New Medicines Committee Briefing July 2011

New Medicines Committee Briefing July 2011 Pramipexole immediate-release (Mirapexin ) and Pramipexole modifiedrelease (Mirapexin prolonged release) for the treatment of Parkinson s Disease Pramipexole is to be reviewed for use within: Primary Care Secondary Care Summary: Pramipexole is a non-ergot dopamine agonist used in the treatment of Parkinson s disease (PD) 1,2 Pramipexole is available as an immediate-release (IR) formulation administered three times daily and a modified-release (MR) preparation administered once daily 1,2 Pramipexole IR and pramipexole MR are licensed for treatment of the signs and symptoms of idiopathic Parkinson's disease alone (i.e. without levodopa) or in combination with levodopa ie over the course of the disease, through to the 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) 1,2 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 3 SMC has accepted pramipexole MR tablets for use within NHS Scotland 4 reviewed IR formulation) (SMC have not SIGN recommends that oral/transdermal dopamine agonists may be considered for the treatment of early PD with motor symptoms and for the management of motor complications in patients with advanced PD 5 Pramipexole IR has been shown to be an effective treatment for the symptoms of PD both as monotherapy in patients with early disease 6,7 and in combination with levodopa in patients with advanced PD 8 Pramipexole MR has been shown to be effective and well tolerated for the treatment of PD, either alone 9,10,11 or in combination with levodopa 12 1

Formulary application: Consultant submitting application: Clinical Director supporting application: Dr Jonathan Partridge (Consultant Neurologist) Dr Simon Ellis Following a review of BNF section 4.9.1 of the formulary it was suggested by Dr Carl Mann (Consultant Neurologist) that pramipexole should be added to the formulary; Dr Jonathan Partridge agreed to support the application at the New Medicine Committee. Current treatment choice in Parkinson s disease is largely dependent on symptoms with the line of treatment being more general than specific ie a monoamine oxidase B (MAO-B) inhibitor, then a dopamine agonist, then levodopa, then a catechol-o-methyltransferase (COMT) inhibitor; pramipexole is currently being prescribed second-line in addition to a mononamine oxidase B inhibitor in patients where tremor or low-mood is a problem. Background: 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 years 13. 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 activities 14. 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 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 combinations 14. 2

Current formulary status: The North Staffordshire Joint Formulary currently lists the following agents: 4.9 DRUGS USED IN PARKINSONISM AND RELATED DISORDERS Parkinson's disease: diagnosis and management in primary and secondary care NICE Clinical Guideline CG35 (date 06/06) 4.9.1 Dopaminergic drugs used in Parkinson s disease CSM Amantadine 2 Restriction: Initiation by specialist Co-beneldopa (Madopar preparations) 2 Restriction: Initiation by specialist Co-careldopa (Sinemet preparations) 2 Restriction: Initiation by specialist Entacapone 2 Restriction: Initiation by specialist MTRAC Restriction: Initiation and stabilisation by Ropinirole 2 specialist MTRAC Rotigotine 2 Restriction: Patients that are NBM or have swallowing difficulties. Prescribing should be MTRAC reviewed on discharge from secondary care Selegiline 2 Restriction: Initiation by specialist Entacapone MTRAC recommendation VS99/01 (date 01/99) A COMT inhibitor for the treatment of Parkinson s Disease RESTRICTED USE Ropinirole MTRAC recommendation VS00/01 (date 01/00) A dopamine agonist for the treatment of Parkinson s Disease RESTRICTED USE Ropinirole MTRAC recommendation VS07/01 (date 01/07) For the treatment of restless leg syndrome Q3, Category A suitable for prescribing in primary care Therapeutic class and mode of action: Pramipexole is non-ergot dopamine agonist that alleviates motor deficit in PD by stimulating dopamine receptors in the striatum 1,2. Licensed indication: Treatment of the signs and symptoms of idiopathic Parkinson's disease alone (i.e. without levodopa) or in combination with levodopa ie over the course of the disease, through to the 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). 1,2 Mirapexin is also licensed for the symptomatic treatment of moderate to severe Restless Legs Syndrome 1 - this indication is not included in the review. 3

Dosage and administration: Immediate-release tablets: Dose * : Initially 88 micrograms 3 times daily, dose doubled every 5 7 days if tolerated to 350 micrograms 3 times daily; further increased if necessary by 180 micrograms 3 times daily at weekly intervals; max. 3.3 mg daily in 3 divided doses 1 Administration: With or without food; swallowed with water 1 Renal impairment: Renal impairment requires dose reduction (slower dose titration and adjustment) 14 Hepatic impairment: No change in dosage required 1 * Doses and strengths are stated in terms of pramipexole (base); equivalent strengths in terms of pramipexole dihydrochloride monohydrate (salt) are as follows: 88 micrograms base 125 micrograms salt; 180 micrograms base 250 micrograms salt; 350 micrograms base 500 micrograms salt; 700 micrograms base 1 mg salt Modified-release tablets: Dose $ : Initially 260 micrograms once daily, dose doubled every 5 7 days to 1.05 mg once daily; further increased if necessary by 520 micrograms daily at weekly intervals; max. 3.15 mg once daily (maintenance dose usually 0.26-3.15mg daily) 2 SMC recommends that patient taking pramipexole immediate-release tablets can be switched to modified-release tablets overnight at the same total daily dose 4 Administration: With or without food; swallowed whole with water 2 Renal impairment: Renal impairment requires dose reduction (slower dose titration and adjustment); avoid in patients with an egfr of less than 30ml/min 14 Hepatic impairment: No change in dosage required 2 $ Doses and strengths are stated in terms of pramipexole (base); equivalent strengths in terms of pramipexole dihydrochloride monohydrate (salt) are as follows: 260 micrograms base 375 micrograms salt; 520 micrograms base 750 micrograms salt; 1.05 mg base 1.5 mg salt; 4

1.57 mg base 2.25 mg salt; 2.1 mg base 3 mg salt; 2.62 mg base 3.75 mg salt; 3.15 mg base 4.5 mg salt Presentation: Immediate-release tablets: 30 tablet pack only of following strength: 88 micrograms 30 and 100-tablet packs of the following strengths: 180 micrograms, 350 micrograms, 700 micrograms Modified-release tablets: 30 tablet packs of the following strengths: 260 micrograms, 520 micrograms, 1.05 mg, 1.57 mg, 2.1 mg, 2.62 mg, 3.15 mg Guidance: NICE Guidance 3 : NICE guidance published Relevant guidance Yes NICE Clinical Guideline Parkinson's disease: diagnosis and management in primary and secondary care (June 2006) NICE guidance 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. In view of the monitoring required with ergot-derived dopamine-agonists, a non-ergot-derived agonists should be preferred in most cases. The guidance recommended that when choosing treatment clinical and lifestyle preferences and patient preference, after informing the patient of the short- and long-term benefits and drawbacks of drug classes, should be taken into account. Scottish Medicines Consortium (SMC) 4 : SMC recommended use within NHS Scotland: Yes Following an abbreviated submission the SMC accepted modified-release tablets for the licensed indication; SMC noted that in patients for whom pramipexole is appropriate, the prolonged- 5

release formulation can provide the same daily dose as existing immediate-release formulations, with the benefit of once-daily rather than thrice daily dosing, at an equivalent cost Cochrane Review 15,16 : Dopamine agonist therapy in early Parkinson s disease 15 : Authors concluded that the meta-analysis confirmed that motor complications are reduced with dopamine agonists compared to levodopa, but also established that other important side-effects are increased and symptom control is poorer with agonists; larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa. Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications 16 : Authors concluded that compared to placebo, adjuvant therapy reduces off-time, levodopa dose, and improves UPDRS scores in PD patients who develop motor complications on levodopa therapy. However, this is at the expense of increased dyskinesia and numerous other sideeffects. Indirect comparisons suggest that dopamine agonist therapy may be more effective than COMTI and MAOBI therapy, which have comparable efficacy. However, as indirect comparisons should be interpreted with caution, direct head-to-head randomised trials assessing the impact of these different drug classes on overall patient-rated quality of life are needed. Scottish Intercollegiate Guidelines Network (SIGN) 5 : SIGN guidelines published Relevant guidelines Yes 113- Diagnosis and pharmacological management of Parkinson s disease (January 2010) SIGN recommends that oral/transdermal dopamine agonists may be considered for: Patients with early Parkinson s disease and motor symptoms; ergot derived dopamine agonists should not be used as first line treatment for Parkinson s disease. Management of motor complications in patients with advanced Parkinson s disease; the non-ergot agonists (ropinirole, pramipexole, and rotigotine) are preferable to the ergot agonists. MTRAC 14 MTRAC reviewed Yes (immediate-release only) MTRAC have recommended that initiation and stabilisation of pramipexole, as monotherapy or as an adjunct to levodpa, should be the responsibility of the specialist. It is then appropriate for GPs to prescribe pramipexole over the long term within the guidance of an ESCA. 6

Efficacy: Outcome measures used to evaluate efficacy of treatment of PD: Unified Parkinson s Disease Rating Scale (UPDRS) is a standardised scale comprising 4 sections that are evaluated by interview and clinical assessment- the higher the UPDRS score, the more severe the disease and a positive change signifies a worsening of the disease. Changes in time spent on and off can be used to evaluate drug efficacy in patients that have developed motor symptoms off time refers to periods when treatment is not working and patient activity is impaired on time refers to periods when treatment in working Immediate-release preparation Summary: pramipexole IR has been shown to be an effective treatment for the symptoms of PD both as monotherapy in patients with early disease 6,7 and in combination with levodopa in patients with advanced PD 8 Early Parkinson s Disease (as monotherapy) Shannon et al 6 a 24-week, multicentre, randomised, double-blind trial (n=335). Patients randomised to receive pramipexole (titrated to 4.5mg od; mean daily dose 3.8mg) or placebo. Pramipexole significantly decreased the UPDRS score (part II and III) from baseline compared to placebo (p<0.0001) CALM-PD 7-4-year, multi-centre, randomised, controlled trial (n=301). Patients randomised to receive 0.5mg pramipexole tds (with levodopa placebo) or 25/100mg carbidopa/levodopa 3 times daily (with pramipexole placeo). Patients allowed to titrate up for 10 weeks and could then be prescribed open-label levodopa or anti-parkinsonian medication. Initial treatment with pramipexole resulted in a significant reduction in the risk of developing dyskinesias compared with initial treatment with levodopa (24.5% v 54% risk (p<0.001)) and fewer patients experienced wearing off with initial treatment with pramipexole (47% v 63% (p=0.02)). By 48 months the occurance of dyskinesias did not significantly differ between the 2 groups. The mean improvement in the total UPDRS score from baseline to 48 months was greater in the levodopa group than in the pramipexole group. Advanced Parkinson s Disease (with levodopa) Liebermann et al 8 a 32-week, double-blind, placebo-controlled, parallel-group study (n=360). Patients randomised to receive pramipexole or placebo. Pramipexole improved motor function of patients during on and off periods, as assessed by the UPDRS score. 7

Modified-release preparation Summary: Pramipexole MR has been shown to be effective and well tolerated for the treatment of PD, either alone 9,10,11 or in combination with levodopa 12 ; non-inferiority to the IR formulation has been shown when used alone 9,10,11 and no clinically relevant differences in efficacy compared to the IR formulation have been shown or in combination with levodopa 12 Early Parkinson s Disease (as monotherapy) The efficacy of pramipexole MR in early PD has been assessed in 2 randomised controlled trials: A 33-week, multi-national, randomised, double-blind, placebo-controlled study- patients were randomised to receive pramipexole MR, pramipexole IR or placebo 9,10,11. Analysis was performed at week 18 9 and week 33 10. At week 18, patients treated with pramipexole IR and MR showed significantly greater improvements in UPDRS II and III score than those treated with placebo (p<0.029) and at week 33 patients treated with pramipexole MR and IR showed improvements compared to placebo. Non-inferiority was demonstrated for pramipexole MR compared with IR as assessed by the UPDRS II and III score at week 33. A 33-week, randomised-controlled trial- patients randomised to receive pramipexole MR, pramipexole IR or placebo (n=259) 11. Analysis was performed at week 18 and week 33. At week 18 superiority of pramipexole MR over placebo was demonstrated; at week 33 non-inferiority was demonstrated between the 2 pramipexole formulations when comparing mean change in UPDRS II and III scores. Advanced Parkinson s Disease (with levodopa) A 33-week, randomised, controlled trial (n=517) 12 -patients randomised to receive pramipexole MR, pramipexole IR or placebo. At week 18 both pramipexole formulations were statistically superior to placebo in terms of change from baseline in UPDRS II and III score and change on off time from baseline. Although the sydy was not powered or designed to test the noninferiority of pramipexole PR compared to IR no clinically relevant differences in efficacy of the pramipexole formulations was reported. Comparison of modified-release and immediate-release tablets The manufacturer suggests that the MR preparation offers the following advantages compared to the IR formulation 17 : Improvements in patient compliance- a study concluded that in PD patients once-daily dosing is associated with significantly higher adherence than more frequent dosing; patients who were more adherent showed significantly better symptom scores 18 Less frequent fluctuations in the pramipexole plasma concentration over 24 hours leading to improved symptom control and fewer off periods 8

Safety and adverse effects: Contraindications: Hypersensitivity to active ingredient/excipient 1,2 Adverse effects: Driving: Commonly reported adverse effects (more frequently occurring than placebo)- nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucination, headache, fatigue 1,2 Manufacturer states that adverse event rates are similar for modifiedrelease and immediate-release formulations 17 Manufacturer states: Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with MIRAPEXIN. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines 1,2. For additional information in adverse effects refer to the Summary of Product Characteristics 1,2. Drug Interactions: Manufacturer advises the following 1,2,14 Avoid co-administration with anti-psychotics (antagonism of effect) Reduce the dose of levodopa when pramipexole is given in combination with levodopa; doses of other anti-parkinson s medicines to be kept constant during pramipexole dose titration Consider reducing the pramipexole dose when administering with inhibitors/competitors of the active renal elimination pathway eg cimetidine, amantadine (ie increased plasma concentration) For additional drug interactions refer to the Summary of Product Characteristics 1,2. 9

Cost analysis Costs of in primary and secondary care: Formulation @ Pramipexole Pack Primary Care (exc. VAT) Secondary Care (inc. VAT) (as base) size (Drug Tariff 19 price) IR 88 micrograms 30 3.74 1.16 (c) IR 180 micrograms 30 5.37 2.06 (c) IR 180 micrograms 100 17.97 *use contracted 30 pack* IR 350 micrograms 30 38.20 4.13 (c) IR 350 micrograms 100 127.34 *use contracted 30 pack* IR 700 micrograms 30 19.01 6.42 (c) IR 700 micrograms 100 71.82 *use contracted 30 pack* MR 260 micrograms 30 28.65 31.63 MR 520 micrograms 30 57.30 63.26 MR 1.05 mg 30 114.60 126.52 MR 1.57 mg 30 171.90 189.78 MR 2.1 mg 30 229.20 253.03 MR 2.62 mg 30 286.50 31.69 MR 3.15 mg 30 343.80 379.56 @ IR= immediate-release; MR=modified-release (c)= available on contract in secondary care The cost of the modified-release formulation compared to equivalent doses of immediaterelease formulation (based on drug tariff prices) Daily dose (base) Pramipexole IR Pramipexole MR Dose Price Cost per Dose Price (30 tablets) day (30 tablets) 0.264mg 3 x 88mcg 3.74 0.37 1 x 260mcg 28.65 0.96 0.54mg 3 x 180mcg 5.37 0.54 1 x 520mcg 57.30 1.91 1.05mg 3 x 350mcg 38.20 3.82 1 x 1.05 mg 114.60 3.82 Cost per day 1.59mg 3 x 350mcg 38.20 4.36 1 x 1.57 mg 171.90 5.73 3 x 180mcg 5.37 2.1mg 3 x 700 mcg 19.01 1.91 1 x 2.1 mg 229.20 7.64 2.64mg 3 x 700 mcg 19.01 2.45 1 x 2.62 mg 286.50 9.55 3 x 180mcg 5.37 3.15mg 3 x 700 mcg 3 x 350mcg 19.01 38.20 5.73 1 x 3.15 mg 343.80 11.46 10

Expenditure in primary and secondary care for a 6-month period: (October 2010- March 2011): Formulation @ Pramipexole UHNS Stoke-on-Trent PCT North Staffordshire PCT (as base) IR 88 micrograms 145 4075 5676 IR 180 micrograms 236 4126 4544 IR 350 micrograms 127 3200 2970 IR 700 micrograms 2993 8262 MR 260 micrograms 526 745 MR 520 micrograms 2722 2087 MR 1.05 mg 248 13597 8761 MR 1.57 mg MR 2.1 mg 6965 4855 MR 2.62 mg 1020 MR 3.15 mg 4285 4749 756 43513 42649 Estimated cost: Pramipexole is currently already in use- please refer above to expenditure data 11

Comparison with other therapy: Early PD as monotherapy: Usual daily dose* Cost for 28 days Class Drug Formulary status # treatment $ Dopamine agonists Rotigotine F 2-8mg daily 77.24-142.79 (non-ergot derived) Ropinirole F 9-16mg 72-135 Pramipexole IR A 0.264mg-3.15mg 10.36-160.44 (as base) Pramipexole A 0.26mg-3.15mg 26.88-320.88 MR (as base) Dopamine agonists Pergolide F 2.1-2.5mg 33.25-41.47 (ergot derived) Levodopa Co-beneldopa F 400-800mg 6.60-13.19 (levodopa) Co-careldopa F 300-800mg 20.54-30.54 (levodopa) MAO-B inhibitor Selegeline F 10mg daily 6.87 Rasagiline A 1mg 70.72 Advanced PD (in combination with L-dopa): Usual daily dose* Cost for 28 days Class Drug Formulary status # treatment $ Dopamine agonists Rotigotine F 4-16mg 117.71-285.58 (non-ergot-derived) Ropinirole F 9-24mg 72-180 Pramipexole IR A 0.264mg-3.15mg 10.36-160.44 (as base) Pramipexole A 0.26mg-3.15mg 26.88-320.88 MR (as base) Dopamine agonists Pergolide F Max. 3mg 35.23 (ergot-derived) MAO-B inhibitor Selegeline F 10mg 6.87 Rasagiline A 1mg 70.72 COMT inhibitor Entacapone F 600-2000mg 48.33-160.86 # F= formulary; NF=non-formulary; A= formulary application under consideration *Doses are for general comparison and do not imply therapeutic equivalence $ Prices from BNF 61 14 12

References 1. Mirapexin 0.088mg Tablets Summary of Product Characteristics. Boehringer Ingelheim Limited. Last updated 21/1/2011. Accessed www.medicines.org 2/6/11. 2. Mirapexin 0.26mg prolonged-release tablets Summary of Product Characteristics. Boehringer Ingelheim Limited. Last updated 21/1/2011. Accessed www.medicines.org 2/6/11. 3. NICE. Clinical Guideline Parkinson's disease: diagnosis and management in primary and secondary care (June 2006). Accessed via http://www.nice.org.uk/cg035 4. Scottish Medicines Consortium (SMC). Pramipexole dihydrochloride monohydrate prolonged release tablets 0.375mg, 0.75mg, 1.5mg, 3.0mg, 4.5mg (equivalent to 0.26mg, 0.52mg, 1.05mg, 2.1mg, 3.15mg pramipexole) (Mirapexin) (No. 580/09). http://www.scottishmedicines.org.uk/files/pramipexole_mirapexin_abbreviated_final_oct _2009_for_website.pdf 5. SIGN. SIGN 113: Diagnosis and pharmacological management of Parkinson s Disease (January 2010). Accessed via http://www.sign.ac.uk/pdf/sign113.pdf 6. Shannon et al. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson s disease. Neurology 1997; 49(3):724-728 7. The Parkinson Study Group. Pramipexole vs Levodopa as Initial Therapy for Parkinson Disease. Arch Neurol 2004; 61: 1044-1053 8. Lieberman A et al. Evaluation of pramipexole in advanced Parkinson s Disease; results of a double-blind, placebo-controlled, parallel-group study. Neurology1997; 49(1):162-168 9. Hauser R et al. Randomised, double-blind, multicentre evaluation of pramipexole extended release once daily in early Parkinson s disease. Movement disorders 2010 e-publication DOI:10.1002/mds.23317. Cited in Boehringer Ingelheim. Mirapexin Prolonged Release Formulary Request Information. 10. Salin et al. Double-blind evaluation of mainternance of pramipexole extended-release in Early Parkinson s Disease. AAN, Seattle, May 2009; P06-150 11. Poewe et al. Pramipexole extended-release os effective in early Parkinson s Disease. The Movement Disporder Society 13 th Annual International Congress of Parkinson s Disease and Movement Disoorders June 2009; Paris, France. Abstract WE-185. 12. Schapira et al. Efficacy and safety of pramipexole extended release for advanced Parkinson s disease. The Movement Disporder Society 13 th Annual International Congress of Parkinson s Disease and Movement Disoorders June 2009; Paris, France. Poster P-199. 13. Midlands Therapeutics Review & Advisory Committee. Verdict and Summary Pramipexole (Mirapexin ) for the treatment of Parkinson s Disease (June 2002). Accessed via http://mtrac.co.uk/ 14. British National Formulary No 61 (March 2011). BMJ and Pharmaceutical Press: London. 15. Stowe R et al. Dopamine agonist therapy in early Parkinson s disease. Cochrane Database of Systematic Reviews 2008, Issue (2): CD006564 16. Stowe R et al. Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications. Cochrane Database of Systematic Reviews 2010, Issue (7): CD007166. 13

17. Boehringer Ingelheim. Mirapexin Prolonged Release Formulary Request Information. 18. Grosset et al. Adherence to antiparkinson medication in a multicenter European study. Movement Disorders 2009; 24(6):826-832 19. Department of Health and Welsh Assembly Government (April 2011). National Health Service England and Wales Drug Tariff. TSO: London Produced by Julie Shenton Primary / Secondary Care Interface Pharmacist University Hospital of North Staffordshire Telephone: 01782 552903 e-mail: julie.shenton@uhns.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes 14

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