` CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`212640Orig1s000
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`LABELING
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`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 -------------------------- (cid:173)
`EXSERVAN is indicated for the treatment of amyotrophic lateral
`sclerosis (ALS) (1)
`
`----------------------DOSAGE AND ADMINISTRATION --------------------- (cid:173)
`• 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 ----------------------- (cid:173)
`• 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
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`• Neutropenia: Advise patients to report any febrile illness (5.2)
`• Interstitial lung disease: Discontinue EXSERVAN if interstitial lung
`disease develops (5.3)
`------------------------------ADVERSE REACTIONS ----------------------------- (cid:173)
`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 ------------------ (cid:173)
`• 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
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`_
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`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
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`*Sections or subsections omitted from the full prescribing information are not
`listed.
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`Reference ID: 4524184
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`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.
`
`DOSAGE FORMS AND STRENGTHS
`
` 3
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`Oral film: 50 mg orange, rectangular-shaped, orally dissolving film with “R50” printed in white
`on one side.
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`4
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`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
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`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)].
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`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.
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`6
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`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
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`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
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`Placebo
`(N=320)
`
`%
`12
`11
`9
`4
`4
`2
`3
`3
`3
`3
`3
`1
`2
`2
`2
`2
`0
`1
`1
`1
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`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
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`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.
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`• Acute hepatitis and icteric toxic hepatitis [see Warnings and Precautions (5.1)]
`• Renal tubular impairment
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`7
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`7.1
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`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,
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`zileuton) with EXSERVAN may increase the risk of EXSERVAN-associated adverse
`reactions [see Clinical Pharmacology (12.3)].
`
`7.2
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`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)].
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`8
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`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(cid:173)
`4% and 15-20%, respectively.
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`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.
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`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.
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`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.
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`8.2
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`Lactation
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`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.
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`8.3
`
`Females and Males of Reproductive Potential
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`In rats, oral administration of riluzole resulted in decreased fertility indices and increases in
`embryolethality [see Nonclinical Toxicology (13.1)].
`
`8.4
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`Pediatric Use
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`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.
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`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.
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`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
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`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.
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`11
`
`DESCRIPTION
`
`Riluzole is a member of the benzothiazole class. The chemical designation for riluzole is 2-
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`amino-6-(trifluoromethoxy)benzothiazole. Its molecular fo1mula is CsHsf3N20S, an d its
`molecular weight is 234.2. The chemical structure is:
`
`Riluzole is a white to slightly yellow powder that is ve1y soluble in dimethylfo1m amide,
`dimethylsulfoxide, an d methanol; freely soluble in dichloromethane; sparingly soluble in 0.1 N
`HCl; an d ve1y slightly soluble in water and in 0.1 N NaOH.
`
`Each EXSERV AN oral film contains 50 mg of riluzole and the following inactive ingredients:
`FD&C yellow #6, fmctose, glycerin, glycerol monooleate, hypromellose, natural honey flavor,
`natural & aitificial lemon, polacrilex resin, polyethylene oxide, polysaccharide, sucralose,
`xanthan gum, and xylitol.
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`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`The mechanism by which riluzole exe1ts its therapeutic effects in patients with ALS is unknown.
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`Pharmacodynamics
`12.2
`The clinical phan nacodynamics of riluzole has not been deten nined in humans.
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`Pharmacokinetics
`12.3
`A phaim acokinetic study in healthy adult subjects under fasting conditions at 50 mg dose level
`demonsti·ated similai· bioavailability for riluzole from EXSERV AN and riluzole tablets. Table 2
`displays the phaimacokinetic parameters of riluzole.
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`Table 2. Pharmacokinetics of Riluzole1
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`Absorption
`Bioavailability (oral)
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`Dose Propo1tionality
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`Food effect2
`Time to peak plasma concentration
`(Median)2
`Distribution
`Plasma Protein Binding
`Elimination
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`Elimination half-life
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`Accumulation
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`Approximately 60%
`Linear over a dose range of 25 mg to 100 mg eve1y 12 hours
`(1/2 to 2 times the recommended dosage)
`AUC J 15% and Cmax J 45% (high fat meal)
`Under fasted state: 1 hour; and under fed state (high-fat meal): 1.5
`hours
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`96% (Mainly to albumin and lipoproteins)
`
`• 12 hours (CV=35%)
`• The high interindividual vruiability in the cleru·ance of
`iiluzole is potentially attributable to variability of CYP1A2.
`The clinical implications are not known.
`Approximately 2-fold
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`Metabolism
`
`Fraction metabolized (% dose)
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`At least 88%
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`Primary metabolic pathway(s) [in
`vitro]
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`• Oxidation: CYP1A2
`• Direct and sequential glucoronidation: UGT-HP4
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`Active Metabolites
`
`Excretion
`
`Some metabolites appear pharmacologically active in vitro, but
`the clinical implications are not known.
`
`Primary elimination pathways (%
`dose)
`1 Unless otherwise stated, information in this table is based on pharmacokinetic studies of riluzole tablets
`2 Information specific to EXSERVAN
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`• Feces: 5%
`• Urine: 90% (2% unchanged riluzole)
`
`
`Specific Populations
`
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`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.
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`Smokers
`The clearance of riluzole in tobacco smokers was 20% greater than in nonsmokers.
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`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.
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`Drug Interaction Studies
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`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.
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`13
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`NONCLINICAL TOXICOLOGY
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`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.
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`14
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`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.
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`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
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`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.
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`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.
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`
`
`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.
`
`
`
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`
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`Reference ID: 4524184
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`

`

`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)].
`
`
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`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
`EXSERVANn1
`(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.
`
`Figure 1
`
`Reference ID 4524184
`
`

`

`
`
`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.
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`Figure 2
`
`Figure 3
`
`
`
`Figure 4
`
`
`
`
`
`
`
`
`
`Figure 5
`
`• Wash your hands after handling EXSERVAN.
`
`• Throw away the empty foil pouch in the regular trash.
`
`Manufactured by:
`Aquestive Therapeutics
`Warren, NJ 07059
`
`For more information or support about EXSERVAN: Call 1-833-AQUESTV (1-833-278-3788).
`
`This Instructions for Use has been approved by the U.S. Food and Drug Administration.
`
`Revision Date: 11/2019
`
`
`Reference ID: 4524184
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`ERIC P BASTINGS
`11/22/2019 02:36:43 PM
`
`Reference ID: 4524184
`
`