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Parkinson’s Disease Prescribing Guidelines for use in Primary and Secondary Care

Document Description

Document Type Prescribing Guidance

Service Application Primary and Secondary Care

Version 3.0

Ratification date July 2019

Review date July 2021

Lead Author(s)

Dr Janine Barnes Neurology Specialist Pharmacist, The Dudley Group NHS Foundation Trust

Dr Alistair Lewthwaite Consultant Neurologist, The Dudley Group NHS Foundation Trust

Change History

Version Date Comments 0.1 14/1/10 Developed by Dr Barnes and Dr Etti 0.2 28/1/10 Updated with comments from Mehul Amin, Team Leader

of Primary Care Neurology Team 0.3 9/2/10 Amended by Clair Huckerby-Pharmaceutical Advisor 0.4 23/2/10 Updated with comments from AMMC 0.5 April 2010 Final comments from neurology consultants 0.6 June 2010 Changes to formatting 1.0 Sept 2010 Final Ratified edition 2.0 Oct 2012 Guidelines reviewed – Ropinirole XL info updated due to

license change 2.1 May 2015 Amended by Dr Barnes

2.2 April 2017 Amended by Dr Barnes-Following publication of new NICE guidance (NG71)

2.3 June 2019 Amended by Dr Barnes 3.0 July 2019 Minor amendments – formats. Final version.

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Reviewers - This Document has been reviewed by

Version Date Name Title/Responsibility

2.1 May 2015 Dr J Barnes Neurology Specialist Pharmacist

2.2 April 2017 Dr J Barnes Neurology Specialist Pharmacist

2.3 June 2019 Dr J Barnes Neurology Specialist Pharmacist

Approvals - This document has been approved by

Version Date Name Title/Responsibility

3.0 July 2019 ACE Area Clinical Effectiveness Committee

DOCUMENT STATUS: This is a controlled document. Whilst this document may be printed, the electronic version posted on the intranet is the controlled copy. Any printed copies of the document are not controlled.

Glossary of Terms

Term Acronym Definition Clinical Commissioning Group

CCG

Link with Care Quality Commission Essential Standards of Quality & Safety

Regulation 10, Outcome 16- Assessing and monitoring the quality of service provision. Regulation 13, Outcome 9- Management of medicines.

Link with Trust Purpose and Values statements

These guidelines are aimed to improve the health and wellbeing of our local community. They link with: ‘We will support, deliver and develop our staff’ ‘We will work to continuously improve services’.

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Summary Sheet

These guidelines have been drawn up to promote the safe, effective and economic use of medication for Parkinson’s disease patients, aiming to improve the quality of patient experience for this group of patients. Recommendations for prescribing are based on NICE and SIGN guidance and from consultations with clinicians from both primary and secondary care in the Dudley Health Economy. These guidelines are for use by all staff within the Dudley Health Economy, who manage patients with Parkinson’s disease. Produced in consultation with:

Dr R Etti Consultant Neurologist, DGoH

Dr M Douglas Consultant Neurologist, DGoH

Clair Huckerby Pharmaceutical Adviser, Dudley CCG

Jane Elvidge Principal Pharmacist, DGoH

Mehul Amin Team Leader, Primary Care Neurology Team

Dr J Stellman Elderly Care consultant, DGoH

Dr S Duja Elderly Care consultant, DGoH

Dr A. Banerjee Elderly Care consultant, DGoH

Dr A McGrath Elderly Care consultant, DGoH

Dr A Michael Elderly Care consultant, DGoH

Primary Care Neurology team

AMMC members

Practice based Commissioning Clusters

The guidelines will be subject to review in two years time or sooner depending on changes in national guidance.

Contents Pg No

Introduction 4

Treatment pathway for Parkinson’s disease 5

Levodopa: Co-careldopa, Co-beneldopa 6

Dopamine agonists: Ropinirole, Pramipexole, Rotigotine 10

Monoamine oxidase B inhibitors: Rasagiline, Selegiline, Safinamide 13

Antimuscarinics: Trihexyphenidyl, Glycopyrronium 14

COMT (catechol-o-methyl-transferase) inhibitors: Entacapone, Opicapone

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Stanek(Levodopa/Carbidopa/Entacapone) 15

Amantadine 15

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Apomorphine 16

References 17

Introduction Aims

To provide a simple pathway for the treatment of Parkinson’s disease

To promote the safe, effective and economic use of Parkinson’s disease medication

To minimise the risk of medication related side effects experienced by this patient group

Principles of Treatment This guidance is based on the best available evidence but its application must be modified by professional judgement The pathway and prescribing guidelines are produced as an aide to prescribing for GPs and specialists within Dudley although often it is not possible to identify a universal first choice therapy for patients with early or late Parkinson’s disease and so the choice of drug prescribed should take into account:

• Clinical and lifestyle characteristics • Patient preference

Roles and Responsibilities It is essential that in order for these guidelines to be implemented that they are easily and conveniently accessible to all healthcare professionals. Specialist Initiation: Where specialist initiation of a drug is suggested, this refers to consultant neurologists, consultants within the elderly care team and prescribers within the neurology primary care team. Identified Standards These guidelines should be read in association with NICE2 and SIGN3 clinical guidelines. Auditing The Prescribing and Medicines Management team working with the Primary Care Neurology team and Dudley group of hospitals, will be responsible for the audit of the prescribing guidelines.

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A. Levodopa:

Co-careldopa, Co-beneldopa (specialist initiation recommended)

Levodopa is the amino-acid precursor of dopamine, acts by replenishing depleted striatal dopamine; is given with an extracerebral dopa-decarboxylase inhibitor that reduces the peripheral conversion of levodopa to dopamine allowing less side effects and lower doses of levodopa to be used. The extracerebral dopa-decarboxylase inhibitors used with levodopa are benserazide (co-beneldopa) and carbidopa (co-careldopa). These combinations are used in the elderly or frail, in patients with other significant illnesses, and in those with more severe symptoms. The preparations are effective and well-tolerated in most patients. Levodopa therapy should be initiated at a low dose and increased in small steps, with the final dose as low as possible. Intervals between doses should be suited to the individual patient needs. Levodopa treatment is associated with the development of potentially troublesome motor complications including response fluctuations and dyskinesias. Response fluctuations are characterised by large variations in motor performance, with normal function during the ‘on’ period, and weakness

Levodopa Formulations

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and restricted mobility during the ‘off’ period. ‘End-of-dose’ deterioration also occurs, where the duration of benefit after each dose becomes progressively shorter. Modified-release preparations may help with ‘end-of-dose’ deterioration or nocturnal immobility and rigidity. Motor complications are particularly problematic in young patients treated with levodopa.

Co-careldopa: Indicated for Parkinsonism (but not drug-induced extrapyramidal symptoms)

Dose Dose Frequency Dose Titration Maximum dose

Expressed as levodopa, initially 100 mg (with carbidopa 25 mg)

3 times daily increased by 50–100 mg (with carbidopa 12.5–25 mg) daily or on alternate days according to response

up to 800 mg (with carbidopa 200 mg) daily in divided doses

or

initially 50–100 mg (with carbidopa 10–12.5 mg)

3–4 times daily increased by 50–100 mg daily or on alternate days according to response

up to 800 mg (with carbidopa 80–100 mg) daily in divided doses

or

initially 125 mg (with carbidopa 12.5 mg, as ½ tablet of co-careldopa 25/250)

1–2 times daily increased by 125 mg (with carbidopa 12.5 mg) daily or on alternate days according to response

NB. At least 70 mg carbidopa daily is necessary to achieve full inhibition of peripheral dopa-decarboxylase. When transferring patients from another levodopa/dopa-decarboxylase inhibitor preparation, the previous preparation should be discontinued at least 12 hours before.

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Co-beneldopa: Indicated for Parkinsonism (but not drug-induced extrapyramidal symptoms)

Dose Dose Frequency Dose Titration Maintenance dose

Expressed as levodopa, initially 50mg

3-4 times daily (100mg 3 times daily in advanced disease)

increased by 100 mg daily once or twice weekly according to response

400–800 mg daily in divided doses

Dose for elderly patients

initially 50 mg once or twice daily

increased by 50 mg daily every 3–4 days according to response

NB. When transferring patients from another levodopa/dopa-decarboxylase inhibitor preparation, the previous preparation should be discontinued 12 hours before (although interval can be shorter).

Levodopa controlled release formulations:

Co-careldopa, Co-beneldopa

Indicated for idiopathic Parkinson's disease, in particular to reduce off-period in patients who previously have been treated with levodopa/decarboxylase inhibitors, or with levodopa alone and who have experienced motor fluctuations. The experience is limited with 'Sinemet CR' and 'Half Sinemet CR' in patients who have not been treated with Levodopa before. In clinical trials, patients with motor fluctuations experienced reduced 'off'-time with 'Sinemet CR' when compared with 'Sinemet'. The reduction of the 'off'-time is rather small (about 10%) and the incidence of dyskinesias increases slightly after administration of 'Sinemet CR' compared to standard 'Sinemet'. Global ratings of improvement and activities of daily living in the 'on' and 'off' state, as assessed by both patient and physician, were better during therapy with 'Sinemet CR' than with 'Sinemet'. Patients considered 'Sinemet CR' to be more helpful for their clinical fluctuations, and preferred it over 'Sinemet'. In patients without motor fluctuations, 'Sinemet CR‘ under controlled conditions, provided the same therapeutic benefit with less frequent dosing than with 'Sinemet'. Generally, there was no further improvement of other symptoms of Parkinson's disease. (see BNF for prescribing advice¹)

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Co-careldopa CR: (Caramet CR, Half Sinemet CR and Sinemet CR)

Co-careldopa CR preparation: (strength expressed as carbidopa:levodopa)

Dose for patients not receiving levodopa/dopa-decarboxylase inhibitor preparations,

Dose frequency Dose titration

Caramet® CR co-careldopa 25/100 50/200

expressed as

levodopa,

initially 100–

200 mg

twice daily (at least 6 hours between doses)

dose adjusted according to response at intervals of at least 2 days

Sinemet® CR 50/200

initially, 1 Sinemet® CR tablet

twice daily

both dose and interval then adjusted according to response at intervals of not less than 3 days

Co-careldopa CR preparation: (strength expressed as carbidopa:levodopa)

Patients transferring from immediate-release levodopa/dopa-decarboxylase inhibitor preparations,

Dose frequency Dose titration

Caramet® CR co-careldopa 25/100 50/200

discontinue previous preparation at least 12 hours before first dose of Caramet® CR;

substitute Caramet® CR to provide a similar amount of levodopa daily and extend dosing interval by 30–50%;

dose then adjusted according to response at intervals of at least 2 days

Sinemet® CR 50/200

1 Sinemet® CR tablet twice daily can be substituted for a daily dose of levodopa 300–400 mg in immediate-release Sinemet® tablets

(substitute Sinemet® CR to provide approx. 10% more levodopa per day and extend dosing interval by 30–50%);

dose and interval then adjusted according to response at intervals of not less than 3 days

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Co-beneldopa CR: (Madopar)

Co-beneldopa CR preparation: (strength expressed as 25/100 beneldopa:levodopa)

Dose and frequency

Maximum dose Dose titration

Dose for patients not receiving levodopa/dopa-decarboxylase inhibitor preparations,

initially 1 capsule 3 times daily

6 capsules daily

Patients transferring from immediate-release levodopa/dopa-decarboxylase inhibitor preparations,

initially 1 capsule substituted for every 100 mg of levodopa and given at same dosage frequency

increased every 2–3 days according to response; average increase of 50% needed over previous levodopa dose and titration may take up to 4 weeks

Supplementary dose of immediate-release Madopar® may be needed with first morning dose; if response still poor to total daily dose of Madopar® CR plus Madopar® corresponding to 1.2 g levodopa, consider alternative therapy.

Levodopa dispersible formulation: Co-beneldopa: Patients requiring a more rapid onset of action, e.g., from early morning or afternoon akinesia, or who exhibit ‘delayed on’ or ‘wearing off’ phenomena, are more likely to benefit from Co-beneldopa dispersible. (see BNF for prescribing advice1) The tablets can be dispersed in water or orange squash (not orange juice) or swallowed whole.

B. Dopamine Agonists: (specialist initiation recommended)

Ropinirole:

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Licensed to treat Parkinson’s disease, either used alone or as an adjunct to levodopa with a dopa-decarboxylase inhibitor. When administered as adjunct to levodopa, concurrent dose of levodopa may be reduced by approx. 20%.

Dose Dose Frequency Dose Titration Maximum dose

initially 750 micrograms daily in 3 divided doses

increased by increments of 750 micrograms at weekly intervals to 3 mg daily

further increased by increments of up to 3 mg at weekly intervals according to response; usual range 9–16 mg daily (but higher doses may be required if used with levodopa);

24 mg daily

Ropinirole XL prescribed as Ipinnia XL brand: Stable Parkinson’s disease in patients transferring from ropinirole immediate-release tablets, initially Ipinnia XL once daily substituted for total daily dose equivalent of ropinirole immediate-release tablets; if control not maintained after switching, in patients receiving less than 8 mg once daily, increase in steps of 2 mg at intervals of at least 1 week to 8 mg once daily according to response; in patients receiving 8 mg once daily or more, increase in steps of 2 mg at intervals of at least 2 weeks according to response; max. 24 mg once daily. Patients can also be initiated on Ipinnia XL with a usual starting dose of 2mg once daily. After a week this dose can be increased to 4mg once daily, when a therapeutic response may be seen. If sufficient symptom control is not achieved or maintained, the daily dose may be increased by 2mg at weekly or longer intervals. NB. When administered as adjunct to levodopa, concurrent dose of levodopa may be reduced.

Pramipexole: Licensed to treat Parkinson’s disease, used alone or as an adjunct to levodopa with dopa-decarboxylase inhibitor. NB. 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

Dose Dose Frequency Dose Titration Maximum dose

Initially 88 3 times daily dose doubled 3.3 mg daily in 3

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micrograms 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

divided doses

During pramipexole dose titration and maintenance, levodopa dose may be reduced. Pramipexole has been associated with somnolence and episodes of sudden sleep onset in a rare number of cases. Patients should be informed of this and advised to exercise caution when driving or operating machinery during treatment with the medication.

Pramipexole prolonged release prescribed as Pipexus brand: The majority of patients are able to switch from immediate release Pramipexole to the prolonged release formulation without the need for dose adjustment.

Rotigotine patch: 4,5 (specialist initiation recommended)

Licensed to treat Parkinson’s disease, either used alone or as an adjunct to levodopa with dopa-decarboxylase inhibitor.

Dose Frequency Dose Titration Maximum dose

Monotherapy ‘2 mg/24 hours’ patch to dry, non-irritated skin on torso, thigh, or upper arm, removing after 24 hours and siting replacement patch on a different area (avoid using the same area for 14 days)

increased in steps of 2 mg/24 hours at weekly intervals if required

8 mg/24 hours

Adjunctive therapy with levodopa

apply ‘4 mg/24 hours’ patch to dry, non-irritated skin on torso, thigh, or upper arm, removing after 24 hours

increased in steps of 2 mg/24 hours at weekly intervals if required

16 mg/24 hours

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and siting replacement patch on a different area (avoid using the same site for 14 days);

Rotigotine patches (Neupro®) are licensed as a monotherapy or as an adjunct to Levodopa with a dopa-decarboxylase inhibitor and it is a useful product where the transdermal route facilitates treatment. C. Monoamine oxidase B inhibitors: (Specialist initiation recommended)

Rasagiline, Selegiline, Safinamide Rasagiline: Licensed to treat Parkinson’s disease, used alone or as adjunct to levodopa with dopa-decarboxylase inhibitor. Dose-1mg daily.

Selegiline: Licensed to treat Parkinson’s disease, used alone or as adjunct to levodopa with dopa-decarboxylase inhibitor. Dose-10 mg in the morning, or 5 mg at breakfast and midday. To avoid initial confusion and agitation, it may be appropriate to start treatment with a dose of 2.5 mg daily, particularly in the elderly.

Selegiline oral lyophilisate: 6 (Zelapar)

(Specialist initiation recommended) The lyophilisate (1.25mg) can be taken daily before breakfast. The tablets should be placed on the tongue and allowed to dissolve. The patient should be advised not to drink, rinse or wash mouth out for 5 minutes after taking the tablet. NB. Patients receiving the 10mg conventional Selegiline tablet can be switched to Zelapar 1.25mg. The lyophilisate may be useful for patients who have difficulty in swallowing as Zelapar dissolves completely within 10 seconds of placing on the tongue and, in contrast to conventional tablets, Selegiline is absorbed primarily pregastrically.

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Safinamide7: (Specialist initiation recommended) Licensed for the treatment of adult patients with idiopathic Parkinson’s disease as add-on therapy to a stable dose of levodopa alone or in combination with other medicinal products for Parkinson’s disease in mid to late-stage fluctuating patients. Dose-Treatment should be started at one 50mg tablet per day. The dose may be increased to 100mg/day on the basis of individual clinical need. No change in dose is required for elderly patients.

D. Antimuscarinics: Trihexyphenidyl:8

(specialist initiation recommended) Found to be useful in treating severe tremor in younger Parkinson’s disease patients. Drug may also be useful in reducing sialorrhoea-but has little effect on bradykinesia and propensity for causing neuropsychiatric side effects.

Glycopyrronium prescribed as Sialanar 320mcg/ml oral solution:2

(Specialist initiation recommended) Sialanar is licensed for severe sialorrhoea in the paediatric population and therefore will be used “off-label” for adult neurology patients. Glycopyrronium (Sialanar) 320 micrograms/ml is equivalent to 400 micrograms/ml glycopyrronium bromide. NICE2 identified glycopyrronium as having the least cognitive side effects of its class. Suggested starting dose of 1ml Sialanar oral solution taken TDS with each dose taken one hour before or at least two hours after meals as co-administration with food results in a marked decrease in systemic medicinal product exposure. Dose can be gradually increased every 7 days up to 2.5ml TDS if needed.

E. COMT (catechol-o-methyl-transferase) inhibitors: (Specialist initiation recommended) Entacapone and tolcapone prevent the peripheral breakdown of levodopa, by inhibiting catechol-O-methyltransferase, allowing more levodopa to reach the brain. They are licensed for use as an adjunct to co-beneldopa or co-careldopa for patients with Parkinson’s disease who experience ‘end-of-dose’

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deterioration and cannot be stabilised on these combinations. Due to the risk of hepatotoxicity, tolcapone should be prescribed under specialist supervision only, when other catechol-O-methyltransferase inhibitors combined with co-beneldopa or co-careldopa are ineffective.

Entacapone: Licensed as adjunct to levodopa with dopa-decarboxylase inhibitor in Parkinson’s disease and ‘end-of-dose’ motor fluctuations. Dose-200 mg with each dose of levodopa with dopa-decarboxylase inhibitor; max. 2 g daily.

Opicapone9,10,11 (specialist initiation recommended)

Licensed as adjunctive therapy to preparations of levodopa/DOPA decarboxylase inhibitors in adult patients with Parkinson’s disease and end-of-dose motor fluctuations who cannot be stabilised on those combinations. Dose-50mg daily, taken at bedtime, at least one hour before or after levodopa combinations. Opicapone enhances the effects of levodopa. Hence, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating treatment with opicapone.

Stanek®: (Levodopa/Carbidopa/Entacapone) Licensed for Parkinson’s disease and end of dose motor fluctuations not adequately controlled with levodopa and dopa decarboxylase treatment. Only 1 tablet to be taken for each dose. See BNF1 for maximum amount of tablets daily as depends on strength of tablet. Patients receiving standard-release co-careldopa or co-beneldopa alone, initiate Stanek at a dose that provides similar (or slightly lower) amount of levodopa Patients with dyskinesia or receiving more than 800 mg levodopa daily, introduce entacapone before transferring to Stanek (levodopa dose may need to be reduced by 10–30% initially). Patients receiving entacapone and standard-release co-careldopa or co-beneldopa, initiate Stanek at a dose that provides similar (or slightly higher) amount of levodopa. Stanek is most cost effective at higher doses.

F. Amantadine:12(specialist initiation recommended)

Licensed for Parkinson’s disease (but not drug-induced extrapyramidal symptoms). Dose-Parkinson’s disease, 100 mg daily increased after one week to 100 mg twice daily, usually in conjunction with other treatment; some patients may

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require higher doses, max. 400 mg daily; elderly 65 years and over, 100 mg daily adjusted according to response.

G. Apomorphine:13,14 (specialist initiation recommended) (intermittent injection, pre-filled syringe. ampoule) Licensed for refractory motor fluctuations in Parkinson’s disease (‘off’ episodes) inadequately controlled by levodopa with dopa-decarboxylase inhibitor or other dopaminergics (for capable and motivated patients under specialist supervision). Dose-By subcutaneous injection, usual range (after initiation as below) 3–30 mg daily in divided doses; subcutaneous infusion may be preferable in those requiring division of injections into more than 10 doses daily; max. single dose 10 mg; child and adolescent under 18 years not recommended. By continuous subcutaneous infusion (those requiring division into more than 10 injections daily) initially 1 mg/hour daily increased according to response (not more often than every 4 hours) in max. steps of 500 micrograms/hour, to usual rate of 1–4 mg/hour (14–60 micrograms/kg/hour); change infusion site every 12 hours and give during waking hours only (24-hour infusions not advised unless severe night-time symptoms)—intermittent bolus boosts also usually needed; child and adolescent under 18 years not recommended. NB Total daily dose by either route (or combined routes) max. 100 mg.

Requirements for initiation: Hospital admission and at least 2 days of pre-treatment with domperidone for nausea and vomiting, after at least 3 days withhold existing antiparkinsonian medication overnight to provoke ‘off’ episode, determine threshold dose, re-establish other antiparkinsonian drugs, determine effective apomorphine regimen, teach to administer by subcutaneous injection into lower abdomen or outer thigh at first sign of ‘off’ episode, discharge from hospital, monitor frequently and adjust dosage regimen as appropriate (domperidone may normally be withdrawn over several weeks or longer)—for full details of initiation requirements, consult product literature.

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References: 1. British National Formulary (2017) British National Formulary 73. Available at

www.bnf.org. (Accessed 27 July 2017).

2. National Institute for Clinical excellence (2017) NICE clinical guideline 71

Parkinson’s disease in adults. Available at : www.nice.org.uk (Accessed 27 July 2017).

3. Scottish Intercollegiate Guidelines Network (2010) SIGN 113 Diagnosis and

pharmacological management of Parkinson’s disease. Available at: www.sign.ac.uk (Accessed 10 September 2012).

4. Giladi, N., Boroojerdi, B., Ko/>rczyn, A.D., Burn, D.J., Clark, C.E., Schapira,

A.H.V. (2007) Rotigotine transdermal patch in early Parkinson’s disease: A randomized, double-blind, controlled study versus placebo and ropinirole. Movement Disorders, 22(16), pp 2398-2404.

5. Poewe, W.H., Rascol, O., Quinn, N., Tolosa, E., Oertel, W.H., Martignoni,

E., Rupp, M., Boroojerdi, B. (2007) Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy, randomised controlled trial. Lancet Neurology, 6, pp 513-520.

6. Lew, M.F., Pawha, R., Leehey, M., Bertoni, J., Kricorian, G., Zydis

Selegiline Study, (2007) Safety and efficacy of newly formulated selegiline orally disintegrating tablets as an adjunct to levodopa in the management of ‘off’ episodes in patients with Parkinson’s disease. Current Medical Research and Opinion, 23(4) pp 741-750.

7. National Institute for Clinical excellence (2017) Parkinson’s disease with

motor fluctuations:safinamide. Evidence summary (ES6). Available at : www.nice.org.uk (Accessed 20 March 2017)

8. Martin, W.E., Loewenson, R.B., Resch, J.A., Baker, A.B. (1974) A controlled

study comparing trihexyphenidyl hydrochloride plus levodopa with placebo plus levodopa in patients with Parkinson’s disease. Neurology, 24/10 (912-9), 0028-3878.

9. Ferreira, J.J., Lees, A., Rocha, J.F., Poewe, W., Rascol, O., Soares-da-

Silva, P. (2015) Opicapone as an adjunct to levodopa in patients with Parkinson’s disease and end-of-dose motor fluctuations: a randomised, double-blind, controlled trial. Lancet Neurology.

10. Lees, A.J., Ferreira, J., Rascol, O., Poewe, W., Rocha, J.F., McCrory, M., et

al., (2016) Opicapone as Adjunct to Levodopa Therapy in Patients With Parkinson’s Disease and Motor Fluctuations: A Randomised Clinical Trial. JAMA Neurology.

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11. National Institute for Clinical excellence (2017) Parkinson’s disease with end of dose motor fluctuations: opicapone: Evidence summary (ES9). Available at : www.nice.org.uk (Accessed 20 March 2017)

12. Verhagen Metman, L., Del Dotto, P., Van Den Munckhof, P., Fang, J.,

Mouradian, M.M., Chase, T.N. (1998) Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology, 50/5 (1323-1326), 0028-3878.

13. Chen, J.J., Obering, C. (2005) A review of intermittent subcutaneous

apomorphine injections for the rescue management of motor fluctuations associated with advanced Parkinson’s disease. Clinical Therapeutics, 27(11), pp1710-1724.

14. Ruiz, P.J.G., Ignacio, A.S., Pensado, B.A., Garcia, A.C., Frech, F.A., Lopez,

M.A.., Gonzalez, J.A., Octavio, J.B. (2008) Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease with motor fluctuations : a multicenter study. Movement Disorders, 23(8) pp 1130-1136.