Riluzole (Systemic)

VA CLASSIFICATION
Primary: CN900

Commonly used brand name(s): Rilutek.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Amyotrophic lateral sclerosis (ALS) therapy agent—

Indications

Accepted

Amyotrophic lateral sclerosis (ALS) (treatment)^{{01}{02}{04}{08}}—Riluzole is indicated in the treatment of ALS; it may slow the progression of ALS by extending the survival and/or time to tracheostomy. ^{{01} {02} {04} {07}}
—In two placebo-controlled studies, riluzole was shown to improve survival early in the trials ^{{01} {02} {04}}; however, muscle strength and neurological functioning were not improved ^{{01} {02}}. Also, no statistically significant difference in mortality was seen at the conclusion of these studies. ^{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Benzothiazole ^{01}
Molecular weight—
    234.20 ^{{01} {03}}

Mechanism of action/Effect:

Riluzole presynaptically ^{{05} {08}} inhibits glutamate release ^{{01} {04} {05} {08}} in the central nervous system (CNS) ^{04} and postsynaptically ^{04} interferes with the effects of excitatory amino acids ^{{01} {02} {04} {06}}. Although the etiology of ALS is unknown ^{07}, current hypotheses suggest that glutamic acid may play a secondary role in mediating the neurodegenerative processes in the disease ^{{05} {09}}. Another pharmacological property of riluzole that may be related to its effect is inactivation of voltage-dependent sodium channels ^{{01} {06} {08}}.


Other actions/effects:

In animal models, riluzole has demonstrated anticonvulsant ^{{01} {05} {06}} effects at doses twice the recommended human daily dose ^{01}, and myorelaxant ^{01} and sedative ^{{01} {06}} properties at doses twenty times the recommended human daily dose. ^{01} Anti-ischemic properties have also been reported. ^{06}

Absorption:

Riluzole is well absorbed (approximately 90%), and has an absolute bioavailability of about 60%. ^{01} Administration with a high fat meal decreases absorption, decreasing the area under the plasma concentration–time curve (AUC) by about 20% and decreasing peak blood levels by about 45%. ^{01}

Distribution:

Riluzole penetrates the brain very readily. ^{05}

Protein binding:

Very high (96%) ^{01}; bound mainly to albumin and lipoproteins. ^{01}

Biotransformation:

Riluzole is extensively metabolized to six major and a number of minor metabolites, which have not all been identified to date. ^{01} Metabolism is mostly hepatic, consisting of cytochrome P450–dependent hydroxylation and glucuronidation. ^{01} P450 1A2 is the primary isozyme involved in N-hydroxylation; CYP 2D6, CYP 2C19, CYP 3A4, and CYP 2E1 are considered unlikely to contribute significantly to riluzole metabolism in humans. ^{01}

Half-life:

Elimination—Approximately 12 hours after multiple dosing. ^{01}

Time to steady-state concentration

Steady-state is reached in less than 5 days. ^{01} The pharmacokinetics of riluzole are linear over the dose range of 25 to 100 mg administered every 12 hours. ^{01}

Elimination:
    There is marked interindividual variability in the clearance of riluzole, most likely due to variability of activity of the CYP 1A2 isoenzyme involved in the N-hydroxylation of the parent compound. ^{01}
    Renal: 90% of a single 150-mg radiolabeled dose administered to healthy males was recovered in the urine over 7 days, of which only 2% was unchanged riluzole. ^{01} More than 85% of the metabolites recovered in the urine were glucuronide metabolites. ^{01}
    Fecal: 5% of a single 150-mg radiolabeled dose administered to healthy males was recovered in the feces over 7 days. ^{01}


Precautions to Consider

Carcinogenicity

Long-term studies to determine the carcinogenic potential of riluzole have not been completed to date. ^{01}

Mutagenicity

There was no evidence of mutagenic or clastogenic potential in the Ames test, the mouse lymphoma assay, or the in vivo assays in the mouse and rat. ^{01} There was an equivocal clastogenic response in the in vitro lymphocyte chromosomal aberration assay. ^{01}

Pregnancy/Reproduction
Fertility—
Riluzole impaired fertility when administered to male and female rats prior to and during mating at a dose of 15 mg per kg of body weight (mg/kg) or 1.5 times the maximum daily dose on a mg per square meter of body surface area basis. ^{01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. ^{01}

Embryotoxicity and maternal toxicity were observed when riluzole was administered to pregnant rats and rabbits during the period of organogenesis at doses of 27 mg/kg and 60 mg/kg, respectively (2.6 and 11.5 times the maximum human recommended dose [MHRD], respectively). ^{01} Administration of riluzole to rats during gestation and lactation at doses of 15 mg/kg (or 1.5 times the MHRD) produced adverse effects such as a decrease in implantations and an increase in intrauterine deaths. ^{01} Viability and growth of the offspring also were adversely affected. ^{01}

FDA Pregnancy Category C. ^{01}

Breast-feeding

It is not known whether riluzole is distributed into human milk. However, it is distributed into maternal milk in rats. Because of the potential for serious adverse effects, it is recommended that women receiving riluzole not breast-feed. ^{01}

Pediatrics

No information is available on the relationship of age to the effects of riluzole in pediatric patients. Safety and efficacy have not been established. ^{01}


Geriatrics


Although appropriate studies on the relationship of age to the effects of riluzole have not been performed in the geriatric population, no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have age-related renal function impairment, which may cause decreased clearance of riluzole. About 30% of the patients included in controlled clinical trials were over 65 years of age; no differences in adverse effects between the younger and older patients were observed. ^{01}


Pharmacogenetics

Riluzole clearance in Japanese subjects native to Japan has been shown to be 50% lower than riluzole clearance in Caucasians after adjusting for body weight. ^{01} Although it is not clear if this effect is due to genetic or environmental factors, alcohol intake, coffee intake, other dietary preferences, or smoking, Japanese subjects may possess a lower capacity (oxidative and/or conjugative) for metabolizing riluzole. ^{01}

Female subjects may possess lower metabolic capacity to eliminate riluzole as compared to males, due to lower activity of the CYP 1A2 isozyme. ^{01} This gender effect may result in increased blood concentration of riluzole and its metabolites. ^{01} However, in controlled trials, no gender effect on favorable or adverse effects of riluzole was noted. ^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Clinical studies designed to evaluate the interaction of riluzole with other drugs have not been conducted. ^{01}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol^{01}    (it is not known if alcohol increases the risk of serious hepatotoxicity with riluzole; patients should be discouraged from drinking excessive amounts of alcohol ^{01})


Allopurinol^{01} or
Hepatotoxic agents^{01} or
Methyldopa^{01} or
Sulfasalazine^{01}    (because of the potential for additive hepatotoxic effects, caution should be exercised in prescribing these medications to a patient receiving riluzole ^{01})


Amitriptyline^{01} or
Caffeine^{01} or
Phenacetin^{01} or
Quinolones^{01} or
Tacrine^{01} or
Theophylline^{01} or
Other agents that potentially inhibit CYP 1A2^{01}    (inhibitors of CYP 1A2 may decrease the rate of elimination of riluzole ^{01})

    (potential interactions may occur when riluzole is administered concomitantly with other agents that are also metabolized by CYP 1A2 ^{01})


Charbroiled food^{01} or
Cigarette smoke^{01} or
Omeprazole^{01} or
Rifampicin^{01}    (inducers of CYP 1A2 may increase the rate of elimination of riluzole ^{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Coombs' (antiglobulin) test, direct^{01}    (positive results may occur ^{01})

With physiology/laboratory test values
Alkaline phosphatase^{01} or
Gamma glutamyl transferase (GGT)^{01} or
Lactic dehydrogenase^{01}    (values may be increased ^{01})


» Aminotransferases, serum^{01}{02}{04}    (elevated values occur in many patients, even those with no prior history of liver disease; experience in nearly 800 ALS patients predicts that about 50% of riluzole-treated patients will experience at least one alanine aminotransferase [ALT (SGPT)] level above the upper limit of normal (ULN), about 8% will have elevations > 3 times the ULN, and about 2% will have elevations > 5 times the ULN ^{01})

    (in clinical trials, maximum increases in serum ALT usually occurred within 3 months after initiation of therapy with riluzole; patients were continued on riluzole if ALT values were < 5 times the ULN, and levels usually decreased to < 2 times the ULN within 2 to 6 months; if ALT values exceeded 5 times the ULN, riluzole was discontinued, so there is no clinical experience to date with continuing riluzole treatment in ALS patients with ALT values > 5 times the ULN ^{01})


Erythrocyte counts^{01} or
Hematocrit values^{01} or
Hemoglobin values^{01}    (levels may fall below the lower limit of normal; in clinical trials the changes were mostly mild and transient, and appeared to show a dose-response relationship ^{01})


Gamma globulins^{01}    (values may be increased ^{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Severe hepatic function impairment^{01}    (increased risk of liver toxicity ^{01})


Risk-benefit should be considered when the following medical problems exist
Hepatic function impairment^{01}    (metabolism of riluzole and its metabolites may be decreased, leading to higher plasma levels ^{01})


Renal function impairment^{01}    (excretion of riluzole and its metabolites may be decreased, leading to higher plasma levels ^{01})


Sensitivity to riluzole^{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Hepatic function tests^{01} including:
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin and
Gamma glutamyl transferase (GGT)    (serum values of aminotransferases should be measured prior to and during riluzole treatment; serum ALT values should be monitored every month for the first 3 months of treatment, every 3 months during the remainder of the first year, and periodically thereafter ^{01})

    (if riluzole therapy is continued in patients with ALT values > 5 times the upper limit of normal [ULN], frequent [at least weekly] monitoring of complete liver function is recommended; treatment should be discontinued if ALT values exceed 10 times the ULN or if clinical jaundice develops ^{01})


White blood cell counts^{01}    (because of the occurrence of rare but marked neutropenia [absolute neutrophil count less than 500 per cubic millimeter], patients reporting febrile illness should have white cell counts checked ^{01})




Side/Adverse Effects

Note: Adverse effects can worsen the quality of life of ALS patients receiving riluzole; however, in one study, adverse reactions to the drug reportedly did not outweigh its therapeutic effect on survival. ^{{02} {04}}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Aggravation reaction^{01} (worsening of symptoms of ALS), including worsening of asthenia^{01}{04} (unusual tiredness or weakness), and spasticity^{04}{08}
    
diarrhea^{01}
    
nausea^{01}{04}
    
vomiting^{01}
Note: Diarrhea, nausea, and worsening of asthenia may be dose-related. ^{01}



Incidence less frequent
    
Respiratory disorders^{04} , including decreased lung function^{01} (difficulty in breathing), increased cough^{01} , and pneumonia^{01}

Incidence rare
    
Angioedema^{01} (swelling of the eyelids, mouth, lips, tongue, and/or throat)
    
dysphagia^{04} (trouble in swallowing)
    
exfoliative dermatitis^{01} (redness, scaling, or peeling of the skin)
    
facial edema^{01} (swelling of face)
    
hypertension^{01} , mild to moderate^{04}{08} (high blood pressure)
    
hypokalemia^{01} (increased thirst; irregular heartbeat; mood or mental changes; muscle cramps, pain, or weakness)
    
hyponatremia^{01} (lack of energy)
    
incoordination^{04} (lack of coordination)
    
jaundice^{01} (yellow eyes or skin)
    
mental depression^{01}{04}
    
neutropenia^{01} (fever; chills; continuing sores in mouth)
    
phlebitis^{01} (pain, tenderness, bluish color, or swelling of foot or leg)
    
seizures^{01}
    
tachycardia^{01} (fast or pounding heartbeat)
    
urinary tract problems, including infections^{01} (bloody or cloudy urine; frequent urge to urinate), and dysuria^{01} (painful or difficult urination)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain or gas^{01}{04}
    
anorexia^{01} (loss of appetite)
    
circumoral paresthesia^{01} (numbness or tingling around the mouth)
    
dizziness^{01}
    
somnolence^{01} (drowsiness)
    
vertigo^{01}
Note: Anorexia, circumoral paresthesia, dizziness, somnolence, and vertigo may be dose-related. ^{01} Dizziness may occur more commonly in females than in males. ^{01}



Incidence less frequent
    
Back or muscle pain or stiffness^{01}{04}
    
constipation^{01}{04}
    
dermatological problems, including alopecia^{01} (hair loss), eczema^{01} (skin rash), and pruritis^{01} (itching)
    
headache^{01}
    
insomnia^{01} (trouble in sleeping)
    
malaise^{01} (general feeling of discomfort or illness)
    
peripheral edema^{01} (swelling of feet or legs)
    
rhinitis^{01}{04} (runny nose)
    
stomatitis^{01} (irritation or soreness of mouth)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
No cases of overdose with riluzole have been reported to date. ^{01}

Treatment of overdose
No specific antidote or information on treatment is available. ^{01}

If an overdose occurs, riluzole should be discontinued immediately. ^{01}

Supportive care—Treatment should be directed toward alleviating symptoms of overdose. ^{01} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Riluzole (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to riluzole ^{01}

Pregnancy—Studies have shown adverse effects in animals receiving doses greater than recommended maximum human daily doses





Breast-feeding—Not recommended because of risk of serious side effects
Other medical problems, especially severe hepatic function impairment

Proper use of this medication
Taking on a regular basis and at the same time of the day (e.g., morning and evening)

Taking on an empty stomach
Missed dose: skipping missed dose; starting again with next scheduled dose

» Proper storage

Precautions while using this medication
Reporting any febrile illnesses promptly to physician

» Caution when driving or doing jobs requiring alertness, because of the potential for drowsiness, dizziness, or vertigo

Avoiding excessive alcohol intake


Side/adverse effects
Aggravation reaction; asthenia; spasticity; diarrhea; nausea; vomiting; respiratory disorders, including decreased lung function, increased cough, and pneumonia; angioedema; dysphagia; exfoliative dermatitis; facial edema; hypertension; hypokalemia; hyponatremia; incoordination; jaundice; mental depression; neutropenia; phlebitis; seizures; tachycardia; and urinary tract problems including infections and dysuria


General Dosing Information
Riluzole should be taken on a regular basis and at the same time of day (e.g., morning and evening). ^{01} To avoid food-related decreases in bioavailability, riluzole should be given on an empty stomach, one hour before or two hours after meals. ^{01}


Oral Dosage Forms

RILUZOLE TABLETS

Usual adult dose
Amyotrophic lateral sclerosis—Oral, 50 mg every twelve hours, taken on an empty stomach. ^{01}

Note: Higher daily doses result in no increased benefit, but increased incidence of adverse effects. ^{01}


Usual adult prescribing limits
100 mg a day. ^{01}

Usual pediatric dose
Safety and efficacy have not been established. ^{01}

Usual geriatric dose
See Usual adult dose.

Strength(s) usually available
U.S.—


50 mg (Rx) [Rilutek]

Canada—
Not commercially available.

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F). ^{01} Protect from bright light. ^{01}

Auxiliary labeling:
   • May cause drowsiness.
   • Take on an empty stomach.
   • Avoid alcoholic beverages.

Developed: 07/30/96

References

1. Rilutek package insert (Rhône-Poulenc Rorer—US), Rev 12/95.
   

2. Lacomblez L, Bensimon G, Leigh PN, et al. for the ALS/Riluzole Study Group II. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 1996 May 25; 347: 1425-31.
   

3. Fleeger CA, editor. USP dictionary of USAN and international drug names 1996. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1995: 609.
   

4. Bensimon G, Lacomblez L, Meininger V, ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994 Mar 3; 330(9): 585-91.
   

5. Doble A. Excitatory amine acid receptors and neurodegeneration. Thérapie 1995 Jul-Aug; 50(4): 319-37.
   

6. Couratier P, Sindou P, Esclaire F, Louvel E, Hugon J. Neuroprotective effects of riluzole in ALS CSF toxicity. Neuroreport 1994 Apr; 5(8): 1012-4.
   

7. Rowland LP. Amyotrophic lateral sclerosis. Curr Opin Neurol 1994; 7: 310-5.
   

8. Riluzole for amyotrophic lateral sclerosis. Med Lett Drugs Ther 1995 Dec 8; 37(963): 113-4.
   

9. Rothstein JD. Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis. Adv Neurol 1995; 68: 7-20.