Riluzole

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

The recommended dosage for riluzole tablets is 50 mg taken orally twice daily. Riluzole tablets should be taken at least 1 hour before or 2 hours after a meal . Measure serum aminotransferases before and during treatment with riluzole tablets . Recommended dosage: 50 mg twice daily, taken at least 1 hour before or 2 hours after a meal Measure serum aminotransferases before and during treatment (2, 5.1)

5 WARNINGS AND PRECAUTIONS

5.1Hepatic Injury

5.2Neutropenia

5.3Interstitial Lung Disease Hepatic

injury: Use of riluzole tablets is not recommended in patients with baseline elevations of serum aminotransferases greater than 5 times upper limit of normal; discontinue riluzole tablets if there is evidence of liver dysfunction Neutropenia: Advise patients to report any febrile illness Interstitial lung disease: Discontinue riluzole tablets if interstitial lung disease develops

5.1Hepatic Injury Cases of

drug-induced liver injury, some of which were fatal, have been reported in patients taking riluzole tablets. Asymptomatic elevations of hepatic transaminases have also been reported, and in some patients have recurred upon rechallenge with riluzole tablets. 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 tablets. 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 . 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 tablets is not recommended if patients develop hepatic transaminases levels greater than 5 times the ULN. Discontinue riluzole tablets if there is evidence of liver dysfunction (e.g., elevated bilirubin).

5.2Neutropenia 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.

5.3Interstitial Lung Disease Interstitial

lung disease, including hypersensitivity pneumonitis, has occurred in patients taking riluzole tablets. Discontinue riluzole tablets immediately if interstitial lung disease develops.

5.1Hepatic Injury Cases of

drug-induced liver injury, some of which were fatal, have been reported in patients taking riluzole tablets. Asymptomatic elevations of hepatic transaminases have also been reported, and in some patients have recurred upon rechallenge with riluzole tablets. 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 tablets. 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 . 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 tablets is not recommended if patients develop hepatic transaminases levels greater than 5 times the ULN. Discontinue riluzole tablets if there is evidence of liver dysfunction (e.g., elevated bilirubin).

5.2Neutropenia 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.

5.3Interstitial Lung Disease Interstitial

lung disease, including hypersensitivity pneumonitis, has occurred in patients taking riluzole tablets. Discontinue riluzole tablets immediately if interstitial lung disease develops.

Riluzole tablets is contraindicated in patients with a history of severe hypersensitivity reactions to riluzole or to any of its components (anaphylaxis has occurred) . Patients with a history of severe hypersensitivity reactions to riluzole tablets or to any of its components

8 USE IN SPECIFIC POPULATIONS

8.1Pregnancy

8.2Lactation

8.3Females and Males of Reproductive Potential

8.4Pediatric Use

8.5Geriatric Use

8.6Hepatic Impairment

8.7Japanese Patients Pregnancy: Based on

animal data, may cause fetal harm See 17 for PATIENT COUNSELING INFORMATION.

8.1Pregnancy 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 2-4% 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 . 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.

8.2Lactation Risk Summary It

is not known if riluzole is excreted in human milk. Riluzole or its metabolites have been detected in milk of lactating rat. 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.

8.3Females and Males of Reproductive Potential In

rats, oral administration of riluzole resulted in decreased fertility indices and increases in embryolethality .

8.4Pediatric Use Safety and

effectiveness of riluzole tablets in pediatric patients have not been established.

8.5Geriatric Use In

clinical studies of riluzole tablets, 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.

8.6Hepatic 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 of adverse reactions. The impact of severe hepatic impairment on riluzole exposure is unknown.

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

8.7Japanese Patients Japanese

patients are more likely to have higher riluzole concentrations. Consequently, the risk of adverse reactions may be greater in Japanese patients .

8.1Pregnancy 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 2-4% 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 . 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.

8.2Lactation Risk Summary It

is not known if riluzole is excreted in human milk. Riluzole or its metabolites have been detected in milk of lactating rat. 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.

8.3Females and Males of Reproductive Potential In

rats, oral administration of riluzole resulted in decreased fertility indices and increases in embryolethality .

8.4Pediatric Use Safety and

effectiveness of riluzole tablets in pediatric patients have not been established.

8.5Geriatric Use In

clinical studies of riluzole tablets, 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.

8.6Hepatic 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 of adverse reactions. The impact of severe hepatic impairment on riluzole exposure is unknown.

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

8.7Japanese Patients Japanese

patients are more likely to have higher riluzole concentrations. Consequently, the risk of adverse reactions may be greater in Japanese patients .

The following adverse reactions are described below and elsewhere in the labeling: Hepatic Injury Neutropenia Interstitial lung disease Most common adverse reactions (incidence greater than or equal to 5% and greater than placebo) were asthenia, nausea, dizziness, decreased lung function, and abdominal pain To report SUSPECTED ADVERSE REACTIONS, contact Quinn Pharmaceuticals at 954-755-0502 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinial 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 tablets 50 mg twice daily . 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 abdominal pain. 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.

Riluzole Tablets 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%

6.2Postmarketing Experience The

following adverse reactions have been identified during postapproval use of riluzole tablets. 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 Renal tubular impairment Pancreatitis