Riluzole

Pronunciation: (RIL-ue-zole)
Class: CNS agent

Trade Names

Rilutek
- Tablets 50 mg

Pharmacology

Unknown; however, the following properties may be related to its effect: inhibition of glutamate release; inactivation of voltage-dependent sodium channels; interference with intracellular events that follow transmitter binding at excitatory amino acid receptors. These effects may protect neural tissues against degenerative changes.

Pharmacokinetics

Absorption

Well absorbed (approximately 90%). Oral bioavailability is approximately 60%. High-fat meals decrease absorption, decreasing AUC approximately 20% and peak blood levels by approximately 45%. Steady state is less than 5 days.

Distribution

Protein binding is 96%, mainly to albumin and lipoproteins.

Metabolism

Extensively metabolized to 6 major and a number of minor metabolites via CYP-450 dependent hydroxylation and glucuronidation. CYP1A2 is the main isoenzyme involved in N-hydroxylation.

Elimination

Eliminated in urine (more than 85% glucuronide metabolites; 2% unchanged) and small amount in feces. Half-life is 12 h (after multiple dosing).

Special Populations

Renal Function Impairment

There is no significant difference in pharmacokinetic parameters between patients with moderate and severe renal insufficiency and healthy patients.

Hepatic Function Impairment

AUC increased by about 1.7- and 3-fold in patients with mild and moderate chronic hepatic insufficiency, respectively. The pharmacokinetics have not been studied in patients with severe hepatic impairment.

Elderly

The pharmacokinetic parameters after multiple-dose administration are not affected in the elderly.

Gender

Mean Cl was found to be 30% lower in women compared with men in 1 clinical trial.

Race

No significant racial differences in pharmacokinetic parameters were found between Japanese and white patients.

Smoking

Riluzole is eliminated 20% faster in patients who smoke.

Indications and Usage

Treatment of patients with amyotrophic lateral sclerosis (ALS; Lou Gehrig disease).

Contraindications

Standard considerations.

Dosage and Administration

Adults

PO 50 mg every 12 h.

Drug Interactions

Alcohol

Because it is unknown whether alcohol increases the risk of serious hepatotoxicity with riluzole administration, discourage patients from drinking excessive amounts of alcohol.

Carbamazepine plus phenobarbital

Epileptic patients receiving concomitant carbamazepine and phenobarbital experienced marked, rapid elevations of liver enzymes with jaundice and bilirubin 4 mo after starting riluzole. Values returned to normal 7 wk after discontinuation of treatment. Use with caution and carefully monitor liver function.

CYP1A2 inducers (eg, cigarette smoke, omeprazole, rifampin)

May enhance riluzole elimination. Monitor the response of the patient. If an interaction is suspected, increase the riluzole dose as needed.

CYP1A2 inhibitors (eg, amitriptyline, caffeine, quinolones, theophylline)

May reduce riluzole elimination. Monitor the response of the patient. If an interaction is suspected, decrease the riluzole dose as needed.

Food

A high-fat meal reduces riluzole absorption. Riluzole should be taken 1 h before or 2 h after a meal to avoid food-related decreases in bioavailability. Charcoal-broiled food may increase the rate of riluzole elimination.

Hepatotoxic drugs (eg, allopurinol, methyldopa, sulfasalazine)

The clinical trials in ALS excluded patients on concomitant medications that were potentially hepatotoxic. Accordingly, there is no information about the safety of administering riluzole in conjunction with such medications. If such a combination is administered, exercise caution.

Adverse Reactions

Cardiovascular

Hypertension (7%); tachycardia (3%); postural hypotension (2%); palpitations (1%).

CNS

Asthenia (20%); dizziness (13%); headache (8%); depression, hypertonia (6%); vertigo (5%); insomnia, somnolence (4%); circumoral paresthesia (3%); aggravation reaction (2%); agitation, hostility, tremor (at least 1%); malaise (1%).

Dermatologic

Pruritus (4%); eczema (2%); alopecia, exfoliative dermatitis (1%).

GI

Nausea (21%); anorexia, diarrhea (9%); abdominal pain (8%); dyspepsia (6%); vomiting (5%); dry mouth (4%); flatulence (3%); oral moniliasis, stomatitis, tooth disorder (1%).

Genitourinary

Urinary tract infection (5%); dysuria (1%).

Metabolic

Weight loss (5%); peripheral edema (4%).

Respiratory

Decreased lung function (16%); rhinitis (9%); increased cough (4%); sinusitis (2%).

Miscellaneous

Arthralgia (5%); back pain (4%); phlebitis (1%).

Precautions

Monitor

Measure serum aminotransferases before and during therapy. Evaluate serum ALT levels every month during the first 3 mo of treatment, every 3 mo during the remainder of the first year, and periodically thereafter.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution in elderly patients whose hepatic function may be compromised because of age.

Hepatic Function

Use with caution in patients with current evidence or history of abnormal liver function indicated by significant elevations of liver enzymes, bilirubin, or GGT levels. Baseline elevations of several LFTs (especially elevated bilirubin) should preclude use of riluzole.

Special Risk Patients

Women may possess a lower metabolic capacity to eliminate riluzole as compared with men.

Hematologic effects

Cases of marked neutropenia (absolute neutrophil count [ANC] less than 500/mm ³ ) have been reported within the first 2 mo of treatment. Hgb, Hct, and erythrocytes counts were reported to fall below the lower limit of normal during treatment.

Interstitial lung disease

Cases have been reported, some of them severe, and many of these cases were hypersensitivity pneumonitis.

Overdosage

Symptoms

Neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma, and methemoglobinemia.

Patient Information

Instruct patient to take medication at least 1 h before or 2 h after a meal.
Instruct patient to take with a full glass of water.
Instruct patient to take medicine at same time each day and, if a dose is missed, to take the next dose as originally planned.
Instruct patient not to change dose or discontinue medication without consulting health care provider. Larger than prescribed doses do not increase effectiveness, but do increase the adverse effects.
Have patient report any serious adverse effects to health care provider, including asthenia, decreased level of consciousness, diarrhea, dizziness, nausea, and respiratory distress.
Inform patient of need for frequent laboratory tests while taking medication. Be sure to keep appointments.
Instruct patient to report fever to health care provider.
Instruct patient to avoid drinking alcohol in excess while taking this medication.
Advise patient that drug may cause dizziness, somnolence, or vertigo, and not to drive or operate machinery until patient has gained enough experience to gauge whether it affects mental or motor performance adversely.