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.

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)].

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.

6.1 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.

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

7.1 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, 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)].

8.1 Pregnancy

8.2 Lactation

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)].

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 have 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.

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.

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.

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 70510-2201-1: 50 mg oral film, 1 pouch

NDC 70510-2201-2: 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.