Rilutek Information
Rilutek () Description
Rilutek () ® (riluzole) is a member of the benzothiazole class. Chemically, riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole. Its molecular formula is CHFNOS and its molecular weight is 234.2. Its structural formula is as follows:
Riluzole is a white to slightly yellow powder that is very soluble in dimethylformamide, dimethylsulfoxide and methanol, freely soluble in dichloromethane, sparingly soluble in 0.1 N HCl and very slightly soluble in water and in 0.1 N NaOH. Rilutek () is available as a capsule-shaped, white, film-coated tablet for oral administration containing 50 mg of riluzole. Each tablet is engraved with "RPR 202" on one side.
Rilutek () Clinical Pharmacology
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 experimental models of neuronal injury involving excitotoxic mechanisms. In 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).
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 C 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 ).
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 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.
Following a single 150 mg dose of C-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.
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 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, 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 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 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.
Rilutek () Indications And Usage
Rilutek () is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole extends survival and/or time to tracheostomy.
Rilutek () Contraindications
Rilutek () is contraindicated in patients who have a history of severe hypersensitivity reactions to riluzole or any of the tablet components.
Rilutek () Warnings
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 and 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 × ULN, but there is the possibility of increased ALT values reoccurring (see ). Therefore, rechallenge is not recommended.
In postmarketing experience, cases of clinical hepatitis associated with riluzole have been reported, including with fatal outcome.
Rilutek () Precautions
Patients should be advised to report any febrile illness to their physicians (see ).
Patients should be advised to report any cough or difficulties in breathing to their physicians (see ).
Patients and caregivers should be advised that Rilutek () should be taken on a regular basis and at the same time of the day ( in the morning and evening) each day. If a dose is missed, take the next tablet as originally planned (see ).
Patients should be warned about the potential for dizziness, vertigo, or somnolence and advised not to drive or operate machinery until they have gained sufficient experience on Rilutek () to gauge whether or not it affects their mental and/or motor performance adversely.
Whether alcohol increases the risk of serious hepatotoxicity with Rilutek () is unknown; therefore, patients being treated with Rilutek () should be discouraged from drinking excessive amounts of alcohol.
Patients should also be made aware that Rilutek () should be stored at temperatures between 20°–25°C (68°–77°F) and protected from bright light.
Rilutek () must be kept out of the reach of children.
Serum aminotransferases including ALT levels should be measured before and during riluzole therapy. Serum ALT levels should be evaluated every month during the first 3 months of treatment, every 3 months during the remainder of the first year, and periodically thereafter. Serum ALT levels should be evaluated more frequently in patients who develop elevations (see ).
As noted in the Section, there is no experience with continued treatment of patients once ALT exceeds 5 × ULN. Treatment should be discontinued if ALT levels are ≥ 5 × ULN or if clinical jaundice develops. 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. Therefore, rechallenge is not recommended.
In the two controlled trials in patients with ALS, the frequency with which values for hemoglobin, hematocrit, and erythrocyte counts fell below the lower limit of normal was greater in Rilutek () -treated patients than in placebo-treated patients; however, these changes were mild and transient. The proportions of patients observed with abnormally low values for these parameters showed a dose-response relationship. Only one patient was discontinued from treatment because of severe anemia. The significance of this finding is unknown.
There have been no clinical studies designed to evaluate the interaction of riluzole with other drugs.
As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
Riluzole was not carcinogenic in mice or rats when administered for 2 years at daily oral doses up to 20 mg/kg and 10 mg/kg, respectively, which are approximately equivalent to the maximum human dose on a mg/m basis.
The genotoxic potential of riluzole was evaluated in the bacterial mutagenicity (Ames) test, the mouse lymphoma mutation assay in L5178Y cells, the chromosomal aberration assay in human lymphocytes and the rat cytogenetic assay and mouse micronucleus assay in bone marrow. There was no evidence of mutagenic or clastogenic potential in the Ames test, the mouse lymphoma assay, or the assays in the mouse and rat. There was an equivocal clastogenic response in the human lymphocyte chromosomal aberration assay, which was not reproduced in a second assay performed at equal or higher concentrations; riluzole was therefore considered non-clastogenic in the human lymphocyte assay.
N-hydroxyriluzole, the major active metabolite of riluzole, caused chromosomal damage in the mammalian mouse lymphoma assay and in the micronucleus assay that used the same mouse lymphoma cell line, L5178Y. N-hydroxyriluzole was not mutagenic in this cell line when tested in the HPRT gene mutation assay, and was negative in the Ames bacterial gene mutation assay (with and without rat or hamster S9), the UDS assay in rat hepatocytes, the chromosomal aberration test in human lymphocytes, and the mouse bone marrow micronucleus test.
Riluzole impaired fertility when administered to male and female rats prior to and during mating at an oral dose of 15 mg/kg or 1.5 times the maximum daily dose on a mg/m basis (see for effects on fertility).
Rilutek () Adverse Reactions
The most commonly observed AEs associated with the use of Rilutek () more frequently than placebo treated patients were: asthenia, nausea, dizziness, decreased lung function, diarrhea, abdominal pain, pneumonia, vomiting, vertigo, circumoral paresthesia, anorexia, and somnolence. Asthenia, nausea, dizziness, diarrhea, anorexia, vertigo, somnolence, and circumoral paresthesia were dose related.
Approximately 14% (n = 141) of the 982 individuals with ALS who received Rilutek () in pre-marketing clinical trials discontinued treatment because of an adverse experience. Of those patients who discontinued due to adverse events, the most commonly reported were: nausea, abdominal pain, constipation, and ALT elevations. In a dose response study in ALS patients, the rates of discontinuation of Rilutek () for asthenia, nausea, abdominal pain, and ALT elevation were dose related.
Rilutek () Overdosage
No specific antidote or information on treatment of overdosage with Rilutek () is available. In the event of overdose, Rilutek () therapy should be discontinued immediately. Experience with riluzole overdose in humans is limited. Neurological and psychiatric symptoms, acute toxic encephalopathy with stupor, coma, and methemoglobinemia have been observed in isolated cases. Treatment should be supportive and directed toward alleviating symptoms.
Severe methemoglobinemia may be rapidly reversible after treatment with methylene blue.
The estimated oral median lethal dose is 94 mg/kg and 39 mg/kg for male mice and rats, respectively.
Rilutek () Dosage And Administration
The recommended dose for Rilutek () is 50 mg every 12 hours. No increased benefit can be expected from higher daily doses, but adverse events are increased.
Rilutek () tablets should be taken at least an hour before, or two hours after, a meal to avoid a food-related decrease in bioavailability.
Rilutek () How Supplied
Rilutek () 50 mg tablets are white, film-coated, capsule-shaped and engraved with "RPR 202" on one side. Rilutek () is supplied in bottles of 60 tablets, NDC 0075-7700-60.
Rilutek ()
Rilutek () Principal Display Panel - Mg - Tablet Bottle
