Riluzole 50 MG Oral Tablet [Rilutek]

DRUG INTERACTIONS

7 • Strong to moderate CYP1A2 inhibitors: Coadministration may increase RILUTEK-associated adverse reactions ( 7.1 ) • Strong to moderate CYP1A2 inducers: Coadministration may result in decreased efficacy ( 7.2 ) • Hepatotoxic drugs: RILUTEK-treated patients that take other hepatotoxic drugs may be at increased risk for hepatotoxicity ( 7.3 ) 7.1 Agents that may Increase Riluzole Blood Concentrations CYP1A2 inhibitors 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 ( 12.3 )] .

7.2 Agents that may Decrease Riluzole Plasma Concentrations CYP1A2 inducers 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 ( 12.3 )] .

7.3 Hepatotoxic Drugs 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 ( 5.1 )] .

OVERDOSAGE

10 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.

DESCRIPTION

11 RILUTEK (riluzole) is a member of the benzothiazole class.

The chemical designation for riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole.

Its molecular formula is C 8 H 5 F 3 N 2 OS, 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.

Chemical Structure

CLINICAL STUDIES

14 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) Figure 1 Figure 2

HOW SUPPLIED

16 /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 24987-700-60.

Store at controlled room temperature, 20°C to 25°C (68°F to77°F), and protect from bright light.

GERIATRIC USE

8.5 Geriatric Use In clinical studies of RILUTEK, 30% of patients were 65 years and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 Tablets: 50 mg film-coated, capsule-shaped, white, with “RPR 202” on one side.

Tablets: 50 mg ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism by which riluzole exerts its therapeutic effects in patients with ALS is unknown.

INDICATIONS AND USAGE

1 RILUTEK is indicated for the treatment of amyotrophic lateral sclerosis (ALS).

RILUTEK is indicated for the treatment of amyotrophic lateral sclerosis (ALS) ( 1 )

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of RILUTEK in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Risk Summary There are no studies of RILUTEK in pregnant women, and case reports have been inadequate to inform the drug-associated risk.

The background risk for major birth defects and miscarriage in patients with amyotrophic lateral sclerosis is unknown.

In the U.S.

general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

In studies in which riluzole was administered orally to pregnant animals, developmental toxicity (decreased embryofetal/offspring viability, growth, and functional development) was observed at clinically relevant doses [see Data ] .

Based on these results, women should be advised of a possible risk to the fetus associated with use of RILUTEK during pregnancy.

Data Animal Data Oral administration of riluzole (3, 9, or 27 mg/kg/day) to pregnant rats during the period of organogenesis resulted in decreases in fetal growth (body weight and length) at the high dose.

The mid dose, a no-effect dose for embryofetal developmental toxicity, is approximately equal to the recommended human daily dose (RHDD, 100 mg) on a mg/m 2 basis.

When riluzole was administered orally (3, 10, or 60 mg/kg/day) to pregnant rabbits during the period of organogenesis, embryofetal mortality was increased at the high dose and fetal body weight was decreased and morphological variations increased at all but the lowest dose tested.

The no-effect dose (3 mg/kg/day) for embryofetal developmental toxicity is less than the RHDD on a mg/m 2 basis.

Maternal toxicity was observed at the highest dose tested in rat and rabbit.

When riluzole was orally administered (3, 8, or 15 mg/kg/day) to male and female rats prior to and during mating and to female rats throughout gestation and lactation, increased embryofetal mortality and decreased postnatal offspring viability, growth, and functional development were observed at the high dose.

The mid dose, a no-effect dose for pre- and postnatal developmental toxicity, is approximately equal to the RHDD on a mg/m 2 basis.

NUSRING MOTHERS

8.3 Females and Males of Reproductive Potential In rats, oral administration of riluzole resulted in decreased fertility indices and increases in embryolethality [see Nonclinical Toxicology ( 13.1 )] .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Hepatic injury: Use of RILUTEK is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal; discontinue RILUTEK if there is evidence of liver dysfunction ( 5.1 ) • Neutropenia: Advise patients to report any febrile illness ( 5.2 ) • Interstitial lung disease: Discontinue RILUTEK if interstitial lung disease develops ( 5.3 ) 5.1 Hepatic Injury Cases of drug-induced liver injury, some of which were fatal, have been reported in patients taking RILUTEK.

Asymptomatic elevations of hepatic transaminases have also been reported, and in some patients have recurred upon rechallenge with RILUTEK.

In clinical studies, the incidence of elevations in hepatic transaminases was greater in RILUTEK-treated patients than placebo-treated patients.

The incidence of elevations of ALT above 5 times the upper limit of normal (ULN) was 2% in RILUTEK-treated patients.

Maximum increases in ALT occurred within 3 months after starting RILUTEK.

About 50% and 8% of RILUTEK-treated patients in pooled Studies 1 and 2, had at least one elevated ALT level above ULN and above 3 times ULN, respectively [see Clinical Studies ( 14 )] .

Monitor patients for signs and symptoms of hepatic injury, every month for the first 3 months of treatment, and periodically thereafter.

The use of RILUTEK is not recommended if patients develop hepatic transaminases levels greater than 5 times the ULN.

Discontinue RILUTEK if there is evidence of liver dysfunction (e.g., elevated bilirubin).

5.2 Neutropenia Cases of severe neutropenia (absolute neutrophil count less than 500 per mm 3 ) within the first 2 months of RILUTEK treatment have been reported.

Advise patients to report febrile illnesses.

5.3 Interstitial Lung Disease Interstitial lung disease, including hypersensitivity pneumonitis, has occurred in patients taking RILUTEK.

Discontinue RILUTEK immediately if interstitial lung disease develops.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise patients to inform their healthcare provider if they experience: • Yellowing of the whites of the eyes [see Warnings and Precautions ( 5.1 )] • Fever [see Warnings and Precautions ( 5.2 )] • Respiratory symptoms—for example, dry cough and difficult or labored breathing [see Warnings and Precautions ( 5.3 )] Manufactured for: Covis Pharmaceuticals, Inc.

Cary, NC 27511 USA © 2016, Covis Pharmaceuticals Inc.

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DOSAGE AND ADMINISTRATION

2 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 ( 12.3 )] .

Measure serum aminotransferases before and during treatment with RILUTEK [see Warnings and Precautions ( 5.1 )] .

• Recommended dosage: 50 mg twice daily, taken at least 1 hour before or 2 hours after a meal ( 2 ) • Measure serum aminotransferases before and during treatment ( 2 , 5.1 )