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Rotigotine Patches (Neupro®) in the Treatment of Parkinson's Disease

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Rotigotine Patches (Neupro®) in the Treatment of Parkinson's Disease New Medicines Committee Briefing May 2011 Rotigotine patches (Neupro®) in the treatment of Parkinson’s Disease Rotigotine patches are to be reviewed for use within: Primary Care Secondary Care Summary . Rotigotine is a dopamine-receptor agonist used in the treatment of Parkinson’s disease (PD) . Rotigotine patches are licensed for the treatment of the signs and symptoms of early- stage idiopathic PD as monotherapy and as adjunctive therapy with levodopa in advanced stage PD with fluctuations . NICE recommends dopamine-agonists as a class as a first-choice option for initial therapy for early PD and as an adjuvant to levodopa in later PD . The SMC has accepted rotigotine as monotherapy for the treatment of early-stage idiopathic PD (June 2007) and restricted use for the treatment of advanced PD in combination with levodopa where the transdermal route would facilitate treatment (July 2007). SIGN guidelines recommend that oral/transdermal dopamine agonists may be considered for the treatment of early PD with motor symptoms and Dopamine agonists (oral or transdermal) and may be considered for the management of motor complications in patients with advanced PD. MTRAC have recommended that rotigotine is suitable for prescribing in primary care after specialist initiation and stabilisation of the dose. In early PD rotigotine has shown statistically significant improvements in Unified Parkinson’s Disease Rating Scale activities of daily living and motor function combined scores over baseline compared to placebo1,2,3. However, in one active- comparator study it was shown to be less effective than ropinirole3. In advanced disease, rotigotine was shown to be more effective than placebo in reducing daily ‘off’ time4,5 , although when compared to pramipexole, responder rates (patients receiving ≥30 improvement in absolute ‘off’ time from baseline) were less with rotigotine5. Rotigotine has a similar side-effect profile to the oral dopamine receptor agonists. 1 Background Dr Mann (Consultant Neurologist) has requested that rotigotine transdermal patches be considered for inclusion in the North Staffordshire Joint Formulary for the treatment of the signs and symptoms of early-stage idiopathic Parkinson's disease (PD) as monotherapy and as adjunctive therapy with levodopa in advanced stage PD with fluctuations. Dr Mann has stated in the application that rotigotine would be for initiation by a hospital consultant with a specialist interest. Dr Mann suggests that rotigotine patches could offer the following potential benefits: Reduction in morbidity/improved quality of life, convenient administration and savings in non-drug costs. In the application Dr Mann outlines the potential advantages of rotigotine over existing formulary agents as: . The potential to confer genuine benefit to the patient with regards overall sleep quality and quality of life (results of the RECOVER study) . No dose adjustment is required in mild to moderate hepatic impairment or mild to severe renal impairment (including those on dialysis) . Convenient once daily application- once daily transdermal application- improved compliance compared to multiple-dose oral agents and may be useful in patients with dysphagia. Simple titration In the application Dr Mann states that as with other transdermal treatments application site reactions occur with rotigotine patches but that these are in the majority mild to moderate in severity. Dr Mann also included in the application that it would be anticipated that the potential expenditure increase for the Trust will be offset by a reduction in length of stay due to better control of PD symptoms especially for patients requiring treatment for other conditions and who may temporarily lose the ability to receive their regular PD medication via the oral route. It would also be anticipated that better control of symptoms will mean that investigations and procedures may be carried out as planned without the same delays seen for those patients without recourse to non-oral PD symptom control which in turn should make better use of Trust resources. Parkinson’s disease is a neurodegenerative disorder characterised by loss of dopaminergic neurons in the substantia nigra. Classic presenting symptoms include hypokinesia, bradykinesia, rigidity and tremor at rest. Parkinson’s disease affects about 120,000 people in the UK (about 200 per 100,000) with symptoms appearing usually in patients aged over 50 years6. Drug therapy does not prevent disease progression, but it improves most patients’ quality of life. The symptoms of PD are not usually treated until they cause significant interruption of daily activities7. Levodopa (in combination with a dopa-decarboxylase inhibitor) is the most potent antiparkisonian drug and is the mainstay of treatment for the majority of the course of the disease in all patients. A complication of long-term levodopa treatment is motor complications including dyskinesias and response fluctuations, or ‘on/off’ episodes. Dopamine-receptor agonists have a direct action on dopamine receptors and are used in early PD and also used as an adjunct to levodopa in more advanced disease. Non- ergot-derived dopamine-receptor agonists include pramipexole, ropinirole and rotigotine 2 and ergot-derived dopamine-receptor agonists are bromocriptine, cabergoline and pergolide; ergot-derived dopamine-receptor agonists are associated with fibrotic reactions. Monoamine-oxidase-B inhibitors (rasagiline and selegiline) are used as monotherapy and as adjuncts to levodopa for the alleviation of end-of-dose fluctuations in patients with later disease. Catechol-O-methyltransferase inhibitors (entacapone and tolcapone) prevent the peripheral breakdown of levodopa and are used with co-beneldopa and co- careldopa for patients with PD who experience end-of-dose deterioration and cannot be stabilised on these combinations7. Rotigotine is a non-ergot-derived dopamine agonist for the treatment of Parkinson's disease. It is believed to elicit its beneficial effect by activation of the D3, D2 and D1 receptors of the caudate-putamen in the brain8. Licensed Indications8 Rotigotine patches are indicated for the treatment of the signs and symptoms of early- stage idiopathic Parkinson's disease as monotherapy (i.e. without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or 'on-off' fluctuations). Rotigotine patches are also licensed for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome in adults. Rotigotine patches are only licensed for use in adults; the manufacturer does not recommend their use in children and adolescents due to a lack of data on safety and efficacy. Dosage and Administration8 Dosing in patients with early-stage Parkinson's disease (ie monotherapy in Parkinson’s disease): A single daily dose should be initiated at 2 mg/24 h and then increased in weekly increments of 2 mg/24 h to an effective dose up to a maximal dose of 8 mg/24 h. 4 mg/24 h may be an effective dose in some patients. For most patients an effective dose is reached within 3 or 4 weeks at doses of 6 mg/24 h or 8 mg/24 h, respectively. Dosing in patients with advanced stage Parkinson's disease with fluctuations (ie adjunctive therapy with levodopa): A single daily dose should be initiated at 4 mg/24 h and then increased in weekly increments of 2 mg/24 h to an effective dose up to a maximal dose of 16 mg/24 h. 4 mg/24 h or 6 mg/24 h may be effective doses in some patients. For most patients an effective dose is reached within 3 to 7 weeks at doses of 8 mg/24 h up to a maximum dose of 16 mg/24 h. For doses higher than 8 mg/24 h multiple patches may be used to achieve the final dose Hepatic and renal impairment: The SPC states that adjustment of the dose is not necessary in patients with mild to moderate hepatic impairment or in patients with mild to severe renal impairment including those requiring dialysis. The manufacturer advises caution when treating patients with severe hepatic impairment, which may result in lower rotigotine clearance and advises that a dose reduction might be needed in case of 3 worsening of the hepatic impairment. The manufacturer also states that unexpected accumulation of rotigotine levels may also occur at acute worsening of renal function. Treatment discontinuation: The manufacturer recommends that Neupro® should be discontinued gradually; the daily dose should be reduced in steps of 2 mg/24 h with a dose reduction preferably every other day, until complete withdrawal. NICE and other guidance NICE Guidance9: NICE guidance on Parkinson’s disease (issued June 2006) stated that it was not possible to identify a universal first-choice drug therapy for either early PD or as an adjuvant drug therapy for later PD; the guidance recommended the following first-choice treatment options: Initial therapy for early PD- levodopa, dopamine agonists and MAO-B inhibitors Adjunctive therapy for later PD to reduce motor complications and improve quality of life in patients taking levodopa- dopamine agonists, MAO-B inhibitors and COMT inhibitors For dopamine agonists NICE recommends: If side effects prevent titration to agonists clinically efficacious dose, replace with another dopamine agonist or another drug class. If using an ergot-derived agonist, ensure a minimum of renal function tests, ESR and chest radiograph performed before starting treatment, and annually
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