Riluzole

(BAN, USAN, rINN)
Riluzole Chemical formula
Synonyms: PK-26124; Rilutsoli; Riluzol; Riluzolum; RP-54274. 2-Amino-6zothiazol-2-ylamine.
Cyrillic synonym: Рилузол.

💊 Chemical information

Chemical formula: C8H5F3N2OS = 234.2.
CAS — 1744-22-5.
ATC — N07XX02.
ATC Vet — QN07XX02.

💊 Adverse Effects and Treatment

Adverse effects associated most commonly with riluzole are asthenia, nausea, elevations in liver enzyme values, headache, and abdominal pain. Other gastrointestinal effects may include diarrhoea or constipation, anorexia, and vomiting. There may be tachycardia, dizziness, vertigo, or somnolence. Circumoral paraesthesia has been reported and decreased lung function and rhinitis may occur. Anaphylactoid reactions, angioedema, pancreatitis, and neutropenia have all been reported rarely.

Effects on the blood.

Severe neutropenia has been reported1in a 71-year old patient with amyotrophic lateral sclerosis receiving standard doses of riluzole. The neutrophil count returned to normal on cessation of riluzole. See also under Overdosage, below.
1. Weber G, Bitterman H. Riluzole-induced neutropenia. Neurology 2004; 62: 1648.

Effects on the kidneys.

A 44-year-old patient developed renal tubular impairment 3 months after starting riluzole for amyotrophic lateral sclerosis.1 Tubular function recovered 1 month after stopping riluzole.
1. Poloni TE, et al. Renal tubular impairment during riluzole therapy. Neurology 1999; 52: 670.

Effects on the liver.

Icteric toxic hepatitis, with jaundice and elevated liver enzyme values, has been reported1 in an elderly woman receiving riluzole for amyotrophic lateral sclerosis (ALS). Acute hepatitis developed in 2 patients several weeks after starting therapy with riluzole for ALS.2 Liver histology showed hepatocellular damage with inflammatory infiltration and microvesicular steatosis without fibrosis. Hepatotoxicity was reversed in all these cases when riluzole was stopped.
1. Castells LI, et al. Icteric toxic hepatitis associated with riluzole. Lancet 1998; 351: 648
2. Remy A-J, et al. Acute hepatitis after riluzole administration. J Hepatol 1999; 30: 527–30.

Effects on the pancreas.

Riluzole was cited1 as the most likely cause of severe pancreatitis that developed in a 77-year-old woman 6 months after starting therapy for sporadic amyotrophic lateral sclerosis; pancreatic symptoms improved when riluzole was stopped.
1. Drory VE, et al. Riluzole-induced pancreatitis. Neurology 1999; 52: 892–3.

Hypersensitivity.

A severe life-threatening systemic inflammatory reaction occurred in a patient 2 weeks after starting treatment with riluzole for amyotrophic lateral sclerosis.1 Symptoms resolved spontaneously on stopping riluzole.
1. Sorenson EJ. An acute, life-threatening, hypersensitivity reaction to riluzole. Neurology 2006; 67: 2260–1.

Overdosage.

Severe neutropenia developed in a 63-year-old woman receiving riluzole for amyotrophic lateral sclerosis 10 days after inadvertent dose increase to 200 mg daily (twice the standard recommended dose).1 Methaemoglobinaemia has been reported2 in a 43-year-old patient with amyotrophic lateral sclerosis after intentional overdose with 2.8 g of riluzole. The patient was treated with gastric lavage followed by activated charcoal; intravenous methylthioninium chloride successfully reversed the methaemoglobinaemia. However, the patient died of respiratory failure related to her underlying disease 7 days after the overdose. An amnesic syndrome that persisted for over a year developed in a woman 4 days after ingestion of 3 g of riluzole.3
1. North WA, et al. Reversible granulocytopenia in association with riluzole therapy. Ann Pharmacother 2000; 34: 322–4.
2. Viallon A, et al. Methemoglobinemia due to riluzole. N Engl J Med 2000; 343: 665–6
3. Haaxma CA, et al. Delayed amnesic syndrome after riluzole autointoxication in Huntington disease. Neurology 2006; 66: 1123–4.

💊 Precautions

Riluzole is contra-indicated in patients with hepatic disease or markedly raised liver enzyme values. Liver function tests should be performed before and throughout treatment with riluzole. In the UK, riluzole is not recommended in patients with renal impairment although US licensed product information states that the pharmacokinetics are not significantly different in renal impairment. Caution should be exercised in those with a history of liver disorders. Patients or their carers should be told how to recognise signs of neutropenia and should be advised to seek immediate medical attention if symptoms such as fever develop; white blood cell counts should be determined in febrile illness and riluzole stopped if neutropenia occurs. Riluzole may cause dizziness or vertigo and patients should be warned not to drive or operate machinery if these symptoms occur. Riluzole has been reported to impair fertility in animals.

💊 Pharmacokinetics

Riluzole is rapidly absorbed from the gastrointestinal tract after oral doses, with peak plasma concentrations occurring in 1 to 1 ⁄ hours. The rate and extent of absorption are decreased when riluzole is given with a high-fat meal. Riluzole is widely distributed throughout the body and is about 97% bound to plasma proteins. It crosses the blood-brain barrier. Riluzole is extensively metabolised to several metabolites in the liver, mainly by the cytochrome P450 isoenzyme CYP1A2, and subsequent glucuronidation. Riluzole is excreted mainly in the urine, mainly as glucuronides, with an elimination half-life of about 9 to 15 hours. About 2% is excreted unchanged in the urine. Small amounts are excreted in faeces. There is some evidence that clearance of riluzole is reduced in Japanese patients.
1. Le Liboux A, et al. Single- and multiple-dose pharmacokinetics of riluzole in white subjects. J Clin Pharmacol 1997; 37: 820–7
2. Le Liboux A, et al. A comparison of the pharmacokinetics and tolerability of riluzole after repeat dose administration in healthy elderly and young volunteers. J Clin Pharmacol 1999; 39: 480–6
3. Groeneveld GJ, et al. Riluzole serum concentrations in patients with ALS: associations with side effects and symptoms. Neurology 2003; 61: 1141–3
4. van Kan HJ, et al. Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis. Br J Clin Pharmacol 2005; 59: 310–13.

💊 Uses and Administration

Riluzole is a glutamate antagonist used in the management of amyotrophic lateral sclerosis, a form of motor neurone disease. Riluzole is indicated to slow progression of early disease but efficacy has not been demonstrated in its late stages. The precise mechanism of action is unknown but it may inhibit presynaptic glutamate release and interfere with its postsynaptic effects. The usual adult dose of riluzole is 50 mg twice daily by mouth on an empty stomach.

Motor neurone disease.

Motor neurone disease (motoneuron disease) represents a group of fatal progressive degenerative disorders that affect upper and/or lower motor neurones in the brain and spinal cord. The most common form of motor neurone disease is amyotrophic lateral sclerosis (known in the USA as Lou Gehrig’s disease), which involves both upper and lower motor neurones. It produces muscular atrophy and weakness and symptoms of progressive bulbar palsy such as slowness of movement and speech disturbances. Most patients die within 2 to 5 years of disease onset, usually from respiratory failure. There is no completely effective treatment and management remains largely supportive with appropriate symptomatic management of spasticity, pain, and sialorrhoea. Tricyclic antidepressants are widely used for their multiple beneficial effects. Occupational and speech therapy also play a crucial role in maximising function. Pathological crying or laughing (pseudobulbar affect) may occur in as many as 50% of patients and has been treated with amitriptyline or fluvoxamine. Dysphagia may eventually compromise food and fluid intake necessitating enteral nutrition as an alternative or supplemental route for oral nutrition. Respiratory support will ultimately be necessary, initially with non-invasive ventilation but progressing eventually to tracheostomy. Although the pathogenesis of motor neurone disease is still uncertain, it is thought that accumulation of the excitatory neurotransmitter glutamate in the CNS may be involved. Clinical studies have shown riluzole, a glutamate antagonist, to be modestly effective in prolonging survival by an average of 3 months and delaying the time to use of tracheostomy. However, there is still insufficient data to be able to assess which patients would derive greatest benefit. Additionally, questions have been raised about the clinical usefulness of riluzole in terms of cost-benefit, and there are concerns about adverse effects, notably hepatotoxicity. Also under study for the treatment of motor neurone disease are somatomedins, in particular mecasermin (insulin-like growth factor I). Neurotrophic factors have been investigated including brain-derived neurotrophic factor (BDNF) and recombinant ciliary neurotrophic factor (CNTF), but results have been generally inconclusive. Glial-cell-derived neurotrophic factor (GDNF) and xaliproden are under investigation. There has been some interest in the antiepileptic drug gabapentin, which may inhibit glutamate formation in the CNS from branched-chain amino acids. Lamotrigine and topiramate have also been tried but with disappointing results. ONO-2506 is an enantiomeric homologue of valproate that is also under investigation. Dextromethorphan has been studied in amyotrophic lateral sclerosis. Minocycline has demonstrated neuroprotective effects in animal studies and is therefore also being studied in this condition; ceftriaxone is also under investigation. Immunoglobulins have been tried in some forms of motor neurone disease such as multifocal motor neuropathy. Antoxidants, including vitamins C and E, are commonly used by patients in the belief that one mechanism for neuronal death is free radical accumulation resulting from oxidative stress. However, despite substantial literature on the subject and widespread use of antoxidants, significant evidence to support their benefit in motor neurone disease is lacking. Creatine supplements have been tried in a bid to preserve motor function and motor neurones, although benefit has not been shown in controlled studies. A small percentage of patients with familial amyotrophic lateral sclerosis has been shown to have a mutation in the gene encoding for the enzyme copper-zinc superoxide dismutase but there has been no consensus as to whether patients with this mutation should be given superoxide dismutase supplements.
1. Ludolph AC, Riepe MW. Do the benefits of currently available treatments justify early diagnosis and treatment of amyotrophic lateral sclerosis? — Arguments against. Neurology 1999; 53 (suppl 5): S46–S49
2. Cashman NR. Do the benefits of currently available treatments justify early diagnosis and announcement? — Arguments for. Neurology 1999; 53 (suppl 5): S50–S52
3. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001; 344: 1688–1700
4. Dib M. Amyotrophic lateral sclerosis: progress and prospects for treatment. Drugs 2003; 63: 289–310
5. Leigh PN, et al. The management of motor neurone disease. J Neurol Neurosurg Psychiatry 2003; 74 (suppl 4): iv32–iv47
6. Ashworth NL, et al.. Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2006 (accessed 28/04/06)
7. Choudry RB, Cudkowicz ME. Clinical trials in amyotrophic lateral sclerosis: the tenuous past and the promising future. J Clin Pharmacol 2005; 45: 1334–44
8. Traynor BJ, et al. Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology 2006; 67: 20–7
9. Miller RG, et al. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Available in The Cochrane Database of Systematic Reviews; Issu
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10. Orrell RW, et al. Antioxidant treatment for amyotrophic lateral sclerosis / motor neuron disease. Available in The Cochrane Database of Systematic Reviews; Issu
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11. Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet 2007; 369: 2031–41
12. Mitsumoto H, Rabkin JG. Palliative care for patients with amyotrophic lateral sclerosis: prepare for the worst and hope for the best. JAMA 2007; 298: 207–16
13. McDermott CJ, Shaw PJ. Diagnosis and management of motor neurone disease. BMJ 2008; 336: 658–62
14. Corcia P, Meininger V. Management of amyotrophic lateral sclerosis. Drugs 2008; 68: 1037–48.

Movement disorders.

Beneficial results have been obtained with riluzole in small studies of patients with Huntington’s chorea.1,2 Riluzole has been tried in a small number of patients with early Parkinson’s disease but no evidence of benefit was observed.3 It has also been tried in levodopa-induced dyskinesias in advanced Parkinson’s disease with conflicting reports of benefit4or no benefit.5
1. Rosas HD, et al. Riluzole therapy in Huntington’s disease (HD). Mov Disord 1999; 14: 326–30
2. Huntington Study Group. Dosage effects of riluzole in Huntington’s disease: a multicenter placebo-controlled study. Neurology 2003; 61: 1551–6
3. Jankovic J, Hunter C. A double-blind, placebo-controlled and longitudinal study of riluzole in early Parkinson’s disease. Parkinsonism Relat Disord 2002; 8: 271–6
4. Merims D, et al. Riluzole for levodopa-induced dyskinesias in advanced Parkinson’s disease. Lancet 1999; 353: 1764–5
5. Braz CA, et al. Effect of riluzole on dyskinesia and duration of the ON state in Parkinson disease patients: a double-blind, placebo-controlled pilot study. Clin Neuropharmacol 2004; 27: 25–9.

Psychiatric disorders.

Glutamate is implicated in the aetiology of various psychiatric disorders and consequently riluzole has been suggested as a potential treatment in view of its glutamatemodulating properties.
1. Zarate CA, et al. An open-label trial of riluzole in patients with treatment-resistant major depression. Am J Psychiatry 2004; 161: 171–4
2. Sanacora G, et al. Riluzole augmentation for treatment-resistant depression. Am J Psychiatry 2004; 161: 2132
3. Zarate CA, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 2005; 57: 430–2
4. Coric V, et al. Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. Biol Psychiatry 2005; 58: 424–8
5. Coric V, et al. Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with trichotillomania. J Clin Psychiatry 2007; 68: 170–1.

💊 Preparations

Proprietary Preparations

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Published May 08, 2019.