CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. Riluzole was not carcinogenic in mice or rats when administered for years at daily oral doses up to 20 and 10 mg/kg/day, respectively, which are approximately equal to the recommended human daily dose (RHDD, 100 mg) on mg/m2 basis.. Mutagenesis. Riluzole was negative in in vitro (bacterial reverse mutation (Ames), mouse lymphoma tk,chromosomal aberration assay in human lymphocytes), and in vivo (rat cytogenetic and mouse micronucleus) assays.N-hydroxyriluzole, the major active metabolite of riluzole, was positive for clastogenicity in the in vitro mouse lymphoma tk assay and in the in vitro micronucleus assay using the same mouse lymphoma cell line. N-hydroxyriluzole was negative in the HPRT gene mutation assay, the Ames assay (with and without rat or hamster S9), the in vitro chromosomal aberration assay in human lymphocytes, and the in vivo mouse micronucleus assay.. Impairment of Fertility. When riluzole (3, 8, or 15 mg/kg) was administered orally to male and female rats prior to and during mating and continuing in females throughout gestation and lactation, fertility indices were decreased and embryolethality was increased at the high dose. This dose was also associated with maternal toxicity. The mid dose, no-effect dose for effects on fertility and early embryonic development, is approximately equal to the RHDD on mg/m2 basis.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling:oHepatic Injury [see Warnings and Precautions (5.1)]oNeutropenia [see Warnings and Precautions (5.2)]oInterstitial lung disease [see Warnings and Precautions (5.3)]. oHepatic Injury [see Warnings and Precautions (5.1)]. oNeutropenia [see Warnings and Precautions (5.2)]. oInterstitial lung disease [see Warnings and Precautions (5.3)]. 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 (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 and 2), total of 313 patients received riluzole tablets 50 mg twice daily [see Clinical Studies (14)]. The most common adverse reactions in the riluzole tablets 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 tablets 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 lists adverse reactions that occurred in at least 2% of riluzole tablet-treated patients (50 mg twice daily) in pooled Study and 2, and at higher rate than placebo.Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials (Studies and 2) in Patients with ALSRiluzole Tablets50 mg twice daily(N 313)Placebo(N 320)Asthenia19%12%Nausea16%11%Decreased lung function10%9%Hypertension5%4%Abdominal pain 5%4%Vomiting 4%2%Arthralgia4%3%Dizziness4%3%Dry mouth4%3%Insomnia4%3%Pruritus4%3%Tachycardia3%1%Flatulence3%2%Increased cough3%2%Peripheral edema3%2%Urinary Tract Infection3%2%Circumoral paresthesia2%0%Somnolence2%1%Vertigo2%1%Eczema2%1%. 6.2Postmarketing Experience The following adverse reactions have been identified during postapproval use of riluzole tablets. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.oAcute hepatitis and icteric toxic hepatitis [see Warnings and Precautions (5.1)]oRenal tubular impairmentoPancreatitis. oAcute hepatitis and icteric toxic hepatitis [see Warnings and Precautions (5.1)]. oRenal tubular impairment. oPancreatitis.

CLINICAL PHARMACOLOGY SECTION.

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 displays the pharmacokinetic parameters of riluzole.Table 2. Pharmacokinetic Parameters of RiluzoleAbsorption Bioavailability (oral)Approximately 60% Dose ProportionalityLinear over dose range of 25 mg to 100 mg every 12 hours (1/2 to times the recommended dosage) Food effectAUC 20% and Cmax 45% (high fat meal)Distribution Plasma Protein Binding96% (Mainly to albumin and lipoproteins)Elimination Elimination half-lifeo12 hours (CV 35%) oThe high interindividual variability in the clearance of riluzole is potentially attributable to variability of CYP1A2. The clinical implications are not known. AccumulationApproximately 2-foldMetabolism Fraction metabolized (% dose)At least 88% Primary metabolic pathway(s) [in vitro] oOxidation: CYP1A2 oDirect and sequential glucoronidation: UGT-HP4 Active MetabolitesSome metabolites appear pharmacologically active in vitro, but the clinical implications are not known.Excretion Primary elimination pathways (% dose)oFeces: 5% oUrine: 90% (2% unchanged riluzole) o12 hours (CV 35%) oThe high interindividual variability in the clearance of riluzole is potentially attributable to variability of CYP1A2. The clinical implications are not known.. oOxidation: CYP1A2 oDirect and sequential glucoronidation: UGT-HP4. oFeces: 5% oUrine: 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of riluzole tablets was demonstrated in two studies (Study and 2) that evaluated riluzole tablets 50 mg twice daily in patients with amyotrophic lateral sclerosis (ALS). Both studies included patients with either familial or sporadic ALS, disease duration of less than years, and baseline forced vital capacity greater than or equal to 60% of normal.Study was randomized, double-blind, placebo-controlled clinical study that enrolled 155 patients with ALS. Patients were randomized to receive riluzole tablets 50 mg twice daily (n 77) or placebo (n 78) and were followed for at least 13 months (up to 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 riluzole tablets compared to placebo. There was an early increase in survival in patients receiving riluzole tablets compared to placebo. Figure 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 = 0.12), the difference was found to be significant by another appropriate analysis (Wilcoxon test = 0.05). As seen in Figure 1, the study showed an early increase in survival in patients given riluzole tablets. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between the riluzole tablets 50 mg twice daily and placebo groups was approximately 90 days.Figure 1. Time to Tracheostomy or Death in ALS Patients in Study (Kaplan-Meier Curves) Study was randomized, double-blind, placebo-controlled clinical study that enrolled 959 patients with ALS. Patients were randomized to riluzole tablets 50 mg twice daily (n 236) or placebo (n 242) and were followed for at least 12 months (up to 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 riluzole tablets compared to placebo. Figure displays the survival curves for time to death or tracheostomy for patients randomized to either riluzole tablets 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 = 0.076), the difference was found to be significant by another appropriate analysis (Wilcoxon test = 0.05). Not displayed in Figure are the results of riluzole tablets 50 mg per day (one-half of the recommended daily dose), which could not be statistically distinguished from placebo, or the results of riluzole tablets 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 riluzole tablets and placebo was approximately 60 days.Although riluzole tablets improved survival in both studies, measures of muscle strength and neurological function did not show benefit.Figure 2. Time to Tracheostomy or Death in ALS Patients in Study (Kaplan-Meier Curves) Figure 1. Time to Tracheostomy or Death in ALS Patients in Study (Kaplan-Meier Curves). Figure 2. Time to Tracheostomy or Death in ALS Patients in Study (Kaplan-Meier Curves).

DESCRIPTION SECTION.

11 DESCRIPTION Riluzole tablets, USP are 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 234.20. The chemical structure is:Riluzole, USP is white to slightly yellow powder or crystalline powder that is very soluble in dimethylformamide, dimethylsulfoxide, and methanol; freely soluble in dichloromethane; sparingly soluble in 0.1 HCl; and very slightly soluble in water and in 0.1 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.. Riluzole Structural Formula.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oStrong to moderate CYP1A2 inhibitors: Coadministration may increase riluzole tablet-associated adverse reactions (7.1)oStrong to moderate CYP1A2 inducers: Coadministration may result in decreased efficacy (7.2)oHepatotoxic drugs: Riluzole tablet-treated patients that take other hepatotoxic drugs may be at increased risk for hepatotoxicity (7.3). oStrong to moderate CYP1A2 inhibitors: Coadministration may increase riluzole tablet-associated adverse reactions (7.1). oStrong to moderate CYP1A2 inducers: Coadministration may result in decreased efficacy (7.2). oHepatotoxic drugs: Riluzole tablet-treated patients that take other hepatotoxic drugs may be at increased risk for hepatotoxicity (7.3). 7.1Agents That May Increase Riluzole Blood Concentrations CYP1A2 Inhibitors. Co-administration of riluzole tablets (a CYP1A substrate) with CYP1A2 inhibitors was not evaluated in 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 tablets may increase the risk of riluzole tablet-associated adverse reactions [see Clinical Pharmacology (12.3)].. 7.2Agents That May Decrease Riluzole Plasma Concentrations CYP1A2 Inducers. Co-administration of riluzole tablets (a CYP1A substrate) with CYP1A2 inducers was not evaluated in clinical trial; however, in vitro findings suggest decrease in riluzole exposure is likely. Lower exposures may result in decreased efficacy [see Clinical Pharmacology (12.3)].. 7.3Hepatotoxic Drugs Clinical trials in ALS patients excluded patients on concomitant medications which were potentially hepatotoxic (e.g., allopurinol, methyldopa, sulfasalazine). Riluzole tablet-treated patients who take other hepatotoxic drugs may be at an increased risk for hepatotoxicity [see Warnings and Precautions (5.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise patients to inform their healthcare provider if they experience:oYellowing of the whites of the eyes [see Warnings and Precautions (5.1)]oFever [see Warnings and Precautions (5.2)]oRespiratory symptoms--for example, dry cough and difficult or labored breathing [see Warnings and Precautions (5.3)] Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India 75076602Revised: 8/2020MX:RILU:R3. oYellowing of the whites of the eyes [see Warnings and Precautions (5.1)]. oFever [see Warnings and Precautions (5.2)]. oRespiratory symptoms--for example, dry cough and difficult or labored breathing [see Warnings and Precautions (5.3)].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. Riluzole was not carcinogenic in mice or rats when administered for years at daily oral doses up to 20 and 10 mg/kg/day, respectively, which are approximately equal to the recommended human daily dose (RHDD, 100 mg) on mg/m2 basis.. Mutagenesis. Riluzole was negative in in vitro (bacterial reverse mutation (Ames), mouse lymphoma tk,chromosomal aberration assay in human lymphocytes), and in vivo (rat cytogenetic and mouse micronucleus) assays.N-hydroxyriluzole, the major active metabolite of riluzole, was positive for clastogenicity in the in vitro mouse lymphoma tk assay and in the in vitro micronucleus assay using the same mouse lymphoma cell line. N-hydroxyriluzole was negative in the HPRT gene mutation assay, the Ames assay (with and without rat or hamster S9), the in vitro chromosomal aberration assay in human lymphocytes, and the in vivo mouse micronucleus assay.. Impairment of Fertility. When riluzole (3, 8, or 15 mg/kg) was administered orally to male and female rats prior to and during mating and continuing in females throughout gestation and lactation, fertility indices were decreased and embryolethality was increased at the high dose. This dose was also associated with maternal toxicity. The mid dose, no-effect dose for effects on fertility and early embryonic development, is approximately equal to the RHDD on mg/m2 basis.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Table displays the pharmacokinetic parameters of riluzole.Table 2. Pharmacokinetic Parameters of RiluzoleAbsorption Bioavailability (oral)Approximately 60% Dose ProportionalityLinear over dose range of 25 mg to 100 mg every 12 hours (1/2 to times the recommended dosage) Food effectAUC 20% and Cmax 45% (high fat meal)Distribution Plasma Protein Binding96% (Mainly to albumin and lipoproteins)Elimination Elimination half-lifeo12 hours (CV 35%) oThe high interindividual variability in the clearance of riluzole is potentially attributable to variability of CYP1A2. The clinical implications are not known. AccumulationApproximately 2-foldMetabolism Fraction metabolized (% dose)At least 88% Primary metabolic pathway(s) [in vitro] oOxidation: CYP1A2 oDirect and sequential glucoronidation: UGT-HP4 Active MetabolitesSome metabolites appear pharmacologically active in vitro, but the clinical implications are not known.Excretion Primary elimination pathways (% dose)oFeces: 5% oUrine: 90% (2% unchanged riluzole) o12 hours (CV 35%) oThe high interindividual variability in the clearance of riluzole is potentially attributable to variability of CYP1A2. The clinical implications are not known.. oOxidation: CYP1A2 oDirect and sequential glucoronidation: UGT-HP4. oFeces: 5% oUrine: 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 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.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. There are no studies of riluzole tablets 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 possible risk to the fetus associated with use of riluzole tablets 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, no-effect dose for embryofetal developmental toxicity, is approximately equal to the recommended human daily dose (RHDD, 100 mg) on 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 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, no-effect dose for pre- and postnatal developmental toxicity, is approximately equal to the RHDD on mg/m2 basis.

RISKS.

Risk Summary. There are no studies of riluzole tablets 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 possible risk to the fetus associated with use of riluzole tablets during pregnancy.

SPL UNCLASSIFIED SECTION.

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 tablet-treated patients than placebo-treated patients. The incidence of elevations of ALT above times the upper limit of normal (ULN) was 2% in riluzole tablet-treated patients. Maximum increases in ALT occurred within months after starting riluzole tablets. About 50% and 8% of riluzole tablet-treated patients in pooled Studies and 2, had at least one elevated ALT level above ULN and above times ULN, respectively [see Clinical Studies (14)].Monitor patients for signs and symptoms of hepatic injury, every month for the first months of treatment, and periodically thereafter. The use of riluzole tablets is not recommended if patients develop hepatic transaminase levels greater than times the ULN. Discontinue riluzole tablets if there is evidence of liver dysfunction (e.g., elevated bilirubin).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: Based on animal data, may cause fetal harm (8.1). oPregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy Risk Summary. There are no studies of riluzole tablets 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 possible risk to the fetus associated with use of riluzole tablets 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, no-effect dose for embryofetal developmental toxicity, is approximately equal to the recommended human daily dose (RHDD, 100 mg) on 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 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, no-effect dose for pre- and postnatal developmental toxicity, is approximately equal to the RHDD on 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 tablets 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 tablets in pediatric patients have not been established.. 8.5 Geriatric 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-Pughs (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 tablets is not recommended in patients with baseline elevations of serum aminotransferases greater than times upper limit of normal or evidence of liver dysfunction (e.g., elevated bilirubin) [see Clinical Pharmacology (12.3)].. 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 [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHepatic injury: Use of riluzole tablets is not recommended in patients with baseline elevations of serum aminotransferases greater than times upper limit of normal; discontinue riluzole tablets if there is evidence of liver dysfunction (5.1)oNeutropenia: Advise patients to report any febrile illness (5.2)oInterstitial lung disease: Discontinue riluzole tablets if interstitial lung disease develops (5.3). oHepatic injury: Use of riluzole tablets is not recommended in patients with baseline elevations of serum aminotransferases greater than times upper limit of normal; discontinue riluzole tablets if there is evidence of liver dysfunction (5.1). oNeutropenia: Advise patients to report any febrile illness (5.2). oInterstitial lung disease: Discontinue riluzole tablets if interstitial lung disease develops (5.3). 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 tablet-treated patients than placebo-treated patients. The incidence of elevations of ALT above times the upper limit of normal (ULN) was 2% in riluzole tablet-treated patients. Maximum increases in ALT occurred within months after starting riluzole tablets. About 50% and 8% of riluzole tablet-treated patients in pooled Studies and 2, had at least one elevated ALT level above ULN and above times ULN, respectively [see Clinical Studies (14)].Monitor patients for signs and symptoms of hepatic injury, every month for the first months of treatment, and periodically thereafter. The use of riluzole tablets is not recommended if patients develop hepatic transaminase levels greater than 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 months of riluzole tablet 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.