Riluzole (Rilutek)
Riluzole Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Amyotrophic lateral sclerosis (ALS) | Adults (familial or sporadic ALS) | Disease-modifying monotherapy | FDA Approved |
Riluzole remains the only oral disease-modifying therapy for ALS with a well-established survival benefit, having been FDA-approved since 1995. In two pivotal trials, riluzole extended time to tracheostomy or death by approximately 60–90 days compared with placebo. It does not improve muscle strength or neurological function; the benefit is a modest but meaningful extension of survival. Riluzole is typically initiated at diagnosis and continued indefinitely unless limited by hepatotoxicity or intolerance. It is available in three oral formulations: standard tablets (Rilutek), an oral suspension (Tiglutik) for patients with dysphagia, and an oral dissolving film (Exservan).
Spinocerebellar ataxia: Small RCTs have suggested possible benefit in reducing ataxia progression. Evidence quality: Low.
Obsessive-compulsive disorder (glutamate modulation): Case series and small trials suggest potential benefit as augmentation therapy. Evidence quality: Low.
Huntington’s disease: Investigated in clinical trials but no consistent evidence of benefit. Evidence quality: Low.
Riluzole Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| ALS — standard adult dosing | 50 mg BID | 50 mg BID | 50 mg BID (100 mg/day) | No titration required; take at least 1 hour before or 2 hours after a meal No increased benefit from higher doses; AEs increase at higher doses (FDA PI) |
| ALS — patient with dysphagia (oral suspension) | 50 mg (10 mL) BID | 50 mg (10 mL) BID | 100 mg/day | Tiglutik 5 mg/mL oral suspension; can be given via feeding tube Oral hypoesthesia reported in 29% with suspension vs 6% with tablets |
| ALS — patient with dysphagia (oral film) | 50 mg BID | 50 mg BID | 100 mg/day | Exservan 50 mg oral dissolving film; place on tongue and allow to dissolve |
| Mild hepatic impairment (CP-A) | Standard dose with enhanced monitoring | AUC 1.7-fold higher; increased risk of AEs; monitor LFTs closely | ||
| Moderate hepatic impairment (CP-B) | Standard dose with enhanced monitoring | AUC 3-fold higher; consider risk-benefit; monitor LFTs closely | ||
| Baseline ALT >5× ULN or liver dysfunction | Not recommended | Do not initiate; if ALT rises >5× ULN during treatment, discontinue | ||
| Female patients | Standard dose; no adjustment | AUC ~45% higher in females; monitor for AEs | ||
| Japanese patients | Standard dose; enhanced monitoring | Clearance 50% lower than Caucasians (weight-normalised); greater AE risk | ||
A high-fat meal reduces riluzole AUC by 20% and Cmax by 45%, hence the requirement to take the drug on an empty stomach (1 hour before or 2 hours after meals). Tobacco smoking increases riluzole clearance by 20% via CYP1A2 induction, which may slightly reduce efficacy. Conversely, CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) can significantly increase riluzole exposure. These pharmacokinetic interactions are clinically important for a drug with a narrow therapeutic window and dose-dependent hepatotoxicity.
Pharmacology
Mechanism of Action
The precise mechanism by which riluzole exerts its therapeutic effect in ALS is unknown (FDA PI). However, its pharmacological properties include three potentially relevant actions: inhibition of glutamate release (possibly through interference with voltage-dependent sodium channels), inactivation of voltage-dependent sodium channels directly, and interference with intracellular events downstream of excitatory amino acid receptor activation. In the context of ALS, where motor neuron death is thought to involve excitotoxic glutamate signalling, these anti-glutamatergic properties provide a plausible basis for the observed survival benefit. Riluzole does not reverse existing motor neuron damage or improve muscle strength, and it has not demonstrated benefit on measures of neurological function in clinical trials.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~60%; linear PK over 25–100 mg Q12H; Tmax ~60–90 min; food reduces AUC by 20% and Cmax by 45% (high-fat meal) | Must be taken on empty stomach for consistent absorption; dose-proportional kinetics within therapeutic range |
| Distribution | Protein binding 96% (mainly albumin and lipoproteins); widely distributed | High protein binding but no clinically significant displacement interactions with warfarin, digoxin, imipramine, or quinine (in vitro) |
| Metabolism | Primarily CYP1A2 (oxidation) + UGT-HP4 (glucuronidation); at least 88% metabolised; active metabolites (N-hydroxyriluzole) present but clinical significance unknown | CYP1A2 is the key interaction pathway; inhibitors (fluvoxamine, ciprofloxacin) raise exposure, inducers (smoking, omeprazole, rifampicin) lower it; high inter-individual variability (CV 35%) partly from CYP1A2 polymorphism |
| Elimination | t½ 12 h (CV 35%); ~2-fold accumulation at steady state; urine 90% (only 2% unchanged riluzole); faeces 5% | BID dosing provides steady-state coverage; predominantly hepatic elimination makes hepatotoxicity monitoring critical |
Side Effects
Adverse reaction data are from pooled Studies 1 and 2 (FDA PI Table 1; N = 313 riluzole 50 mg BID vs N = 320 placebo). The most common adverse reactions leading to discontinuation were nausea, abdominal pain, constipation, and elevated ALT. Dizziness was more common in females (11%) than males (4%).
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Asthenia | 19% (vs 12% placebo) | Most frequently reported; difficult to distinguish from ALS-related fatigue; assess functional impact |
| Nausea | 16% (vs 11% placebo) | One of the most common reasons for discontinuation; taking on empty stomach may contribute; consider anti-emetic if needed |
| Decreased lung function | 10% (vs 9% placebo) | Marginal excess over placebo; likely reflects underlying ALS progression; monitor FVC regardless |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Hypertension | 5% (vs 4%) | Monitor blood pressure periodically |
| Abdominal pain | 5% (vs 4%) | A common reason for discontinuation; evaluate for pancreatitis if severe |
| Vomiting | 4% (vs 2%) | May limit tolerability; evaluate for liver injury if persistent |
| Arthralgia | 4% (vs 3%) | Mild joint pain; generally does not require treatment change |
| Dizziness | 4% (vs 3%) | Higher incidence in females (11% vs 4% in males) |
| Dry mouth | 4% (vs 3%) | Manage with sips of water; may compound sialorrhoea-related distress in some ALS patients |
| Insomnia | 4% (vs 3%) | Dose timing (morning and evening) may help; avoid taking dose near bedtime |
| Pruritus | 4% (vs 3%) | Evaluate for concurrent liver enzyme elevation |
| Tachycardia | 3% (vs 1%) | Notable 2% excess over placebo; monitor heart rate |
| Flatulence | 3% (vs 2%) | GI-related; generally mild |
| Increased cough | 3% (vs 2%) | Distinguish from ALS-related respiratory decline; evaluate for ILD if new dry cough |
| Peripheral oedema | 3% (vs 2%) | Assess for cardiac or hepatic causes |
| UTI | 3% (vs 2%) | May reflect immobility-related risk in ALS patients |
| Circumoral paraesthesia | 2% (vs 0%) | Characteristic of riluzole; noted especially with oral suspension formulation |
| Somnolence | 2% (vs 1%) | Advise caution with driving |
| Vertigo | 2% (vs 1%) | Differentiate from ALS-related balance problems |
| Eczema | 2% (vs 1%) | Dermatological; evaluate if widespread |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Drug-induced liver injury (DILI) | ALT >5× ULN: 2%; ALT >ULN: ~50%; ALT >3× ULN: ~8% | Maximum within first 3 months | Fatal cases reported; monitor ALT monthly ×3 then periodically; discontinue if ALT >5× ULN or evidence of liver dysfunction (elevated bilirubin); rechallenge not recommended |
| Neutropenia (ANC <500/mm³) | Rare (post-marketing) | Within first 2 months | Advise patients to report febrile illness; obtain urgent FBC; consider discontinuation |
| Interstitial lung disease | Rare (post-marketing) | Variable | Includes hypersensitivity pneumonitis; discontinue riluzole immediately; evaluate with chest imaging |
| Pancreatitis | Rare (post-marketing; NEW warning 9/2025) | Weeks to years after initiation | Fatal and non-fatal necrotising pancreatitis reported; promptly discontinue if pancreatitis suspected; may reinitiate if alternative cause identified |
| Anaphylaxis | Very rare (post-marketing) | Any time | Emergency management; permanent discontinuation (contraindicated if serious hypersensitivity) |
About 50% of riluzole-treated patients develop at least one ALT elevation above the upper limit of normal during treatment. However, clinically significant elevations (>5× ULN) occur in only 2%. The maximum ALT increase typically occurs within the first 3 months, making early monthly monitoring critical. Elevations have recurred upon rechallenge in some patients, so re-initiation after hepatotoxicity is not recommended. Concomitant use of other hepatotoxic drugs (e.g., allopurinol, methyldopa, sulfasalazine) may compound the risk.
Drug Interactions
Riluzole is primarily metabolised by CYP1A2, making it susceptible to pharmacokinetic interactions with CYP1A2 inhibitors and inducers. The FDA PI specifically warns about these interactions. Additionally, because riluzole carries a hepatotoxicity risk, concurrent use of other hepatotoxic agents requires careful monitoring.
Monitoring
- Serum aminotransferases (ALT/AST)Before treatment, monthly ×3 months, then periodically
RoutineMost critical monitoring parameter. ALT >ULN in ~50% of patients; ALT >3× ULN in ~8%; ALT >5× ULN in 2%. Maximum elevations within first 3 months. Do not initiate if baseline ALT >5× ULN. Discontinue if ALT >5× ULN or evidence of liver dysfunction (e.g., elevated bilirubin). - BilirubinBaseline, then with LFTs
RoutineElevated bilirubin at baseline should preclude use. Rising bilirubin during treatment indicates liver dysfunction requiring discontinuation. - Full blood countIf febrile illness develops
Trigger-basedSevere neutropenia (ANC <500/mm³) reported within first 2 months. Advise patients to report any febrile illness immediately. - Respiratory function (FVC)Every 3 months (standard ALS care)
RoutinePart of standard ALS monitoring, not specifically required by riluzole. New dry cough or dyspnoea should prompt evaluation for interstitial lung disease (ILD). - Symptoms of pancreatitisEach visit
RoutineNEW warning (9/2025): fatal necrotising pancreatitis reported. Abdominal pain, nausea, vomiting, and/or anorexia require prompt medical evaluation. Onset weeks to years after initiation.
Contraindications & Cautions
Absolute Contraindications
- History of severe hypersensitivity to riluzole or any component (anaphylaxis has occurred)
Relative Contraindications (Specialist Input Recommended)
- Baseline ALT >5× ULN: Use is not recommended (FDA PI)
- Evidence of liver dysfunction (e.g., elevated bilirubin): Do not initiate
- Moderate hepatic impairment (CP-B): AUC 3-fold higher; significantly increased hepatotoxicity risk; careful risk-benefit assessment required
- Severe hepatic impairment (CP-C): Not studied; avoid
Use with Caution
- Mild hepatic impairment (CP-A): AUC 1.7-fold higher; monitor LFTs more frequently
- Japanese patients: Clearance 50% lower (weight-normalised); greater AE risk
- Female patients: AUC ~45% higher than males; no dose adjustment but monitor
- Concomitant CYP1A2 inhibitors: Increased riluzole exposure and AE risk
- Concomitant hepatotoxic drugs: Additive liver injury risk
Cases of drug-induced liver injury, some of which were fatal, have been reported in patients taking riluzole. Asymptomatic elevations of hepatic transaminases have also been reported and in some patients have recurred upon rechallenge. The incidence of ALT elevations >5× ULN was 2% in riluzole-treated patients, and approximately 50% had at least one ALT above ULN. Monitor serum aminotransferases before and during treatment: monthly for the first 3 months, then periodically thereafter. Not recommended if ALT >5× ULN at baseline. Discontinue if there is evidence of liver dysfunction.
Acute pancreatitis, including fatal and non-fatal necrotising pancreatitis, has been observed in patients treated with riluzole in the post-marketing setting. Pancreatitis has occurred weeks to several years after initiation. Patients and caregivers should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis requiring prompt medical evaluation. If pancreatitis is suspected, promptly discontinue riluzole. If an alternative cause is identified, reinitiation may be considered.
Patient Counselling
Purpose of Therapy
Riluzole is prescribed to help extend survival in people with ALS (motor neurone disease). It works by reducing the activity of a brain chemical called glutamate that may contribute to motor neurone damage. Riluzole does not cure ALS and does not improve muscle strength, but clinical trials showed it can extend the time before a tracheostomy or death by approximately 2–3 months. It is taken as a tablet, liquid, or dissolving film twice daily on an empty stomach.
Sources
- Rilutek (riluzole) tablets — FDA-approved Prescribing Information. Covis Pharma. Revised September 2025. accessdata.fda.govPrimary source for dosing, adverse reactions (Table 1, pooled n = 633), pharmacokinetics (Table 2), hepatotoxicity warning, new pancreatitis warning (9/2025), and clinical trial data (Studies 1 and 2).
- Tiglutik (riluzole) oral suspension — FDA-approved Prescribing Information. Revised 2020. accessdata.fda.govSource for oral suspension formulation data, feeding tube administration, and oral hypoesthesia incidence (29% vs 6% with tablets).
- Bensimon G, Lacomblez L, Meininger V; ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994;330(9):585–591. doi:10.1056/NEJM199403033300901Study 1: 155 patients, randomised to riluzole 50 mg BID or placebo; median survival difference ~90 days (tracheostomy or death endpoint); Wilcoxon p = 0.05. First RCT demonstrating riluzole’s survival benefit.
- Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V; ALS/Riluzole Study Group-II. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet. 1996;347(9013):1425–1431. doi:10.1016/S0140-6736(96)91680-3Study 2: 959 patients, dose-ranging (50, 100, 200 mg/day vs placebo); 100 mg/day confirmed as effective dose; median survival difference ~60 days; higher doses did not improve efficacy but increased AEs.
- Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;(3):CD001447. doi:10.1002/14651858.CD001447.pub3Cochrane meta-analysis confirming riluzole extends median survival by approximately 2–3 months; number needed to treat (NNT) ~11 for one additional survivor at 12 months.
- Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, Kalra S, Katz JS, Mitsumoto H, Rosenfeld J, Shoesmith C, Strong MJ, Woolley SC; Quality Standards Subcommittee of the AAN. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review). Neurology. 2009;73(15):1218–1226. doi:10.1212/WNL.0b013e3181bc0141AAN practice parameter recommending riluzole be offered to slow ALS disease progression (Level A recommendation).
- National Institute for Health and Care Excellence (NICE). Motor neurone disease: assessment and management. NICE guideline [NG42]. 2016 (updated 2024). nice.org.uk/guidance/ng42UK guideline recommending riluzole for ALS/MND with regular hepatic monitoring; includes guidance on multidisciplinary care.
- Doble A. The pharmacology and mechanism of action of riluzole. Neurology. 1996;47(6 Suppl 4):S233–S241. doi:10.1212/WNL.47.6_Suppl_4.233SComprehensive review of riluzole’s pharmacological properties including glutamate release inhibition, sodium channel blockade, and post-synaptic receptor interference.
- Bellingham MC. A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther. 2011;17(1):4–31. doi:10.1111/j.1755-5949.2009.00116.xUpdated mechanistic review covering riluzole’s neuroprotective actions, clinical efficacy data, and PK considerations for optimising treatment.
- Groeneveld GJ, van Kan HJ, Kalmijn S, Veldink JH, Guchelaar HJ, Wokke JH, van den Berg LH. Riluzole serum concentrations in patients with ALS: associations with side effects and symptoms. Neurology. 2003;61(8):1141–1143. doi:10.1212/01.WNL.0000090459.76784.49PK study demonstrating inter-individual variability in riluzole concentrations and association between higher levels and hepatic side effects.