Exservan
(riluzole)Exservan Prescribing Information
EXSERVAN is indicated for the treatment of amyotrophic lateral sclerosis (ALS).
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 ].
Monitoring to Assess Safety
Measure serum aminotransferases before and during treatment with EXSERVAN [see Warnings and Precautions ].
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.
Oral film: 50 mg orange, rectangular-shaped, orally dissolving film with “R50” printed in white on one side.
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.
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.
Females and Males of Reproductive Potential
In rats, oral administration of riluzole resulted in decreased fertility indices and increases in embryolethality [see Nonclinical Toxicology ].
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
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.
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 ].
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 ].
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 ].
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 ].
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 ].
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.
Interstitial Lung Disease
EXSERVAN can cause interstitial lung disease, including hypersensitivity pneumonitis. Discontinue EXSERVAN immediately if interstitial lung disease develops.