ncentrations cyp1a2 inducers co-administration of exservan (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). exservan-treated patients who take other hepatotoxic drugs may be at an increased risk for hepatotoxicity [see warnings and precautions ( 5.1 )] .

ated patients. maximum increases in alt occurred within 3 months after starting riluzole. about 50% and 8% of riluzole-treated patients in pooled controlled efficacy studies (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 exservan is not recommended if patients develop hepatic transaminases levels greater than 5 times the uln. discontinue exservan if there is evidence of liver dysfunction (e.g., elevated bilirubin). concomitant use with other hepatotoxic drugs may increase the risk for hepatotoxicity [see drug interactions ( 7.3 )] . 5.2 neutropenia exservan can cause neutropenia. cases of severe neutropenia (absolute neutrophil count less than 500 per mm 3 ) within the first 2 months of riluzole treatment have been reported. advise patients to report febrile illnesses. 5.3 interstitial lung disease exservan can cause interstitial lung disease, including hypersensitivity pneumonitis. discontinue exservan immediately if interstitial lung disease develops.

should refrain from chewing, spitting or talking. only one oral film should be taken at a time.

clinical trials of riluzole tablets 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 [see clinical studies ( 14 )] . the most common adverse reactions in the riluzole-treated patients (in at least 5% of patients and more frequently than on placebo) were asthenia, nausea, decreased lung function, hypertension, and abdominal pain. the most common adverse reactions leading to discontinuation in the riluzole‑ treated patients 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 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 additional adverse reaction with exservan in an open-label pharmacokinetic study in healthy subjects (n=32), oral hypoesthesia was observed in 38% of subjects taking exservan, compared to no subjects taking riluzole tablets, under fasting conditions. 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

ncentrations cyp1a2 inducers co-administration of exservan (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). exservan-treated patients who take other hepatotoxic drugs may be at an increased risk for hepatotoxicity [see warnings and precautions ( 5.1 )] .

he 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. 8.2 lactation risk summary there are no data on the presence of riluzole in human milk, the effects on the breastfed infant, or the effects on milk production. riluzole or its metabolites have been detected in milk of lactating rat. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for exservan and any potential adverse effects on the breastfed infant from exservan or from the underlying maternal condition. 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 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. 8.6 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 exservan 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 )] .

gh 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.

ur; and under fed state (high-fat meal): 1.5 hours distribution plasma protein binding 96% (mainly to albumin and lipoproteins) elimination 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 metabolism fraction metabolized (% dose) at least 88% primary metabolic pathway(s) [ in 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 .

e of riluzole is potentially attributable to variability of cyp1a2. the clinical implications are not known. accumulation approximately 2-fold metabolism fraction metabolized (% dose) at least 88% primary metabolic pathway(s) [ in 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 .

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, a no-effect dose for effects on fertility and early embryonic development, is approximately equal to the rhdd on a mg/m 2 basis.

, 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, a no-effect dose for effects on fertility and early embryonic development, is approximately equal to the rhdd on a mg/m 2 basis.

iving riluzole tablets compared to placebo. there was an early increase in survival in patients receiving riluzole tablets 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 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 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 riluzole tablets 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 riluzole tablets compared to placebo. figure 2 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 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 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 a benefit. figure 2. time to tracheostomy or death in als patients in study 2 (kaplan-meier curves) figure 1 figure 2

)] . interstitial lung disease advise patients that exservan can cause interstitial lung disease, and to report to their healthcare provider if they have respiratory symptoms (e.g., dry cough and difficult or labored breathing) [see warnings and precautions ( 5.3 )] . pregnancy advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during exservan therapy [see use in specific populations ( 8.1 )] . lactation advise patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed during exservan therapy [see use in specific populations ( 8.2 )] .

a meal. how should i store exservan? • store exservan at room temperature between 68°f to 77°f (20°c to 25°c). • keep exservan in the foil pouch until you are ready to use. use right away after opening foil pouch. do not cut or split the film • protect from bright light. • any films that were spit out or not used after opening should be flushed down the toilet or placed in a sink and rinsed with water until film is no longer visible. • keep exservan and all medicines out of the reach of children. step 1. before giving exservan • ensure hands are clean and dry before handling exservan so the film does not stick to your fingers. • check expiration date printed on foil pouch before use as shown in figure. do not use exservan if expired. step 2. open pouch • fold foil pouch along solid line at top as shown in figure 2. • while keeping top of pouch folded over at solid line, tear down at the slit along the arrow on the side of the pouch to open. step 3. remove film • remove exservan film from foil pouch. each pouch contains one dose of exservan. step 4. place film on tongue • place exservan film on top of the tongue as shown in figure 4. the film will stick to the tongue and begin to dissolve. step 5. close mouth and swallow saliva normally • close mouth as shown in figure 5 and swallow saliva normally as exservan dissolves. • do not take exservan with liquids • do not chew, spit or talk while exservan dissolves. • wash your hands after handling exservan. • throw away the empty foil pouch in the regular trash. manufactured by: aquestive therapeutics warren, nj 07059 distributed by: mitsubishi tanabe pharma america, inc. jersey city, nj 07310 for more information or support about exservan: call 1-888-292-0058. this instructions for use has been approved by the u.s. food and drug administration. [126636] revision date: 04/2021 ifu figure 1 ifu figure 2 ifu figure 3 ifu figure 4 ifu figure 5