Purpose of review: To help clinicians optimize the conversion of a patient's Parkinson disease pharmacotherapy from immediate-release carbidopa/levodopa (IR CD/LD) to an extended-release formulation (ER CD/LD). Recent findings: Eleven movement disorders specialists achieved consensus positions on the modification of trial-based conversion guidelines to suit individual patients in clinical practice. Summary: Because the pharmacokinetics of ER CD/LD differ from those of IR CD/LD, modification of dosage and dosing frequency are to be expected. Initial regimens may be based on doubling the patient's preconversion levodopa daily dosage and choosing a division of doses to address the patient's motor complications, e.g., wearing-off (warranting a relatively high ER CD/LD dose, possibly at a lower frequency than for IR CD/LD) or dyskinesia (warranting a relatively low dose, perhaps at an unchanged frequency). Patients should know that the main goal of conversion is a steadier levodopa clinical response, even if dosing frequency is unchanged.

Purpose of review: To help clinicians optimize the conversion of a patient9s Parkinson disease pharmacotherapy from immediate-release carbidopa/levodopa (IR CD/LD) to an extended-release formulation (ER CD/LD). Recent findings: Eleven movement disorders specialists achieved consensus positions on the modification of trial-based conversion guidelines to suit individual patients in clinical practice. Summary: Because the pharmacokinetics of ER CD/LD differ from those of IR CD/LD, modification of dosage and dosing frequency are to be expected. Initial regimens may be based on doubling the patient9s preconversion levodopa daily dosage and choosing a division of doses to address the patient9s motor complications, e.g., wearing-off (warranting a relatively high ER CD/LD dose, possibly at a lower frequency than for IR CD/LD) or dyskinesia (warranting a relatively low dose, perhaps at an unchanged frequency). Patients should know that the main goal of conversion is a steadier levodopa clinical response, even if dosing frequency is unchanged.

A discussion between Dr. Dee Silver and Dr. Richard Trosch provides insight and advice for physicians considering a switch from immediate-release carbidopa-levodopa (IR CD-LD) to RYTARY as a treatment for patients with Parkinson disease (PD). The dialogue describes how they identify patients with PD who may and may not be successful switching to RYTARY, how they approach the conversion process and patient compliance, and how they address some side effects that may occur after patients begin taking RYTARY. The clinicians also discuss their experiences with how long it takes to establish a stable regimen as well as provide general advice regarding conversion from treatment with IR CD-LD to RYTARY.

IPX066 is a multiparticulate extended-release formulation of carbidopa–levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson’s disease (PD).

OBJECTIVE: Summarize the efficacy of IPX066 across three phase 3 clinical trials in Parkinson's disease (PD) BACKGROUND: IPX066 is an investigational, extended-release formulation of carbidopa-levodopa (CD-LD) with an initial absorption rate similar to immediate-release CD-LD (IR), but which also provides an extended duration of therapeutic LD plasma concentrations allowing ~q6h dosing. DESIGN/METHODS: IPX066 was examined in LD-naïve patients (APEX-PD: 145mg, 245mg, or 390mg TID vs. placebo for 30 weeks, N=381) and in advanced patients (ADVANCE-PD: IPX066 vs. IR for 13 weeks, N=393; ASCEND-PD: IPX066 vs. CD-LD+entacapone [CL+E] using a 2 week/period crossover, N=91). Efficacy endpoints included Unified Parkinson's Disease Rating Scale (UPDRS) Parts II+III (all trials); PD diary (ADVANCE-PD/ASCEND-PD); Patient, Clinician Global Impression (PGI, CGI; APEX-PD/ADVANCE-PD); and Subject Preference of Treatment (ASCEND-PD). RESULTS: In APEX-PD, improvements from baseline on UPDRS Parts II+III were ˗11.7 to ˗14.9 points for IPX066 dose groups vs. ˗0.6 for placebo (all P<.0001 vs. placebo) and were maintained throughout the study. IPX066 improved UPDRS Part II+III by ˗5.7 points vs. ˗2.1 by IR (P<.0001) in ADVANCE-PD, and by ˗2.7 points vs. ˗0.3 by CL+E (P=.0233) in ASCEND-PD. IPX066 produced a significantly greater reduction from baseline in "off" time compared to IR (˗2.2 vs. ˗1.0 hr, P<.0001) and CL+E (˗2.1 vs. ˗0.7 hr, P<.0001). "On" time with troublesome dyskinesia did not differ from comparators (P=.6047 vs. IR, P=.3051 vs CL+E). PGI and CGI were significantly improved by all doses of IPX066 vs. placebo (all P<.0001) and vs. IR (P<.0001). In ASCEND-PD, more patients preferred IPX066 (52.4[percnt]) than CL+E (27.4[percnt], P<.001). Across studies, 57.5[percnt] of patients reported 蠅1 adverse event. The most frequent were nausea (10.4[percnt]), dizziness (7.6[percnt]), headache (7.1[percnt]), and dyskinesia (5.4[percnt]). CONCLUSIONS: IPX066 significantly improved PD symptoms with an adverse event profile similar to other dopaminergic therapies. A low proportion of patients reported dyskinesia. SUPPORT: Impax

ABSTRACTDopamine agonists (DA) are often used as first‐line monotherapy for the symptomatic control of Parkinson's disease (PD). However, DA monotherapy typically becomes inadequate within a few years, at which time the DA dosage must be increased or other antiparkinsonian medications added. Adding a monoamine oxidase‐B (MAO‐B) inhibitor to DA monotherapy might improve symptomatic control while maintaining good safety and tolerability. We conducted an 18‐week, randomized, double‐blind, placebo‐controlled trial of rasagiline 1 mg/d as an add‐on to DA therapy (ropinirole ≥ 6 mg/d or pramipexole ≥ 1.0 mg/d) in early PD patients whose conditions were not adequately controlled on their current treatment regimen. The primary efficacy variable was the change in total Unified Parkinson Disease Rating Scale (UPDRS) score (sum of parts I, II, and III) from baseline to week 18, comparing rasagiline and placebo groups. The modified intent‐to‐treat (ITT) population included 321 subjects whose mean ± SD age was 62.6 ± 9.7, and duration of PD was 2.1 ± 2.1 years. Results demonstrated a significantly greater improvement in total UPDRS scores from baseline to week 18 in the rasagiline group compared with the placebo group (least squares [LS] mean difference ± SE, −2.4 ± 0.95; 95% confidence interval [CI], −4.3, −0.5; P = 0.012). Mean improvement (LS mean ± SE) was −3.6 ± 0.68 in the rasagiline group and −1.2 ± 0.68 in the placebo group. Rasagiline was well tolerated, and the most common adverse events (AEs; rasagiline vs. placebo) were dizziness (7.4% vs. 6.1%), somnolence (6.8% vs. 6.7%), and headache (6.2% vs. 4.3%). Rasagiline 1 mg/d provided statistically significant improvement when added to dopamine agonist therapy and was well tolerated. © 2014 International Parkinson and Movement Disorder Society

Background: Dopamine agonists (DAs) are often used as initial PD monotherapy. However with disease progression DA monotherapy alone becomes sub-optimal and patients often require additional dopaminergic therapy to maintain symptomatic efficacy. Traditional options at this stage include levodopa (associated with risk of dyskinesia) or increasing DA dose (associated with higher risks for ICDs and other AEs). Rasagiline is a selective, irreversible MAO-B inhibitor providing a distinct rationale as add-on therapy to DAs for additional symptomatic benefit.

ABSTRACT Background: Bradykinesia has a significant impact on the lives of Parkinson's disease (PD) patients. Consequently, treating this symptom is of particular concern for patients and clinicians. A number of studies have documented the efficacy of rasagiline in reducing the severity of PD symptoms. Objective: To summarize studies that specifically examined the impact of rasagiline on bradykinesia symptoms in PD patients across disease severity. Methods: The EMBASE database was searched for relevant articles published between 2000 and November 2010. Results: Three studies were identified that explicitly examined the effect of rasagiline on the bradykinesia subscale of the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. In each, 1 mg/day rasagiline significantly reduced bradykinesia scores in patients. Conclusion: As a monotherapy or an adjunctive therapy, rasagiline is an effective drug for reducing the severity of bradykinesia in PD patients.

Objective: Rasagiline, a monoamine oxidase type B inhibitor, is indicated for both the initial treatment of Parkinson disease (PD) and as adjunctive (add-on) treatment for patients already taking dopaminergic therapy. This open-label prospective community-based clinical trial was designed to determine the time-to-onset and the magnitude of the beneficial effects of rasagiline in PD patients. Methods: Patients received rasagiline of 1.0 mg once daily as monotherapy or 0.5 mg once daily as adjunct therapy (adjunct therapy dose could be increased to 1 mg/d if clinically indicated) for 12 weeks. Dietary restrictions and recommendations regarding concurrent antidepressant treatment consistent with the Food and Drug Administration (FDA) regulations were in keeping with typical usage. Effectiveness was measured as change from baseline in bradykinesia scores and physicians’ and patients’ global impression. Patients were prospectively monitored for treatment emergent dopaminergic side effects, tyramine reactions, and possible interactions with commonly used antidepressants. Results: Objective and subjective measures of symptom severity improved at 1 week in 272 PD patients treated with once-daily rasagiline (n=123 monotherapy, n=149 adjunct therapy). The magnitude of beneficial effect was similar in monotherapy and adjunct therapy patients. No significant dopaminergic side effects, tyramine reactions, or interactions with antidepressants were observed in the 12-week trial. Conclusions: Rasagiline has a measurable beneficial effect on PD symptoms within 1 week of treatment. Rasagiline has a similar magnitude of benefit in monotherapy and adjunct therapy patients. Adverse interactions between antidepressants and rasagiline were not observed in patients in this trial. The usual use of rasagiline in community neurology practice, consistent with the FDA labeling, seems safe and effective.

Background: Bradykinesia has a significant impact on the lives of Parkinson's disease (PD) patients. Consequently, treating this symptom is of particular concern for patients and clinicians. A number of studies have documented the efficacy of rasagiline in reducing the severity of PD symptoms. Objective: To summarize studies that specifically examined the impact of rasagiline on bradykinesia symptoms in PD patients across disease severity. Methods: The EMBASE database was searched for relevant articles published between 2000 and November 2010. Results: Three studies were identified that explicitly examined the effect of rasagiline on the bradykinesia subscale of the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. In each, 1 mg/day rasagiline significantly reduced bradykinesia scores in patients. Conclusion: As a monotherapy or an adjunctive therapy, rasagiline is an effective drug for reducing the severity of bradykinesia in PD patients.

OBJECTIVE:Rasagiline, a monoamine oxidase type B inhibitor, is indicated for both the initial treatment of Parkinson disease (PD) and as adjunctive (add-on) treatment for patients already taking dopaminergic therapy. This open-label prospective community-based clinical trial was designed to determine the time-to-onset and the magnitude of the beneficial effects of rasagiline in PD patients.METHODS:Patients received rasagiline of 1.0 mg once daily as monotherapy or 0.5 mg once daily as adjunct therapy (adjunct therapy dose could be increased to 1 mg/d if clinically indicated) for 12 weeks. Dietary restrictions and recommendations regarding concurrent antidepressant treatment consistent with the Food and Drug Administration (FDA) regulations were in keeping with typical usage. Effectiveness was measured as change from baseline in bradykinesia scores and physicians' and patients' global impression. Patients were prospectively monitored for treatment emergent dopaminergic side effects, tyramine reactions, and possible interactions with commonly used antidepressants.RESULTS:Objective and subjective measures of symptom severity improved at 1 week in 272 PD patients treated with once-daily rasagiline (n=123 monotherapy, n=149 adjunct therapy). The magnitude of beneficial effect was similar in monotherapy and adjunct therapy patients. No significant dopaminergic side effects, tyramine reactions, or interactions with antidepressants were observed in the 12-week trial.CONCLUSIONS:Rasagiline has a measurable beneficial effect on PD symptoms within 1 week of treatment. Rasagiline has a similar magnitude of benefit in monotherapy and adjunct therapy patients. Adverse interactions between antidepressants and rasagiline were not observed in patients in this trial. The usual use of rasagiline in community neurology practice, consistent with the FDA labeling, seems safe and effective.

Selegiline is a monoamine-B specific inhibitor used to treat Parkinson’s disease. A Zydis sublingual preparation has more efficient absorption and less first pass amphetamine metabolites. We conducted an open label oral to Zydis switch study to evaluate tolerability of rapid switch, and relative efficacy, in 48 subjects from 5 sites. Overall patients preferred the Zydis preparation. Per clinician global impressions, fluctuations improved and the “on” UPDRS part II scores improved. Total UPDRS and measures of fatigue and sleep were unchanged. Adverse events were mild. Patients generally preferred the Zydis selegiline preparation but the modest difference is of unclear clinical significance given the open label nature of the trial.

OBJECTIVE:To determine whether adding orally disintegrating selegiline (ODS) while decreasing dopamine agonist (DA) dosages would reduce DA-related adverse effects (AEs) of excessive daytime sleepiness (EDS), pedal edema, hallucinations, and impulse control disorders (ICDs) without compromising efficacy in Parkinson disease (PD) patients.METHODS:This was a 12-week open-label study of 60 PD patients with motor fluctuations and DA-related AEs of EDS, pedal edema, hallucinations, and ICDs. Orally disintegrating selegiline was initiated at 1.25 mg once daily, and down titration of the DA was started with a goal of a 50% reduction by 1 week. At week 6, ODS was increased to 2.5 mg, and further reductions of the DA were allowed if the AEs were not resolved.RESULTS:The addition of ODS allowed a reduction in the mean daily dose of pramipexole from 2.3 to 0.5 mg and immediate-release ropinirole from 11.2 to 2.9 mg. Most subjects reported a reduction or resolution of DA-related AEs; 94% with EDS (n = 50), 73% with pedal edema (n = 26), 86% with hallucinations (n = 15), and 84% with ICDs (n = 25). Mean activities of daily living and motor scores from the Unified Parkinson's Disease Rating Scale as well as quality-of-life scores were significantly improved without an increase in daily "off" time. The most common AEs, most of which resolved after titration, were worsening of PD, nausea/vomiting, dyskinesia, increased off time, body aches, insomnia, orthostatic hypotension, and increased anxiety and depression.CONCLUSIONS:In most subjects, the addition of ODS with decreasing dosages of DAs substantially reduced EDS, pedal edema, hallucinations, and ICDs without compromising efficacy.

Our objective was to perform a meta-analysis of randomized controlled trials of dopamine agonists (DA) as monotherapy as well as adjunctive therapy for the early treatment of Parkinson's disease (PD). A systematic literature search was conducted through April 2007. Both efficacy and safety endpoints were evaluated. DA monotherapy showed superior efficacy but more frequent adverse events compared to placebo. In addition, DA demonstrated inferior efficacy to levodopa, but was associated with fewer motor complications. However, DAs were associated with a greater incidence of nuisance side effects, such as hallucinations, somnolence and dizziness. The use of DA is an effective treatment option for the treatment of early PD and appears especially useful among PD patients with wearing-off phenomenon or dyskinesias on levodopa; however it may result in more adverse events and higher withdrawal rates.

PURPOSE:The outpatient follow-up phase of the apomorphine (APO) 303 study assessed the long-term efficacy and safety of intermittent subcutaneous apomorphine for 'off' episodes in patients with advanced Parkinson's disease.METHODS:We conducted a 6-month open-label outpatient extension of an in-office dose-escalation study. Patients received apomorphine at a dose considered optimal based on safety and efficacy assessments during the dose-titration phase. Outpatient evaluation visits were scheduled at 1 and 2 weeks, and 1, 4 and 6 months. Efficacy parameters included changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores; safety assessments included blood pressure (BP) monitoring.RESULTS:Apomorphine significantly (p<0.05) reduced UPDRS motor scores at 20, 40 and 90 minutes post-dose versus pre-dose at all evaluation visits. Significant (p<0.1) reductions from pre-dose in seated and standing systolic BP and diastolic BP were noted at various timepoints post-dose at evaluation visits; however, the changes did not increase over the course of the outpatient phase. The incidence of symptomatic hypotension also did not increase with long-term apomorphine use.CONCLUSIONS:The efficacy and general tolerability of subcutaneous apomorphine throughout this open-label outpatient study suggest that it is suitable for the long-term acute treatment of 'off' episodes in patients with advanced Parkinson's disease.

Many patients with advanced Parkinson's disease (PD) experience motor complications, which negatively impact quality of life, despite optimized oral therapy. It is important for patients to have a treatment option that may provide rapid relief from "off" episodes. In three pivotal, randomized, placebo-controlled trials, subcutaneous apomorphine was effective in acutely treating "off" episodes, significantly improving Unified Parkinson Disease Rating Scale motor scores and reducing the number of "off" hours per day, with a significantly shorter time to patient-declared onset of relief than placebo. Thus, clinical trial data support the efficacy of intermittent subcutaneous apomorphine as a rapid acute treatment for "off" episodes in advanced PD.