who eml antiparkinson annexes · dopamine agonists as shown in figure 4 below. this indirect...

Review of the available evidence on

Oral Dopamine Agonists For Parkinson’s Disease

FOR THE WHO MODEL LIST OF ESSENTIAL MEDICINES

ANNEXES

Emilia Romagna Health and Social Care Agency - Drug Evaluation Unit,

WHO Collaborating Centre in Evidence-Based Research Synthesis and Guideline Development Emilia Romagna Health and Social Care Agency

Viale Aldo Moro, 21 - 40127 Bologna, Italy

Email: [email protected]

Update of the Cochrane systematic review of dopamine agonist therapy in early Parkinson’s disease Clare P. Herd1, Caroline Rick2, Laila Shah2, Rita Champaneria2, Natalie Ives2, Carl E. Clarke1,3

1School of Clinical and Experimental Medicine, College of Medicine and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK 2Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, B15 2TT, UK 3Department of Neurology, Sandwell and West Birmingham Hospitals NHS Trust, City Hospital, Birmingham, B18 7QH, UK

BackgroundA Cochrane systematic review of the evidence for Dopamine agonist therapy in early Parkinson’s disease was published in 2008 [1]. The authors found 29 eligible trials involving 5247 participants and concluded that although motor complications appeared reduced with dopamine agonists compared with levodopa, other important side effects were increased and symptom control was poorer. They called for further long‐term trials which included assessment of quality of life measures.

For this report, an update of the search used in this Cochrane review has been carried out using the major databases. An overlap of at least 6 months was incorporated to account for delayed addition of citations to the databases. In addition to the therapies reviewed previously, trials of the transdermal dopamine agonist rotigotine are included in this report.

Methods

TypesofstudiesEligible studies were any randomised trials in early Parkinson's disease comparing an orally or transdermally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa, with all other aspects of planned treatment being the same in both arms. Trials involving dopamine agonists administered intravenously were excluded.

TypesofparticipantsPatients with early Parkinson's disease entered into the relevant randomised trials. Early disease was defined as idiopathic Parkinson's disease, diagnosed using specified criteria such as the UK PDS Brain Bank criteria, with no history of motor complications, either untreated or with limited (generally less than 12 months) exposure to anti‐parkinsonian medication. There were no age restrictions.

TypesofinterventionsAny orally or transdermally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa, with all other aspects of planned treatment being the same in both arms.

TypesofoutcomemeasuresData extracted included clinician‐rated disability scales, e.g. Unified Parkinson's Disease Rating Scale (UPDRS), motor complications, quality of life scales, other side‐effects, treatment compliance and withdrawals, levodopa dose and mortality.

SearchstrategyWe searched Medline, Embase and CENTRAL using MeSH and free text terms for Parkinson’s disease as well as specific and generic dopamine agonist terms as described fully in the Medline search detailed in Appendix 1, these were combined with appropriate study design filter as described in section 6.4.11 of The Cochrane Handbook of Systematic Reviews of Interventions. No language restrictions were applied but date limits were used to create an overlap of 6 months with the search carried out in the relevant Cochrane review [1]. Protocols were retrieved from controlled‐trials.com for included trials when available.

Results

DescriptionofstudiesThis search was carried out on the 29th October 2014 and 2603 abstracts were retrieved and screened. A total of 32 relevant articles and abstracts as well as 4 available protocols were retrieved contributing to 12 new trials involving 5102 participants. Of these 12 new trials, nine compared dopamine agonist with placebo and three dopamine agonist with levodopa. Trial duration varied from 10 weeks to over 7 years. Trial quality was good overall, with eight of these trials using a computer generated randomisation code and seven using a central randomisation service. Nine trials were double blind, two were open label and one did not provide enough information to determine the level of blinding. Withdrawal rates were generally high ranging from 14% to 60%. Further details of the trials identified by this search can be found in Table 1, which also gives the full reference lists for each trial as well as the primary reference which will be used to identify studies throughout the rest of this report.

Effectsofinterventions

Trials of orally administered dopamine agonists versus placebo Although no data analysis could be carried out to assess the efficacy of dopamine agonists versus placebo in the Cochrane review carried out in 2008, the reviewers tabulated the various clinician rated disability scales used across the trials and the reported results in the form of p‐values. They were then able to qualitatively assess the treatment effect and conclude that dopamine agonists gave a significant improvement in symptom control compared with placebo [1]. Seven new trials reporting a comparison between an orally administered dopamine agonist and placebo were found in the updated search [2‐7]. Many of these trials provided sufficient data for meta‐analysis of UPDRS ADL and/or motor sub‐scores as shown in figures 1 and 2. The results of the forests plots for these newer trials support the conclusions of the 2008 Cochrane review, with both sub‐scores for this clinician rated disability scale showing a significant improvement in favour of dopamine agonist treatment (‐1.24, 95% CI ‐1.58 to ‐0.9, p

Figure 1: UPDRS ADL sub‐scores for trials of dopamine agonists (Experimental) versus placebo (Control).

Figure 2: UPDRS Motor sub‐scores for trials of dopamine agonists (Experimental) versus placebo (Control).

Of these seven trials, five reported on the quality of life outcome PDQ‐39 [4‐7]. Only two of these provided data in a usable format for meta‐analysis and the results of this are shown in figure 3 below. Again, a statistically significant result in favour of dopamine agonist treatment was seen.

Figure 3: PDQ‐39 scores for trials of dopamine agonists (Experimental) versus placebo (Control).

Trials of transdermally administered dopamine agonist versus placebo Three trials were found reporting on the transdermally administered dopamine agonist rotigotine [3, 8, 9]. Symptom control measured using UPDRS ADL and motor sub‐scores combined was reported in several trials with enough data to compare the efficacy of the patches with orally administered dopamine agonists as shown in figure 4 below. This indirect comparison shows that there is no statistically significant heterogeneity between the two subgroups (‐6.6, 95% CI ‐8.0 to ‐5.2 versus ‐4.7, 95% CI ‐6.4 to ‐4.9; p=0.10). Both subgroups result in an improvement in excess of minimum clinically important changes (MCIC’S) reported in the recent literature for UPDRS ADL and motor sub‐scores reported to be around ‐0.7 points and ‐2.3 to ‐2.7 points respectively [10, 11].

This result should be interpreted with caution due to the small number of studies with data available for inclusion in this analysis as well as the short duration of those studies (10‐39 weeks). Giladi et al provided the only head‐to‐head comparison of rotigotine patch treatment and orally administered dopamine agonists identified by this search. In contrast with our indirect comparison they found a significantly increased symptomatic effect of 3.8 points in combined UPDRS ADL and Motor sub‐scores in favour of ropinirole when compared with rotigotine patch therapy (95% CI’s 1.9 to 5.7; p

assessed in their allocated groups for 5 years. If the investigator judged it necessary to start additional therapy for PD because of medical reasons, levodopa and cabergoline were added to the initial cabergoline and levodopa groups but alternative dopamine agonist therapy could not be used. The primary outcome for this trial was incidence of motor complications, they also reported on UPDRS total and sub‐scores (ADL and motor) and gave a complete breakdown of reported adverse events. No quality of life measures were reported for this study. The hazard ratio reported for incidence of motor complications was 0.57 (95% CI, 0.18, ‐1.81; p=0.347) showing no significant difference between the groups, there was also no significant difference in UPDRS ADL, motor or total scores (p=0.280, p=0.398, p=0.140 respectively). The only statistically significant outcome was incidence of adverse events in favour of levodopa treatment (28% versus 53% in cabergoline group; p=0.019). Only the PD MED EARLY 2014 [14] trial compared dopamine agonist versus levodopa using quality of life outcome measures. This trial randomised 1620 participants into its open label parallel group design study. This trial included a third arm of initial monoamine oxidase B inhibitors (MAOBi) therapy, but this arm is not eligible for inclusion in this review. The patients were followed up for over 7 years. Any antiparkinsonian therapy could be added to any arm if symptoms were not adequately controlled by the maximum tolerated dose of the allocated medication. The primary analysis reported in the published report is for levodopa versus levodopa sparing groups, pooling dopamine agonist and MAOBi group data. However, some comments were made about levodopa versus dopamine agonist performance. The trialists stated that levodopa treatment achieved better scores than dopamine agonist treatment on the primary PDQ‐39 mobility outcome, and other patient‐related outcome measures, including ADL and overall quality of life as measured by the PDQ‐39 and EQ‐5D quality of life measures (data not currently available). 179 (28%) of 632 patients allocated dopamine agonists discontinued allocated treatment because of side effects compared with 11 (2%) of 528 patients allocated levodopa (p

patch therapy and orally administered dopamine agonists should be analysed to reliably test the non‐inferiority of this type of treatment [3]. The Cochrane review published in 2008 identified 11 trials of dopamine agonists versus levodopa and, using qualitative analysis of reported outcomes, concluded that levodopa initially provides better motor control, but that there is an increased likelihood of motor complications when compared with dopamine agonists therapy. The new trials provide data on quality of life which was not available for analysis in the 2008 review. The results of the PD MED trial found that quality of life was rated more highly by patients given levodopa compared with dopamine agonist therapy. Further analysis of data made available from this trial showed no difference between levodopa and dopamine agonist treated groups for motor fluctuations (p=0.18) and a reduced incidence of dyskinesia with an odds ratio of 0.56 in favour of the dopamine agonist arm. The conclusion drawn by PD MED trialists was that levodopa treatment is more effective and results in no clinically significant increase in involuntary movement over seven years compared with dopamine agonist therapy [14].

TrialDesignSince 2008 there has been an improvement in the standards of reporting in trials of dopamine agonists for early Parkinson’s disease with a larger proportion of trials providing usable data for meta‐analysis and fully disclosing trial methods needed for quality assessment. Inclusion of quality of life outcomes in trial designs, as recommended by the 2008 Cochrane reviewers, has increased with half of the new trials recording and reporting on the Parkinson’s Disease Questionnaire‐39.

Table 1: Characteristics of included studies: Further information for 12 studies included in this report, following abbreviations used, Adverse Event (AE), Dopamine Agonist (DA), Levodopa (L‐dopa, Unified Prkinson’s Disease Rating Scale (UPDRS), Activities of Daily Living (ADL), 39‐item Parkinson’s Disease Questionnaire (PDQ‐39), EuroQol (EQ‐5D)

Trial Label/1ry reference

Dopamine Agonist dose Comparator Treatment schedule Concomitant PD medications Summary of results

Bronzova 2010 [2, 15‐17] 1ry ref: Bronzova 2010 [2]

Pardoprunox Placebo

Pardoprudox was titrated from 0.3 mg to 45mg/day over a 2 ‐ 6 week titration phase, treatment discontinued if 9 mg not reached. Individual best maintenance dose (9‐45mg/day) was continued for 3 weeks, followed by 2‐4 days of down titration and discontinuation during a 1 week follow up period.

Not permitted

Both UPDRS‐Motor and ADL scores were improved in pardoprunox group compared to placebo (p=0.0001, 0.0007). There were high levels of nausea in the pardoprunox group compared with placebo group (47% versus 4%).

Brusa 2013 [12, 18] 1ry ref: Brusa 2013 [12]

Cabergoline (mean 6 mg/day) and Rotigotine (patch) (mean 8 mg/day)

Levodopa (mean 357 mg/day)

3 month treatment then cross‐over 15 day wash out period pre‐treatment.

Trial focussed on cognitive function outcomes but reported that UPDRS motor scores showed no significant difference between L‐dopa and DA treated groups.

CASTLE 2012 [13] 1ry ref: Utsumi 2012 [13]

Cabergoline 6 mg/day

Levodopa 600 mg /day

Treatment initiated with doses of Cab 0.25‐2 mg once daily and LD 100‐300 mg/day 2‐3 times daily and titrated up to 6 mg/day and 600 mg/day respectively. 5 year study duration

If necessary for PD symptom control, levodopa and cabergoline were added to the initial cabergoline and levodopa groups. Administration of selegiline and other dopamine agonists was prohibited. Administration of anticholinergics and amantadine was permitted prior to study enrolment only. After onset of the primary endpoint, administration of any anti‐PD drug was permitted.

Trial found no statistically significant difference between incidence of motor complications in cabergoline and L‐dopa groups. The AE rate in the initial L‐dopa group was lower than that in the initial cabergoline group (p=0.019).

Giladi 2007 [3, 19‐22]

Rotigotine (patch) maximum dose 8

Placebo

4 week screening period, ropinirole titrated from 0.25 mg t.i.d to maximal dose of 8 mg t.i.d over 13 weeks, rotigotine titrated from 2 mg/day to max dose 8 mg/day over 4

Patients were permitted to take selegiline, amantadine, or anticholinergic agents or other CNS active drugs if maintained at stable

Responder rate, measured using UPDRS (motor + ADL) scores, was significantly higher in the rotigotine and ropinirole groups than the

1ry ref: Giladi 2007 [3]

mg/day and Ropinirole maximum dose 8 mg/day

weeks, followed by a 24‐36‐week maintenance phase, a dose de‐escalation (up to 12 days) and a 4‐week safety follow‐up period.

dosages for 28 days before baseline and throughout the trial.

placebo group. Rotigotine transdermal patch has a similar profile of adverse events to those reported for other dopamine agonists with the exception of application site reactions, the severity of which were mild to moderate.

Jankovic 2007 [8, 23‐26] 1ry ref: Jankovic 2007 [8]

Rotigotine patch Placebo

Titration phase: week 1 2mg, week 2 4mg, week 3 6mg rotigotine patch, 24 week maintenance phase, weaned off the drug stepwise decrements every 2 days ,followed by a final clinical visit 28 days later.

Participants receiving anticholinergic agents, MAOBi, NMDA antagonists, must have had a stable dose for at least 28 days before baseline and were required to maintain that dose for the duration of the trial.

The rotigotine transdermal system consistently demonstrated statistically significant and clinically relevant efficacy over placebo in patients with early Parkinson’s disease (change in UPDRS Motor + ADL score, p=6 months by the time of acquisition of informed consent or other drugs that could possibly affect PD symptoms from at least 4 weeks before the date of first treatment. Patients who had received L‐dopa before study entry had to discontinue L‐dopa at least 2 weeks before the date of the first treatment administration.

The mean change in UPDRS (motor + ADL) scores were more improved in the rotigotine transdermal patch group than in the placebo group (p=0.002), at a level similar to or better than that seen in similar trials for orally administered dopamine agonists. No serious drug related AE’s were reported.

PD MED 2014 [14] 1ry ref: Gray 2014 [14]

Clinician selects preferred DA and dosage

Levodopa Drug titration schedule and dose selected by treating clinician. Patients followed up for at over 7 years.

LD could be added to other treatment arms if symptoms were not adequately controlled by maximum tolerated dose. Patients could only switch drug class if symptoms were still not adequately controlled or because of adverse events.

L‐Dopa treatment achieved better scores than dopamine agonist treatment on the primary PDQ‐39 mobility outcome, and other patient‐related outcome measures, including ADL and overall quality of life as measured by the PDQ‐39 and EQ‐5D quality of life measures. Patient developed more involuntary

movements in L‐dopa group.

Poewe 2011 [4, 28‐30] 1ry ref: Poewe 2011 [4]

Pramipexole ER and Pramipexole IR both up to 4.5 mg/day

Placebo

7‐week flexible titration, dose escalation up to 4.5 mg once daily (ER) and 1.5 mg 3 times daily (IR) as tolerated to a response level judged satisfactory by the investigator and at which the patients rated themselves a "little better" on PGI‐I. Maintenance phase of up to 26 weeks at this dose level.

For patients who experienced increased parkinsonism during the maintenance period open label adjunct levodopa was permitted as rescue medication. These subjects were allowed to stay in the trial but their efficacy data was censored after the last assessment before levodopa rescue.

Both pramipexole formulations showed a significant decrease in mean change in UPDRS (motor + ADL) scores (p=

mg/day) permitted this level was kept for entire 24 week maintenance phase. Dose reduction by 1 level for patients on pardoprunox ≥18 mg/day was permitted if required. Total duration 31 weeks followed by 4 day down titration during 1 week follow‐up.

study. number of drop‐outs due to treatment emergent AE’s (44% versus placebo 8%) and also the overall incidence of these.

Vermeer 2011 [7, 35] 1ry ref: Sampaio 2011 [7]

Pardoprunox flexible dose (12‐42 mg/day) and Pramipexole flexible dose (1.5‐4.5 mg/day)

Placebo

Titration took place over a 4‐7 week period. In flexible dose groups, individual dose adjustments were allowed from week 4 of titration phase, doses above 12 mg/day for pardoprunox and above 1.5 mg/day for pramipexole, in order to find the optimal dose. A decrease by 1 dose level was permitted and this dose level was kept for the entire 24 week maintenance phase with dose reduction by 1 level for patients on pardoprunox ≥18 mg/day or pramipexole ≥2.25 mg/day permitted if required. Total duration 31 weeks followed by 7 day down titration during 1 week follow‐up.

With the exception of levodopa and dopamine agonists (which must have been terminated ≥ 90 days prior to baseline), anti‐PD medication was allowed, with doses stabilised ≥28 days prior to baseline and during the study.

Both pardoprunox and pramipexole showed significantly superior improvements in UPDRS motor score compared to placebo but the difference in PDQ‐39 scores was not significant for either drug. Drop‐out rates due to treatment emergent AE’s were 46%, 15% and 7% for pardoprunox, pramipexole and placebo respectively.

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Appendix 1 1‐10 RCT sensitivity and precision maximising filter as described in section 6.4.11 of The Cochrane Handbook of Systematic Reviews of Interventions. 11 exp Parkinson Disease/ or Parkinson*.mp. 12 exp Dopamine Agonists/ 13 dopamine agonist*.mp. 14 expBromocriptine/ or bromocriptine*.mp. 15 Parlodel*.mp. 16 ropinirole*.mp. 17 Adartrel*.mp. 18 Requip*.mp. 19 Spiroco*.mp. 20 Ralnea*.mp. 21 cabergoline*.mp. 22 cabaser*.mp. 23 expLisuride/ or lisuride*.mp. 24 dopergin*.mp. 25 Proclacam*.mp. 26 Revanil*.mp. 27 expPergolide/ or pergolide*.mp. 28 expPiribedil/ or piribedil*.mp. 29 trivastal*.mp. 30 pronoran*.mp. 31 Trivastan*.mp. 32 trastal*.mp. 33 alpha‐dihydroergotamine*.mp. 34 alpha DHEC*.mp. 35 "CQA 206‐291*".mp. 36 Pramipexole.mp. 37 Mirapexin*.mp. 38 rotigotine.mp. 39 neupro*.mp. 40 Pardoprunox.mp. 41 "SLV‐308*".mp. 42 "SME‐308*".mp. 43 aplindore.mp. 44 "DAB‐452*".mp. 45 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 (32191) 46 10 and 11 and 45 47 limit 46 to yr="2007 ‐Current"

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Annex B International availability and proprietary names of DAs *

** According to the 36th edition of Martindale, the drug is still marketed in the countries listed in the table. Though, accessing the individual national drug agencies of most countries, the drug seems to be unavailable also in some of the countries included in the table.

International availability of dopamie agonists (Source: Martindale 36th edition) Medicine Country and trade name Bromocriptine Argentina: Parlodel; Serocryptin¤; Australia: Bromohexal; Bromolactin¤; Kripton; Parlodel; Austria: Antipark¤; Broman¤; Bromed; Cehapark; Maylaktin¤;

Parlodel; Umprel; Belgium: Parlodel; Brazil: Bagren; Parlodel; Canada: Parlodel; Chile: Criten; Grifocriptina; Kriptonal; Parlodel; Prigost; Czech Republic: Medocriptine; Parlodel; Serocryptin¤; Denmark: Bromergon¤; Bromopar¤; Parlodel; Finland: Parlodel; France: Bromo-Kin; Parlodel; Germany: Bromocrel¤; kirim gyn; kirim; Pravidel; Greece: Parlodel; Hong Kong: Bromtine; Medocriptine; Parlodel; Serocryptin¤; Zolac¤; Hungary: Serocryptin¤; India: Sicriptin; Indonesia: Cripsa; Parlodel; Ireland: Parlodel; Israel: Parilac; Parlodel; Italy: Parlodel; Serocryptin¤; Japan: Parlodel¤; Malaysia: Butin¤; Criptamine¤; Medocriptine; Parlodel; Zolac¤; Mexico: Broptin; Crilem; Cryocriptina; Inovapar¤; Kriptiser; Lactess¤; Mesiken; Parlodel; Serocryptin¤; Netherlands: Parlodel; Norway: Parlodel; New Zealand: Parlodel¤; Philippines: Parlodel; Provasyn; Poland: Bromergon; Bromocorn; Ergolaktyna; Parlodel; Portugal: Parlodel; Russia: Bromergon (Бромэргон); Parlodel (Парлодел); South Africa: Parlodel; Singapore: Butin¤; Parlodel; Serocryptin¤; Suplac¤; Spain: Lactismine¤; Parlodel; Sweden: Pravidel; Switzerland: Parlodel; Serocryptin¤; Thailand: Brocaden; Bromergon; Parlodel; Serocryptin¤; Suplac; Turkey: Gynodel; Parlodel; United Arab Emirates: Antiprotin; United Kingdom: Parlodel; United States: Parlodel; Venezuela: Parlodel; Serocryptin

Cabergoline # Argentina: Cabaser; Caberpar; Cieldom; Dostinex; Lac Stop; Lactamax; Triaspar; Australia: Cabaser; Dostinex; Austria: Cabaseril; Dostinex; Belgium: Dostinex; Sostilar; Brazil: Dostinex; Canada: Dostinex; Chile: Dostinex; Czech Republic: Cabera; Dostinex; Denmark: Cabaser; Dostinex; Finland: Cabaser; Dostinex; France: Dostinex; Germany: Cabaseril; Dostinex; Greece: Dostinex; Hong Kong: Dostinex; India: Caberlin; Camforte¤; Ireland: Cabaser; Dostinex; Israel: Cabaser; Dostinex; Italy: Actualene; Cabaser; Dostinex; Malaysia: Dostinex; Mexico: Dostinex; Netherlands: Dostinex; Norway: Cabaser; Dostinex; New Zealand: Dostinex; Poland: Dostinex; Portugal: Dostinex; Russia: Dostinex (Достинекс); South Africa: Dostinex; Singapore: Dostinex; Spain: Dostinex; Sogilen; Sweden: Cabaser; Dostinex; Switzerland: Cabaser; Dostinex; Turkey: Cabaser; Dostinex; United Kingdom: Cabaser; Dostinex; United States: Dostinex¤; Venezuela: Dostinex

Dihydro-ergocryptine mesylate **

Germany: Almirid; Cripar; Italy: Daverium; Myrol¤; Mexico: Diamin; Poland: Almirid; Portugal: Striatal; Russia: Vasobral (Вазобрал)

Pergolide § Argentina: Aroltex; Breator¤; Celance; Geranil¤; Parlide¤; Brazil: Celance; Chile: Celance¤; France: Celance; Germany: Parkotil; Greece: Celance; Hong Kong: Celance¤; Hungary: Parkotil¤; Ireland: Celance; Poland: Hizest¤; Portugal: Permax; Singapore: Celance¤; Spain: Pharken; Thailand: Celance¤

Pramipexole Argentina: Maxtenk; Mirapex¤; Nixol; Parfeno; Parxium; Portiv; Sifrol; Australia: Sifrol; Austria: Sifrol; Belgium: Mirapexin; Brazil: Mirapex; Sifrol; Canada: Mirapex; Chile: Sifrol; Czech Republic: Mirapexin; Sifrol; Denmark: Mirapexin; Sifrol; Finland: Sifrol; France: Sifrol; Germany: Sifrol; Greece: Mirapexin; Hungary: Mirapexin; Indonesia: Sifrol; Ireland: Mirapexin; Italy: Mirapexin; Japan: BI-Sifrol; Malaysia: Sifrol; Mexico: Sifrol; Netherlands: Daquiran¤; Sifrol; Norway: Sifrol; New Zealand: Sifrol; Philippines: Sifrol; Poland: Mirapexin; Portugal: Mirapexin; Sifrol; Russia: Mirapex (Мирапекс); South Africa: Pexola; Singapore: Sifrol; Spain: Mirapexin; Sweden: Sifrol; Switzerland: Sifrol; Thailand: Sifrol; Turkey: Pexola; United Kingdom: Mirapexin; United States: Mirapex; Venezuela: Sifrol/Mirapex;

Ropinirole Argentina: Requip; Australia: Repreve; Austria: Requip; Belgium: Requip; Canada: Requip; Chile: Requip; Czech Republic: Adartrel; Requip; Denmark: Requip; Finland: Requip; France: Adartrel; Requip; Germany: Requip; Greece: Adartrel; Requip; Hong Kong: Requip; Hungary: Requip; Ireland: Requip; Israel: Requip; Italy: Requip; Malaysia: Requip; Netherlands: Requip; Norway: Requip; New Zealand: Requip; Poland: Requip; Portugal: Requip; Zyatrol; South Africa: Requip; Singapore: Requip; Spain: Requip; Sweden: Requip; Switzerland: Adartrel; Requip; Turkey: Requip; United Kingdom: Adartrel; Requip; United States: Requip;

December 1, 2014

§ Pergolide marketed as Permax ® has been withdrawn in these countries: Australia; Belgium; Canada; Czech Republic; Denmark; Finland; Mexico; Netherlands; New Zealand; South Africa; Switzerland; Turkey. (Micromedex- Drug summary Last Modified: August 08, 2014). In the US pergolide is no more available for the treatment of PD. Pergolide drug products were voluntarily removed from the market by the manufacturer on March 29, 2007 due to safety concerns of an increased risk for serious heart valve damage in patients taking pergolide for PD. (FDA pergolide) # In the US cabergoline is no more available for the treatment of PD; the drug is only available as 0.5 mg tablets that have the following indication: “treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas”. (FDA cabergoline) International availability of DAs as reported in the Drug Master File (DMF), Food and Drug administration * (as of 3Q 2014EXCEL) * DMF# SUBMIT DATE HOLDER SUBJECT

6955 11/05/1987 EUTICALS SPA BROMOCRIPTINE MESYLATE AS MFG IN MILAN ITALY;

7088 24/07/1987 LABOCHIM BROMOCRIPTINE MESYLATE AS MFG IN MILAN, ITALY 14768 03/03/2000 TEVA PHARMACEUTICAL INDUSTRIES LTD BROMOCRIPTINE MESYLATE AS MFG IN OPAVA CZECH REPUBLIC

6984 08/05/1987 CHEMAPOL LTD BROMOCRIPTINE MESYLATE MANUFACTURED BY GALENA IN CZECHOSLOVAKIA. 11973 06/05/1996 GALENA AS BROMOCRIPTINE MESYLATE MANUFACTURED IN OPAVA, CZECH REPUBLIC.

10679 15/12/1993 CHEMICAL PHARMACEUTICAL RESEARCH INSTITUTE NIHFI LTD BROMOCRIPTINE MESYLATE MANUFACTURED IN SOFIA, BULGARIA.

6737 16/12/1986 GEDEON RICHTER LTD BROMOCRIPTINE MESYLATE USP AS MFG. IN BUDAPEST, HUNGARY 6827 13/02/1987 LEK PHARMACEUTICALS DD BROMOCRIPTINE MESYLATE USP AS MFG. IN MENGES, SLOVENIA 7533 23/05/1988 ANTIBIOTICOS SPA CABERGOLINE ACTIVE DRUG SUBSTANCE AS MFG. IN MILANO, ITALY

18199 21/03/2005 GEDEON RICHTER PLC CABERGOLINE AS MANUFACTURED IN BUDAPEST AND DOROG, HUNGARY. 18113 21/02/2005 TEVA PHARMACEUTICAL INDUSTRIES LTD CABERGOLINE AS MANUFACTURED IN OPAVA, CZECH REPUBLIC. 15933 18/03/2002 IVAX CR CABERGOLINE AS MANUFACTURED IN OPAVA-KOMAROV, CZECH REPUBLIC 23918 29/12/2010 APICORE US LLC CABERGOLINE AS MANUFACTURED IN SOMERSET NJ 15423 30/04/2001 FINETECH PHARMACEUTICAL LTD CABERGOLINE AS MFG IN NESHER, ISRAEL 18972 25/11/2005 RESOLUTION CHEMICALS LIMITED CABERGOLINE DRUG SUBSTANCE AS MANUFACTURED IN HERTFORDSHIRE, UNITED KINGDOM.

7534 23/05/1988 ANTIBIOTICOS SPA CABERGOLINE FINISHED DOSAGE AS MFG. IN MILANO ITALY 26235 13/07/2012 APOTEX PHARMACHEM INDIA PVT LTD CABERGOLINE USP AS MANUFACTURED IN BANGALOR, INDIA 22620 13/03/2009 APOTEX PHARMACHEM INDIA PVT LTD CABERGOLINE USP AS MANUFACTURED IN BANGALORE INDIA 15180 06/12/2000 GALENA AS PERGOLIDE MESYLATE AS MANUFACTURED IN CZECH REPUBLIC

24323 28/10/2010 TEVA PHARMACEUTICAL INDUSTRIES LTD PERGOLIDE MESYLATE AS MANUFACTURED IN OPAVA-KOMAROV CZECH REPUBLIC FOR TEVA PHARMACEUTICAL INDUSTRIES LTD

17982 12/01/2005 OLON SPA PERGOLIDE MESYLATE AS MANUFACTURED IN RODANO (MI), ITALY. 15013 24/08/2000 BACHEM SA PERGOLIDE MESYLATE AS MFG IN VIONNAZ, SWITZERLAND 20330 07/03/2007 PERRIGO API LTD PRAMIPEXOLE BASE AS MANUFACTURED IN BEER SHEVA ISRAEL 19853 10/10/2006 HETERO DRUGS LTD PRAMIPEXOLE DIHYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH INDIA

22860 28/08/2009 ORCHID CHEMICALS AND PHARMACEUTICALS LTD PRAMIPEXOLE DIHYDROCHLORIDE AS MANUFACTURED IN MAHARASHTRA INDIA

21082 28/11/2007 SANDOZ PRIVATE LTD PRAMIPEXOLE DIHYDROCHLORIDE AS MANUFACTURED IN MAHASHTRA, INDIA

December 1, 2014

22209 17/11/2008 NURAY CHEMICALS PVT LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE (NON-STERILE BULK DRUG SUBSTANCE) AS MANUFACTURED IN TAMIL NADU, INDIA

23900 22/06/2010 MSN LABORATORIES LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE [ROUTE CODE PP] AS MANUFACTURED IN ANDHRA PRADESH, INDIA

21095 30/11/2007 APOTEX PHARMACHEM INDIA PVT LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED BY APOTEX PHARMACHEM INDIA PVT LTD IN KARNATAKA, INDIA FOR APOTEX PHARMACHEM INC

22789 15/05/2009 AUROBINDO PHARMA LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN ANDHRA PRADESH INDIA 20116 03/01/2007 PERRIGO API LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN BE'ER SHEVA ISRAEL 21791 11/07/2008 CRYSTAL PHARMA SAU PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN BEOCILLO (VALLADOLID), SPAIN 20130 08/01/2007 CADILA HEALTHCARE LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN GUJARAT INDIA 18836 06/10/2005 ALEMBIC PHARMACEUTICALS LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN GUJARAT, INDIA.

21413 12/03/2008 BOEHRINGER INGELHEIM PHARMA GMBH AND CO KG PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN INGELHEIM AM RHEIN, GERMANY

18297 21/04/2005 AMINO CHEMICALS LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE AS MANUFACTURED IN MARSA, MALTA. 21631 19/05/2008 TORRENT PHARMACEUTICALS LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE DRUG SUBSTANCE AS MANUFACTURED IN GUJARAT, INDIA

24331 25/10/2010 ERREGIERRE SPA PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE PH EUR AS MANUFACTURED IN SAN PAOLO D'ARGON (BG) ITALY

23163 07/10/2009 MACLEODS PHARMACEUTICALS LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE USP (EUSB) AS MANUFACTURED IN GUJARAT INDIA 25907 30/03/2012 UNICHEM LABORATORIES LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE USP AS MANUFACTURED IN DIST. RAIGAD, INDIA 21899 25/10/2008 SUN PHARMACEUTICAL INDUSTRIES LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE USP AS MANUFACTURED IN GUJARAT, INDIA 18701 25/08/2005 CIPLA LTD PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE USP AS MANUFACTURED IN MAHARASHTRA, INDIA. 24781 23/06/2011 WOCKHARDT LTD PRAMIPEXOLE DIHYDROCHLORIDE USP AS MANUFACTURED IN GUJARAT, INDIA 21712 28/05/2008 MYLAN LABORATORIES LTD PRAMIPEXOLE DIHYDROCHLORIDE USP AS MANUFACTURED IN MAHARASHTRA 26414 14/09/2012 NEULAND LABORATORIES LTD ROPINIROLE AS MANUFACTURED IN ANDHRA PRADESH, INDIA

21938 18/10/2008 ORCHID CHEMICALS AND PHARMACEUTICALS LTD ROPINIROLE HYDROCHLORIDE (NON-STERILE BULK API) AS MANUFACTURED IN MAHARASHTRA, INDIA

18412 09/06/2005 DR REDDYS LABORATORIES LTD ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH, INDIA. 19590 10/07/2006 NEULAND LABORATORIES LTD ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN ANDHRA PRADESH, INDIA. 17880 08/12/2004 URQUIMA SA ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN BARCELONA, SPAIN. 19933 18/08/2006 CADILA PHARMACEUTICALS LTD ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA 20593 12/06/2007 GLENMARK GENERICS LTD ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN GUJARAT INDIA 21331 07/02/2008 WATSON PHARMA PRIVATE LTD ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN MAHARASHTRA, INDIA 19045 19/12/2005 USV LIMITED ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN MAHARASHTRA, INDIA. 18564 30/07/2005 IND SWIFT LABORATORIES LTD ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN PUNJAB, INDIA 19198 22/02/2006 PCAS ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN TURKU, FINLAND. 20829 25/04/2007 ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD ROPINIROLE HYDROCHLORIDE AS MANUFACTURED IN ZHEJIANG, CHINA 18777 14/09/2005 TORRENT PHARMACEUTICALS LTD ROPINIROLE HYDROCHLORIDE DRUG SUBSTANCE AS MANUFACTURED IN GUJARAT, INDIA. 19780 11/09/2006 ALEMBIC PHARMACEUTICALS LTD ROPINIROLE HYDROCHLORIDE, USP AS MANUFACTURED IN GUJARAT INDIA

7513 07/06/1988 NOVARTIS PHARMACEUTICALS CORP STARTING MATERIALS 1 & 3, IN NEW JERSEY AND SWITZERLAND

December 1, 2014

In the US cabergoline and pergolide are no more available for the treatment of PD. Pergolide drug products were voluntarily removed from the market by the manufacturer on March 29, 2007 due to safety concerns of an increased risk for serious heart valve damage in patients taking pergolide for PD. Cabergoline is only available as 0.5 mg tablets that have the following indication: “treatment of hyperprolactinemic disorders, either idiopathic or due to pituitary adenomas”. (FDA pergolide, FDA cabergoline)

December 1, 2014

Annex C Indications for use of DAs

Medicine Indications Parkinson ‘s Disease Other conditions different from Parkinson’s Disease

Bromocriptine ITA, UK, US, China*, Sudan*, Marocco*, India*

Acromegaly (US, ITA, UK) Female infertility - In vitro fertilization (US: indication not labeled as a therapeutic use) Female infertility of pituitary - hypothalamic origin – Hyperprolactinemia (US, ITA, UK) Hyperprolactinemia (US, ITA, UK) Non-pregnancy related A-G syndrome (US, ITA, UK) Prolactinoma (US, ITA, UK) Type 2 diabetes mellitus (US) Inhibition of lactation (UK) Menstrual cycle disorders (ITA, UK)

Cabergoline ITA, UK Hyperprolactinemia (US, ITA, UK) Acromegaly (US: indication not labeled as a therapeutic use) Erectile dysfunction (US: indication not labeled as a therapeutic use) Lactation suppression, Puerperal (ITA, UK) Restless legs syndrome, Idiopathic (US: indication not labeled as a therapeutic use)

Dihydroergocryptine Mesilate

ITA#, Germany*, Mexico**, Poland*, Portugal*; Russia**, China* Hyperprolactinemia (ITA)

Pergolide § Acromegaly (no FDA) Cocaine withdrawal (no FDA) Depression (no FDA) Gilles de la Tourette's syndrome (no FDA) Hyperprolactinemia (no FDA) Restless legs syndrome (no FDA) Supranuclear paralysis (no FDA)

Pramipexole ITA, UK, US, China* Restless legs syndrome (Moderate to Severe) (ITA, UK, US) Ropinirole ITA, UK, US, China* Restless legs syndrome Moderate to Severe (UK, US) # ITA: Available until end of supply; * Indications not available from national drug database; ** National drug database not available on-line § Pergolide is not available in most developed countries, where drug databases are available on-line. Countries where drug databases are not available for on-line access have not been assessed.

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* National Regulatory Agencies’ Databases

The information summarized in the tables of Annexes … and … has been retrieved from the following on-line drug databases [all accessed on November 25,

2014]:

UK - https://www.medicines.org.uk/emc/; http://www.nhs.uk/medicine-guides/pages/selectorshow.aspx?medicine=Aliskiren

ITA - www.codifa.it; Compendio Farmaceutico Ospedaliero (Farmadati); http://www.agenziafarmaco.gov.it/

USA - http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Czech Republic - http://www.sukl.eu/modules/medication/search.php

France - http://www.ansm.sante.fr/

Germany - http://www.bfarm.de/DE/Home/home_node.html

Greece - http://www.eof.gr/web/guest;jsessionid=6de1cb917905ddaf468c14709d7c

Ireland - http://www.hpra.ie/

Poland - http://en.urpl.gov.pl/general-information

Portugal - http://www.infarmed.pt/infomed/pesquisa.php

Spain - http://www.aemps.gob.es/medicamentosUsoHumano/portada/home.htm

Switzerland - https://www.swissmedic.ch/arzneimittel/00156/00221/00222/00230/index.html?lang=en

Marocco - http://www.assurancemaladie.ma/anam.php?id_espace

Sudan - http://www.nmpb.gov.sd/drugsearch.php

India - http://www.nppaindia.nic.in/index1.html; http://www.tnmsc.com/tnmsc/new/index.php

China -

http://app1.sfda.gov.cn/datasearcheng/face3/base.jsp?tableId=85&tableName=TABLE85&title=Database%20of%20approved%20Active%20Pharmaceutical

%20Ingredients%20(APIs)%20and%20API%20manufacturers%20in%20China&bcId=136489131226659132460942000667

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Annex D Results of the search strategy and process of inclusion Clinical Guidelines Systematic Reviews

Citations excluded: 22 - 4 focused on transdermal DAs - 18 topic not pertinent

Relevant SRs included in this document: 10

Documents excluded: 12 - 7 not systematic reviews - 1 low quality (mixing RCTs with observational non-controlled studies) - 2 relevant conflict of interest issues - 1 full text version in German - 1 search date superseded by one of the selected reference SRs (Stowe 2010)

Citations excluded: 83

Documents excluded: 6 (not pertinent or duplicated)

Relevant clinical guidelines included in this document: 7

Potentially relevant citations identified and screened for retrieval: 96 (AAN=1; EFNS=2; HAS=1; ISS=1; MDS=1; NGC=88; NICE=1; SIGN=1)

Potentially relevant documents retrieved for evaluation: 13 (AAN=1; EFNS=2; HAS=1; ISS=1; MDS=1; NGC=5; NICE=1; SIGN=1)

Potentially relevant documents retrieved for evaluation: 22

Potentially relevant citations identified and screened for retrieval: 44

December 1, 2014

Annex E Summary of the recommendations on the use of DAs from international guidelines on PD. Use of DAs in the treatment of PD: synopsis of the recommendations from guidelines.

DAs offered as mono therapy DAs offered as add-on therapy with L-dopa

NICE 2006 Early PD

Dopamine agonists may be used as a symptomatic treatment for people with early PD. [A]

A dopamine agonist should be titrated to a clinically efficacious dose. If side effects prevent this, another agonist or a drug from another class should be used in its place. [D (GPP)]

If an ergot-derived dopamine agonist is used, the patient should have a minimum of renal function tests, erythrocyte sedimentation rate (ESR) and chest radiograph performed before starting treatment, and annually thereafter. [D (GPP)]

In view of the monitoring required with ergot-derived dopamine agonists, a non-ergotderived agonist should be preferred in most cases. [D (GPP)]

…

NICE 2006 Advanced PD …

Dopamine agonists may be used to reduce motor fluctuations in people with later PD. [A]

If an ergot-derived dopamine agonist is used, the patient should have a minimum of renal function tests, ESR and chest radiograph performed before starting treatment and annually thereafter. [D (GPP)]

A dopamine agonist should be titrated to a clinically efficacious dose. If side effects prevent this, then another agonist or a drug from another class should be used in its place. [D (GPP)]

In view of the monitoring required with ergot-derived dopamine agonists, a nonergot-derived agonist should be preferred in most cases. [D (GPP)]

SIGN 2010 Early PD

Patients with early Parkinson’s disease and motor symptoms may be considered for treatment with oral/transdermal dopamine agonists. [A]

Ergot derived dopamine agonists should not be used as first line treatment for Parkinson’s disease. [B] When an ergot derived dopamine agonist is used patients should undergo: 1. baseline echocardiographic screening and regular follow up scans to identify cardiac abnormalities; 2.baseline laboratory and radiological investigations with regular follow up surveillance to identify serosal fibrosis.

Patients should be warned about the potential for dopamine agonists to cause impulse control disorders and excessive daytime somnolence and be informed of the implications for driving/operating machinery. [A] Healthcare professionals should discuss impulse control disorders with patients with Parkinson’s disease who are taking dopamine agonists.

…

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SIGN 2010 Advanced PD … Dopamine agonists (oral or transdermal) may be considered for the management of

motor complications1 in patients with advanced Parkinson’s disease. The non-ergot agonists (ropinirole, pramipexole, and rotigotine) are preferable to the ergot agonists. [A]

AMDA 2010 (AHRQ 2010) Early PD

Step 13. Implement appropriate pharmacologic interventions. Pharmacotherapy should be combined with nonpharmacologic therapy (e.g., education, exercise, social support, nutrition). Input from a consultant pharmacist is encouraged. Levodopa combined with carbidopa has long been considered the gold standard for treating PD. Dopamine agonists or monoamine oxidase inhibitors (e.g., rasagiline, selegiline) are considered an appropriate first-line therapy for younger patients. In younger patients, because of the risk of developing levodopa-associated motor complications, initiation of levodopa may be reserved for later in the course of PD.2

Side effects from dopamine agonists include confusion, hallucinations, hypotension, impulse control disorders, memory impairment, nausea and vomiting, and excessive daytime sedation. Patients over age 70 or those with dementia are at higher risk for side effects from dopamine agonists.3

…

AMDA 2010 Errore. Il segnalibro non

è definito. (AHRQ 2010)

Advanced PD … …

HAS 2014 Early PD

Lorsque la gêne est minime, peuvent être utilisés en fonction du symptôme prédominant et de l’âge: […] Des agonistes dopaminergiques. […]

Lorsqu’il existe un retentissement fonctionnel, l’âge du patient conditionne le traitement: chez le sujet jeune (moins de 65 ans), privilégier les agonistes dopaminergiques, le plus longtemps possible. […]

…

1 This statement, included in the Quick reference leaflet, is slightly different from the one in the Full Report/Summary of Recommendations, stating: “Dopamine agonists (oral or transdermal) may be considered for the management of complications in patients with advanced Parkinson’s disease.” The term “Motor complications” is also featured in the Full Text Key Recommendations. 2 Text from “Recommendations (Major Recommendations)” section. For grading schemes see “Summary_Grading.doc”. 3 This statement this is not a recommendation, being listed in the section “Benefits/Harms of Implementing the Guideline Recommendations”.

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HAS 2014 Advanced PD …

En 1ere intention : Les agonistes dopaminergiques en administration orale ou transdermique:

- non derives de l’ergot de seigle en premiere intention: ropinirole, piribedil pramipexole, rotigotine (dispositif transdermique). - agonistes derives de l’ergot de seigle («ergopeptines») qui demandent une surveillance cardiaque annuelle par echocardiographie (risque de survenue de valvulopathies): bromocriptine, lisuride;

AAN 2006 Early PD … …

AAN 2006 Advanced PD …

Patients with motor fluctuations: Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce

off time (Level B). Tolcapone (hepatotoxicity) and pergolide (valvular fibrosis) should be used with caution and require monitoring.

Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level c).

Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C)

Ropinirole may be chosen over bromocriptine for reducing off time (Level C). Otherwise, there is insufficient evidence to recommend one agent over another

(Level U).

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EFNS 2011 Early PD

Drug Symptomatic control of parkinsonism Prevention of motor

complications Bromocriptineb Effective (level B) Effective (level B) Cabergolineb Effective (level B) Effective (level A) Dihydroergocryptineb Effective (level A) No recommendationc Lisurideb Effective (level B) Effective (level C) Pergolideb Effective (level A) Effective (level B) Piribedil Effective (level C) No recommendationc Pramipexole Effective (level A) Effective (level A) Pramipexole CRe Effective (level A) Not available Ropinirole Effective (level A) Effective (level A) Ropinirole CRe Effective (level A) No recommendation

b Ergot derivates cannot be recommended as a first-line treatment because of the risk of valvular heart disorder. c No recommendation can be made because of insufficient data. e Controlled release. Practical recommendations for the treatment of early untreated PD

The choice of drug depends on the impact of improving motor disability (better with levodopa) compared with the risk of motor complications (more common in younger patients, delayed by agonists) and neuropsychiatric complications (more common in older and cognitively impaired patients; greater with agonists) o Oral or transdermal dopamine agonist.4

Pramipexole, piribedil, ropinirole and rotigotine are effective (Level A). Initial treatment with an agonist can be recommended in younger patients (GPP). Ergot derivatives are not recommended as first-line medication because of the risk of fibrotic reactions

Practical recommendations for the adjustment of initial therapy in patients without motor complications5 o Patients not on dopaminergic therapy

If a patient has started on an MAO-B inhibitor, anticholinergic, amantadine or a combination of these, a stage will come when there is a requirement for adding levodopa or a dopamine agonist (GPP)

o Patients on dopaminergic therapy If on dopamine agonist therapy: Increase the dose (GPP) Switch between agonists (Level C) Add levodopa (GPP) If on levodopa: Increase the dose (GPP) Add an agonist (GPP) Add a COMT inhibitor (GPP)

4 In the original GL: orally active dopamine agonist. Pramipexole, piribedil, and ropinirole immediate ‐ or controlled ‐ release are effective as monotherapy in early PD (Level A), with a lower risk of motor complications than levodopa for pramipexole or ropinirole (Level A). Older drugs like bromocriptine are supported by lower class evidence, giving a Level B recommendation. However, there is no convincing evidence that they are less effective in managing patients with early PD. The benefit of agonists in preventing motor complications (Level A, with data up to 5 years only) must be balanced with the smaller effect on symptoms and the greater incidence of hallucinations, impulse ‐ control disorders, somnolence, and leg oedema, as compared with levodopa. Patients must be informed of these risks, e.g. excessive daytime somnolence is especially relevant to drivers. Younger patients are more prone to developing levodopa ‐ induced motor complications, and therefore initial treatment with an agonist can be recommended in this population (GPP). Ergot derivatives such as pergolide, bromocriptine, and cabergoline are not recommended as first – line medication because of the risk of fibrotic reactions. Rotigotine is administered transdermally using a patch and ropinirole CR once daily orally, as opposed to the other agonists that are administered orally three times a day. Subcutaneous apomorphine is not appropriate at this stage of the disease. The early combination of low doses of a dopamine agonist with low doses of levodopa is another option, although the benefits of such a combination have not been properly documented. 5 In the original GL: If on dopamine agonist therapy: • increase the dopamine agonist dose (GPP). However, even when the dopamine agonist dose is increased over time, it cannot control parkinsonian symptoms for more than about 3 – 5 years of follow ‐ up in most patients; • switch between dopamine agonists (Level C); • add levodopa (GPP). If on levodopa: • increase the levodopa dose (GPP); • add a dopamine agonist (GPP), although the efficacy of adding an agonist has been insufficiently evaluated; • add a COMT ‐ inhibitor to levodopa at the transition of a non ‐ fluctuating to a fluctuating status, i.e. if motor fluctuations evolve (GPP) – preferably in older patients and multimorbid patients of any age.

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EFNS 2011 Advanced PD …

Motor fluctuations Add dopamine agonists: non-ergot dopamine agonists are first-line compounds.

Dopamine agonists reduce OFF time. None has proven superior, but switching from one agonist to another can be helpful (Level B/C)6

Dyskinesias Reduce levodopa dose, at the risk of increasing OFF. The latter can be compensated

for by increasing the number of doses or a dopamine agonist (Level C)7 Off-period and early-morning dystonias Additional doses of levodopa or dopamine agonist at night may be effective (GPP)8

6 In the original GL: Add dopamine agonists. Non ‐ ergot dopamine agonists are first ‐ line compounds. Pergolide and other ergot agonists are reserved for second ‐ line treatment, due to their association with lung, retroperitoneal, and heart valve fibrosis. Oral dopamine agonists are efficacious in reducing OFF time in patients experiencing wearing ‐ off. Currently, no dopamine agonist has proven better than another, but switching from one agonist from one agonist to another can be helpful in some patients (Level B/C). 7 In the original GL: Reduce individual levodopa dose size , at the risk of increasing OFF time. The latter can be compensated for by increasing the number of daily doses of levodopa or increasing the doses of a dopamine agonist (Level C). 8 In the original GL: Additional doses of levodopa or dopamine agonist therapy at night may be effective for the control of dystonia appearing during the night or early in the morning (GPP).

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MDS, 20119, 10 Early PD

Efficacy

Drug Prevention/delay of clinical progression Symptomatic monotherapy

Piribedil Insufficient evidence Efficacious Pramipexole Insufficient evidence Efficacious Pramipexole (ER*) Insufficient evidence Efficacious Ropinirole Insufficient evidence Efficacious Ropinirole (PR**) Insufficient evidence Likely efficacious Bromocriptine Insufficient evidence Likely efficacious Cabergoline Insufficient evidence Efficacious Dihydroergocryptine Insufficient evidence Efficacious Lisuride Insufficient evidence Likely efficacious Pergolide Unlikely efficacious Efficacious

Practice implications

Drug Prevention/delay of clinical progression Symptomatic monotherapy

Piribedil Investigational Clinically useful Pramipexole Investigational Clinically useful Pramipexole (ER*) Investigational Clinically useful Ropinirole Investigational Clinically useful Ropinirole (PR**) Investigational Possibly useful Bromocriptine Investigational Possibly useful Cabergoline Investigational Clinically useful Dihydroergocryptine Investigational Clinically useful Lisuride Investigational Possibly useful Pergolide Unlikely useful Clinically useful

* extended release ** prolonged release

Efficacy Drug Symptomatic adjunct to levodopa

Piribedil Efficacious Pramipexole Efficacious Pramipexole (ER*) Efficacious Ropinirole Efficacious Ropinirole (PR**) Efficacious Bromocriptine Efficacious Cabergoline Efficacious Dihydroergocryptine Insufficient evidence Lisuride Likely efficacious Pergolide Efficacious

Practice implications Drug Symptomatic adjunct to levodopa

Piribedil Clinically useful Pramipexole Clinically useful Pramipexole (ER*) Clinically useful Ropinirole Clinically useful Ropinirole (PR**) Clinically useful Bromocriptine Clinically useful Cabergoline Clinically useful Dihydroergocryptine Investigational Lisuride Possibly useful Pergolide Clinically useful

* extended release ** prolonged release

9 Transdermal (Rotigotine) and Parenteral (Apomorphine) Nonergot Dopamine Agonist were not included in this summary. 10 Safety details were not reported in this summary. For all Oral Nonergot Dopamine Agonists (Piribedil, Pramipexole, Pramipexole (ER*), Ropinirole, Ropinirole (PR**)) Safety is reported as “Acceptable risk without specialized monitoring”. For all Ergot Dopamine Agonists (Bromocriptine, Cabergoline, Dihydroergocryptine, Lisuride, Pergolide) Safety profile is reported as “Acceptable risk with specialized monitoring”.

December 1, 2014


MDS, 20119, 10, Errore. Il segnalibro non è

definito. Advanced PD

Efficacy

Drug Prevention/delay of motor complications Treatment of motor

complications Piribedil Insufficient evidence (F, D) Insufficient evidence (F, D)

Pramipexole Efficacious (F, D) Efficacious (F) Insufficient evidence (D)

Pramipexole (ER*) Insufficient evidence (F, D) Efficacious (F) Insufficient evidence (D)

Ropinirole Insufficient evidence (F) Efficacious (D) Efficacious (F) Insufficient evidence (D)

Ropinirole (PR**) Insufficient evidence (F) Efficacious (D) Efficacious (F) Insufficient evidence (D)

Bromocriptine Insufficient evidence (F) Likely efficacious (D) Likely efficacious (F) Insufficient evidence (D)

Cabergoline Efficacious (F, D) Likely efficacious (F) Insufficient evidence (D) Dihydroergocryptine Insufficient evidence (F, D) Insufficient evidence (F, D) Lisuride Insufficient evidence (F, D) Insufficient evidence (F, D)

Pergolide Insufficient evidence (F) Likely efficacious (D) Efficacious (F) Insufficient evidence (D)

Practice implications

Drug Prevention/delay of motor complications Treatment of motor

complications Piribedil Investigational (F, D) Investigational (F, D)

Pramipexole Clinically useful (F, D) Clinically Useful (F) Investigational (D)

Pramipexole (ER*) Investigational (F, D) Clinically Useful (F) Investigational (D)

Ropinirole Investigational (F), Clinically useful (D) Clinically useful (F), Investigational (D)

Ropinirole (PR**) Investigational (F), Clinically useful (D) Clinically useful (F), Investigational (D)

Bromocriptine Investigational (F), Possibly useful (D) Possibly useful (F), Investigational (D)

Cabergoline Clinically useful (F, D) Possibly useful (F), Investigational (D) Dihydroergocryptine Investigational (F, D) Investigational (F, D) Lisuride Investigational (F, D) Investigational (F, D)

Pergolide Investigational (F), Possibly useful (D) Clinically useful (F), Investigational (D)

* extended release ** prolonged release F = motor fluctuations D = dyskinesia

Early PD= without motor fluctuations; Advanced PD=with motor fluctuations

December 1, 2014

Grading systems adopted in the recommendations summarized above

SIGN 2010

December 1, 2014

NICE 2006

December 1, 2014

AMDA 2010 (AHRQ 2010)

Methods Used to Assess the Quality and Strength of the Evidence: Expert Consensus

Rating Scheme for the Strength of the Evidence: Not applicable

[…]

Methods Used to Formulate the Recommendations: Expert Consensus

Rating Scheme for the Strength of the Recommendations: Not applicable

EFNS 2011

December 1, 2014

AAN 2006

Classification of Evidence for Therapeutic Articles: Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) is/are clearly defined b) exclusion/inclusion criteria are clearly defined c) adequate accounting for drop-outs and cross-overs with numbers sufficiently low to have minimal potential for bias d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-d above OR a RCT in a representative population that lacks one criterion a-d. Class III: All other controlled trials including well-defined natural history controls or patients serving as own controls in a representative population, where outcome assessment is independently assessed or independently derived by objective outcome measurement.* Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion. • Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., bloos tests, administrative outcome data) Classification of Evidence for Prognostic Articles: Class I: Evidence provided by a prospective study of a broad spectrum of persons who may be risk of developing the outcome (e.g. target disease, work status). The study measures the predictive ability using an independent gold standard for case definition. The predictor is measured in an evaluation that is masked to clinical presentation and, the outcome is measured in an evaluation that is masked to the presence of the predictor. All patients have the predictor and outcome variables measured. Class II: Evidence provided by a prospective study of a narrow spectrum of persons at risk for having the condition, or by a retrospective study of a broad spectrum of persons with the condition compared to a broad spectrum of controls. The study measures the prognostic accuracy of the risk factor using an acceptable independent gold standard for case definition. The risk factor is measured in an evaluation that is masked to the outcome. Class III: Evidence provided by a retrospective study where either the persons with the condition or the controls are of a narrow spectrum. The study measures the predictive ability using an acceptable independent gold standard for case definition. The outcome, if not objective, is determined by someone other than the person who measured the predictor. Class IV: Any design where the predictor is not applied in an independent evaluation OR evidence provided by expert opinion or case series without controls. Classification of Recommendations: A=Established as effective, ineffective, or harmful for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.) B=Probably effective, ineffective, or harmful for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.) C=Possibly effective, ineffective, or harmful for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.) U=Data inadequate or conflicting given current knowledge, treatment is unproven.

December 1, 2014

MDS 2011

All Level-I studies were rated for study quality. The study quality score was derived from a list of key methodological topics, according to a published checklist13, relevant for determining the methodological soundness of the trial (Table 3). A percentage score (not absolute values) was calculated for each study and is used as an indicator of the overall quality of the study.

HAS 2014

Not reported.

December 1, 2014

ANNEX F GRADE TABLES

Author(s): Francesco NoninoDate: 2014-11-30Question: Should L-dopa vs L-dopa sparing strategy be used in patients with early PD?Settings: outpatientsBibliography: PD MED Collaborative Group. Long-term eff ectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial Lancet 2014; 384: 1196–205

1 Mean follow up 3 years. Analyses of continuous outocme measures up to 7 years2 The difference is statistically significant in favour of L-dopa, but its value is below the minimum threshold of clinically important difference

Quality assessment No of patients Effect

Quality ImportanceNo of studies Design Risk of bias Inconsistency Indirectness Imprecision

Otherconsiderations

L-dopa

L-dopa sparing strategy

Relative(95%CI)

Absolute

Mobility (self-rated functional status) (follow-up 0-9 years1; measured with: PDQ-39 mobility subscale; range of scores: 0-100; Better indicated by lower values)1 randomised

trialsno serious risk of bias

no serious inconsistency

no serious indirectness

no serious imprecision

none 1092 528 - mean 1.8 higher (0.5 to 3 higher)2

��HIGH

Activities of daily living (self-rated functional status) (follow-up 0-9 years1; measured with: PDQ-39 ADL subscale; range of scores: 0-100; Better indicated by lower values)1 randomised





none 1092 528 - mean 1.9 higher (0.7 to 3 higher)2

��HIGH

Stigma (self-rated functional status) (follow-up 0-9 years1; measured with: PDQ-39 stigma subscore; range of scores: 0-100; Better indicated by lower values)1 randomised





none 1092 528 - mean 1.3 higher (0.2 to 2.3 higher)2

��HIGH

Communication (self-rated functional status) (follow-up 0-9 years1; measured with: PDQ-39 communication subscore; range of scores: 0-100; Better indicated by lower values)1 randomised





none 1092 528 - mean 0.9 higher (0 to 1.8 higher)2

��HIGH

Cognition (self-rated functional status) (follow-up 0-9 years1; measured with: PDQ-39 cognition subscore; range of scores: 0-100; Better indicated by lower values)1 randomised





none 1092 528 - mean 1 higher (0 to 2 higher)2

��HIGH

Bodily discomfort (self-rated functional status) (Copy) (follow-up 0-9 years1; measured with: PDQ-39 cognition subscore; range of scores: 0-100; Better indicated by lower values)1 randomised






��HIGH

PDQ-39 Summary Index (self-rated functional status) (follow-up 0-9 years1; measured with: PDQ-39 overall score; range of scores: 0-100; Better indicated by lower values)1 randomised





none 1092 528 - mean 1 higher (0.3 to 1.7 higher)2

��HIGH

quality-adjusted life-years (QALYs) (follow-up 0-9 years1; measured with: EuroQol EQ-5D14 generic quality-of-life measure; Better indicated by higher values)1 randomised





none 1092 528 - mean 0.03 higher (0.01 to 0.05 higher)

��HIGH

05/12/2014GRADE

Page 1 of 1

Author(s): Francesco NoninoDate: 2014-12-01Question: Should MAOBI vs DA be used in patients with early PD?Settings: outpatientsBibliography: PD MED Collaborative Group. Long-term eff ectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet 2014; 384: 1196–205

1 Mean follow up 3 years. Analyses of continuous outocme measures up to 7 years2 The difference is statistically significant in favour of L-dopa, but its value is below the minimum threshold of clinically important difference

Quality assessment No of patients Effect

Quality ImportanceNo of

studies Design Risk of bias Inconsistency Indirectness ImprecisionOther

considerations MAOBI DARelative

(95%CI)

Absolute

Mobility (self-rated functional status) (follow-up 0-9 years1; measured with: PDQ-39 mobility subscore; range of scores: 0-100; Better indicated by lower values)1 randomised





none 460 632 - mean 1.4 higher (0 to 2.9 higher)

��HIGH

Cognition (self-rated functional status) (follow-up 0-9 years1; measured with: PDQ-39 cognition subscore; range of scores: 0-100; Better indicated by lower values)1 randomised






��HIGH

PDQ-39 Summary index (self-rated functional status) (Copy) (follow-up 0-9 years1; measured with: PDQ-39 overall score; range of scores: 0-100; Better indicated by lower values)1 randomised





none 460 632 - mean 0.8 higher (0 to 1.7 higher)2

��HIGH

05/12/2014GRADE

Page 1 of 1

Author(s): Francesco NoninoDate: 2014-12-05Question: Should DAs vs levodopa be used in patients with early PD?Settings: outpatientsBibliography: Stowe RL, Ives NJ, Clarke C, van Hilten J, Ferreira J, Hawker RJ, Shah L, Wheatley K, Gray R. Dopamine agonist therapy in early Parkinson's disease. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006564

1 Most trials did not provide details about allocation concealment. Unclear how many patients were included in the final analysis.2 High heterogeneity, explained mainly by different trial design (open, single-blinded, double-blinded) 3 publication bias not assessed

Quality assessment No of patients EffectQuality ImportanceNo of

studies DesignRisk of

bias Inconsistency Indirectness ImprecisionOther

considerations DAs LevodopaRelative(95% CI) Absolute

overall patient withdrawal (assessed with: number of patients withdrawn)10 randomised

trialsserious1 serious2 no serious

indirectnessno serious imprecision

none3 571/1253

(45.6%)

334/1135(29.4%)

OR 2.02 (1.7 to 2.4)

300 more per 1000 (from 206 more to 412 more)

��LOW

0% -dyskinesia (follow-up 4 to 120 months; assessed with: number of events)10 randomised

trialsserious1 no serious

inconsistencyno serious indirectness


none3 277/1247

(22.2%)

429/1138(37.7%)

OR 0.45 (0.37 to 0.54)

163 fewer per 1000 (from 131 fewer to 194 fewer)

��MODERATE

dystonia (follow-up 4 to 120 months; assessed with: number of events)7 randomised




none3 193/899(21.5%)

241/794(30.4%)

OR 0.64 (0.50 to 0.81)


��MODERATE

withdrawal due to AEs (assessed with: number of patients withdrawn)8 randomised



none3 256/1159

(22.1%)

98/1047(9.4%)

OR 2.47 (1.96 to 3.11)


��LOW

0% -withdrawal due to lack of efficacy (assessed with: number of patients withdrawn)5 randomised



none3 79/628(12.6%)

23/523(4.4%)

OR 2.93 (1.94 to 4.42)


��LOW

0% -motor fluctuations (follow-up 4 to 120 months; assessed with: number of events)7 randomised




none3 310/892(34.8%)

361/875(41.3%)

OR 0.71 (0.58 to 0.87)


��MODERATE

05/12/2014GRADE

Page 1 of 1

Author(s): Francesco NoninoDate: 2014-12-05Question: Should DAs +/- levodopa vs levodopa be used in persons with early PD?Settings: outpatientBibliography: Stowe RL, Ives NJ, Clarke C, van Hilten J, Ferreira J, Hawker RJ, Shah L, Wheatley K, Gray R. Dopamine agonist therapy in early Parkinson's disease. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006564

1 Most trials did not provide details about allocation concealment. Unclear how many patients were included in the final analysis.2 publication bias not assessed




considerationsDAs +/-

levodopa LevodopaRelative(95% CI) Absolute

oedema (follow-up 3 to 5 years; assessed with: number of events)5 randomised




none2 133/712(18.7%)

35/605(5.8%)

OR 3.68 (02.62 to 5.18)


��MODERATE

constipation (follow-up 6 to 60 months; assessed with: number of events)4 randomised




none2 89/562(15.8%)

53/455(11.6%)

OR 1.59 (1.11 to 2.28)


��MODERATE

dizziness (follow-up 2 to 60 months; assessed with: number of events)6 randomised




none2 153/722(21.2%)

98/615(15.9%)

OR 1.45 (1.09 to 1.92)


��MODERATE

hallucinations (follow-up 2 to 60 months; assessed with: number of events)9 randomised




none2 76/832(9.1%)

35/691(5.1%)

OR 1.69 (1.13 to 2.52)


��MODERATE

nausea (follow-up 6 to 60 months; assessed with: number of events)8 randomised




none2 273/786(34.7%)

191/661(28.9%)

OR 1.32 (1.05 to 1.66)


��MODERATE

insomnia (follow-up 2 to 60 months; assessed with: number of events)5 randomised




none2 127/712(17.8%)

95/605(15.7%)

OR 1.32 (1.05 to 1.66)


��MODERATE

somnolence (follow-up 6 to 60 months; assessed with: number of events)6 randomised




none2 152/760(20%)

92/657(14%)

OR 1.49 (1.12 to 2.00)


��MODERATE

05/12/2014GRADE

Page 1 of 1

Author(s): Francesco NoninoDate: 2014-12-05Question: Should DAs vs placebo be used in patients with advanced PD?Settings: outpatientsBibliography: Stowe R, Ives N, Clarke CE, Deane K; van Hilten, Wheatley K, Gray R, Handley K, Furmston A. Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications. Cochrane Database Syst Rev. 2010 Jul 7;(7):CD00166

1 Most trials did provided details about allocation concealment. Unclear how many patients were included in the final analysis.2 Mean age ranged from 57 to 66 years, while the majority of persons with advanced PD are older. Follow up duration (up to 9 months) short in relation to the natural history of the disease3 significant statistical heterogeneity4 two placebo arms with zero events5 low number of events:14/335 and 3/272. Zero events in one arm of one study




considerations DAs PlaceboRelative(95% CI) Absolute

overall side effects (follow-up 2 to 36 weeks; assessed with: number of events)12 randomised


inconsistencyserious2 no serious

imprecisionnone 907/1166

(77.8%)

616/970(63.5%)

OR 1.52 (1.22 to 1.90)


��LOW

0% -overall patient withdrawal (follow-up 4 to 36 weeks; assessed with: number of events)17 randomised

trialsserio