sodium oxybate, 500mg/ml oral solution (Xyrem) No. (246/06) UCB Pharma Ltd

Transcription

1 Scottish Medicines Consortium Resubmission sodium oxybate, 500mg/ml oral solution (Xyrem) No. (246/06) UCB Pharma Ltd 10 August 2007 The Scottish Medicines Consortium has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a resubmission sodium oxybate (Xyrem ) is not recommended for use within NHS Scotland for the treatment of cataplexy in adult patients with narcolepsy. The manufacturer s justification of the treatment s cost in relation to its health benefits was not sufficient to gain acceptance by SMC. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium 1

2 Indication Treatment of cataplexy in adult patients with narcolepsy Dosing information 4.5 g/day divided into two equal doses taken upon getting into bed and again between 2.5 to 4 hours later. The dose should be titrated to effect in dose increments of 1.5 g/day based on efficacy and tolerability up to a maximum of 9 g/day. A minimum of one to two weeks is recommended between dosage increments. Product availability date February This product has Orphan Drug Status. Summary of evidence on comparative efficacy Sodium oxybate, the sodium salt of gamma hydroxybutyrate (GHB) is an endogenous 4- carbon fatty acid that is thought to act as a neurotransmitter in the regulation of sleep cycles, blood flow, emotion and memory. It is a central nervous system depressant however the precise mechanism by which sodium oxybate produces anti-cataplectic activity in patients with narcolepsy is unknown. Cataplexy is an abrupt, reversible, decrease in muscle tone caused by emotion, such as laughter, elation or anger and is reported by approximately 75% of patients with narcolepsy. A double-blind study recruited 136 patients 18 years with a current diagnosis of narcolepsy for at least 6 months based on criteria established by the American Sleep Disorders Association and a positive polysomnogram (PSG) within the previous five years. Following a screening visit, patients entered a 4-week period where any medications used to treat cataplexy were withdrawn. Patients (83%, n=113/136) were permitted to stay on stimulant medications for daytime sleepiness providing that stable doses were used beginning five days prior to baseline and continuing until the end of the trial. There followed a washout period of 5 days or five times the half-life of the discontinued medication up to 28 days where daily diary use was initiated. A day baseline period followed where patients recorded the frequency of cataplexy events, as well as other specified symptoms in the daily diary. Patients were required to have at least three cataplexy attacks per week during the last 2 weeks of the baseline period to enter the double-blind treatment period. Patients were then randomised to placebo or sodium oxybate 3g, 6g, 9g nightly without titration taken as two equally divided doses at bedtime and 2.5 to 4 hours later for a period of 4 weeks. The primary efficacy variable was the change from baseline to endpoint in weekly cataplexy attacks in the intent-to-treat population (Table 1). Sodium oxybate 9g was associated with a significantly greater reduction in cataplexy attacks compared with placebo. Using analysis of co-variance (with baseline value as the co-variate) statistical significance was not reached for the 6g group (p=0.0529) but following FDA reanalysis using analysis of variance (ANOVA), statistical significance was achieved (p=0.0451). There was no significant difference for the 3g group versus placebo. 2

3 Table 1: Primary efficacy variable; change in weekly cataplexy attacks Treatment N Baseline Median Median Change Median Percent Change from group Number of from Baseline in Change in Weekly Baseline Weekly Weekly Cataplexy Cataplexy Attacks Compared to Cataplexy Attacks Attacks placebo (p-value) ANCOVA/ANOVA placebo % sodium % / oxybate 3g sodium % / oxybate 6g sodium oxybate 9g % / A 12-month open-label extension study recruited 118 patients who were enrolled in the previous study to evaluate the safety and efficacy of sodium oxybate for the treatment of narcolepsy. A 3-5 day wash out period occurred at the end of the double-blind study and patients were initially treated with sodium oxybate 6g nightly. The investigator could adjust the dose in 1.5g increments at 2-weekly intervals within a range of 3 to 9g nightly based on clinical efficacy or adverse events. Concomitant stimulants were permitted at a stable dose and were taken by 88% (n=104/118) of patients. The primary efficacy measure was the change in weekly cataplexy attacks, from the baseline period of the 4-week double-blind trial to the end of the 12-month period. The cataplexy attacks/week (percent change in median) following the 4- week double-blind trial decreased from -58% at month 0 to -93% at 12 months. A double-blind study recruited 55 patients 16 years who had previously entered the open label study, to assess rebound cataplexy and any evidence of withdrawal syndrome following abrupt cessation. Patients were required to have at least 5 cataplexy attacks per week and have received continuous treatment with sodium oxybate (3g to 9g nightly) for 6months (mean duration 21 months). Following a screening visit, patients entered a 2-week single - blind baseline phase where they remained on the same dose. Patients were then equally randomised to remain on their established dose of sodium oxybate or receive placebo for 2 weeks. Patients used daily diaries to record the frequency of cataplexy attacks and adverse events. The primary efficacy variable was the change in the number of cataplexy attacks between baseline and endpoint (double-blind treatment phase). At baseline the median number of cataplexy attacks was 1.9 and 4.0 for the sodium oxybate and placebo groups respectively. The median change in the number of cataplexy attacks was 0 for the sodium oxybate group compared with 21.0 for the placebo group (p<0.001). The authors noted a gradual increase in cataplexy attacks on withdrawal of treatment in the placebo group and no evidence of rebound cataplexy characterised as a return to a level that exceeded the original baseline levels. A double-blind study recruited 228 patients 16 years with a positive history of narcolepsy based on an overnight PSG and multiple sleep latency test (MSLT) performed within the previous 5 years. A secondary endpoint of this study was the change in the total number of weekly cataplexy events from baseline to endpoint. After a 14-day lead-in period where patients recorded narcolepsy symptoms and adverse events in daily diaries, withdrawal and washout periods followed as in previous trials. Prior to entering the 14-day baseline period, patients were randomised to their eventual treatment dose and during the baseline period were required to have 8 cataplexy attacks per week to enter the final 8 week dose-titration phase. Following one week of treatment with placebo or sodium oxybate 4.5g, patients on sodium oxybate were randomised to continue at a dose of 4.5g for the duration of the trial or receive sodium oxybate 6g. 3

4 After a further week patients in the 6g group were randomised to continue at a dose of 6g for the duration of the trial or receive sodium oxybate 7.5g. After a further week patients in the 7.5g group increased their dose to sodium oxybate 9g for 5 weeks. There were significant decreases in weekly cataplexy attacks for all sodium oxybate doses versus placebo (Table 2). Table 2: Secondary endpoint: change in weekly cataplexy attacks Treatment N Baseline Median Median Number of Median Percent Change Change from group Number of Weekly Weekly Cataplexy in Weekly Cataplexy Baseline Cataplexy Attacks Attacks at 8 weeks Attacks from baseline Compared to to endpoint placebo (p-value) placebo sodium oxybate 4.5g sodium oxybate 6g sodium oxybate 9g <0.001 Summary of evidence on comparative safety In the first randomised controlled trial, adverse events believed to be related to sodium oxybate were nausea, vomiting, dizziness and enuresis and occurred with greater frequency at higher doses. Most occurred within the first few days following the start of treatment and abated over time. Ten of the 16 patients who did not complete the study withdrew due to adverse events; all but one was considered to be mild or moderate in severity. In the withdrawal study, 31% (n=17/55) of patients experienced at least one adverse event over the trial period. In the double-blind phase adverse events were reported by 12% (3/26) of patients in the sodium oxybate group and 9/29 (31%) of patients in the placebo group. Adverse events occurring in the placebo group included insomnia, dizziness, somnolence, headache and anxiety and were attributed to return of narcolepsy rather than a withdrawal syndrome. A comparison of the occurrence of adverse events between treatment groups was not significant. No adverse events were considered serious and none led to patient discontinuation. In the 12-month open-label extension study, headache, nausea, viral infection, dizziness, pain, enuresis and somnolence were most commonly reported and of these only dizziness was significant for overall treatment group comparisons. Three patients experienced a serious adverse event; one event was considered to be possibly related to the medication and one patient withdrew from the study. In the large randomised controlled trial adverse events occurring with >5% incidence and with significantly greater frequency than placebo were nausea and dizziness. 4

5 Summary of clinical effectiveness issues Sodium oxybate has the potential to induce respiratory depression. It is noted in the summary of product characteristics (SPC) that it is not known whether the concurrent use of stimulants in clinical trials may have affected respiration during the night. Stimulants to control the symptoms of excessive daytime sleepiness were maintained by approximately 80% of patients in the trials and are likely to be required in practice. Patients should be questioned regarding signs of CNS or respiratory depression. During dose titration, prescribers should be aware that sleep apnoea occurs in up to 50% of patients with narcolepsy. In addition, the European Medicines Agency in the European Public Assessment Report warn that the benefit-risk of doses greater than 6g/day should be stringently evaluated in patients with concomitant sleep apnoea. Sodium oxybate is the sodium salt of gamma hydroxybutyrate which has known abuse potential. Patients should not take alcohol whilst taking sodium oxybate and should be warned against the concurrent administration of sedative hypnotics or other CNS depressants. Whilst there is no clear evidence of emergence of dependence at therapeutic doses, this possibility cannot be excluded. The SPC notes that, although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, in rare cases, events such as insomnia, headache, anxiety, dizziness, sleep disorder, somnolence, hallucinations and psychotic disorders were observed after sodium oxybate discontinuation. Patients must take the second dose of sodium oxybate 2.5 to 4 hours after the first dose, which is taken upon getting into bed. This dosing regimen may be problematic, although patients with narcolepsy often have sleep disruption and frequent awakenings such that waking once to take the second dose is likely to be manageable. There is no direct comparison between sodium oxybate and clomipramine, the only other licensed product for treatment of cataplexy in adult patients with narcolepsy. In March 2007 the European Commission approved a change to the indication for sodium oxybate. It is now indicated for the treatment of narcolepsy with cataplexy in adult patients, based on data showing improvements in daytime sleepiness. The applicant requested to submit this re-submission for the original indication and indicated that a further submission would follow for the licence extension. Summary of comparative health economic evidence The manufacturer submitted a cost-utility analysis of sodium oxybate compared to clomipramine. The patient group was those with a diagnosis of narcolepsy and at least one cataplexy attack per week at baseline. The estimation of the clinical benefits came from a 6 month open-label trial that used a generic SF-36 instrument to measure changes in quality of life. The cost per QALY was estimated to be 65,980 for sodium oxybate 6g daily dose, falling to 49,590 per QALY at 9g doses. Sensitivity analyses showed the result was sensitive to the utility values and drug costs. 5

6 The choice of comparator, form of model and presentation of results and sensitivity analyses were adequate. The main weaknesses were: The utility values for standard care may not be representative of clomipramine- treated patients because 60% of the patients in the open label trial were not taking a TCA or SSRI; The assumed clinical resource savings, particularly in the hospital setting, are unlikely to be realised from the treatment of cataplexy only. However, additional analysis suggested that the result was relatively insensitive to changes in this parameter; No costs for the treatment of adverse events were included; and Non-responders may be on sodium oxybate for more than three months before reverting to standard care. Given the high reported cost per QALY, the concerns that the potential costs of adverse events are not included in the model and that the clinical resource savings may not be realised, the economic case has not been demonstrated. Summary of patient and public involvement Patient Interest Group Submission: UK Association of Narcoleptics Additional information: guidelines and protocols Guidelines on the diagnosis and management of narcolepsy in adults and children, published in December 2002, were developed by an independent multi-disciplinary working party based on widespread consultation with the medical community and patient representatives and a thorough review of the published literature. The guidelines were sponsored by Cephalon UK Ltd, the manufacturer of clomipramine and modafinil. The Cochrane review, Antidepressants for narcolepsy, published in 2005 concludes that there is scarce evidence to recommend the use of antidepressant drugs to treat cataplexy. Additional information: previous SMC advice In March 2006 following a full submission, sodium oxybate (Xyrem ) was not recommended for use within NHS Scotland for the treatment of cataplexy in adult patients with narcolepsy. In two studies the median percent decrease in weekly cataplexy attacks ranged from 49% to 85% for the dose range included in the product licence. However, the economic case was not demonstrated. Additional information: comparators Clomipramine is the only medicine, in addition to sodium oxybate, licensed in the UK for the treatment of cataplexy. 6

7 Cost of relevant comparators Drug Dose regimen Cost per year ( ) sodium oxybate 4.5-9g/day orally Anafranil SR 75mg/day orally 115 clomipramine 10-75mg/day orally Doses are for general comparison and do not imply therapeutic equivalence. Costs from evadis for clompiramine products, on 01/06/07. Cost for sodium oxybate from BNF March Additional information: budget impact The manufacturer estimated the gross budget impact of sodium oxybate at 126k in year 1, rising to 475k in year 5. There has been no attempt to calculate the cost savings from other medicines or other resources savings in order to give an estimate of the net budget impact. The manufacturer assumed that the prevalence of narcolepsy is 4.7 in 10,000, of whom 20% are diagnosed and 75% are assumed to have cataplexy. Applying these data to Scotland gives in year 1, 360 potentially diagnosed cataplexy patients, rising to 470 by year 5. Assuming 40% of these patients are treated and sodium oxybate gains a 10% market share in year 1, rising to 29% in year 5, then the estimated number of patients treated would be 14 in year 1, rising to 54 in year 5. 7

8 Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. This assessment is based on data submitted by the applicant company up to and including 13 July 2007 Drug prices are those available at the time the papers were issued to SMC for consideration. These have been confirmed from the evadis drug database. The undernoted references were supplied with the submission. US Xyrem Multicenter Study Group. Study OMC-GHB-2. A randomized, double-blind, placebo-controlled multi center trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep : US Xyrem Multicenter Study Group. Study OMC-GHB-3. A 12 month open-label multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep (1): US Xyrem Multicenter Study Group. Study OMC-SXB-21. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. Journal of Toxicology. Clinical Toxicology (2): US Xyrem Multicenter Study Group. [Study OMC-SXB-21.] Sodium oxybate demonstates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Medicine 2004:5; Xyrem International Study Group. [Study OMC-SXB-15.] Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Medicine :