RILUTEK (riluzole) is a member of the benzothiazole class. The chemical designation for riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole. Its molecular formula is C8H5F3N2OS, and its molecular weight is 234.2. The chemical structure is:
RILUTEK 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.
Each film-coated tablet for oral use contains 50 mg of riluzole and the following inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.
RILUTEK is indicated for the treatment of amyotrophic lateral sclerosis (ALS).
DOSAGE AND ADMINISTRATION
The recommended dosage for RILUTEK is 50 mg taken orally twice daily. RILUTEK should be taken at least 1 hour before or 2 hours after a meal [see CLINICAL PHARMACOLOGY].
Measure serum aminotransferases before and during treatment with RILUTEK [see WARNINGS AND PRECAUTIONS].
Dosage Forms And Strengths
Tablets: 50 mg film-coated, capsule-shaped, white, with “RPR 202” on one side.
Storage And Handling
RILUTEK 50 mg tablets are white, capsule-shaped, film-coated, and engraved with “RPR 202” on one side. RILUTEK is supplied in bottles of 60 tablets, NDC 70515-700-60.
Store at controlled room temperature, 20°C to 25°C (68°F to 77°F), and protect from bright light.
Manufactured for: Covis Pharma, Zug, 6300 Switzerland. Revised: Mar 2020
The following adverse reactions are described below and elsewhere in the labeling:
- Hepatic Injury [see WARNINGS AND PRECAUTIONS]
- Neutropenia [see WARNINGS AND PRECAUTIONS]
- Interstitial lung disease [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse Reactions In Controlled Clinical Trials
In the placebo-controlled clinical trials in patients with ALS (Study 1 and 2), a total of 313 patients received RILUTEK 50 mg twice daily [see Clinical Studies]. The most common adverse reactions in the RILUTEK group (in at least 5% of patients and more frequently than in the placebo group) were asthenia, nausea, dizziness, decreased lung function, and abdominal pain. The most common adverse reactions leading to discontinuation in the RILUTEK group were nausea, abdominal pain, constipation, and elevated ALT.
There was no difference in rates of adverse reactions leading to discontinuation in females and males. However, the incidence of dizziness was higher in females (11%) than in males (4%). The adverse reaction profile was similar in older and younger patients. There were insufficient data to determine if there were differences in the adverse reaction profile in different races.
Table 1 lists adverse reactions that occurred in at least 2% of RILUTEK-treated patients (50 mg twice daily) in pooled Study 1 and 2, and at a higher rate than placebo.
Table 1: Adverse Reactions in Pooled Placebo-Controlled Trials (Studies 1 and 2) in Patients with ALS
|RILUTEK 50 mg twice daily|
|Decreased lung function||10%||9%|
|Urinary Tract Infection||3%||2%|
The following adverse reactions have been identified during postapproval use of RILUTEK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Acute hepatitis and icteric toxic hepatitis [see WARNINGS AND PRECAUTIONS]
- Renal tubular impairment
Agents That May Increase Riluzole Blood Concentrations
Co-administration of RILUTEK (a CYP1A substrate) with CYP1A2 inhibitors was not evaluated in a clinical trial; however, in vitro findings suggest an increase in riluzole exposure is likely. The concomitant use of strong or moderate CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin, fluvoxamine, methoxsalen, mexiletine, oral contraceptives, thiabendazole, vemurafenib, zileuton) with RILUTEK may increase the risk of RILUTEK-associated adverse reactions [see CLINICAL PHARMACOLOGY].
Agents That May Decrease Riluzole Plasma Concentrations
Co-administration of RILUTEK (a CYP1A substrate) with CYP1A2 inducers was not evaluated in a clinical trial; however, in vitro findings suggest a decrease in riluzole exposure is likely. Lower exposures may result in decreased efficacy [see CLINICAL PHARMACOLOGY].
Clinical trials in ALS patients excluded patients on concomitant medications which were potentially hepatotoxic (e.g., allopurinol, methyldopa, sulfasalazine). RILUTEK-treated patients who take other hepatotoxic drugs may be at an increased risk for hepatotoxicity [see WARNINGS AND PRECAUTIONS].
Reported symptoms of overdose following ingestion of RILUTEK ranging from 1.5 to 3 grams (30 to 60 times the recommended dose) included acute toxic encephalopathy, coma, drowsiness, memory loss, and methemoglobinemia.
No specific antidote for the treatment of RILUTEK overdose is available. For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org.
RILUTEK is contraindicated in patients with a history of severe hypersensitivity reactions to riluzole or to any of its components (anaphylaxis has occurred) [see ADVERSE REACTIONS].
Mechanism Of Action
The mechanism by which riluzole exerts its therapeutic effects in patients with ALS is unknown.
The clinical pharmacodynamics of riluzole has not been determined in humans.
Table 2 displays the pharmacokinetic parameters of riluzole.
Table 2: Pharmacokinetic Parameters of Riluzole
|Bioavailability (oral)||Approximately 60%|
|Dose Proportionality||Linear over a dose range of 25 mg to 100 mg every 12 hours (½ to 2 times the recommended dosage)|
|Food effect||AUC ↓20% and Cmax ↓ 45% (high fat meal)|
|Plasma Protein Binding||96% (Mainly to albumin and lipoproteins)|
|Fraction metabolized (% dose)||At least 88%|
|Primary metabolic pathway(s) [in vitro]|
|Active Metabolites||Some metabolites appear pharmacologically active in vitro, but the clinical implications are not known.|
|Primary elimination pathways (% dose)|
Compared with healthy volunteers, the AUC of riluzole was approximately 1.7-fold greater in patients with mild chronic hepatic impairment (CP score A) and approximately 3-fold greater in patients with moderate chronic hepatic impairment (CP score B). The pharmacokinetics of riluzole have not been studied in patients with severe hepatic impairment (CP score C) [see Use In Specific Populations].
The clearance of riluzole was 50% lower in male Japanese subjects than in Caucasian subjects, after normalizing for body weight [see Use In Specific Populations].
The mean AUC of riluzole was approximately 45% higher in female patients than male patients.
The clearance of riluzole in tobacco smokers was 20% greater than in nonsmokers.
Geriatric Patients And Patients With Moderate To Severe Renal Impairment
Age 65 years or older, and moderate to severe renal impairment do not have a meaningful effect on the pharmacokinetics of riluzole. The pharmacokinetics of riluzole in patients undergoing hemodialysis are unknown.
Drug Interaction Studies
Drugs Highly Bound To Plasma Proteins
Riluzole and warfarin are highly bound to plasma proteins. In vitro, riluzole did not show any displacement of warfarin from plasma proteins. Riluzole binding to plasma proteins was unaffected by warfarin, digoxin, imipramine and quinine at high therapeutic concentrations in vitro.
The efficacy of RILUTEK was demonstrated in two studies (Study 1 and 2) that evaluated RILUTEK 50 mg twice daily in patients with amyotrophic lateral sclerosis (ALS). Both studies included 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% of normal.
Study 1 was a randomized, double-blind, placebo-controlled clinical study that enrolled 155 patients with ALS. Patients were randomized to receive RILUTEK 50 mg twice daily (n=77) or placebo (n=78) and were followed for at least 13 months (up to a maximum duration of 18 months). The clinical outcome measure was time to tracheostomy or death.
The time to tracheostomy or death was longer for patients receiving RILUTEK compared to placebo. There was an early increase in survival in patients receiving RILUTEK compared to placebo. Figure 1 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 in Figure 1, the study showed an early increase in survival in patients given RILUTEK. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between the RILUTEK 50 mg twice daily and placebo groups was approximately 90 days.
Figure 1: Time to Tracheostomy or Death in ALS Patients in Study 1 (Kaplan-Meier Curves)
Study 2 was a randomized, double-blind, placebo-controlled clinical study that enrolled 959 patients with ALS. Patients were randomized to RILUTEK 50 mg twice daily (n=236) or placebo (n=242) and were followed for at least 12 months (up to a maximum duration of 18 months). The clinical outcome measure was time to tracheostomy or death.
The time to tracheostomy or death was longer for patients receiving RILUTEK compared to placebo. Figure 2 displays the survival curves for time to death or tracheostomy for patients randomized to either RILUTEK 100 mg per day 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 RILUTEK 50 mg per day (one-half of the recommended daily dose), which could not be statistically distinguished from placebo, or the results of RILUTEK 200 mg per day (two times the recommended daily dose), which were not distinguishable from the 100 mg per day results. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between RILUTEK and placebo was approximately 60 days.
Although RILUTEK improved survival in both studies, measures of muscle strength and neurological function did not show a benefit.
Figure 2: Time to Tracheostomy or Death in ALS Patients in Study 2 (Kaplan-Meier Curves)
Advise patients to inform their healthcare provider if they experience:
- Yellowing of the whites of the eyes [see WARNINGS AND PRECAUTIONS]
- Fever [see WARNINGS AND PRECAUTIONS]
- Respiratory symptoms - for example, dry cough and difficult or labored breathing [see WARNINGS AND PRECAUTIONS]
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