Rasagiline (Azilect®▼)

VERDICT & SUMMARY Rasagiline (Azilect®▼)

For the treatment of Parkinson’s Disease

Committee’s Verdict: CATEGORY B (Q3) BNF: 4.9.1 Parkinson’s disease should be diagnosed and managed in secondary care. Rasagiline is suitable for prescribing in primary care with the guidance of an ESCA, upon the advice of a specialist, which could include a Specialist Nurse in a neurology clinic or a GP with a special interest in neurology. Caution should be exercised when prescribing rasagiline and an antidepressant concomitantly. Category B: Suitable for restricted prescribing under defined conditions Q rating: The evidence for the efficacy and safety of rasagiline was Q2 Q1 considered to be relatively strong. In five randomised controlled trials in higher place higher place patients with early and advanced Parkinson’s disease, it was more weaker evidence stronger evidence effective than placebo and showed clinically relevant improvements in the patients’ condition. The need for specialist involvement gives rasagiline a low place in therapy in primary care. Q4 Q3 The Q rating relates to the drug’s position on the effectiveness indicator lower place lower place grid. The strength of the evidence is determined by the quality and quantity of weaker evidence stronger evidence

studies that show significant efficacy of the drug compared with placebo or care therapy in primary Place in alternative therapy. Its place in therapy in primary care takes into account safety Strength of evidence for efficacy and practical aspects of using the drug in primary care, alternative options, relevant NICE guidance, and the need for secondary care input.

MTRAC reviewed this drug because it is a new product with potential for prescribing in primary care. Licensed indication however, have warned of adverse reactions with the use of these drugs.3,4 Rasagiline is indicated for the treatment of idiopathic Parkinson's disease (PD) as monotherapy (without Levodopa (in combination with the dopa- levodopa) or as adjunct therapy (with levodopa) in decarboxylase inhibitors benserazide or carbidopa) is patients with end-of-dose fluctuations.1 the most potent antiparkinsonian drug. It is the mainstay of treatment for the majority of the course of Background information the disease in all patients. One complication of long- Parkinson’s disease is a neurological condition term levodopa treatment is motor complications associated with resting tremor and progressive motor including response fluctuations and dyskinesia. disability, i.e. rigidity and bradykinesia.2 Pathological Selegiline, entacapone, tolcapone and amantadine findings from brain sections show that nigral are used as adjuncts to levodopa for the alleviation of dopamine neurons are greatly diminished in number end-of-dose fluctuations or dyskinesia. and Lewy bodies are present in the remaining Rasagiline is a new treatment for early and advanced 2 neurons. Depression is common and affects nearly Parkinson’s disease launched in June 2005. It is a 2 half of patients. Parkinson’s disease affects about monoamine-oxidase-B (MAO-B) inhibitor believed to 120,000 people in the UK (about 200 per 100,000), increase dopamine levels in the brain by inhibition of with symptoms appearing usually in patients aged dopamine metabolism. over 50 years. Clinical efficacy The symptoms of Parkinson’s disease are not usually treated until they cause significant interruption of daily Five randomised controlled trials evaluated rasagiline activities. (0.5 to 4 mg/day) as monotherapy or as adjunct to levodopa therapy for the treatment of Parkinson’s Dopamine agonists (bromocriptine, cabergoline, disease (the licensed dose is 1 mg/day). Endpoints lisuride, pergolide, pramipexole and ropinirole) are included the United Parkinson’s Disease Rating Scale generally used first-line in younger and healthier (UPDRS) in most trials, and total mean daily off-time patients because they rarely cause dyskinesia in levodopa-treated patients with advanced disease. (fragmentary or incomplete movements); they are also used as an adjunct to levodopa in more advanced Two placebo-controlled studies (n = 404, 56; duration disease. The Committee on Safety of Medicines, 52, 10 weeks)5-7 evaluated rasagiline (1 mg to 4 mg/day) as monotherapy in patients with early

January 2006 Page 1 of 2 Parkinson’s disease who were not yet treated with adverse events were dyskinesia, hallucinations, sleep levodopa. Participants were adults aged over 35 disorder, dizziness, and nausea. Depression, weight years with a Hoehn and Yahr stage less than 3 on a loss and anorexia were also reported in the SPC.1 disease progression scale from 1 to 5 (posture and Additional information gait affected, minimal disability). Results from the 5,6 larger TEMPO trial showed significantly greater • The recommended dose for rasagiline given as improvements in UPDRS score from baseline mono- or adjunct therapy is 1 mg/day with or compared with placebo (p < 0.001). There was no without food. significant difference between the groups in the • Rasagiline should not be administered with other number of patients who progressed to levodopa MAO-inhibitors, fluoxetine, fluvoxamine, or therapy during the 12 months of the TEMPO study. pethidine. Serious adverse reactions have been Significantly greater improvements in UPDRS scores reported with the concomitant use of selective (p < 0.05), response to treatment (p = 0.04), and serotonin reuptake inhibitors, tricyclic and Activities of Daily Living scores (p = 0.005) were seen tetracyclic antidepressants. See the SPC for more after 12 months compared with six months treatment. 1 information. However, this cannot be taken as evidence that rasagiline may slow progression of Parkinson’s • The National Institute for Health and Clinical disease. Excellence is due to issue a Guideline on the treatment of Parkinson’s disease in June 2006. The smaller trial was insufficiently powered to assess clinical efficacy or safety.7 However, it found • At current prices a year’s treatment with rasagiline significantly greater improvements in UPDRS score 1 mg/day costs £922. for patients treated with 2 mg/day rasagiline compared References with placebo (p < 0.05), but not for other doses (1 mg 7 1. Teva Pharmaceuticals Ltd. Azilect. Summary of Product or 4 mg/day). Characteristics 2006. Three RCTs (n = 687, 472, 70; duration 18 or 26 2. Samil A, Nutt G, Ransom BR. Parkinson's disease. 8-10 Lancet 2004;363:1783-93. weeks) evaluated rasagiline (0.5 to 2 mg/day) in 3. Committee on safety of medicines. Fibrotic reactions patients with advanced Parkinson’s disease who were with pergolide and other ergot-derived dopamine receiving levodopa therapy and experiencing motor receptor agonists. Current Problems 2002;28:3. fluctuations. Participants were adults over 30 years of 4. Committee on safety of medicines. Dopaminergic drugs age with a Hoehn and Yahr stage less than 5 (severe and sudden sleep onset. Current Problems 2003;29:9. symptoms, limited walking, unable to live alone). All 5. Parkinson study group. A controlled trial of rasagiline in three studies were placebo controlled; the LARGO early Parkinson disease: the TEMPO Study. Arch Neurol study8 had an additional entacapone-treatment arm 2002;59:1937-43. (200 mg with each dose of levodopa). The two larger 6. Parkinson study group. A controlled, randomized, 9 delayed-start study of rasagiline in early Parkinson studies (LARGO, PRESTO ) found significantly disease. Arch Neurol 2004;61:561-6. greater reductions in the mean total daily off-time for 7. Stern MB, Marek KL, Friedman J et al. Double-blind, rasagiline or entacapone compared with placebo (0.5 randomized, controlled trial of rasagiline as monotherapy to 1 hour, p = 0.02) at 18 or 26 weeks. In the LARGO in early Parkinson's disease patients. Mov Disord study there were also significantly greater 2004;19:916-23. improvements from baseline in the Clinician’s Global 8. Rascol O, Brooks DJ, Melamed E et al. Rasagiline as Impression of Change (p = 0.0002), and the UPDRS an adjunct to levodopa in patients with Parkinson's Activities of Daily living during periods of off-time disease and motor fluctuations (LARGO, Lasting effect (p = 0.0006) for both rasagiline and entacapone in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. compared with placebo.8 Results from the third, 10 Lancet 2005;365:947-54. smallest study were not significantly different 9. Parkinson study group. A randomized placebo- between rasagiline and placebo treatment. controlled trial of rasagiline in levodopa-treated patients Adverse effects with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005;62:241-8. Adverse events that occurred commonly in patients 10. Rabey JM, Sagi I, Huberman M et al. Rasagiline treated with rasagiline as monotherapy were mesylate, a new MAO-B inhibitor for the treatment of headache, nausea, pain and dizziness. In the trials of Parkinson's disease: a double-blind study as adjunctive therapy to levodopa. Clin Neuropharmacol 2000;23:324- rasagiline as adjunctive therapy to levodopa, common 30.

Launch date: June 2005 Manufacturer: Teva Pharmaceuticals Ltd EU/1/04/304/001-7 WARNING: This sheet should be read in conjunction with the Summary of Product Characteristics This guidance is based upon the published information available in English at the time the drug was considered. It remains open to review in the event of significant new evidence emerging. MTRAC can be contacted at the Dept. of Medicines Management, Keele University, Keele, Staffs ST5 5BG Tel: 01782 584131 Fax: 01782 713586 Email: [email protected] Web: www.mtrac.co.uk RELEVANT NICE GUIDANCE WAS NOT AVAILABLE AT THE TIME OF ISSUE OF THIS VERDICT Date: January 2006 ©Midlands Therapeutics Review & Advisory Committee VS06/02