AHFS Class:

• Amyotrophic Lateral Sclerosis (ALS) Agents 28:44

Generic Name(s):

• Riluzole

Riluzole is an antiglutamate agent that acts in the CNS.2,3,4,5,6,7,10,11,12,13,27

Amyotrophic Lateral Sclerosis

Riluzole is used in the management of amyotrophic lateral sclerosis (ALS)1,7,11,15,22,24,27 and has been designated an orphan drug by the FDA for use in this condition.26

ALS (i.e., Lou Gehrig disease, Charcot sclerosis) is a fatal, progressive neurodegenerative disease affecting both upper and lower motor neurons; manifestations include gradual weakness and atrophy in limb, thoracic, abdominal, and bulbar muscles with related deficits in activities of daily living.28,29,30,33,34 Some patients also experience mood, cognitive (e.g., frontotemporal dementia), or behavioral changes.30,31 Typically, the disease is fatal within 2-5 years of clinical onset, often as a result of respiratory failure.28,29,30,31,33 There is no cure for ALS and treatment options are limited.1,28,29,30,31,34 Riluzole has been shown to slow disease progression and prolong survival to a modest degree (e.g., by about 2-3 months); because of this possible benefit, experts recommend that the drug should be offered to patients with ALS.1,24,27,34,35 Other interventions (e.g., noninvasive ventilation, percutaneous gastrotomy [PEG]) also should be considered for symptomatic treatment of the disease.34 Management of ALS requires a multidisciplinary approach to address patients' physical deficits (e.g., loss of mobility, respiratory failure, dysarthria, dysphagia) as well as their social and psychological needs.31,34

Clinical Experience

The current indication for riluzole is based principally on 2 double-blind, placebo-controlled studies in patients with familial or sporadic ALS (probable or definite) who had a disease duration of less than 5 years and a baseline forced vital capacity (FVC) of 60% or greater.1,24,27,35 In these studies, the time to death or insertion of a tracheostomy in patients receiving riluzole for at least 1 year (maximum of 18 months) was prolonged compared with that in placebo recipients.1,24,27

In the first placebo-controlled study, survival benefit with riluzole therapy occurred principally in patients with bulbar- versus limb-onset ALS, possibly an artifact of the small sample size;12,22,24,25,27 site of disease onset did not influence survival benefit in the second, larger study.22,24 Differences in survival in both studies were observed early in treatment and diminished thereafter; mortality at the end of the studies was not significantly different between the treatment and placebo groups.20,22,24 In the first study in 155 patients, 57 of 77 patients (74%) receiving riluzole 100 mg daily (50 mg twice daily) were alive at 12 months compared with 45 of 78 patients (58%) receiving placebo.1,7,15,27 Survival benefit was attributable almost entirely to increased survival in patients with bulbar-onset ALS; 1-year survival rates with riluzole and placebo were 73 and 35%, respectively, in patients with bulbar-onset disease, compared with 74 and 64%, respectively, in patients with limb-onset disease.7,27 In the second placebo-controlled study in 959 patients, which included a dose-ranging evaluation, the probability of survival at the end of the study was greater in patients receiving riluzole 100 mg daily (50 mg twice daily) compared with those receiving placebo; survival was not substantially different between the 50-mg daily dosage and placebo, or between the 100- and 200-mg daily dosages.1,22,24,35 Median survival was prolonged by approximately 60-90 days with riluzole in these studies.1 Muscle strength and neurologic function did not improve with riluzole therapy in these studies, although in the first study a slower rate of deterioration in muscle strength was observed.1,7,10,15,22,24,27

General

Serum aminotransferase concentrations (e.g., ALT) should be monitored before initiation of riluzole and periodically during treatment.1

Administration

Riluzole is administered orally twice daily.1,22,24,27 Because food decreases oral bioavailability of the drug, the manufacturer recommends that riluzole be taken in a fasting state (e.g., 1 hour before or 2 hours after meals).1

Dosage

For the management of amyotrophic lateral sclerosis (ALS), the recommended dosage of riluzole is 50 mg twice daily.1 Higher daily dosages have not been shown to provide any additional benefit but may increase the risk of adverse effects.22,24

Special Populations

The manufacturer makes no specific recommendations for dosage adjustment in patients with hepatic impairment; however, use of riluzole is not recommended in patients with aminotransferase concentrations exceeding 5 times the upper limit of normal (ULN) or evidence of liver dysfunction.1 (See Hepatic Effects under Cautions: Warnings/Precautions.)

Contraindications

Riluzole is contraindicated in patients with a history of severe hypersensitivity reactions to the drug or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis has been reported in patients receiving riluzole.1

Hepatic Effects

Liver injury, including fatalities, has been reported in patients receiving riluzole.1 Asymptomatic elevations of aminotransferase concentrations (e.g., ALT) also have been reported and have recurred following rechallenge with the drug in some patients.1 In clinical studies, the incidence of elevated aminotransferase concentrations was greater in patients receiving riluzole than in those receiving placebo; among riluzole-treated patients, approximately 50% had at least one elevated ALT concentration above the upper limit of normal (ULN) and 8% had ALT concentrations exceeding 3 times the ULN.1 Elevations in ALT concentrations exceeding 5 times the ULN were reported in 2% of patients receiving the drug.1 Maximum increases in ALT concentrations occurred within the first 3 months of therapy.1 Acute hepatitis and icteric toxic hepatitis have been reported during postmarketing experience with riluzole.1

Serum aminotransferase concentrations should be monitored prior to and during riluzole therapy;1 in addition, patients should be monitored for signs and symptoms of hepatic injury (monthly for the first 3 months of treatment, then periodically thereafter).1 Use of riluzole is not recommended in patients with aminotransferase concentrations exceeding 5 times the ULN.1 The drug should be discontinued if there is evidence of liver dysfunction (e.g., elevated bilirubin concentrations).1

Neutropenia

Cases of severe neutropenia (absolute neutrophil count less than 500/mm³) have been reported within the first 2 months of riluzole therapy.1 Patients should be advised to report febrile illness.1

Interstitial Lung Disease

Interstitial lung disease, including hypersensitivity pneumonitis, has occurred in patients receiving riluzole.1 Riluzole should be discontinued immediately if interstitial lung disease develops.1

Specific Populations

Pregnancy

There are no adequate data to determine whether riluzole is associated with a risk of developmental abnormalities when used during pregnancy.1 In animal studies, administration of riluzole to pregnant rats and rabbits resulted in adverse developmental effects (e.g., decreased embryofetal/offspring viability, growth, and functional development) at clinically relevant doses.1

If riluzole is used during pregnancy, the patient should be advised of the potential risk to the fetus.1

Lactation

It is not known whether riluzole is distributed into human milk.1 Riluzole or its metabolites have been detected in milk of lactating rats.1

Patients should be advised that the potential for serious adverse effects in nursing infants from riluzole is not known.1

Pediatric Use

Efficacy and safety of riluzole have not been established in pediatric patients.1

Geriatric Use

No overall differences in safety and efficacy have been observed in geriatric patients 65 years of age or older compared with younger adults.1 Age does not appear to have a clinically important effect on the pharmacokinetics of riluzole.1 However, greater sensitivity in some older individuals cannot be ruled out.1

Hepatic Impairment

In patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, the area under the concentration-time curve (AUC) of riluzole increased by 1.7- or 3- fold, respectively, compared with individuals with normal hepatic function.1 Such patients may be at increased risk of adverse effects.1

The pharmacokinetics of riluzole have not been studied in patients with severe hepatic impairment.1

Use of riluzole is not recommended in patients with preexisting signs or symptoms of liver dysfunction.1 (See Hepatic Effects under Cautions: Warnings/Precautions.)

Renal Impairment

Moderate to severe renal impairment is not expected to have a clinically important effect on the pharmacokinetics of riluzole.1 The pharmacokinetics of riluzole have not been studied in patients undergoing hemodialysis.1

Gender

The mean AUC of riluzole was approximately 45% higher in female patients compared with male patients.1 In clinical studies, dizziness was reported with higher frequency in females (11%) versus males (4%).1

Race

The clearance of riluzole was 50% lower in Japanese patients compared with Caucasian patients after normalizing for body weight.1 Based on this finding, Japanese patients may be more likely to have increased riluzole concentrations and risk of associated adverse effects.1

Smokers

The clearance of riluzole was approximately 20% higher in smokers compared with nonsmokers.1

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving riluzole and more frequently than with placebo include asthenia,1 nausea,1 decreased lung function,1 hypertension,1 abdominal pain,1 vomiting,1 arthralgia,1 dizziness,1 dry mouth,1 insomnia,1 pruritus,1 tachycardia,1 flatulence,1 increased cough,1 peripheral edema,1 urinary tract infection,1 circumoral paresthesia,1 somnolence,1 vertigo,1 and eczema.1

Drugs Affecting Hepatic Microsomal Enzymes

Riluzole is a substrate of cytochrome P-450 (CYP) 1A2.1 In vitro data suggest that increased riluzole exposure is likely if the drug is used concomitantly with CYP1A2 inhibitors.1 Concomitant use of riluzole with moderate or potent CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine, methoxsalen, mexiletine, oral contraceptives, vemurafenib, zileuton) may increase the risk of riluzole-associated adverse effects.1

In vitro data suggest that decreased riluzole exposure is likely if the drug is used concomitantly with CYP1A2 inducers.1 Reduced riluzole exposure may result in decreased efficacy of the drug.1

Hepatotoxic Drugs

Patients receiving potentially hepatotoxic drugs (e.g., allopurinol, methyldopa, sulfasalazine) were excluded from clinical studies of riluzole.1 Patients receiving riluzole concomitantly with hepatotoxic drugs may be at increased risk for hepatotoxicity.1

Protein-bound Drugs

Protein-binding displacement interactions have not been observed with riluzole.1 In vitro studies indicate that riluzole binding to plasma proteins is not affected by warfarin, digoxin, imipramine, or quinine at high therapeutic concentrations.1

In vitro, riluzole did not show displacement of warfarin from plasma proteins.1

Description

Riluzole, a synthetic aryl-substituted benzothiazolamine,1,2,3,4,5,6,7,9,27 is an antiglutamate agent that acts in the CNS.2,3,4,5,6,7,10,11,12,13,27 It has been suggested that the motor neuron degeneration associated with amyotrophic lateral sclerosis (ALS) may be related to accumulation of excitatory amino acids (EAAs), principally glutamate, at synapses in the CNS and resultant “excitotoxicity” and cell death.6,7,11,12,15,16,17,27

The precise mechanism of action of riluzole in patients with ALS has not been fully elucidated1 but appears to involve interference with the effects mediated by EAAs in the CNS, possibly through inhibition of glutamic acid release,2,3,4,5,6,9,11,12,15,17,18,27 blockade or inactivation of voltage-dependent sodium channels,4,5,6,7,15,17,18,19,27 and/or activation of a G-protein-dependent signal transduction pathway.6,17,27 While some data also suggest that riluzole may act via noncompetitive blockade of EAA receptors,5,14 the drug has not been shown to bind to any known glutamate receptor.2,4,6 Riluzole has exhibited neuroprotective properties in vitro and in vivo in animals, including inhibition of neuronal toxicity associated with exposure to EAAs7 or cerebrospinal fluid from ALS patients,6,7 and inhibition of neuronal toxicity associated with anoxia4,7,9 or focal or global ischemia.2,3,4,6,7,9 Riluzole prolonged survival in a study in a transgenic mouse model of ALS but did not delay onset of the disease.21,22

Riluzole exhibits dose-proportional pharmacokinetics over the dosage range of 25-100 mg every 12 hours.1 The oral bioavailability of the drug is approximately 60%.1 Administration of riluzole with food decreases the area under the concentration-time curve (AUC) by 20% and peak plasma concentrations by 45%.1 Riluzole is 96% bound to plasma proteins, principally to albumin and lipoproteins.1 The drug is metabolized by cytochrome P-450 (CYP) 1A2 and by direct and sequential glucuronidation;1 some metabolites appear to be active in vitro, but the clinical importance is not known.1 At least 88% of a dose is metabolized;1 90% is excreted in urine (only 2% as unchanged drug) and 5% is excreted in feces.1 The half-life of riluzole is 12 hours.1

Advice to Patients

Importance of patients informing clinician of any manifestations of possible liver injury (e.g., yellowing of the whites of the eyes).1

Importance of patients informing clinician of any febrile illness.1

Importance of patients informing clinician of any respiratory symptoms (e.g., dry cough, difficult or labored breathing).1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Covis. Rilutek^® (riluzole) tablets prescribing information. Cary, NC; 2016 Apr.

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