Guidance on the use of Riluzole (Rilutek) for the treatment of Motor Neurone Disease

# Guidance
Riluzole is recommended for the treatment of individuals with the amyotrophic lateral sclerosis (ALS) form of Motor Neurone Disease (MND).
Riluzole therapy should be initiated by a neurological specialist with expertise in the management of MND. Routine supervision of therapy should be managed by locally agreed shared care protocols undertaken by general practitioners.# Clinical Need and Practice
Motor neurone disease (MND) is characterised by progressive degeneration of the motor neurones of the brain, brain stem or spinal cord. Depending on the site of the lesions, characteristic signs may include spasticity, muscle stiffness, brisk or diminished reflexes, muscle wasting and fasciculation, and both flaccid and/or spastic weakness.
The classification and terminology used to describe the different Motor Neurone Disease syndromes are not always clear or consistent. This partly reflects uncertainties surrounding the underlying causes of MND and the mechanism of neuronal damage. There is also debate about the extent to which different syndromes are simply manifestations of the same disease process or whether there are several different disease mechanisms.
The term 'Motor Neurone Disease' is used to describe variants of the disease  namely progressive muscular atrophy (PMA) and amyotrophic lateral sclerosis (ALS) which includes Progressive Bulbar Palsy (PBP). ALS, which is characterised by both upper and lower motor neurone signs, is the most common form of MND, accounting for 65% to 85% of all cases. Adult onset MND usually starts insidiously with symptoms and signs including stumbling, foot drop, weakened grip, slurred speech, cramp, muscle wasting, twitching and tiredness. Other symptoms of MND include muscle stiffness, paralysis, incoordination and impaired speech, swallowing and breathing. Most individuals die from ventilatory failure, resulting from progressive weakness and wasting of limb, respiratory and bulbar muscles within approximately 3 years of the onset of symptoms.
The Institute was advised that, despite the terms of the product licence, it has been common clinical practice for riluzole to be used in all of the forms of MND referred to in paragraph 2.3. This may in part be because the mainland European and UK nomenclature for the disease differs. In mainland Europe, the terms MND and ALS are often used interchangeably. This document refers to ALS specifically in accordance with the terminology used in the current product licence for riluzole.
There is no diagnostic test for MND. The diagnosis requires the demonstration of clinical signs affecting both the brain and spinal cord. Diagnosis is often delayed and can take more than 16 months from the onset of initial symptoms, which are commonly non-specific and include general fatigue.
The incidence of ALS ranges from 1.8 to 2.2 per 100,000 population and prevalence ranges from 4.0 to 4.7 per 100,000 population in UK. Therefore at any one time about 2000 individuals per year in England and Wales are affected by ALS.
There is a range of pharmacological interventions that provide symptomatic relief for people with MND. Surgical intervention may be necessary. Such interventions include percutaneous gastrostomy to enable feeding as the ability to swallow decreases and tracheostomy with or without ventilatory support to aid breathing as respiratory muscle weakness increases.
Supportive and palliative care is currently available for people with MND. A wide range of multidisciplinary health and social services is required, particularly in the late stages of the disease, and need to be tailored to suit individual needs. NHS, personal social service and voluntary sector services needed include physiotherapy, occupational therapy, speech and language therapy and augmentative communication, mobility aids and district nursing support. In the later stages of the disease, the following interventions may also be required: enteral feeding (for severe dysphagia), domiciliary or hospice care, and ventilatory support, including mechanical ventilation and tracheostomy.# The Technology
Riluzole (Rilutek) is currently the only drug licensed for treating ALS in the UK. The licensed indication of riluzole is to extend life or the time to mechanical ventilation for individuals with ALS. The Summary of Product Characteristics (SPC) recommends that riluzole should not be used in any other form of Motor Neurone Disease. The SPC also suggests that treatment should only be initiated by specialist physicians with experience in the management of Motor Neurone Disease.
It is hypothesised that excessive stimulation of glutamate receptors on neurones may cause or play an important role in the destruction of motor neurones in MND. Glutamate is a neurotransmitter that tends to excite motor neurone cells. In vitro, riluzole inhibits the release of glutamate; decreases firing of motor neurones induced by glutamate receptor agonists and thus protects cells from glutamate-mediated damage.
The main caution for use of riluzole is history of abnormal hepatic function. Regular blood testing (every month for 3 months, then every 3 months for a further 9 months and annually thereafter) is recommended to monitor hepatic function. Side effects include nausea, vomiting, weakness, tachycardia, somnolence, headache, dizziness, vertigo, pain, parasthesia and alterations in liver function tests. Side effects of dizziness or vertigo may affect the performance of skilled tasks such as driving. Riluzole is contraindicated in the presence of hepatic and/or renal impairment and during pregnancy and breast-feeding.
The license dosage of riluzole is 100mg per day (50mg twice per day). The NHS list price (excluding VAT) of riluzole is 286 per treatment course, which amounts to an annual cost of 3718. An additional cost, incurred for monitoring liver enzymes, has been estimated to be a maximum of 24 per year, giving a total annual cost of treatment with riluzole of 3742.# Evidence
Four randomised controlled trials (including a number of UK centres) in patients who fall within the diagnostic category of ALS have compared riluzole with placebo (a total of 1477 individuals). Three trials used riluzole at 100 mg/day and one used doses of 50, 100 and 200mg/day. Individuals were under 75 years, had a Forced Vital Capacity (FVC) 60% in three trials, with two of these also excluding patients who had suffered from MND for more than 5 years. The fourth trial recruited individuals who were older or who had a greater duration of disease (> 5 years) or who had a FVC<60%.
All trials used tracheostomy-free survival as a primary outcome. Most individuals (in all four trials) were prevalent, rather than incident cases.
The assessment report reviewed the results from all four of the trials identified and reported riluzole to be associated with a relative reduction in hazard ratio for tracheostomy-free survival at 18 months of 17% (i.e. hazard ratio of 0.88, 95% CI: 0.75- 1.02). There was some evidence of heterogeneity across the results of these four trials.
When data on functional status were combined, a small reduction in the rate of deterioration of functional status was observed, although the statistical methods used to calculate changes were questionable. Furthermore it is not clear whether the estimated differences obtained using these methods were clinically significant.
There was little evidence of a difference in adverse events between riluzole and placebo.
There is strong clinical support for the use of riluzole in forms of MND other than ALS but the current licensed indications limit its use to ALS alone. The inclusion criteria for the published clinical trials has been restricted to a diagnosis of the ALS form of MND alone.
Current estimates of the cost-effectiveness of riluzole must be viewed cautiously. Some of the key remaining uncertainties on benefits for the economic analysis concern the disease stage(s) in which the survival gain is experienced, the quality of life utility weights for ALS health states and the mean gain in life expectancy for individuals who take riluzole. Estimates from the two fully published trials suggest a gain in median tracheostomy free survival time of 2 months to 4 months. It is clear that riluzole is associated with a net increase in costs to the health service, though the magnitude of the increase is difficult to predict accurately.
Using a published Markov model and 18 month trial follow up data, the manufacturer's submission provided a base case cost per quality adjusted life year (cost/QALY) estimate of 18,000 to 29,000 for riluzole. Based on a re-analysis of this Markov model using an alternative, more conservative, estimate of time-dependant probabilities, the assessment report derived discounted cost per QALY estimates for riluzole of between approximately 34,000 to 43, 500. These later estimates are consistent with the results obtained by the assessment report authors when using Weibull and Gompertz models to extrapolate survival over time.
The Appraisal Committee considered the evidence of the clinical and cost effectiveness of this technology by reference to the Directions to the Institute issued by the Secretary of State. The Committee took account of the severity and relatively short life span of people with ALS and in particular, as directly reported to it, of the values which patients place on the extension of tracheostomy free survival time. With these considerations in mind, the Committee considered that the net increase in cost for the NHS of the use of riluzole in this indication was reasonable when set against the benefit, assessed as extended months of an acceptable (to patients) quality of life.
The documentation and opinion available to the Appraisals Committee is set out in Appendix B.# Implications for the NHS
It is estimated that the potential budget impact to the NHS in the England and Wales of making riluzole available to all individuals with ALS would be at maximum around 7.5 million per annum. Given an estimated current level of funding of riluzole for ALS of about 2 million per annum, this represents an additional cost to the NHS in England and Wales of about 5 million. However, there is considerable uncertainty about the proportion of patients who will take up this therapy. Moreover, these figures do not take into account the additional NHS costs of patient survival.
A diagnosis of MND should be made or confirmed by a specialist physician with experience in the management of Motor Neurone Disease after appropriate investigations. In most cases, the specialist will be responsible for monitoring the progress of the disease and the safe use of riluzole. The needs of people with MND demand flexibility, and this monitoring role can be taken up by the general practitioner or by other physicians involved in providing shared care.
In the latter stages of their disease, patients may wish to review their continued use of riluzole and they should be provided with the opportunity to discontinue treatment, if after discussion with the responsible clinician, they consider it appropriate.# Further research
Further trials of riluzole are required to examine the relative effectiveness of differing dosing regimens.
Methods for the early diagnosis of MND require development as they may enable earlier treatment and enhanced clinical outcomes.# Review of guidance
Information on the review of the guidance on this technology is available on the NICE website
Andrew DillonChief ExecutiveJanuary 2001# Appendix B: Sources of Evidence
. The following documentation and opinion was made available to the Committee:
a. Assessment Report
Assessment report 'The clinical effectiveness and cost effectiveness of Riluzole in the Treatment of Motor Neurone Disease' by Stewart, Sandercock, Bryan, Hyde, Fry- Smith, Burls.West Midlands Development & Evaluation Service, University of Birmingham
Update Assessment Report prepared by the West Midlands Development and Evaluation Service (The clinical effectiveness and cost-effectiveness of Riluzole for Motor Neurone Disease, August 2000)
b. Manufacturer/Sponsor submissions:
Aventis Pharma
c. Professional/Specialist Group, Patient/Carer Group and Trade Association submissions:
Association of British Neurologists & Royal College of Physicians
Association for Palliative Medicine of Great Britain and Ireland
Chartered Society of Physiotherapy
Motor Neurone Disease Association
Royal College of General Practitioners
Royal College of Nursing
Royal College of Speech and Language Therapists
d. External expert and patient advocate submissions:
Professor Pamela Shaw, Section of Neurology, Royal Hallamshire Hospital, Sheffield
Ms. Julia Johnson, Speech and Language Therapist, King's College Hospital
Mr. George Levvy, Chief Executive, MND Association
Mr. Chris Davies, Member of MND Association.# Appendix C: Guidance on the use of Riluzole (Rilutek) for the Treatment of Motor Neurone Disease  patient information
'Understanding NICE Guidance', a summary of this guidance for patients and carers can be found on our website.# Changes after publication
March 2014: minor maintenance
March 2012: minor maintenance# About this guidance
NICE technology appraisal guidance is about the use of new and existing medicines and treatments in the NHS in England and Wales.
We have produced a summary of this guidance for patients and carers. Tools to help you put the guidance into practice and information about the evidence it is based on are also available.
Your responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the evidence available. Healthcare professionals are expected to take it fully into account when exercising their clinical judgement. However, the guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers. Commissioners and providers are reminded that it is their responsibility to implement the guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a way which would be inconsistent with compliance with those duties.
Copyright
 National Institute for Health and Clinical Excellence 2001. All rights reserved. NICE copyright material can be downloaded for private research and study, and may be reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the written permission of NICE.