Riluzole: Package Insert and Label Information

RILUZOLE — riluzole tablet
Ascend Laboratories, LLC

1 INDICATIONS & USAGE

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

2 DOSAGE & ADMINISTRATION

The recommended dosage for riluzole is 50 mg taken orally twice daily. Riluzole 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 riluzole [see Warnings and Precautions (5.1)].

3 DOSAGE FORMS & STRENGTHS

Riluzole Tablets, USP 50 mg is available as a white to off-white coloured, capsule-shaped film coated tablet, debossed with “RIL” on one side and “50” on other side.

4 CONTRAINDICATIONS

Riluzole 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 (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hepatic Injury

Cases of drug-induced liver injury, some of which were fatal, have been reported in patients taking riluzole. Asymptomatic elevations of hepatic transaminases have also been reported, and in some patients have recurred upon rechallenge with riluzole.

In clinical studies, the incidence of elevations in hepatic transaminases was greater in riluzole-treated patients than placebo-treated patients. The incidence of elevations of ALT above 5 times the upper limit of normal (ULN) was 2% in riluzole-treated patients. Maximum increases in ALT occurred within 3 months after starting riluzole. About 50% and 8% of riluzole -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 riluzole is not recommended if patients develop hepatic transaminase levels greater than 5 times the ULN. Discontinue riluzole 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 mm3) within the first 2 months of riluzole 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 riluzole. Discontinue riluzole immediately if interstitial lung disease develops.

6 ADVERSE REACTIONS

The following adverse reactions are described below and elsewhere in the labeling:

· Hepatic Injury [see Warnings and Precautions (5.1)]

· Neutropenia [see Warnings and Precautions (5.2)]

· Interstitial lung disease [see Warnings and Precautions ( 5.3)]

6.1 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 riluzole 50 mg twice daily [see Clinical Studies (14)]. The most common adverse reactions in the riluzole group (in at least 5% of patients and more frequently than in the placebo group) were asthenia, nausea, dizziness, decreased lung function, and abdominalpain. The most common adverse reactions leading to discontinuation in the riluzole 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 riluzole-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

Riluzole 50 mg twice daily (N=313) Placebo (N=320)
Asthenia 19% 12%
Nausea 16% 11%
Decreased lung function 10% 9%
Hypertension 5% 4%
Abdominal pain 5% 4%
Vomiting 4% 2%
Arthralgia 4% 3%
Dizziness 4% 3%
Dry mouth 4% 3%
Insomnia 4% 3%
Pruritus 4% 3%
Tachycardia 3% 1%
Flatulence 3% 2%
Increased cough 3% 2%
Peripheral edema 3% 2%
Urinary Tract Infection 3% 2%
Circumoral paresthesia 2% 0%
Somnolence 2% 1%
Vertigo 2% 1%
Eczema 2% 1%

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of riluzole. 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 (5.1)]

· Renal tubular impairment· Pancreatitis

7 DRUG INTERACTIONS

7.1 Agents that may Increase Riluzole Blood Concentrations

CYP1A2 inhibitors

Co-administration of riluzole (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 riluzole may increase the risk of riluzole-associated adverse reactions [see Clinical Pharmacology (12.3)].

7.2 Agents that may Decrease Riluzole Plasma Concentrations

CYP1A2 inducers

Co-administration of riluzole (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). Riluzole-treated patients who take other hepatotoxic drugs may be at an increased risk for hepatotoxicity [see Warnings and Precautions (5.1)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary There are no studies of riluzole 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 to 4% and 15 to 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 riluzole 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/m2 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/m2 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/m2 basis.

8.2 Lactation

Risk Summary

It is not known if riluzole is excreted in human milk. Riluzole or its metabolites have been detected in milk of lactating rats. Women should be advised that many drugs are excreted in human milk and that the potential for serious adverse reactions in nursing infants from riluzole is unknown.

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)].

8.4 Pediatric Use

Safety and effectiveness of riluzole in pediatric patients have not been established.

8.5 Geriatric Use

In clinical studies of riluzole, 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.

8.6 Hepatic Impairment

Patients with mild [Child-Pugh’s (CP) score A] or moderate (CP score B) hepatic impairment had increases in AUC compared to patients with normal hepatic function. Thus, patients with mild or moderate hepatic impairment may be at increased risk of adverse reactions. The impact of severe hepatic impairment on riluzole exposure is unknown.

Use of riluzole is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal or evidence of liver dysfunction (e.g., elevated bilirubin) [Clinical Pharmacology (12.3)].

8.7 Japanese Patients

Japanese patients are more likely to have higher riluzole concentrations. Consequently, the risk of adverse reactions may be greater in Japanese patients [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Reported symptoms of overdose following ingestion of riluzole 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 riluzole 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.

11 DESCRIPTION

Riluzole is a member of the benzothiazole class. The chemical designation for riluzole is 2-amino-6-(trifluoromethoxy)benzothiazole. Its molecular formula is C8 H5 F3 N2 OS, and its molecular weight is 234.2. The chemical structure is:

riluzole-st

Riluzole is a white to slightly yellow powder that is freely soluble in acetonitrile, in alcohol, in methylene chloride, very slightly soluble in hexane and water. Riluzole Tablets, USP is available as a white to off-white coloured, capsule shaped film coated tablet, debossed with “RIL” on one side and “50” on other side.

Each film-coated tablet for oral use contains 50 mg of riluzole and the following inactive ingredients:

Core: dibasic calcium phosphate dihydrate, USP; croscarmellose sodium, USP/NF; hypromellose, USP; microcrystalline cellulose, USP/NF; magnesium stearate, USP/NF; colloidal silicon dioxide, USP/NF.

Film coating: Opadry Y-1-7000H White (hypromellose, USP; titanium dioxide, USP; polyethylene glycol 400, NF)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

The clinical pharmacodynamics of riluzole has not been determined in humans.

12.3 Pharmacokinetics

Table 2 displays the pharmacokinetic parameters of riluzole.

Table 2. Pharmacokinetic Parameters of Riluzole

A bsorption
Bioavailability (oral) Approximately 60%
Dose Proportionality Linear over a dose range of 25 mg to 100 mg every 12 hours(1/2 to 2 times the recommended dosage)
Food effect AUC ↓ 20% and Cmax ↓ 45% (high fat meal)
D i stribution
Plasma Protein Binding 96% (Mainly to albumin and lipoproteins)
E li m i n ation
Elimination half-life • 12 hours (CV=35%)• The high interindividual variability in the clearance of riluzole is potentially attributable to variability of CYP1A2. The clinical implications are not known.
Accumulation Approximately 2-fold
M etabolism
Fraction metabolized (% dose) At least 88%
Primary metabolic pathway(s) [i n vitro ] • Oxidation: CYP1A2• Direct and sequential glucoronidation: UGT-HP4
Active Metabolites Some metabolites appear pharmacologically active in vitro, but the clinical implications are not known.
Excretion
Primary elimination pathways (% dose) • Feces: 5%• Urine: 90% (2% unchanged riluzole)

Specific Populations

Hepatic Impairment

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 (8.6)].

Race

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 (8.7)].

Gender

The mean AUC of riluzole was approximately 45% higher in female patients than male patients.

Smokers

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.

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