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New 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 - used in the treatment of Parkinson’s disease (PD)

. Rotigotine patches are licensed for the treatment of the of early- stage idiopathic PD as monotherapy and as adjunctive therapy with levodopa in advanced stage PD with fluctuations

. NICE recommends dopamine- 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 , 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 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- 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 neurons in the . Classic presenting symptoms include , bradykinesia, rigidity and 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 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- -derived dopamine-receptor agonists include pramipexole, and rotigotine 2

and ergot-derived dopamine-receptor agonists are , and ; ergot-derived dopamine-receptor agonists are associated with fibrotic reactions.

Monoamine-oxidase-B inhibitors ( and ) 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 ( and ) 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 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 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 . 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

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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 thereafter. 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.

NICE did not consider the use of rotigotine specifically.

Scottish Medicines Consortium (SMC)10,11,12:

The SMC initially rejected rotigotine for use within NHS Scotland for the treatment of the signs and symptoms of early-stage idiopathic Parkinson’s disease as monotherapy (i.e.without levodopa) in July 200610 as non-inferiority to another non-ergolinic dopamine agonist comparator was not shown in one active comparator study and the economic case had not been demonstrated. Following a re-submission in June 200711 rotigotine was accepted for the treatment of early PD the SMC stating that rotigotine transdermal patches offered an alternative non-ergolinic agonist at a lower cost in a formulation that does not need to be taken by mouth.

The SMC accepted rotigotine (Neupro®) for restricted use within NHS Scotland for its late-stage licensed indication in July 200712 stating that ‘Rotigotine increased the proportion of patients achieving ≥ 30% reduction in “off” time compared with placebo, but appeared to be less effective than another non-ergolinic dopamine agonist. Rotigotine trans-dermal patch offers an alternative non-ergolinic dopamine agonist at a lower cost

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in a formulation that does not have to be taken by mouth. It is restricted to patients where this route would facilitate treatment’.

Cochrane Review:

The authors of a Cochrane review of dopamine agonist therapy in early Parkinson’s disease13 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.

The authors of an evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson´ s disease patients with motor complications14 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 and numerous other side- effects. 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)15:

SIGN guidelines for the diagnosis and pharmacological management of Parkinson’s disease include the following recommendations:

Patients with early Parkinson’s disease and motor symptoms may be considered for treatment with oral/transdermal dopamine agonists; Ergot derived dopamine agonists should not be used as first line treatment for Parkinson’s disease.

Dopamine agonists (oral or transdermal) may be considered for the 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.

MTRAC16

MTRAC have recommended that Parkinson’s disease should be diagnosed and managed in secondary care and that rotigotine is suitable for prescribing in primary care after specialist initiation and stabilisation of the dose. MTRAC stated that the need for specialist initiation and stabilisation of the dose, and the availability of alternative give rotigotine a low place in therapy in primary care.

Efficacy

Early Parkinson’s Disease (as monotherapy)

In studies1,2,3 comparing rotigotine to placebo the primary outcome was the mean change in the sum of the Unified Parkinson’s Disease Rating Scale (UPDRS) subscore for part II

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(activities of daily living (ADL)) and part III (motor skills) from baseline to the end of treatment. 2 of the studies2,3 also measured the responders rates, defined as the proportion of patients who showed at least a 20% improvement in the sum of part II and part III of the UPDRS.

A 14-week dose-ranging study evaluated the efficacy of patches delivering 2 to 8mg rotigotine in 24 hours compared with placebo in 242 patients with early PD1. The authors reported significant dose-related improvements in the motor and ADL UPDRS score between baseline and week 11 were found in the group treated with patches delivering rotigotine 6mg/24 hours (p=0.001) and patches delivering rotigotine 8mg/24 hours (p<0.001).

In a second double-blind study2 (n=277) comparing the efficacy and safety of rotigotine to placebo patients were randomised (2:1) to rotigotine (2-6mg/24 hours) or placebo. Rotigotine treated patients started at a dose of 2mg/24hrs and a three week dose escalation period allowed titration to optimal (defined as the dose that gave maximal reduction in PD symptoms without intolerable side effects) or maximal dose. Placebo treated patients also underwent a titration to maintain blinding. The dose maintenance period lasted 24 weeks. The numbers of patients randomised to rotigotine and placebo were 181 and 96 respectively. The mean difference between rotigotine and placebo groups in the in UPDRS (part II and III) was -5.28 and statistically significant (p<0.0001). The percentages of 20% responders in the UPDRS (part II and III) in the rotigotine and placebo groups were 48% and 19%, respectively (difference 29%; p<0.0001). The authors concluded that transdermal rotigotine when titrated to a dose of 6mg/24 h was effective for the treatment of early-stage PD.

A trial conducted by Giladi et al3 to investigate the efficacy and safely of rotigotine patches in early PD vs ropinirole and placebo randomised patients (2:2:1) to rotigotine transdermal patch 2-8mg/24h, ropinirole (dose titrated from 0.75 to 24mg/day) or placebo. The dose escalation period for rotigotine lasted up to 4 weeks and for ropinirole 13 weeks, resulting in the dose maintenance period of at least 33 and 24 weeks for rotigotine and ropinirole respectively. The trial was powered to test for non-inferiority between rotigotine and ropinirole. The numbers of patients randomised to rotigotine, ropinirole and placebo were 215, 228 and 118, respectively, and the percentages of 20% responders in the UPDRS (part II and III)-the primary end-point- were 52%, 68% and 30% respectively. The difference between rotigotine and placebo was significant. However, non-inferiority between rotigotine and ropinirole was not shown based on a non-inferiority margin of 15%. A post hoc analysis was conducted which compared rotigotine with different dose groups of ropinirole (≤ 9mg/day, 12-21mg/day and 24mg/day). Results showed that rotigotine and ropinirole (≤ 9mg/day) were comparable. Results of the comparisons of the two higher dose groups of ropinirole with rotigotine favoured ropinirole.

Advanced Parkinson’s Disease (with levodopa)

Two double blind, controlled trials evaluated the efficacy, safety and tolerability of rotigotine adjuvant to levodopa in advanced idiopathic Parkinson’s disease (PD) as compared to placebo and4, in one trial, also to pramipexole5. Patients were included if they had been diagnosed with idiopathic PD of > 3 years duration, had a Hoehn and Yahr stage II – IV in both the “on” and “off” state, were on a stable dose of levodopa of ≥ 300mg/day in the active-controlled trial, and ≥ 200mg/day in the placebo-controlled trial, for at least 28 days and had ≥ 2.5 hours of daily “off” time. In both trials the primary efficacy outcome was determined by response to therapy. A responder was defined as 6

having achieved ≥ 30% decrease in absolute time spent “off” from baseline to end of double blind maintenance phase. Home diaries were used to record time spent “off”, “on with troublesome dyskinesia”, “on without troublesome dyskinesia”, or asleep.

The PREFER study4 (a parallel, randomised, double-blind placebo-controlled trial) evaluated the efficacy and safety of rotigotine in patients with advanced disease receiving concomitant levodopa therapy ≥ 200mg/day with at least 2.5 hours daily ‘off’ time. After a 4 week screening phase, 351 patients were randomised equally to titration to an optimal dose of rotigotine (up to 8mg/24 hours), or rotigotine (up to 12mg/24 hours) or placebo. The titration phase was up to 5 weeks and the maintenance phase was 24 weeks. The primary outcomes were the change in number of daily hours in the ‘off’ state and the proportion of patients achieving a ≥ 30% decrease (responders) in absolute time spent “off” from baseline to end of the study. The proportions of responders were significantly higher for rotigotine 8mg/24 hours and 12mg/24 hours compared with placebo (55% and 57% respectively vs 35%; p≤0.001). Compared to placebo there were significant decreases in mean daily ‘off’ time of 1.8 hours/day for the rotigotine 8 mg/24 hours group and 2.1 hours/day for the 12 mg/24 group (p<0.005). The authors concluded that transdermal rotigotine therapy showed clinically relevant reductions in ‘off’ time as an adjunct to levodopa.

In an randomised, double-blind active-controlled trial5 to investigate the efficacy of rotigotine vs placebo and pramipexole in levodopa treated patients (levodopa≥ 300mg/day) , after a 4-week screening phase, 506 patients were randomised in a 2:2:1 ratio to titration to an optimal dose of rotigotine (up to 16mg/24 hours) or pramipexole (up to 4.5mg salt daily) or placebo. The titration phase was up to 7 weeks and the maintenance phase was 16 weeks. Primary efficacy variables were absolute change in total hours ‘off’ and patients with a ≥30% reduction in absolute ‘off’ time per day. Responder rates were 60% for the rotigotine group and 67% for the pramipexole group and were significantly higher than in the placebo group 35% (both p<.0.0001 vs placebo). For the secondary endpoint of mean change from baseline in absolute time “off” at the end of the maintenance period, results were -2.5 hours for rotigotine, -2.8 hours for pramipexole and -0.9 hours for placebo and were significant for rotigotine compared to placebo. Rotigotine was shown to be non-inferior to pramipexole for the change in ‘off’ time.

Early-morning motor function and sleep in patients with advanced PD

A further double-blind, randomised, placebo-controlled study (RECOVER)17 assessed the effects on early morning motor function and sleep in patients with late-stage PD. Patients were randomised to either rotigotine (n=190) or placebo (n=97) and titrated to an optimal dose (2 to 16 mg/24 h or placebo) over a ≤8-week titration period followed by a 4-week maintenance period. The primary efficacy variables were change from baseline in the early morning UPDRS Part III- motor function and the change in sleep quality as measured by the Parkinson’s Disease Sleep Scale version 2 (PDSS-2). The improvement in UPDRS Part III was 7.0 points at the end of maintenance compared with 3.9 in the placebo group (p=0.0002) and the improvement in PDSS-2 scores in the rotigotine group was 5.9 points compared to 1.9 with placebo (p,0.0001). The author concluded that rotigotine was associated with a clinically relevant and statistically significant improvement in both early morning Parkinson's dysfunction (as measured with the UPDRS Part III) and sleep (as measured with the PDSS).

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Safety and adverse effects

The SPC states that adverse drug reactions (ADRs) reported in more than 10% of patients treated with Neupro® transdermal patch are , , application site reactions, , and headache. Rotigotine can also cause other ADRs including dyskinesia, and peripheral oedema.

The SPC states that application site skin reactions may occur and are usually mild or moderate in intensity. It is recommended that the application site should be rotated on a daily basis (e.g. from the right side to the left side and from the upper body to the lower body and the same site should not be used within 14 days). The manufacturer states that in trials where the application sites were rotated as reflected in the instructions provided in SPC and package leaflet, 35.7% of 830 patients using the Neupro® transdermal patch, experienced application site reactions. The majority of these reactions were mild or moderate in intensity, limited to the application areas and resulted in discontinuation of treatment with Neupro® in only 4.3% of all subjects receiving Neupro®.

The SPC states that other adverse effects include , pathologic gambling, increased and , fibrotic complications, postural/orthostatic and symptoms suggestive of neuroleptic malignant syndrome have been reported.

The manufacturer also advises that the patches contain aluminium they should be removed before magnetic resonance imaging or cardioversion to avoid burns.

For additional information in adverse effects refer to the Summary of Product Characteristics8.

Neupro® is a black-triangle drug in the BNF and is therefore under intensive safety monitoring by the MHRA7.

Drug Interactions 8

The SPC advises that because rotigotine is a dopamine agonist, it is assumed that dopamine antagonists, such as neuroleptics (e.g. , butyrophenones, ) or , may diminish the effectiveness of Neupro®

For additional information on drug interactions refer to the Summary of Product Characteristics8.

Dosage Forms8

Neupro transdermal patches are available as 6 strengths, releasing rotigotine continuously over a 24 hour period: 1mg/24 hours, 2mg/24 hours, 3mg/24hours. 4mg/24 hours, 6mg/24 hours and 8mg/24 hours.

The patches are thin, matrix-type, square-shaped with rounded edges, consisting of three layers. The outside of the backing layer is tan-coloured and imprinted with Neupro and the strength of the patch ie 1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours or 8 mg/24 hours. 8

Each strength is available in pack sizes of 28 patches.

A 28-day starter pack of 7 x 2mg/24 hours, 7 x 4mg/24 hours, 7 x 6mg/24 hours and 7 x 8mg/24 hours are available.

NB For the treatment of Parkinson’s disease the licensed doses are in increments of 2mg ie starting at 2mg/24 hours as monotherapy and 4mg/24 hours as adjunctive therapy with levodopa; the licensed dose for restless legs syndromes is 1mg/24 hours increased in steps of 1mg/24 hours at weekly intervals if required to a maximum dose of 3mg/24 hours.

Cost Analysis

Costs of Neupro® in primary and secondary care:

Rotigotine patch strength Pack size Primary Care (exc. Secondary Care (inc. VAT) VAT) (Drug Tariff18 price) 1mg/24 hours 28 £77.24* £92.69 2mg/24 hours 28 £77.24 £92.69 3mg/24 hours 28 £97.48* £116.08 4mg/24 hours 28 £117.71 £141.25 6mg/24 hours 28 £142.79 £171.35 8mg/24 hours 28 £142.79 £171.35 28-day starter pack 28¥ £142.79 £171.35

* Price from BNF 617 as not listed in Drug Tariff April 2011 ¥ 28-day starter pack=7x2mg/24 hours, 7x4mg/24 hours, 7x6mg/24 hours and 7x8mg/24 hours patches

Expenditure on Neupro® in primary and secondary care for a 6-month period: (August 2010- January 2011):

Rotigotine patch strength UHNS Stoke-on-Trent North PCT Staffordshire PCT 1mg/24 hours £71 £478 2mg/24 hours £827 £2,289 £1,849 3mg/24 hours 4mg/24 hours £2,260 £5,356 £2,384 6mg/24 hours £520 £2,629 £1,578 8mg/24 hours £337 £4,207 £3,549 28-day starter pack* Total £3,944 £14,551 £9,837 * 28-day starter pack=7x2mg/24 hours, 7x4mg/24 hours, 7x6mg/24 hours and 7x8mg/24 hours patches

Dr Mann estimates that 15-20 patients per year would be prescribed rotigotine patches. Based on a dose of 16mg (the maximum dose for advanced disease in combination with levodopa) this would cost approx. £3440 per patient per year (based on drug tariff price).

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Scottish Medicines Consortium (SMC):

Early-stage PD as monotherapy11:

The manufacturer presented a simple one year cost-utility model based around the responder rates of the that compared rotigotine with ropinirole. The additional comparators of pramipexole and cabergoline were also considered. Pramipexole effectiveness estimates were drawn from the literature, while expert opinion suggested that cabergoline was of equal effectiveness compared to rotigotine. A utility increment of 0.1 for responders was estimated through the EQ-5D visual analogue scale which had been administered during the trial. Adverse events impacted upon costs but not upon quality of life. Trial drop-outs were not considered within the modelling.

Two scenarios were modelled based on different average daily dosing regimes. The first scenario adopted the average doses for rotigotine and ropinirole taken within the clinical trial, 7.7mg and 14.1mg per day, with pramipexole and cabergoline doses of 2.1mg and 2.0mg per day. The second scenario adopted lower dosing that was felt to be possibly more reflective of likely clinical practice, reducing the average daily dose for rotigotine and ropinirole to 6mg and 9mg respectively.

Several issues were noted with the analysis. Concerns remain as to the modelled evolution of responders, since trial data indicated that responder rates were largely attained during titration rather than after, as was assumed within the modelling. The short duration of the modelling increases the likely effects of this assumption. There are also concerns that the base case modelling did not take into account the lower costs per mg of ropinirole for higher dosing regimens, with additional analyses supplied by the manufacturer suggesting that this would somewhat reduce the anticipated savings relative to ropinirole. Despite these concerns, the SMC concluded that rotigotine is likely to be of acceptable cost effectiveness.

Advanced Parkinson’s Disease (with levodopa)12:

The manufacturer presented a simple one year cost utility model based around the responder rates of the clinical trial that compared rotigotine with pramipexole. The additional comparators of ropinirole and cabergoline were also considered. Expert opinion was used in the model to support the assumption that ropinirole would attain a response rate of the midpoint between pramipexole and rotigotine, and cabergoline a response rate equivalent to rotigotine.

Treatment during the titration phase was assumed to result in no patient benefit, which is likely to have been to the detriment of ropinirole with a 16 week titration phase in contrast to the 7 weeks required for the other treatments. The full response rates of 59.7% for rotigotine and 60.0% for pramipexole were only achieved by week 24. The 24 week response rates were assumed to continue to week 52. As it is likely that greater proportions of patients were benefiting from the treatments prior to the 24 week point, these assumptions may have underestimated the relative benefit of pramipexole over rotigotine.

A utility increment of around 0.1 for responders was estimated through the EQ-5D visual analogue scale which had been administered during the trial assessing rotigotine relative to placebo. Adverse events impacted upon costs and quality of life, rates for these being drawn from the trial for rotigotine and pramipexole. Adverse event rates for ropinirole and cabergoline were drawn from their product monographs. Trial drop-outs were not

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considered. Dosing for rotigotine and pramipexole was drawn from the trial, while for ropinirole and cabergoline it was drawn from expert opinion.

The modelling found that pramipexole was more cost effective than rotigotine. The indirect comparison with cabergoline suggested that while rotigotine was more expensive, the lower rates of adverse events associated with rotigotine could enable it to be cost effective relative to cabergoline. The indirect comparison with ropinirole suggested that while rotigotine would be more expensive, it would be cost effective. This last estimate may have been sensitive to the assumptions around titration phases and maintenance phases as outlined above. The differences in the annual costs of treatments ranged between £400 and £800, while the differences in accrued QALYs were small.

Current Formulary Status

The North Staffordshire Joint Formulary currently lists the following agents:

4.9 DRUGS USED IN 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 parkinsonism CSM 2 Restriction: Initiation by specialist

Bromocriptine 2 Restriction: Initiation by specialist CSM Co-beneldopa 2 Restriction: Initiation by specialist (Madopar® preparations) Co-careldopa 2 Restriction: Initiation by specialist (Sinemet® preparations) Entacapone 2 Restriction: Initiation by specialist MTRAC Pergolide 2 Restriction: Initiation by specialist CSM Ropinirole 2 Restriction: Initiation and stabilisation by specialist MTRAC 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

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Alternative therapies

Comparison to other agents for Parkinson’s Disease:

Early PD as monotherapy:

Class Drug Formulary Usual daily Cost for 28 days status dose* treatment** Dopamine agonists Rotigotine NF 2-8mg daily £77.24-£142.79 (non-ergot derived) Ropinirole F 9-16mg £72-£135 Pramipexole NF 0.264mg-3.3mg £53.48-£292.00 (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 NF 1mg £70.72

Advanced PD (in combination with L-dopa):

Class Drug Formulary Usual daily Cost for 28 days status dose* treatment** Dopamine agonists Rotigotine NF 4-16mg £117.71- (non-ergot-derived) £285.58 Ropinirole F 9-24mg £72-£180 Pramipexole NF 0.264mg-3.3mg £53.48-£292.00 (as base) Dopamine agonists Pergolide F Max. 3mg £35.23 (ergot-derived) MAO-B inhibitor Selegeline F 10mg £6.87 Rasagiline NF 1mg 70.72 COMT inhibitor Entacapone F 600-2000mg £48.33-£160.86

*doses are for general comparison and do not imply therapeutic equivalence ** Prices from BNF 617

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References

1. The Parkinson Study Group. A controlled trial of rotigotine monotherapy in early Parkinson’s disease. Arch Neurol 2003;60(12):1721-8 2. Watts R.L. et al. Randomised, blind, controlled trail of transdermal rotigotine in early Parkinson Disease. Neurology 2007; 68: 272 - 276 3. Giladi N. et al. Rotigotine Transdermal Patch in Early Parkinson’s Disease: A Randomized, Double-Blind, Controlled Study Versus Placebo and Ropinirole. Movement Disorders 2007; 22(16):2398–2404 4. LeWitt P.A. et al. Advanced Parkinson disease treated with rotigotine transdermal system. Neurology 2007; 68: 1262 - 1267 5. Poewe W.H. et al. Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy, randomised controlled trial. Lancet Neurol 2007; 6: 513–20 6. UKMi New Medicines Profile. Rotigotine (July 2006). Issue No 06/09. 7. British National Formulary No 61 (March 2011). BMJ and Pharmaceutical Press: London. 8. Neupro 1 mg/24 h, 2 mg/24 h, 3 mg/24 h, 4 mg/24 h, 6 mg/24 h, 8 mg/24 h Transdermal Patch & Parkinson’s disease Treatment Initiation Pack® Summary of Product Characteristics. UCB Pharma Limited. Last updated 03/06/2010. Accessed www.medicines.org 4/4/11. 9. NICE. Clinical Guideline– Parkinson's disease: diagnosis and management in primary and secondary care (June 2006). Accessed via http://www.nice.org.uk/CG035 10. Scottish Medicines Consortium. Rotigotine 2mg/24 hours, 4mg/24 hours, 6mg/24 hours, 8mg/24 hours transdermal patch (Neupro®) (No. 289/06). Accessed via http://www.scottishmedicines.org.uk/SMC_Advice/Advice/rotigotine_2mg_24_hours_ _4mg_24_hours__6mg_24_hours__8mg_24_hours_transdermal_patch__Neupro__ __/rotigotine_2mg_24_hours__4mg_24_hours__6mg_24_hours__8mg_24_hours_tr ansdermal_patch__Neupro_ 11. Scottish Medicines Consortium. Re-Submission- rotigotine 2mg/24 hours, 4mg/24 hours, 6mg/24 hours, 8mg/24 hours transdermal patch (Neupro®) (No. 289/06). Accessed via http://www.scottishmedicines.org.uk/SMC_Advice/Advice/rotigotine_2mg_24_hours_ _4mg_24_hours__6mg_24_hours__8mg_24_hours_transdermal_patch__Neupro__ __/rotigotine_2mg_24_hours__4mg_24_hours__6mg_24_hours__8mg_24_hours_tr ansdermal_patch__Neupro_1 12. Scottish Medicines Consortium. Rotigotine 2mg/24 hours, 4mg/24 hours, 6mg/24 hours, 8mg/24 hours transdermal patch, (Neupro®) (No. 392/07). Accessed via http://www.scottishmedicines.org.uk/SMC_Advice/Advice/392_07_rotigotine_transde rmal_patch__Neupro_/rotigotine__Neupro_ 13. Stowe R et al. Dopamine agonist therapy in early Parkinson’s disease. Cochrane Database of Systematic Reviews 2008, Issue (2): CD006564 14. 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.

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15. SIGN. SIGN 113: Diagnosis and pharmacological management of Parkinson’s Disease (January 2010). Accessed via http://www.sign.ac.uk/pdf/sign113.pdf 16. Midlands Therapeutics Review & Advisory Committee. Verdict and Summary Rotigotine (Neupro®) for the treatment of Parkinson’s Disease (April 2007). Accessed via http://mtrac.co.uk/ 17. Trenkwalder C. et al. Rotigotine Effects on Early Morning Motor Function and Sleep in Parkinson’s Disease: A Double-Blind, Randomized, Placebo-Controlled Study (RECOVER). Movement Disorders 2011; 26(1): 90-99 18. 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: [email protected]

Produced for use within the NHS. Not to be reproduced for commercial purposes

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