• Neutropenia: Advise patients to report any febrile illness (5.2)
`
`
`
`• Interstitial lung disease: Discontinue EXSERVAN if interstitial lung
`
`
`
` disease develops (5.3)
`
`
` ------------------------------ADVERSE REACTIONS ----------------------------- ­
`
`
`
`
` Most common adverse reactions (incidence greater than or equal to 5% and
` greater than placebo) were oral hypoesthesia, asthenia, nausea, decreased
`
`
`
` lung function, hypertension, and abdominal pain (6.1)
`
`
`
` To report SUSPECTED ADVERSE REACTIONS, contact Aquestive
`
`Therapeutics at 1-877-394-5045 or FDA at 1-800-FDA-1088 or
`
` www.fda.gov/medwatch.
`
`
`
` ------------------------------DRUG INTERACTIONS ----------------------------­
`
`
`• Strong to moderate CYP1A2 inhibitors: Coadministration may increase
`
`
`
`
` EXSERVAN-associated adverse reactions (7.1)
`• Strong to moderate CYP1A2 inducers: Coadministration may result in
`
`
`
`
`
` decreased efficacy (7.2)
`• Hepatotoxic drugs: EXSERVAN-treated patients that take other
`
`
` hepatotoxic drugs may be at increased risk for hepatotoxicity (7.3)
`
`
`
`
` -----------------------USE IN SPECIFIC POPULATIONS ------------------ ­
`
`
`
`• Pregnancy: Based on animal data, may cause fetal harm (8.1)
`
`
`
`
`
`
`
`
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and FDA-approved
`
` patient labeling.
`
`
`
` Revised: 11/2019
`
`
`
`
`
` _
`
`
`
`
`
`
`
`
` 8.4 Pediatric Use
`
`
`
` 8.5 Geriatric Use
`
`
` 8.6 Hepatic Impairment
`
`8.7
`
`
` Japanese Patients
`
` 10 OVERDOSAGE
`
`
` 11 DESCRIPTION
`
`
` 12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
`
` 12.2 Pharmacodynamics
`
`
` 12.3 Pharmacokinetics
`
`
`
` 13 NONCLINICAL TOXICOLOGY
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` 14 CLINICAL STUDIES
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
` 16.1 How Supplied
`
`
` 16.2 Storage and Handling
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
`
`
`
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed.
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`EXSERVAN™ safely and effectively. See full prescribing information for
`
` EXSERVAN.
`
`
` EXSERVAN (riluzole) oral film
`
` Initial U.S. Approval: 1995
`
` ----------------------------INDICATIONS AND USAGE--------------------------­
`
`
`
`
` EXSERVAN is indicated for the treatment of amyotrophic lateral
`
` sclerosis (ALS) (1)
`
`
`
` ----------------------DOSAGE AND ADMINISTRATION --------------------- ­
`
`
`
`
`• Recommended dosage: 50 mg twice daily, taken at least 1 hour before or 2
`
`
`
`
`
`
`
`
`
`
`
`
` hours after a meal (2.1)
`
`
`• Measure serum aminotransferases before and during treatment (2.2, 5.1)
`
`
`
`
`
`
`
`
`
` ---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
` Oral Film: 50 mg (3)
`
`
`
` -------------------------------CONTRAINDICATIONS ---------------------------­
`
`
` Patients with a history of severe hypersensitivity reactions to riluzole or to any
`
`
` of its components (4)
`
` -----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
`• Hepatic injury: Use of EXSERVAN is not recommended in patients with
`
`
`
`baseline elevations of serum aminotransferases greater than 5 times upper
`limit of normal; discontinue EXSERVAN if there is evidence of liver
`
`
` dysfunction (5.1)
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`1
` INDICATIONS AND USAGE
`
` 2 DOSAGE AND ADMINISTRATION
`
` 2.1 Dosage Information
`
`
`
`
` 2.2 Monitoring to Assess Safety
`
` 2.3 Important Administration Instructions
`
` 3 DOSAGE FORMS AND STRENGTHS
`
`
`
` 4 CONTRAINDICATIONS
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
` 5.1 Hepatic Injury
`
`
` 5.2 Neutropenia
`
`
`
`5.3
` Interstitial Lung Disease
`
` 6 ADVERSE REACTIONS
`
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
` 6.2 Postmarketing Experience
`
`
` 7 DRUG INTERACTIONS
`
`
`
`
`
` 7.1 Agents that may Increase Riluzole Blood Concentrations
`
`
` 7.2 Agents that may Decrease Riluzole Plasma Concentrations
`
`
` 7.3 Hepatotoxic Drugs
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
`
`
` 8.2 Lactation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4524184
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`1
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
` EXSERVAN is indicated for the treatment of amyotrophic lateral sclerosis (ALS).
`
`
`
`
`2
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
` 2.1 Dosage Information
`
`
`
`
` The recommended dosage for EXSERVAN is 50 mg taken orally twice daily. EXSERVAN should
`
`
` be taken at least 1 hour before or 2 hours after a meal [see Clinical Pharmacology (12.3)].
`
`
`
`
` 2.2 Monitoring to Assess Safety
`
`
`
`Measure serum aminotransferases before and during treatment with EXSERVAN [see
`
` Warnings and Precautions (5.1)].
`
` 2.3 Important Administration Instructions
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Instruct patients and/or caregivers to read the “Instruction for Use” carefully for complete
`
`
` directions on how to properly dose and administer EXSERVAN oral films.
`
`
`
`
`
` Apply EXSERVAN on top of the tongue where it adheres and dissolves. Do not cut or split the
`
` film.
`
`
`
` Do not administer with liquids. As the film dissolves, saliva should be swallowed in a normal
`
`
` manner, but the patient should refrain from chewing, spitting or talking.
`
`
`
` Only one oral film should be taken at a time.
`
`
`
`3
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
` Oral film: 50 mg orange, rectangular-shaped, orally dissolving film with “R50” printed in white
`
` on one side.
`
`
`4
`
`
`
` CONTRAINDICATIONS
`
`EXSERVAN is contraindicated in patients with a history of severe hypersensitivity reactions
`to riluzole or to any of its components (anaphylaxis has occurred) [see Adverse Reactions
`
` (6.1)].
`
`
`5
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
` 5.1 Hepatic Injury
`
`
`
`
`
`EXSERVAN can cause liver 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 in placebo-treated patients. The incidence of elevations of ALT above 5 times
`
`
`
` the upper limit of normal (ULN) was 2% in riluzole-treated patients. Maximum increases in ALT
` occurred within 3 months after starting riluzole. About 50% and 8% of riluzole-treated patients in
`
`
`
`
`
` pooled 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)].
`
`
`
`Reference ID: 4524184
`
`

`

` 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 mm3) 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.
`
`
`6
`
`
`
` ADVERSE REACTIONS
`
`
`
`The following clinically significant adverse reactions are described below and elsewhere in the
` labeling:
`
`• Hepatic Injury [see Warnings and Precautions (5.1)]
`
`
`
`• Neutropenia [see Warnings and Precautions (5.2)]
`
`
`
`
`•
`
` Interstitial Lung Disease [see Warnings and Precautions (5.3)]
`
`
`
`
`
`6.1
`
`
`
` Clinical Trials Experience
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`
` of another drug and may not reflect the rates observed in practice.
`
`
`
` Adverse Reactions in Controlled Clinical Trials 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
`
`
`Reference ID: 4524184
`
`

`

`
`
`
`
`
`
`
` Asthenia
`
` Nausea
` Decreased lung function
`
` Hypertension
` Abdominal pain
`
` Vomiting
`
` Arthralgia
`
` Dizziness
`
` Dry mouth
`
` Insomnia
`
` Pruritus
`
` Tachycardia
`
` Flatulence
` Increased cough
`
` Peripheral edema
`
` Urinary tract infection
`
` Circumoral paresthesia
`
`
` Somnolence
`
` Vertigo
`
` Eczema
`
`
`
` RILUZOLE Tablets
`
`50 mg twice daily
`
` (N=313)
`
` %
`
` 19
`
` 16
`
` 10
`
` 5
`
` 5
`
` 4
`
` 4
`
` 4
`
` 4
`
` 4
`
` 4
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
` 2
`
` 2
`
` 2
`
` 2
`
`Placebo
`
` (N=320)
`
`
` %
`
` 12
`
` 11
`
` 9
`
` 4
`
` 4
`
` 2
`
` 3
`
` 3
`
` 3
`
` 3
`
` 3
`
` 1
`
` 2
`
` 2
`
` 2
`
` 2
`
` 0
`
` 1
`
` 1
`
` 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
`
`
`
`
`
`7
`
`
`7.1
`
`
`
` DRUG INTERACTIONS
`
`
`
`
`
` Agents that may Increase Riluzole Blood Concentrations
`
`
`
` CYP1A2 Inhibitors
`
` Co-administration of EXSERVAN (a CYP1A substrate) with CYP1A2 inhibitors was not
`
`
`
`
` evaluated in a clinical trial; however, in vitro findings suggest an increase in riluzole exposure is
`
` likely.
`
`The concomitant use of strong or moderate CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin,
`fluvoxamine, methoxsalen, mexiletine, oral contraceptives, thiabendazole, vemurafenib,
`
`
`
`
`Reference ID: 4524184
`
`

`

` zileuton) with EXSERVAN may increase the risk of EXSERVAN-associated adverse
`
`
` reactions [see Clinical Pharmacology (12.3)].
`
`
`
`
`7.2
`
`
`
` Agents that may Decrease Riluzole Plasma Concentrations
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`8
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`
`
`
`8.1
`
`
`
` Pregnancy
`
` Risk Summary
`
` There are no studies of riluzole in pregnant women, and case reports have been inadequate to
`
`inform the drug-associated risk. The background risk for major birth defects and miscarriage in
`
` patients with amyotrophic lateral sclerosis is unknown. In the U.S. general population, the
`background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2­
`
` 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 a
` possible risk to the fetus associated with use of EXSERVAN 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.
`
`
`
`
`
`
`Reference ID: 4524184
`
`

`

`
`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 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)].
`
`
`10
`
`
`
` OVERDOSAGE
`
` Reported symptoms of overdose following ingestion of riluzole tablets ranging from 1.5 to 3
`
`grams (30 to 60 times the recommended dose) included acute toxic encephalopathy, coma,
`
` drowsiness, memory loss, and methemoglobinemia.
`
`No specific antidote for the treatment of EXSERVAN overdose is available. For current
`
` information on the management of poisoning or overdosage, contact a certified poison control
`
` center.
`
`
`11
`
`
`
` DESCRIPTION
`
`
`
` Riluzole is a member of the benzothiazole class. The chemical designation for riluzole is 2­
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4524184
`
`

`

`amino-6-(trifluoromethoxy)benzothiazole. Its molecular formula is C8H5F3N2OS, and its
`
`
` molecular weight is 234.2. The chemical structure is:
`
`
`
`Riluzole is a white to slightly yellow powder that is very soluble in dimethylformamide,
`dimethylsulfoxide, and methanol; freely soluble in dichloromethane; sparingly soluble in 0.1 N
`
` HCl; and very slightly soluble in water and in 0.1 N NaOH.
`
`
`
` Each EXSERVAN oral film contains 50 mg of riluzole and the following inactive ingredients:
` FD&C yellow #6, fructose, glycerin, glycerol monooleate, hypromellose, natural honey flavor,
`
`
`
` natural & artificial lemon, polacrilex resin, polyethylene oxide, polysaccharide, sucralose,
`xanthan gum, and xylitol.
`
`
`
`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
`
`
`
`A pharmacokinetic study in healthy adult subjects under fasting conditions at 50 mg dose level
`demonstrated similar bioavailability for riluzole from EXSERVAN and riluzole tablets. Table 2
`
`
` displays the pharmacokinetic parameters of riluzole.
`
`
`
` Table 2. Pharmacokinetics of Riluzole1
`
`
`
`
`
` Absorption
`
`
`
` Bioavailability (oral)
`
`
`
` Approximately 60%
`
`
`
` Dose Proportionality
`
`
`
` Food effect2
`
`Time to peak plasma concentration
`
`(Median)2
` Distribution
`
`
`
`
` Plasma Protein Binding
`
`
`
` Elimination
`
`
`
`
`
` Elimination half-life
`
`Linear over a dose range of 25 mg to 100 mg every 12 hours
`
`
` (1/2 to 2 times the recommended dosage)
`
`
`
` AUC ↓ 15% and Cmax ↓ 45% (high fat meal)
`
`
`
` Under fasted state: 1 hour; and under fed state (high-fat meal): 1.5
`
` hours
`
`
`
`
`
` 96% (Mainly to albumin and lipoproteins)
`
`
`
`• 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
`
`
`Reference ID: 4524184
`
`

`

`
`
` Metabolism
`
`
`
` Fraction metabolized (% dose)
`
`
`
` Primary metabolic pathway(s) [in
`
` vitro]
`
`
`
` Active Metabolites
`
`
`
` Excretion
`
` At least 88%
`
`• Oxidation: CYP1A2
`
`
`
`• Direct and sequential glucoronidation: UGT-HP4
`
`
`
`
`
`
`
` Some metabolites appear pharmacologically active in vitro, but
`
`
` the clinical implications are not known.
`
`
`
`
`
`• Feces: 5%
`
`
`
`Primary elimination pathways (%
`• Urine: 90% (2% unchanged riluzole)
`
`
`
`
` dose)
`1 Unless otherwise stated, information in this table is based on pharmacokinetic studies of riluzole tablets
`
`
`
`2 Information specific to EXSERVAN
`
`
`
`
` 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.
`
`
`
`
`
`
`Reference ID: 4524184
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`13
`
`
`
` NONCLINICAL TOXICOLOGY
`
`
`
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
` Carcinogenesis
`
` Riluzole was not carcinogenic in mice or rats when administered for 2 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 a 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, a no-effect dose for effects on fertility and early embryonic
`
` development, is approximately equal to the RHDD on a mg/m2 basis.
`
`
`
`14
`
`
`
` CLINICAL STUDIES
`
`
`
` The efficacy of EXSERVAN is based upon relative bioavailability and food-effect study in
`
`
`
`
` healthy subjects comparing oral riluzole tablets to EXSERVAN oral film [see Clinical
`
` Pharmacology (12.3)].
`
`
` The efficacy of riluzole was demonstrated in two studies (Study 1 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, a disease duration of less than 5 years,
`
` and a baseline forced vital capacity greater than or equal to 60% of normal.
`
`
`
`
`
`Study 1 was a 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 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. 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
`
`
`Reference ID: 4524184
`
`

`

`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`Reference ID: 4524184
`
`

`

`
`
` Figure 2. Time to Tracheostomy or Death in ALS Patients in Study 2 (Kaplan-
`
` Meier Curves)
`
`
`
`
`16
`
`
`
` HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`
` 16.1 How Supplied
`
`
`
`
` Each EXSERVAN oral film is an orange, rectangular-shaped film that contains 50 mg of
` riluzole with “R50” printed in white ink on one side. Each film is packaged in a pouch.
`
`
`
` NDC 10094-350-60: 50 mg oral film, carton of 60 pouches
`
`
`
`
`
` 16.2 Storage and Handling
`
`
`
` Store EXSERVAN oral film pouches at 20°C to 25°C (68°F to 77°F); excursions permitted to
`
`
`
`
` 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature) and protect from bright
`
` light.
`
`
`17
`
`
`
` PATIENT COUNSELING INFORMATION
`
`
`
`Advise patients to read the FDA-approved patient labeling (Instructions for Use).
`
`
`
` Administration Instructions
`
`Instruct patients to place EXSERVAN on the top of the tongue where it will adhere and dissolve.
`
` Do not cut or split the film. Advise patients to not administer liquid, but saliva should be
`swallowed in a normal manner. Instruct patients to not chew, spit, or talk while EXSERVAN is
`
` dissolving.
`
` Hepatic Injury
`
` Advise patients that EXSERVAN can cause liver injury, which can be fatal. Inform patients of the
`
`
`
`clinical signs or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting,
`abdominal pain, fatigue, anorexia, or jaundice and/or dark urine) and to contact a healthcare
`
` provider promptly if these signs or symptoms occur [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4524184
`
`

`

`
`
` Neutropenia
`
` Advise patients that EXSERVAN can cause neutropenia, and to report to their healthcare provider
`
`
`if they have a fever [see Warnings and Precautions (5.2).]
`
` 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)].
`
`
`
`
`
`
`
`
` RILUTEK® is a registered trademark of Covis Pharmaceuticals Inc.
`
`
`
`
`
`
`
` Manufactured by:
`
`
`
`
`
` Aquestive Therapeutics
`
`Warren, NJ 07059
`
`
`
`
`
`
`
`
`Reference ID: 4524184
`
`

`

`Instructions for Use
`
`
`EXSERVAN™
`
`
`(ex-ser-van)
`
`
`(riluzole)
`
`
`
`oral film
`
`
`
`
`
`
`
`
`
`
`
` Read this Instructions for Use before you start using EXSERVAN and each time you get a
`
`
` refill. There may be new information. The information does not take the place of talking with
`
`
`
`
`
`
`
`
` your healthcare provider about your medical condition or treatment. Ask your healthcare
`
`
` provider or pharmacist if you have any questions about how to use EXSERVAN the right
`
`
`
`
`
`
`
`
`
`
`
` way.
`
` Important Information for Patient and Caregiver:
`
`• Do not take EXSERVAN until:
`
`
`
`
`
`
`
`
`o you have read and understand these instructions
`
`
`
`o you have reviewed the steps with your healthcare provider on how to take it
`
`
`
`
`o you know the right time, how often, and the dose to take
`
`
`
`
`
`o you feel comfortable with how to use EXSERVAN
`
`
`
`
`
`•
`
`
`
`
` If you are not sure about giving treatment or when to give treatment, call your healthcare
`
`
`
` provider before using EXSERVAN.
`
`
`
`
`
`• EXSERVAN should be taken at least one hour before or two hours after 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
`
`
`• Make sure 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
`
` 1. Do not use EXSERVAN if expired.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4524184
`
`
`
` Figure 1
`
`

`

`
`
`
`
` 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, as shown in Figure 3. Each
`
` pouch contains 1 dose of
`
`
`
`EXSERVAN.
`
`
`
`
`
`
`
`
`
`
`
`
` Figure 2
`
`
`
` Figure 3
`
`
`
`
`
` 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.
`
`
`
`
`
` Figure 4
`
`
`
`
`
`
`
`
`
`
`
` Figure 5
`
`
`
`
`
` Step 5. Close Mouth and Swallow
`
` Saliva Normally
`• Close mouth, as shown in Figure 5
`
`
`
` and swallow saliva normally as
`
`
`
`
` EXSERVAN dissolves.
`• Do not t