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  • CLASSES

    ALS Drugs

    DEA CLASS

    Rx

    DESCRIPTION

    Oral glutamate antagonist
    Used for treatment of amyotrophic lateral sclerosis (ALS)
    Does not cure disease or improve symptoms, but may prolong survival by 3 months

    COMMON BRAND NAMES

    Rilutek, Tiglutik

    HOW SUPPLIED

    Rilutek/Riluzole Oral Tab: 50mg
    Riluzole Oral Susp: 1mL, 5mg

    DOSAGE & INDICATIONS

    For the treatment of amyotrophic lateral sclerosis (ALS).
    Oral dosage
    Adults

    50 mg PO every 12 hours.

    For the treatment of chorea associated with Huntington's Disease (Huntington's Chorea)†.
    Oral dosage
    Adults

    100 mg PO twice daily. A randomized, placebo-controlled dose ranging trial evaluated the change in maximal chorea scores determined by the Unified Huntington's Disease Rating Scale (UHDRS) achieved at 8 weeks with riluzole 100 mg/day PO (n = 18), riluzole 200 mg/day PO (n = 23), or placebo (n = 22). Total daily dosages were divided and given twice daily. Subjects who received 200 mg/day had significant reductions in total chorea scores (-2.2 +/- 3.3, p = 0.01) compared to placebo (+0.7 +/- 3.4); effects appear to be dose related, as no significant reductions were found with riluzole 100 mg/day. In a second randomized controlled trial, patients were randomized to riluzole 50 mg twice daily or placebo for 3 years; no significant differences in UHDRS chorea scores between riluzole and placebo were found at 3 years.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    100 mg/day PO for ALS; 200 mg/day PO off-label for Huntington's Chorea.

    Geriatric

    100mg/day PO for ALS; 200 mg/day PO off-label for Huntington's Chorea.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Use is not recommended in patients with baseline elevation of serum transaminases more than 5 times the upper limit of normal (ULN) or evidence of liver dysfunction (e.g., elevated bilirubin).

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Riluzole has not been studied in patients undergoing hemodialysis.

    ADMINISTRATION

    Oral Administration

    Administer at least 1 hour before or 2 hours after a meal.

    Oral Liquid Formulations

    Oral suspension
    Gently shake the bottle for at least 30 seconds until mixed well.
    Measure dosage using the provided calibrated syringe.
    Storage: After opening the riluzole suspension bottle, use within 15 days.

    STORAGE

    Rilutek:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tiglutik:
    - Discard unused product 15 days after first opening
    - Do not freeze
    - Protect from light
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Riluzole is contraindicated in patients with a history of severe hypersensitivity reactions to riluzole or to any of its components.

    Hepatic disease

    Riluzole use is not recommended in patients with baseline elevation of serum aminotransferases greater than 5 times the upper limit of normal (ULN) or evidence of liver dysfunction (e.g., elevated bilirubin). Cases of drug-induced liver injury, some of which have been fatal, have occurred. Asymptomatic elevations of hepatic transaminases have been reported and have occurred upon rechallenge with riluzole. Maximum ALT elevations occurred within 3 months after starting riluzole in clinical trials. Patients with mild or moderate hepatic disease had increases in AUC compared to patients with normal hepatic function; therefore, patients with mild or moderate hepatic disease may be at increased risk for adverse reactions. Monitor for signs and symptoms of hepatic injury, every month for the first 3 months of treatment, and periodically thereafter. Riluzole use is not recommended if patients develop hepatic transaminase concentrations more than 5 times the ULN. Discontinue therapy if there is evidence of liver dysfunction.

    Hematological disease, neutropenia

    Caution is advisable when administering riluzole to patients with hematological disease. In rare cases, neutropenia has been reported during riluzole administration, including one case with marked anemia as well as neutropenia. Patients should report the appearance of fever, sore throat, lethargy, weakness, or other signs of decreased blood cell counts or infection to their health care provider immediately. The report of a febrile illness should prompt treating physicians to evaluate white blood cell counts.

    Pneumonitis, pulmonary disease

    Caution is advisable when administering riluzole to patients with pulmonary disease. Cases of interstitial lung disease have been reported. Subsequent evaluation revealed that many of these cases were hypersensitivity pneumonitis. If respiratory symptoms develop, such as dry cough or dyspnea, chest radiography should be performed. If there are findings suggestive of interstitial lung disease or hypersensitivity pneumonitis (e.g., bilateral diffuse lung opacities), riluzole should be discontinued immediately. Symptoms generally resolve after drug discontinuation and symptomatic treatment. Patients should be advised to report any cough or breathing difficulties to their healthcare provider.

    Pregnancy

    There are no adequate human data to inform the drug-associated risk with riluzole use during pregnancy. Increased mortality and other adverse developmental effects were observed during reproductive animal studies with riluzole at clinically relevant doses. When riluzole was given orally (3, 10, or 60 mg/kg/day) to pregnant rabbits during organogenesis, embryofetal mortality was increased at the high dose, and decreased fetal body weight and increased morphological variations were observed at all but the lowest dose. The no-effect dose (3 mg/kg/day) for embryofetal developmental toxicity is less than the recommended human daily dose (RHDD, 100 mg) on mg/m2 basis. Administration of oral riluzole (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 at the high dose; the no-effect dose (8 mg/kg/day) for embryofetal developmental toxicity was approximately equal to the RHDD on mg/m2 basis. Fertility indices were decreased at the high dose.

    Breast-feeding

    Advise women that the potential for serious adverse reactions in breast-feeding infants from riluzole is unknown. Riluzole is excreted in human milk. The average riluzole breast milk concentration was 94.4 mcg/L during a regimen of 50 mg twice daily in a breast-feeding woman with amyotrophic lateral sclerosis (ALS). A study predose breast milk sample was 33.8 ng/mL, suggesting steady-state riluzole concentrations; the peak riluzole concentration was 229.5 ng/mL at 2 hours after the dose. The calculated infant dose was 14.1 mcg/kg/day, and the calculated relative infant dose was 1.6% of the maternal weight-adjusted dosage with an average milk intake of 150 mL/kg/day.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    hypertension / Early / 5.0-5.0
    sinus tachycardia / Rapid / 3.0-3.0
    cystitis / Delayed / 3.0-3.0
    peripheral edema / Delayed / 3.0-3.0
    neutropenia / Delayed / 0-0.1
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    headache / Early / 44.4-44.4
    hypoesthesia / Delayed / 6.0-29.0
    drowsiness / Early / 2.0-19.4
    asthenia / Delayed / 19.0-19.0
    dizziness / Early / 4.0-16.7
    nausea / Early / 16.0-16.0
    rhinitis / Early / 13.9-13.9
    flatulence / Early / 3.0-8.3
    abdominal pain / Early / 5.0-5.0
    vomiting / Early / 4.0-4.0
    xerostomia / Early / 4.0-4.0
    insomnia / Early / 4.0-4.0
    pruritus / Rapid / 4.0-4.0
    arthralgia / Delayed / 4.0-4.0
    anorexia / Delayed / 3.2-3.2
    cough / Delayed / 3.0-3.0
    diarrhea / Early / 2.9-2.9
    paresthesias / Delayed / 2.0-2.0
    vertigo / Early / 2.0-2.0

    DRUG INTERACTIONS

    Allopurinol: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and allopurinol. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Amiodarone: (Moderate) Coadministration of riluzole with amiodarone may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and hepatotoxicity. Monitor for signs and symptoms of hepatic injury during coadministration. Discontinue riluzole if clinical signs of liver dysfunction are present. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and amiodarone is a CYP1A2 inhibitor.
    Amlodipine; Atorvastatin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and atorvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Coadministration of riluzole with omeprazole may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and omeprazole is a CYP1A2 inducer.
    Aspirin, ASA; Omeprazole: (Moderate) Coadministration of riluzole with omeprazole may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and omeprazole is a CYP1A2 inducer.
    Atorvastatin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and atorvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Atorvastatin; Ezetimibe: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and atorvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Auranofin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and auranofin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Azathioprine: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and azathioprine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Barbiturates: (Moderate) Coadministration of riluzole with barbiturates may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and barbiturates are CYP1A2 inducers.
    Black Cohosh, Cimicifuga racemosa: (Moderate) Black cohosh, Cimicifuga racemosa, has been reported to cause liver problems; however, causality has not been established. It is possible that black cohosh would act synergistically with other medications that can have adverse effects on the liver. Until more is known, the concurrent use of black cohosh in patients taking riluzole is not recommended as a precaution.
    Busulfan: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and busulfan. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Cannabidiol: (Moderate) Coadministration of riluzole with cannabidiol may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and cannabidiol is a CYP1A2 inducer.
    Carbamazepine: (Moderate) Monitor for signs and symptoms of hepatic injury and decreased riluzole efficacy during coadministration of riluzole and carbamazepine. Concomitant use may increase the risk for hepatotoxicity and may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and carbamazepine is a CYP1A2 inducer.
    Chlorpromazine: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and chlorpromazine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ciprofloxacin: (Moderate) Coadministration of riluzole with ciprofloxacin may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and ciprofloxacin is a CYP1A2 inhibitor.
    Dantrolene: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and dantrolene. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of riluzole with ritonavir may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
    Deferasirox: (Moderate) Coadministration of riluzole with deferasirox may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and deferasirox is a CYP1A2 inhibitor.
    Dextromethorphan; Quinidine: (Major) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and quinidine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Diclofenac: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and diclofenac. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Diclofenac; Misoprostol: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and diclofenac. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Didanosine, ddI: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and didanosine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Diphenhydramine; Ibuprofen: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ibuprofen. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Disulfiram: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and disulfarim. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Efavirenz: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and efavirenz. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and efavirenz. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and efavirenz. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Erythromycin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and erythromycin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Erythromycin; Sulfisoxazole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and erythromycin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ezetimibe; Simvastatin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and simvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Famotidine; Ibuprofen: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ibuprofen. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Floxuridine: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and floxuridine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Flutamide: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and flutamide. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Fluvoxamine: (Moderate) Coadministration of riluzole with fluvoxamine may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and fluvoxamine is a CYP1A2 inhibitor.
    Fosphenytoin: (Moderate) Monitor for signs and symptoms of hepatic injury and decreased riluzole efficacy during coadministration of riluzole and fosphenytoin. Concomitant use may increase the risk for hepatotoxicity and may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and fosphenytoin is a CYP1A2 inducer.
    Green Tea: (Minor) Some green tea products contain caffeine, which may inhibit the CYP1A2-mediated metabolism of riluzole. Also, as a substrate for CYP1A2, riluzole might affect the clearance of other drugs that depend on CYP1A2 for hepatic oxidative metabolism, including caffeine. Clinical documentation is lacking.
    Guarana: (Minor) Caffeine is an active component of guarana. As a substrate for the hepatic CYP1A2 isoenzyme, riluzole might also affect the clearance of other drugs that depend on CYP1A2 for hepatic oxidative metabolism, including caffeine. Clinical documentation of an interaction is lacking.
    Halothane: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and halothane. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Hydralazine: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and hydralazine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and hydralazine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and hydralazine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and methyldopa. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ibuprofen. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ibuprofen: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ibuprofen. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ibuprofen; Oxycodone: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ibuprofen. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ibuprofen. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Infliximab: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and infliximab. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Interferon Alfa-2a: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon alfa. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Interferon Alfa-2b: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon alfa. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Interferon Alfa-2b; Ribavirin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon alfa. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Interferon Alfacon-1: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon alfa. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Interferon Alfa-n3: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon alfa. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Interferon Beta-1a: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon beta. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Interferon Beta-1b: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and interferon beta. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Isoniazid, INH: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and isoniazid. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for signs and symptoms of hepatic injury and decreased riluzole efficacy during coadministration of riluzole and rifampin. Concomitant use may increase the risk for hepatotoxicity and may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and rifampin is a CYP1A2 inducer. (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and isoniazid. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present. (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and pyrazinamide. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Isoniazid, INH; Rifampin: (Moderate) Monitor for signs and symptoms of hepatic injury and decreased riluzole efficacy during coadministration of riluzole and rifampin. Concomitant use may increase the risk for hepatotoxicity and may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and rifampin is a CYP1A2 inducer. (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and isoniazid. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Kava Kava, Piper methysticum: (Major) The concurrent use of kava kava in patients on riluzole or other medications that may cause rare but significant hepatotoxicity is not recommended. Kava kava, Piper methysticum has been reported to cause liver problems. It is possible that kava kava would act synergistically with other medications that can have adverse effects on the liver, such as riluzole.
    Ketoconazole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ketoconazole. Concomitant use may increase the risk for hepatotoxicity. Discontinue therapy if clinical signs of liver dysfunction are present.
    Leflunomide: (Moderate) Coadministration of riluzole with leflunomide may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and leflunomide is a CYP1A2 inducer.
    Lesinurad; Allopurinol: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and allopurinol. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Lopinavir; Ritonavir: (Moderate) Coadministration of riluzole with ritonavir may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
    Mercaptopurine, 6-MP: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and mercaptopurine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Methotrexate: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and methotrexate. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Methoxsalen: (Moderate) Coadministration of riluzole with methoxsalen may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and methoxsalen is a CYP1A2 inhibitor.
    Methyldopa: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and methyldopa. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Mexiletine: (Moderate) Coadministration of riluzole with mexiletine may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and mexiletine is a CYP1A2 inhibitor.
    Minocycline: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and minocycline. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Modafinil: (Moderate) Coadministration of riluzole with modafinil may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and modafinil is a CYP1A2 inducer.
    Nevirapine: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and nevirapine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Niacin; Simvastatin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and simvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Nitrofurantoin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and nitrofurantoin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of riluzole with ritonavir may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
    Omeprazole: (Moderate) Coadministration of riluzole with omeprazole may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and omeprazole is a CYP1A2 inducer.
    Omeprazole; Sodium Bicarbonate: (Moderate) Coadministration of riluzole with omeprazole may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and omeprazole is a CYP1A2 inducer.
    Peginterferon Alfa-2a: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and peginterferon alfa-2a. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Peginterferon Alfa-2b: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and peginterferon alfa-2b. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Peginterferon beta-1a: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and peginterferon beta-1a. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Phenytoin: (Moderate) Monitor for signs and symptoms of hepatic injury and decreased riluzole efficacy during coadministration of riluzole and phenytoin. Concomitant use may increase the risk for hepatotoxicity and may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and phenytoin is a CYP1A2 inducer.
    Propylthiouracil, PTU: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and propylthiouracil. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Pyrazinamide, PZA: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and pyrazinamide. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Quinidine: (Major) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and quinidine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Quinine: (Moderate) Coadministration of riluzole with quinine may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and quinine is a CYP1A2 inducer.
    Rifampin: (Moderate) Monitor for signs and symptoms of hepatic injury and decreased riluzole efficacy during coadministration of riluzole and rifampin. Concomitant use may increase the risk for hepatotoxicity and may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and rifampin is a CYP1A2 inducer.
    Ritonavir: (Moderate) Coadministration of riluzole with ritonavir may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
    Rucaparib: (Moderate) Coadministration of riluzole with rucaparib may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and rucaparib is a CYP1A2 inhibitor.
    Simvastatin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and simvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Simvastatin; Sitagliptin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and simvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    St. John's Wort, Hypericum perforatum: (Moderate) Coadministration of riluzole with St. John's Wort may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and St. John's Wort is a CYP1A2 inducer.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and sulfamethoxazole. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Sulfasalazine: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and sulfasalazine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Sulindac: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and sulindac. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Tacrine: (Major) Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs, such as tacrine, and riluzole has not been established. Caution is recommended if tacrine is used concomitantly with riluzole.
    Telithromycin: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and telithromycin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Teriflunomide: (Moderate) Coadministration of riluzole with teriflunomide may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and teriflunomide is a CYP1A2 inducer.
    Thiabendazole: (Moderate) Coadministration of riluzole with thiabendazole may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and thiabendazole is a CYP1A2 inhibitor.
    Thioguanine, 6-TG: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and thioguanine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Ticlopidine: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and ticlopidine. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Tipranavir: (Moderate) Coadministration of riluzole with tipranavir may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and tipranavir is a CYP1A2 inducer.
    Tobacco: (Moderate) Tobacco smokers might eliminate riluzole more quickly than nonsmokers; the significance of this interaction has not been assessed in terms of a need for riluzole dosage adjustment. The sudden cessation of tobacco smoking may result in a reduced clearance of riluzole, despite the initiation of a nicotine replacement product. Patients taking riluzole should be monitored carefully when changes in smoking status occur.
    Valproic Acid, Divalproex Sodium: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and valproic acid. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Vemurafenib: (Moderate) Coadministration of riluzole with vemurafenib may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and vemurafenib is a CYP1A2 inhibitor.
    Zafirlukast: (Moderate) Coadministration of riluzole with zafirlukast may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and zafirlukast is a CYP1A2 inhibitor.
    Zileuton: (Moderate) Coadministration of riluzole with zileuton may increase the risk for riluzole-related adverse reactions, such as gastrointestinal symptoms and elevated hepatic enzymes. In vitro findings suggest an increase in riluzole exposure is likely; riluzole is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate human data to inform the drug-associated risk with riluzole use during pregnancy. Increased mortality and other adverse developmental effects were observed during reproductive animal studies with riluzole at clinically relevant doses. When riluzole was given orally (3, 10, or 60 mg/kg/day) to pregnant rabbits during organogenesis, embryofetal mortality was increased at the high dose, and decreased fetal body weight and increased morphological variations were observed at all but the lowest dose. The no-effect dose (3 mg/kg/day) for embryofetal developmental toxicity is less than the recommended human daily dose (RHDD, 100 mg) on mg/m2 basis. Administration of oral riluzole (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 at the high dose; the no-effect dose (8 mg/kg/day) for embryofetal developmental toxicity was approximately equal to the RHDD on mg/m2 basis. Fertility indices were decreased at the high dose.

    Advise women that the potential for serious adverse reactions in breast-feeding infants from riluzole is unknown. Riluzole is excreted in human milk. The average riluzole breast milk concentration was 94.4 mcg/L during a regimen of 50 mg twice daily in a breast-feeding woman with amyotrophic lateral sclerosis (ALS). A study predose breast milk sample was 33.8 ng/mL, suggesting steady-state riluzole concentrations; the peak riluzole concentration was 229.5 ng/mL at 2 hours after the dose. The calculated infant dose was 14.1 mcg/kg/day, and the calculated relative infant dose was 1.6% of the maternal weight-adjusted dosage with an average milk intake of 150 mL/kg/day.

    MECHANISM OF ACTION

    Riluzole modulates the actions of glutamate. The mechanism by which this happens is not clearly known but may include direct effects on the neurotransmitter itself and target receptors, the inhibition of glutamate release, blockade or inactivation of voltage-dependent sodium channels that are important for glutamate release, interference with intracellular events that result from binding of glutamate to receptors, and/or inhibition of arachidonic acid metabolism. Animal studies have shown that riluzole has a neuroprotective effect that delays neuronal injury or death.

    PHARMACOKINETICS

    Riluzole is administered orally. Riluzole is highly bound to plasma protein (about 96%), mainly to albumin and lipoproteins. Hepatic metabolism is extensive, producing 6 major and a number of minor metabolites. The cytochrome P450 enzyme system is involved in hydroxylation and glucuronidation. The main isozyme involved in hydroxylation is CYP1A2. Approximately 90% of a dose is excreted in the urine; however, only 2% is excreted as unchanged drug. Elimination in the feces accounts for 5% of a dose. Riluzole is largely excreted as its glucuronide metabolites (85%). The elimination half-life is 12 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2
    Riluzole is primarily metabolized by CYP1A2.

    Oral Route

    Riluzole is well absorbed from the GI tract (90%) and has absolute bioavailability of about 60%. Absorption is affected by high-fat meals, which reduce the AUC by about 20% and peak blood concentrations by about 45%. Riluzole exhibits linear pharmacokinetics. Steady-state plasma concentrations are achieved within 5 days of multiple-dose administration.