amyotrophic lateral sclerosis and improve survival in patients with bulbar onset of the disease. Another double-blind, placebo-controlled, multicenter study was carried out to confirm these findings and to assess drug efficacy at different doses (14). The study confirmed that riluzole is well tolerated and lengthens survival of patients with amyotrophic lateral sclerosis. Efficacy and safety results suggest that a 100 mg dose of riluzole has the best benefit-to-risk ratio. Over an 18-month period, there was a 35% decreased risk of death with a 100 mg dose compared with placebo.

The Cochrane Review of controlled clinical trials concluded that riluzole is reasonably safe and probably prolongs median survival of patients with amyotrophic lateral sclerosis by about 2 to 3 months (18).

As of October 2021, 114 clinical trials of riluzole are listed on the United States government website: ClinicalTrials.gov. Only 62 of these are for amyotrophic lateral sclerosis and the rest are for other indications.

Indications

Riluzole is indicated for the treatment of amyotrophic lateral sclerosis.

Off-label uses

Contraindications

Riluzole is contraindicated in patients with hypersensitivity to riluzole or any of the tablet components.

Goals and duration of treatment

The aim of riluzole is to extend survival time of patients with amyotrophic lateral sclerosis. Riluzole is not a cure for amyotrophic lateral sclerosis, but the modest prolongation of survival that riluzole provides represents a first step forward in treating amyotrophic lateral sclerosis patients.

Most population studies that compared riluzole to riluzole-free patients with amyotrophic lateral sclerosis found significant differences in median survival between the two groups, ranging from 6 to 19 months, which is substantially longer than the 2- to 3-month survival benefit observed in the pivotal clinical trials of riluzole (01).

A 10-year observational study in Italy has evaluated the impact of riluzole and other therapeutic interventions on the survival of patients with amyotrophic lateral sclerosis in a setting that resembles clinical practice more closely than randomized controlled trials (10). Riluzole was shown to prolong life significantly longer than noninvasive ventilation and enteral nutrition.

Dosing

Dosing of riluzole is 50 mg every 12 hours.

Special considerations

Riluzole should be used with caution in patients with hepatic and renal insufficiency.

Pediatric. The safety and efficacy of riluzole in this age group have not been established.

Geriatric. Age-related decreases in liver and kidney function may cause a decrease in clearance of riluzole. Otherwise, there are no differences in adverse effects between younger patients and those over the age of 65 years.

Pregnancy. Embryotoxicity has been observed in experimental animals given doses of riluzole equivalent to the maximum human therapeutic dose. No adequate and well-controlled studies have been conducted with pregnant women. Riluzole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Anesthesia. No special precautions.

Interactions

No clinical studies have been done to determine drug interactions, but a potential interaction exists with hepatotoxic drugs and with those drugs that are highly bound to plasma proteins. Drugs that inhibit cytochrome P450 can increase the elimination of riluzole.

Adverse effects

Commonly observed adverse events in clinical trials with riluzole were asthenia, nausea, abdominal pain, dizziness, and liver enzyme elevation. Most of these are dose-related. Riluzole treatment may be associated with mild blood pressure elevations. Riluzole may rarely cause neutropenia. Moderately severe acute pancreatitis has been associated with riluzole therapy (13). Two patients were reported to develop severe recurrent acute pancreatitis with portal vein thrombosis during treatment with riluzole (07).

Management. Most of the adverse effects usually disappear after reduction of dose or discontinuation of therapy.