RILUZOL EN VADEMECUM

RILUZOL

Description: Riluzole is a glutamate antagonist and is the first drug to be approved for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. ALS is a progressive degenerative neuromuscular disease associated with limited survival. Riluzole does not cure the disease or improve symptoms, but it might prolong the survival of patients by approximately 3 months. The cause of ALS is unknown, and prior to the introduction of riluzole there was no treatment available that affected survival. Riluzole appears to be more effective in patients with bulbar-onset disease than for those with limb-onset disease.[1140] There has been some skepticism voiced as to the true effectiveness of riluzole because other glutamate antagonists have failed to provide relief.[1141] Riluzole received FDA approval December 12, 1995, less than 6 months after it was submitted as an NDA. Evaluation of its efficacy in the treatment of Huntington's disease, Parkinson's disease, and in stroke patients is being contemplated. Mechanism of Action: Riluzole is believed to modulate the release of glutamate. Glutamate neuronal damage is one of several theories that have been proposed as a cause of ALS. Glutamate is an excitatory amino acid neurotransmitter. It has been hypothesized that in ALS, glutamate accumulates in toxic concentrations at synapses and causes neurons to die. This theory is supported by evidence of reduced tissue glutamate levels and reduced glutamate reuptake in ALS, while at the same time CSF glutamate levels are increased.[1142] Riluzole has several pharmacological properties, although its exact mode of action is not known. Riluzole apparently interferes with the effects of excitatory amino acids, mainly glutamate. The mechanism by which this happens is not clearly known. Mechanisms that have been postulated include the inhibition of glutamate release, blockade or inactivation of voltage-dependent sodium channels, and/or an inactivation of a G-protein mediated pathway. Animal studies have shown that riluzole can protect motor neurons from excitotoxic effects of glutamic acid and prevent death of corticol neurons induced by anoxia. Pharmacokinetics: Riluzole is administered orally. It is well absorbed from the gastrointestinal tract (about 90%) and has absolute bioavailability of about 60%. The absorption of riluzole is affected by high-fat meals, which reduce the AUC by about 20% and peak blood levels by about 45%. Riluzole exhibits linear pharmacokinetics. Steady-state plasma concentrations are achieved within 5 days of multiple-dose administration. Riluzole is highly bound to plasma protein (about 96%), mainly to albumin and lipoproteins. Hepatic metabolism of riluzole is extensive, producing six major and a number of minor metabolites. The cytochrome P450 enzyme system is involved in hydroxylation and glucuronidation. The main isozyme involved in hydroxylation is CYP 1A2. The rate of clearance can vary between individuals because CYP 1A2 has considerable inter-individual variability. CYP 1A2 is also reportedly more active in men than in women. Cigarette smoking induces this isozyme and might also affect riluzole clearance. Although direct glucuronidation is slow, N-hydroxyriluzole readily conjugates to form glucuronides. Reduced hepatic function will delay plasma clearance of riluzole and require dosage adjustments. Japanese patients were found to clear riluzole 50% less efficiently than their caucasian counterparts. Japanese could have a lower capacity for metabolism. Possible genetic and environmental factors also might be involved. Excretion of riluzole is mainly renal. Over a period of 7 days, 90% of a 150 mg dose appears in the urine of healthy subjects and 5% in the feces. Riluzole is largely excreted as glucuronides. Only about 2% is excreted as unchanged drug. Because excretion is mainly renal, decreased renal function will result in higher plasma concentrations of riluzole and necessitates dosage adjustment

Indications...Dosage For the treatment of amyotrophic lateral sclerosis (ALS) to extend survival and/or time to tracheostomy: Oral dosage: Adults: 50 mg PO every 12 hours. The findings of the ALS/Riluzole Study Group were published first in 1994. This study revealed that a dose of 50 mg PO twice daily appeared to slow the progression of ALS. The treatment effect was greater in patients with bulbar-onset disease than in those with limb-onset disease.[1140] Following this, a dose-ranging study was conducted in a larger number of patients. Doses of 25 mg PO twice daily, 50 mg PO twice daily, and 100 mg PO twice daily were compared to placebo. After 18 months, 50.4% of placebo group, 55.3% of the low-dose group, 56.8% of the intermediate-dose group, and 57.8% of the high-dose group were alive without tracheostomy. After adjustment for prognostic factors, the authors concluded that a significant drug effect was seen. Some ADRs were more frequent in the high-dose group. The authors concluded that the intermediate-dose group (e.g., 50 mg PO twice daily) provided the best benefit-to-risk ratio.[1286] Elderly: Dosage adjustment may be needed, but no specific recommendations are available. Patients with renal impairment: Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Patients with hepatic impairment: Dosage adjustments may be necessary, but no specific recommendations are available. Specific patient populations: Dosage modification may be necessary in the elderly, females, and Japanese patients, but no quantitative recommendations are available.

Oral Administration �Administer at least one hour before, or two hours after, a meal.

Contraindications The metabolism of riluzole depends largely on the activity of a specific isozyme, CYP 1A2. This isozyme reportedly is more active in males than females. Higher blood concentrations of riluzole and its metabolites may be present in women. Tobacco smoking can induce the isozyme CYP 1A2. Smokers might eliminate riluzole more quickly than nonsmokers. The significance of this reaction has not been assessed in terms of dosage adjustment. Native Japanese patients have been found to clear riluzole less effectively than caucasians; clearance of riluzole is 50% less. It is uncertain whether this effect is the result of different metabolic function or of environmental factors such as smoking, alcohol, coffee, or diet. Hepatic disease, renal disease, or renal impairment can affect the clearance of riluzole, which is extensively metabolized in the liver and excreted in the urine. The presence of elevated LFTs prior to use should preclude treatment with riluzole, which is known to elevate hepatic enzymes. About 50% of all patients treated will have an ALT/SGPT level above the upper limit of normal. Elderly patients are more likely to have age-related changes in hepatic or renal function. No specific recommendations for dosage in any of these special population groups have been made, but these patients should be treated with caution. Riluzole is classified as pregnancy category C. Riluzole affected fetal development and viability in animal studies. There have been no adequate studies of the effect of riluzole on human pregnanc,y and it should be administered only when the benefits outweigh the risks. It is not known whether riluzole is excreted into human breast milk. Breast-feeding should be avoided because the potential for adverse effects on the infant are unknown.

Interactions Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs (e.g., allopurinol, methyldopa, sulfasalazine) and riluzole has not been established. Caution is recommended if any of these drugs are to be used concomitantly with riluzole. The risk of hepatic injury can be increased by concomitant use of other known hepatic enzyme inducers (e.g., barbiturates, carbamazepine). In clinical trials, a non-ALS epileptic patient taking carbamazepine and phenobarbital experienced a rapid rise in liver enzymes with jaundice 4 months after riluzole therapy was initiated. Seven weeks after discontinuation of riluzole, enzyme levels returned to normal (manufacturer's data on file.) The principal isozyme involved in initial oxidative metabolism of riluzole is CYP 1A2. Inhibitors of this enzyme (e.g., caffeine, theophylline, amitriptyline, and the quinolones) could increase plasma concentrations of riluzole by inhibiting the rate of clearance. Conversely, CYP 1A2 inducers (e.g., cigarette smoke, charcoal-broiled food, rifampin, and omeprazole) could increase the rate of clearance of riluzole. In turn, riluzole might also affect other drugs that depend on the CYP 1A2 isozyme for oxidative metabolism. Drugs that are primarily metabolized by CYP 1A2 include caffeine, theophylline, and tacrine. Riluzole is highly bound to plasma proteins. It does not appear to displace warfarin, however, and it is unaffected by the addition of warfarin, digoxin, imipramine, and quinine at high therapeutic concentrations.

Adverse Reactions NOTE: The evaluation of adverse events caused by riluzole presents some difficulty because the disease state being treated exhibits a number of manifestations often associated with adverse drug reactions. ALS affects motor neurons but does not affect sensory function. Ultimate neuronal cell death leads to muscular weakness, muscle atrophy and fasciculations, spasticity, dysarthria (slurred speech), dysphagia, and respiratory compromise. Decreasing lung function ultimately results in tracheostomy. In reviewing the adverse events reported most frequently for patients taking riluzole, natural disease progression must be considered. The most frequently reported adverse events with riluzole therapy were: asthenia, nausea/vomiting, dizziness, hypoventilation, diarrhea, abdominal pain, pneumonia, vertigo, circumoral paresthesias, anorexia, and drowsiness. Other adverse events occurring more frequently in the riluzole group (at a dose of 100 mg/day) than in the placebo group include cough, stomatitis, malaise, sinus tachycardia, hypertension, and back pain. Of these events, asthenia, nausea, dizziness (occurring in 11% of females vs. 4% of males), diarrhea, anorexia, vertigo, and drowsiness were dose-related. Although there were a number of other adverse events reported, with an incidence greater than 2% following a dose of 100 mg/day of riluzole, these were equal to or less than those reported in the placebo group. Overall, riluzole has a positive effect on muscle function and survival time that outweighs the adverse effects of the drug. Riluzole causes serum aminotransferase elevations in patients without a history of abnormal liver function. Measurement of ALT/SGPT levels recorded above the upper limit of normal (ULN) for patients taking riluzole are likely to be: 50% of patients will have >=1 event above normal; 8% of patients will have events >3 times ULN; and 2% of patients will have events >5 times ULN. Jaundice has rarely been reported, but patients were withdrawn from the trial if ALT at values >5 times ULN. Elevated hepatic enzymes was one of the most frequently cited causes of withdrawal from trials.

Riluzole Rilutek�

1140. Bensimon G, Lacomblez L, Meininger V et al. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994;330:585�91.

1141. Rowland LP. Riluzole for the treatment of amyotrophic lateral sclerosis � too soon to tell? N Engl J Med 1994;330:636�7.

1142. Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 1992;326:1464�8.

1286. Lacomblez L, Bensimon G, Leigh PN et al. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 1996;347:1425�31.