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    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

    HOW SUPPLIED

    Rilutek/Riluzole Oral Tab: 50mg

    DOSAGE & INDICATIONS

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

    50 mg PO twice daily.

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

    100 mg PO twice daily is considered the target dose. The American Academy of Neurology advises that lower doses should not be prescribed, based on available data reporting no short-term or long-term benefit at lower doses. 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.

    STORAGE

    Rilutek:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    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

    It is not known if riluzole is excreted in human milk. Riluzole or its metabolites have been detected in rat milk. Advise breast-feeding women that many drugs are excreted in breast milk and that the potential for serious adverse reactions in a breast-feeding infant from riluzole is unknown.

    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
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    headache / Early / 44.4-44.4
    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

    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Acetaminophen; Butalbital; Caffeine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Aldesleukin, IL-2: (Moderate) Aldesleukin may cause nephrotoxicity. Concurrent administration of drugs possessing hepatotoxic effects with Aldesleukin, such as riluzole, may increase the risk of liver dysfunction. In addition, reduced kidney function secondary to Aldesleukin treatment may delay elimination of concomitant medications and increase the risk of adverse events from those drugs.
    Allopurinol: (Moderate) Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs like allopurinol and riluzole has not been established. Caution is recommended if these drugs are to be used concomitantly.
    Amitriptyline: (Moderate) Monitor patients for increased riluzole-related adverse events, such as gastrointestinal symptoms and elevated hepatic enzymes, when coadministered with amitriptyline. Serum concentrations of riluzole, a CYP1A2 substrate, may increase when amitriptyline, a CYP1A2 inhibitor, is initiated.
    Amitriptyline; Chlordiazepoxide: (Moderate) Monitor patients for increased riluzole-related adverse events, such as gastrointestinal symptoms and elevated hepatic enzymes, when coadministered with amitriptyline. Serum concentrations of riluzole, a CYP1A2 substrate, may increase when amitriptyline, a CYP1A2 inhibitor, is initiated.
    Amoxicillin; Clarithromycin; Omeprazole: (Minor) The principal isozyme involved in the initial oxidative metabolism of riluzole is CYP1A2. CYP1A2 inducers, such as omeprazole could increase the rate of clearance of riluzole. Monitor for decreased effects of riluzole.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Aspirin, ASA; Omeprazole: (Minor) The principal isozyme involved in the initial oxidative metabolism of riluzole is CYP1A2. CYP1A2 inducers, such as omeprazole could increase the rate of clearance of riluzole. Monitor for decreased effects of riluzole.
    Barbiturates: (Moderate) The risk of hepatic injury can be increased by concomitant use of other known hepatic enzyme inducers, such as barbiturates, with riluzole.
    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.
    Caffeine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn effect the clearance of caffeine. (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Caffeine; Ergotamine: (Minor) Caffeine may increase plasma concentrations of riluzole via CYP1A2 inhibition. Also, because riluzole is a substrate for the CYP1A2 isoenzyme, it may in turn, effect the clearance of caffeine.
    Carbamazepine: (Moderate) Riluzole can cause hepatic injury. The risk of hepatic injury may be increased by the concomitant use of other known hepatic enzyme inducers, such as carbamazepine.
    Ciprofloxacin: (Moderate) Monitor patients for increased riluzole-related adverse events, such as gastrointestinal symptoms and elevated hepatic enzymes, when coadministered with ciprofloxacin. Serum concentrations of riluzole, a CYP1A2 substrate, may increase when ciprofloxacin, a CYP1A2 inhibitor, is initiated.
    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.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Caution is recommended if methyldopa is used concomitantly with riluzole. Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs, such as methyldopa, and riluzole has not been established.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) CYP1A2 inducers, such as rifampin, could reduce the effect of riluzole by increasing the rate of clearance of riluzole.
    Isoniazid, INH; Rifampin: (Major) CYP1A2 inducers, such as rifampin, could reduce the effect of riluzole by increasing the rate of clearance of riluzole.
    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.
    Leflunomide: (Major) Concomitant use of riluzole with leflunomide may increase the risk for hepatotoxicity. Caution and close monitoring are advised if these drugs are used together.
    Lesinurad; Allopurinol: (Moderate) Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs like allopurinol and riluzole has not been established. Caution is recommended if these drugs are to be used concomitantly.
    Methotrexate: (Major) Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs, such as methotrexate, and riluzole has not been established. Caution is recommended if methotrexate is to be used concomitantly with riluzole.
    Methyldopa: (Moderate) Caution is recommended if methyldopa is used concomitantly with riluzole. Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs, such as methyldopa, and riluzole has not been established.
    Obeticholic Acid: (Moderate) Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates, such as riluzole. Therapeutic monitoring is recommended with coadministration.
    Omeprazole: (Minor) The principal isozyme involved in the initial oxidative metabolism of riluzole is CYP1A2. CYP1A2 inducers, such as omeprazole could increase the rate of clearance of riluzole. Monitor for decreased effects of riluzole.
    Omeprazole; Sodium Bicarbonate: (Minor) The principal isozyme involved in the initial oxidative metabolism of riluzole is CYP1A2. CYP1A2 inducers, such as omeprazole could increase the rate of clearance of riluzole. Monitor for decreased effects of riluzole.
    Perphenazine; Amitriptyline: (Moderate) Monitor patients for increased riluzole-related adverse events, such as gastrointestinal symptoms and elevated hepatic enzymes, when coadministered with amitriptyline. Serum concentrations of riluzole, a CYP1A2 substrate, may increase when amitriptyline, a CYP1A2 inhibitor, is initiated.
    Rifampin: (Major) CYP1A2 inducers, such as rifampin, could reduce the effect of riluzole by increasing the rate of clearance of riluzole.
    Rucaparib: (Moderate) Monitor for an increase in riluzole-related adverse reactions if coadministration with rucaparib is necessary. Riluzole is a CYP1A2 substrate and rucaparib is a moderate CYP1A2 inhibitor. Concomitant use of riluzole with CYP1A2 inhibitors was not evaluated in a clinical trial; however, in vitro findings suggest an increase in riluzole exposure is likely.
    Sulfasalazine: (Major) Riluzole can cause hepatic injury. The safety profile of concomitant use of potentially hepatotoxic drugs, such as sulfasalazine, and riluzole has not been established. Caution is recommended if sulfasalazine is to be used concomitantly with riluzole.
    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.
    Tobacco: (Minor) 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.

    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.

    It is not known if riluzole is excreted in human milk. Riluzole or its metabolites have been detected in rat milk. Advise breast-feeding women that many drugs are excreted in breast milk and that the potential for serious adverse reactions in a breast-feeding infant from riluzole is unknown.

    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.