DESCRIPTION SECTION.


11 DESCRIPTION. Riluzole is 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:Riluzole is 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 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) riluzole-st.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE ADMINISTRATION. The recommended dosage for riluzole is 50 mg taken orally twice daily. Riluzole should be taken at least hour before or hours after meal [see Clinical Pharmacology (12.3)]. Measure serum aminotransferases before and during treatment with riluzole [see Warnings and Precautions (5.1)]. . Recommended dosage: 50 mg twice daily, taken at least hour before or hours after meal (2) Measure serum aminotransferases before and during treatment (2, 5.1).

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS STRENGTHS. Riluzole Tablets, USP 50 mg is available as white to off-white coloured, capsule-shaped film coated tablet, debossed with RIL on one side and 50 on other side.. Tablets: 50 mg (3).

ADVERSE REACTIONS SECTION.


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 )] 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 Ascend Laboratories, LLC at 1-877-ASCRX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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 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 lists adverse reactions that occurred in at least 2% of riluzole-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 ALS Riluzole50 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. Acute hepatitis and icteric toxic hepatitis [see Warnings and Precautions (5.1)] Renal tubular impairment. Pancreatitis.

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.

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 Riluzole Ab sorp ion ioa va il ab il ity (o a l) Ap pro i a e ly 60% ose ro por i on li ty ine ar ver dose ran ge of 25 mg to 100 mg ve ry 12 hou rs (1 /2 to t mes the reco mended dosa ge) Food f ect AUC 20% and max 45% (h gh at mea l) is r ib t ion la ma ro te in ind ing 6% (M i ly to l bu in nd lip op o e ns) li i na ion li ina ion a f life 12 ho urs C V= 35%)o The igh in te i nd iv id ual va i ab l ty in he le r an ce of i uzo le is o en ia lly tt ib t ab le to a iab il ity of Y P1 2. The l in cal mp lic ti ons re ot kno wn. ccu u a i on Ap pro i a e ly - fo ld Me ta bo ism rac i on me tabo li zed (% do se) At lea st 8% ri ma ry me tabo ic pa th wa ( s) [i v itro] Ox ida ti on: CYP A2o irect nd se qu n tial l c r on d ati on: UG - P4 c ive Me ta bo i tes So me me tabo i es ap pear pha maco lo ic lly c ti ve in itro, but the l in cal mp lic t ions re not kno wn. Excre ion ri ma ry l m in tion pa th ays (% dose) Feces: 5%o rine: 0% 2% unch an ged ri lu zo le) 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 was demonstrated in two studies (Study and 2) that evaluated riluzole 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 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 compared to placebo. There was an early increase in survival in patients receiving riluzole 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 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 riluzole. Among the patients in whom the endpoint of tracheostomy or death was reached during the study, the difference in median survival between the riluzole 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 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 compared to placebo. Figure displays the survival curves for time to death or tracheostomy for patients randomized to either riluzole 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 are the results of riluzole 50 mg per day (one-half of the recommended daily dose), which could not be statistically distinguished from placebo, or the results of riluzole 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 and placebo was approximately 60 days.Although riluzole 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) riluzole-fig-1. riluzole-fig-2.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. Riluzole is contraindicated in patients with history of severe hypersensitivity reactions to riluzole or to any of its components (anaphylaxis has occurred) [see Adverse Reactions (6.1)].. Patients with history of severe hypersensitivity reactions to riluzole or to any of its components (4).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Strong to moderate CYP1A2 inhibitors: Coadministration may increase riluzole -associated adverse reactions (7.1) Strong to moderate CYP1A2 inducers: Coadministration may result in decreased efficacy (7.2) Hepatotoxic drugs: Riluzole -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 riluzole (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 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 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)] .. 7.3 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)].

GERIATRIC USE SECTION.


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.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. Riluzole Tablets, USP are white to off-white coloured, capsule-shaped film coated tablets, debossed with RIL on one side and 50 on other side. Riluzole Tablets, USP are supplied in the following presentations: Bottles of 60 tablets NDC 67877-286-60Bottles of 90 tablets NDC 67877-286-90Bottles of 500 tablets NDC 67877-286-05Bottles of 1000 tablets NDC 67877-286-10Blister pack of 140 (10 14) Tablets NDC 67877-286-14 Store at 20 to 25C (68 to 77F). [See USP controlled room temperature.] and protect from bright light.. Keep out of the reach of children.

INDICATIONS & USAGE SECTION.


1 INDICATIONS USAGE. Riluzole is indicated for the treatment of amyotrophic lateral sclerosis (ALS). Riluzole is indicated for the treatment of amyotrophic lateral sclerosis (ALS) (1).

INFORMATION FOR PATIENTS SECTION.


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)] Revised: July, 2020Manufactured by: ALKEM LABORATORIES LTD. Mumbai 400 013, INDIADistributed by:Ascend Laboratories, LLCParsippany, NJ 07054 Revised: July, 2020 PT 1789-02.

LABOR & DELIVERY SECTION.


8.2 Lactation. Risk SummaryIt 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.

MECHANISM OF ACTION SECTION.


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

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.

NURSING MOTHERS SECTION.


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)].

OVERDOSAGE SECTION.


10 OVERDOSAGE. Reported symptoms of overdose following ingestion of riluzole ranging from 1.5 to 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Ascend Laboratories, LLCNDC 67877-286-60 Riluzole Tablets, USP 50 mg60 TabletsRx OnlyAscend Laboratories, LLCNDC 67877-286-14 Riluzole Tablets, USP 50 mg10 14 TabletsRx Only Rluzole Tablets USP 50 mg. Riluzole Tablets USP 50 mg. Riluzole Tablets USP 50 mg.

PEDIATRIC USE SECTION.


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

PHARMACODYNULLMICS SECTION.


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

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Table displays the pharmacokinetic parameters of riluzole. Table 2. Pharmacokinetic Parameters of Riluzole Ab sorp ion ioa va il ab il ity (o a l) Ap pro i a e ly 60% ose ro por i on li ty ine ar ver dose ran ge of 25 mg to 100 mg ve ry 12 hou rs (1 /2 to t mes the reco mended dosa ge) Food f ect AUC 20% and max 45% (h gh at mea l) is r ib t ion la ma ro te in ind ing 6% (M i ly to l bu in nd lip op o e ns) li i na ion li ina ion a f life 12 ho urs C V= 35%)o The igh in te i nd iv id ual va i ab l ty in he le r an ce of i uzo le is o en ia lly tt ib t ab le to a iab il ity of Y P1 2. The l in cal mp lic ti ons re ot kno wn. ccu u a i on Ap pro i a e ly - fo ld Me ta bo ism rac i on me tabo li zed (% do se) At lea st 8% ri ma ry me tabo ic pa th wa ( s) [i v itro] Ox ida ti on: CYP A2o irect nd se qu n tial l c r on d ati on: UG - P4 c ive Me ta bo i tes So me me tabo i es ap pear pha maco lo ic lly c ti ve in itro, but the l in cal mp lic t ions re not kno wn. Excre ion ri ma ry l m in tion pa th ays (% dose) Feces: 5%o rine: 0% 2% unch an ged ri lu zo le) 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.

PREGNULLNCY SECTION.


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 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 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, 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.

SPL UNCLASSIFIED SECTION.


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 times the upper limit of normal (ULN) was 2% in riluzole-treated patients. Maximum increases in ALT occurred within months after starting riluzole. About 50% and 8% of riluzole -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 is not recommended if patients develop hepatic transaminase levels greater than times the ULN. Discontinue riluzole if there is evidence of liver dysfunction (e.g., elevated bilirubin).

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1) 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 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 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, 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 SummaryIt 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-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 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) [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)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Hepatic injury: Use of riluzole is not recommended in patients with baseline elevations of serum aminotransferases greater than times upper limit of normal; discontinue riluzole if there is evidence of liver dysfunction (5.1). Neutropenia: Advise patients to report any febrile illness (5.2) Interstitial lung disease: Discontinue riluzole 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 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 times the upper limit of normal (ULN) was 2% in riluzole-treated patients. Maximum increases in ALT occurred within months after starting riluzole. About 50% and 8% of riluzole -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 is not recommended if patients develop hepatic transaminase levels greater than 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 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.