Summary Basis of Decision for Neupro

Clinical Pharmacology

Neupro (active ingredient rotigotine) is a non-ergolinic dopamine agonist for the treatment of signs and symptoms of idiopathic Parkinson's disease, and idiopathic Restless Legs Syndrome (RLS). Rotigotine is believed to elicit its beneficial effect on Parkinson's disease by activation of the dopaminergic receptors in the brain, including D₃, D₂, and D₁ in a descending order of affinity. The precise mechanism of action of rotigotine as a treatment for RLS is unknown. As RLS is understood to be associated with a subtle central dopaminergic dysfunction, it is thought that rotigotine may exert its activity mainly via dopamine receptors. Rotigotine also acts as an agonist at the D₅, D_4.4 dopamine receptors at concentrations relevant to its therapeutic actions. In functional assays, rotigotine demonstrated antagonistic activity on the alpha_2B and alpha_2C adrenergic receptors and agonistic activity on the 5-HT_1A and 5-HT_1D serotonergic receptors. Rotigotine has no meaningful affinity to the 5-HT_2B receptor at concentrations relevant to clinical use.

Approximately 45% of the rotigotine content in the patch is released within 24 hours. Rotigotine reaches steady-state plasma concentrations within 2 to 3 days of daily dosing. The binding of rotigotine to human plasma proteins is approximately 89.5% in vivo. Rotigotine is extensively metabolized by conjugation and N-dealkylation. Multiple cytochrome P450 (CYP) isoenzymes catalyze the metabolism of rotigotine. Plasma rotigotine delivered through the patch has a terminal half-life of 5 to 7 hours. Rotigotine is primarily excreted in urine (~71 %) and a smaller proportion is excreted in feces (~23 %).

A comprehensive Drug-Drug Interaction program was performed with rotigotine during its development program. No specific issue was identified with CYP inducers or inhibitors, nor with other concomitant medications likely used in the target populations.

In patients with moderate hepatic impairment, the plasma concentrations and exposure of unconjugated rotigotine are comparable to patients with normal hepatic function; however the plasma concentrations and exposure of the total rotigotine are increased by 38% and 14% respectively. Rotigotine has not been studied in patients with severe hepatic impairment. For patients with severe renal impairment, exposure to the inactive conjugates of rotigotine is doubled based on single-dose studies, while rotigotine exposure remains comparable to subjects without renal impairment. Rotigotine is not eliminated through dialysis.

The main safety issues of rotigotine identified in the pharmacology studies included orthostatic hypotension and lower prolactin concentrations and higher aldosterone concentrations. Moreover, heat application to the area where the patch is applied is expected to increase rotigotine release from the patch. Accordingly, appropriate warnings are in place in the Neupro Product Monograph to address the need of avoiding external sources of direct heat on the patch, including the other safety concerns.

For further details, please refer to the Neupro Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Clinical Trials in Parkinson's Disease

The efficacy of Neupro in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of four randomized, double-blind placebo-controlled Phase III trials. Two trials (SP512 and SP513) were conducted in patients with early-stage Parkinson's disease (EPD) who were not receiving concomitant levodopa, and two studies (SP650 and SP515) were conducted in patients with advanced-stage Parkinson's disease (APD) who were receiving concomitant levodopa.

Clinical Trials in Patients with Early-Stage Parkinson's Disease (EPD)

Patients enrolled in the two Phase III EPD trials (SP512 and SP513) had limited or no prior exposure to levodopa. Patients were excluded from either trial if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine were required to be on a stable dose and able to maintain that dose for the duration of the trial.

Changes from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS), Part II & III served as the primary outcome measures in both SP512 & SP513 trials. A "responder" for this EPD patient population was a patient with a 20% or greater decrease in the sum of scores from the Activities of Daily Living (ADL) and Motor Examination sections in the UPDRS (Parts II & III; a UPDRS subtotal) from the baseline visit to end of the double-blind maintenance period.

Study SP512 was a two-arm parallel group efficacy trial with randomized placebo-control to evaluate the efficacy of Neupro (2 mg/24 h, 4 mg/24 h, or 6 mg/24 h rotigotine) in reducing the symptoms of EPD. A total of 277 patients were randomized to treatment, with 96 on placebo and 181 on Neupro. After a run-in period of 4 weeks, patients underwent a weekly titration over 3 weeks up to a maximal dose of 6 mg/24 h rotigotine depending on efficacy and tolerability in achieving best symptomatic relief. Patients then received maintenance treatment over a 24-week period, followed by a 4-day dose de-escalation period and a 4-week safety follow-up period for patients who did not enroll in an open-label extension. The average age of the study population was 63 years with slightly more men (65%) than women enrolled.

In Study SP512, the Full Analysis Set (FAS) included 273 patients, with 96 on placebo and 177 on Neupro. The mean baseline subscore of the combined UPDRS (Part II & III) was similar in both groups (29.9 Neupro, 30.0 placebo). Neupro-treated patients experienced a mean change in the UPDRS (Parts II + III) subscore from baseline to end of treatment of 4.0, and the difference from placebo was statistically significant. Symptomatic improvement started to appear as titration progressed. The responder rates, based on a 20% reduction on the primary endpoint UPDRS (Part II + III), were 48% of the patients on Neupro versus (vs.) 19% on placebo.

Study SP513 was a three-arm parallel group efficacy trial with randomized placebo-control to evaluate the efficacy of Neupro (2 mg/24 h, 4 mg/24 h, 6 mg/24 h, or 8 mg/24 h) in reducing the symptoms of EPD. A total of 561 enrolled patients were randomized to treatment with 118 on placebo, 215 on Neupro and 228 on active oral comparator (ropinirole) for up to 39 weeks. After a run-in period of 4 weeks, the patients underwent a 13-week titration period to a maximal dose of 8 mg/24 h rotigotine depending on efficacy and tolerability in achieving best symptomatic relief. Patients then received maintenance treatment over a 24-week period, followed by a 12-day dose de-escalation period and a 4-week safety follow-up period for patients who did not enroll in an open-label extension. The average age of the study population was 61 years with slightly more men (58%) than women enrolled.

In Study SP513, the Full Analysis Set (FAS) included 557 patients, with 117 on placebo, 213 on Neupro, and 227 on active comparator. The mean baseline UPDRS (Parts II + III) sub-score was similar across all groups (33.2 Neupro, 31.3 placebo, 32.2 active comparator). Neupro-treated patients experienced a mean change in the UPDRS (Parts II + III) subscore from baseline to end of treatment of -6.8, and the difference from placebo was statistically significant. Symptomatic improvement started to appear as titration progressed. The responder rates, based on a 20% reduction on the primary endpoint UPDRS (Part II + III), were 52% of the patients on Neupro vs. 30% on placebo. The active comparator performed as expected.

Clinical Trials in Patients with Advanced-Stage Parkinson's Disease (APD)

Patients enrolled in the two Phase III APD trials (SP650 and SP515) had to be experiencing "on-off" periods at baseline, despite treatment with optimal doses of levodopa. Patients continued concomitant administration of levodopa (L-dopa) during the trial; however, reductions in the dosage of levodopa were allowed if patients experienced adverse events that the investigator considered related to dopaminergic therapy. Patients were excluded from the trials if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine were required to be on a stable dose and able to maintain that dose for the duration of the study. In the SP650 trial, catechol-O-methyltransferase (COMT)-inhibitors were not permitted.

Change from baseline in time spent "off" (hours) based on daily diaries was the primary outcome measure in these two APD trials. A "responder" for this APD patient population was defined as a patient with a ≥30% decrease in absolute time spent "off" from baseline to the end of the double-blind maintenance period.

Study SP650 was a three-arm, parallel group efficacy trial with randomized placebo-control to evaluate the efficacy of Neupro (8 mg/24 h or 12 mg/24 h) in reducing the symptoms of APD. A total of 351 patients were randomized, 120 on placebo, 120 on Neupro 8 mg/24, and 111 on Neupro 12 mg/24 h. After a run-in period of 4 weeks, the patients underwent a 3 to 5-week titration period with either placebo or Neupro (8 mg/24 h or 12 mg/24 h) where back titration was permitted to achieve optimal symptomatic relief. Patients then received maintenance treatment over a 24-week period. During the maintenance treatment, there was a permitted L-dopa reduction window of 1 to 3 weeks and then a stable L-dopa dose of 21 to 23 weeks. The maintenance period was then followed by an 8-day de-escalation period and a 4-week safety follow-up period for patients who did not enroll in an open-label extension. The average age of the study population was 66 years with slightly more men than women.

The Full Analysis Set (FAS) included 341 patients, 119 on placebo, 113 on Neupro 8 mg/24 h, and 109 on Neupro 12 mg/24 h. Mean baseline "off" times were similar among all treatment groups (6.4, 6.8, and 6.3 h for the placebo, Neupro 8 mg/24 h and 12 mg/24 h treatment groups, respectively). Neupro-treated patients experienced a mean change in "off" time from baseline to end of treatment of -2.7 h for the 8 mg/24 h treatment arm and -2.1 h for the 12 mg/24 h treatment arm, and the difference from placebo was statistically significant for both Neupro doses (8 mg/24 h, 12 mg/24 h). Symptomatic improvement started to appear as titration progressed. The responder rates, based on a 30% reduction on the primary endpoint ("off" time at the end of treatment) were 57% and 55% for the Neupro 8mg/24 h and 12mg/24 h groups respectively vs. 34% on placebo.

Study SP515 was a three-arm, parallel group trial using a double-dummy treatment to evaluate the efficacy of Neupro, up to a maximal dose of 16 mg/24 h with doses ranging from 4 mg/24 h to 16 mg/24 h in reducing the symptoms of APD. Enrolled patients were assigned to treatment with either a placebo or Neupro or an active oral comparator (pramipexole). A total of 506 patients were randomized, 101 on placebo vs. 204 on Neupro and 201 on pramipexole. After a run-in period of 4 weeks, the patients underwent an up to 7 week titration period with either Neupro, placebo or pramipexole to obtain best symptomatic relief. Patients then received maintenance treatment over a 16 week period, with a permitted L-dopa reduction window of 1 to 3 weeks, and stable L-dopa dose of 13 to 15 weeks. The maintenance period was then followed by a dose de-escalation period of up to 6 days and a 4-week safety follow-up period for patients who did not enroll in an open-label extension. The average age of the study population was 64 years with more men than women.

The Full Analysis Set (FAS) included 501 patients, 100 on placebo vs. 201 on Neupro, and 200 on pramipexole. Mean baseline "off" times were similar among all treatment groups (6.6, 6.2, and 6.0 h for the placebo, Neupro, and comparator treatment groups, respectively). Neupro-treated patients experienced a mean 2.5 hour decrease change in "off" time from baseline to end of treatment, and the difference from placebo was statistically significant. Symptomatic improvement started to appear as titration progressed. The responder rates, based on a 30% reduction on the primary endpoint ("off" time at the end of treatment) were 60% of the patients on Neupro vs. 35% on placebo.

Clinical Trials in Restless Legs Syndrome

The efficacy of Neupro was also evaluated for use in patients with moderate and severe idiopathic Restless Legs Syndrome (RLS) in two Phase III pivotal trials, SP790 and SP792. Both trials were fixed-dose, randomized, double-blind, placebo-controlled studies with maintenance periods of 6 months duration.

The primary outcome measurement (primary endpoint) used to assess treatment effect in both trials was the absolute change from baseline in the International Restless Legs Scale (IRLS Scale) sum score at the end of the maintenance period.

Across the two studies, the mean duration of RLS was 2.1 to 3.1 years, mean age was approximately 55 years (range of 19 to 78 years), approximately 67% were women, and 97% were Caucasian. A total of 746 patients were treated with Neupro in these two studies.

Study SP790 was a 4-arm, parallel-group, placebo-control efficacy trial conducted in moderate-to-severe RLS patients. Enrolled RLS patients were randomized to receive either placebo or one of the following three Neupro doses (1 mg/24 h, 2 mg/24 h, and 3 mg/24 h). A total of 458 patients were randomized (117 on placebo, 115 on Neupro 1 mg/24 h, 112 on Neupro 2 mg/24 h, and 114 on Neupro 3 mg/24 h). After a run-in period of 7 days, patients underwent a 3-week titration period up to their target daily dose. Patients then received maintenance treatment for 6 months, followed by a 7-day dose de-escalation phase and a 4-week safety follow-up period for patients who did not enroll in an open-label extension. The trial permitted one-step back-titration during the forced titration period, but none during the maintenance period. The average age of the study population was 58 years with more women than men.

The Full Analysis Set (FAS) included 447 patients: 114 on placebo; 112 on Neupro 1 mg/24 h; 109 on Neupro 2 mg/24 h; and 112 on Neupro 3 mg/24 h. Study results showed mean baseline IRLS sum scores were similar among all treatment groups (28.1, 28.1, 28.2, and 28.0 for the placebo, Neupro 1 mg/24 h, 2 mg/24 h, and 3 mg/24 h groups, respectively). Patients experienced a mean change in the IRLS sum score from baseline to the end of treatment for each of the 3 Neupro dose groups, and the difference from placebo was significant. The primary endpoint mean change from baseline in IRLS sum score at end of the maintenance period were as follows: -8.0 ± 9.7 (LS Mean ± SD) on placebo vs. -13.2 ± 10.0 on Neupro 1 mg/24 h; -15.6 ± 9.5 on Neupro 2 mg/24 h; and -16.1 ± 10.9 on Neupro 3 mg/24 h. The responder rates with a 50% cut-off on the IRLS were 25.4% on placebo vs. 51.8% on Neupro 1 mg/24 h; 57.8% on Neupro 2 mg/24 h; and 55.4% on Neupro 3 mg/24 h. The high dose at 3 mg/24 h did not result in an appreciable level of symptomatic relief than the mid-dose. The profiles of treatment-emergent adverse events and serious adverse events were similar to those observed in the patients with Parkinson's disease. The relatively higher rate of discontinuation, ranging from 22% to 42%, resulted mainly from the design of the trial (forced up-titration), inefficacy (in those on placebo), and adverse reactions to rotigotine (e.g. those on 3 mg/24 h).

Study SP792 was similar in design to the SP790 study; however this study was a 5-arm, parallel-group trial conducted in moderate-to-severe RLS patients. Enrolled RLS patients were randomized to receive either placebo or one of the following four Neupro doses (0.5 mg/24 h, 1 mg/24 h, 2 mg/24 h, and 3 mg/24 h). A total of 505 patients were randomized: 100 on placebo; 99 on Neupro; 0.5 mg/24 h; 101 on Neupro 1 mg/24 h; 99 on Neupro 2 mg/24 h; and 106 on Neupro 3 mg/24 h. After a run-in period of 7 days, the patients then underwent a 4-week titration period up to the target daily dose. The maintenance period was 6 months, followed by a 7-day dose de-escalation period and a 4-week safety follow-up period for patients who did not enroll in an open-label extension. The trial permitted one-step back-titration during the forced titration period, but none during the maintenance period. The average age of the study population was 52 years with slightly more women than men.

The Full Analysis Set (FAS) included 494 patients: 99 on placebo; 98 on Neupro 0.5 mg/24 h; 99 on Neupro 1 mg/24 h; 95 on Neupro 2 mg/24 h; and 103 on Neupro 3 mg/24 h. Study results showed mean baseline IRLS sum scores were similar among all treatment groups (23.5, 23.1, 23.2, 23.3, and 23.6 for the placebo, Neupro 0.5 mg/24 h, 1 mg/24 h, 2 mg/24 h, and 3 mg/24 h groups, respectively). Patients experienced a mean change in the IRLS sum score from baseline to the end of treatment for each of the 4 Neupro dose groups. The difference between the two highest treatment groups (Neupro 2 mg/24 h and 3 mg/24 h) and placebo was significant. The mean change from baseline in IRLS Scale sum score at end of the maintenance period were as follows: -9.0 ± 7.7 (LS Mean ± SD) on placebo vs. -10.9 ± 8.9 on Neupro 0.5 mg/24 h; -11.1 ± 9.3 on Neupro 1 mg/24 h; -13.4 ± 9.2 on Neupro 2 mg/24 h; and -14.3 ± 9.4 on Neupro 3 mg/24 h. The responder rates with a 50% cut-off on the IRLS were: 37% on placebo vs. 48% on Neupro 0.5 mg/24 h; 52% on Neupro 1 mg/24 h; 60% on Neupro 2 mg/24 h; and 67% on Neupro 3 mg/24 h.

Overall, six Phase III pivotal studies (two studies for each indication), demonstrated the efficacy of Neupro for use in the management of EPD, APD, and moderate to severe idiopathic RLS.

For additional information, refer to the Neupro Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Neupro was based primarily on pooled safety data from the four Phase III pivotal trials conducted in patients with Parkinson's disease, in addition to the two Phase III pivotal trials conducted in patients with RLS. These six pivotal trials have been previously described in Clinical Efficacy section. Additional safety data derived from Phase II studies were also assessed in establishing the safety profile of Neupro. The description of the safety profile is intended to inform the health-care provider and the patient for optimal safety management. Because of the complex scenarios of patient pathophysiology and therapeutics, the general safety profile makes no statement on causality.

Adverse Events in Early-Stage Parkinson's Disease (EPD)

The safety of Neupro was evaluated in 649 patients with EPD. The most frequently observed adverse events (AEs) reported with an incidence rate of ≥5% in Neupro-treated patients compared to placebo-treated patients were those of nausea, application and instillation site reactions, somnolence, dizziness, headache, vomiting, fatigue, insomnia, peripheral edema, and constipation.

Approximately 6.8% of Neupro-treated patients reported serious adverse events (SAEs), vs. 5.9% of patients on placebo. The most frequent SAE was application site reactions (0.5% on Neupro vs. 0.0% on placebo).

Approximately 13% of 649 Neupro-treated patients discontinued treatment because of AEs, compared with 6% of 290 patients who received placebo. The AEs causing most discontinuations of treatment were those of application site reaction, nausea, and vomiting.

Adverse Events in Advanced-Stage Parkinson's Disease (APD)

The safety of Neupro was evaluated in 658 patients with APD. The most frequently observed AEs reported with an incidence rate of ≥5% in Neupro-treated patients compared to placebo-treated patients were those of application site reactions, nausea, somnolence, dyskinesia, dizziness, vomiting, insomnia, and peripheral edema.

Approximately 7.4% of Neupro-treated patients reported SAEs vs. 6.9% of patients on placebo. The most frequent SAEs included nausea and application site dermatitis (both 0.6% Neupro vs. 0.0% placebo).

Approximately 11% of 658 Neupro-treated patients discontinued treatment because of AEs, compared with 8% of patients who received placebo. The AEs causing most discontinuations of treatment were those of nausea, vomiting, dizziness, and application site reactions.

Adverse Events in Restless Legs Syndrome (RLS)

The safety of Neupro was evaluated in 748 Neupro-treated patients with RLS. The most frequently observed AEs reported with an incidence rate of ≥5% in Neupro-treated patients compared to placebo-treated patients were those of application and instillation site reactions, nausea, headache, fatigue, nasopharyngitis, somnolence, dizziness, and pruritus.

Approximately 5.6% of Neupro-treated patients reported SAEs vs. 4.1% of patients on placebo. The most frequent SAE was application site and instillation reactions (0.8% on Neupro vs. 0.0% on placebo).

Approximately 18% of 748 Neupro-treated patients discontinued treatment because of AEs, compared with 6% of patients who received placebo. The AEs most commonly causing discontinuation of treatment were those of application site reactions, dizziness, and nausea.

Other Adverse Events

Other AEs, such as hallucination, orthostatic hypotension, tachycardia, and hypertension, have also been reported with use of Neupro. However, these AEs are known to be associated with use of a dopamine agonist, like that of Neupro, due to the drug's stimulation of the dopaminergic system.

Several less frequent but potentially serious adverse events (SAEs) reported with use of Neupro in clinical trials included sudden onset of sleep, peripheral edema, impulse-control disorders, melanoma, fall, fibrotic complications, hyperglycaemia, heart failure, urinary retention and infection, constipation, and augmentation of RLS. While the majority of these events are known to occur in the Parkinson's disease patient population irrespective of drug exposure, sudden onset of sleep, peripheral edema, impulse-control disorders and augmentation of RLS are known to occur with Neupro as well as with other non-ergolinic dopamine agonists.

A Black Box Warning describing serious warnings and precautions has been included in the Product Monograph for Neupro. Patients receiving treatment with Neupro and other dopaminergic agents have reported excessive daytime somnolence and episodes of sudden onset of sleep while engaged in activities of daily living. Although some of the patients reported somnolence while on Neupro, others perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event.

In clinical trials, the pattern of deaths and SAEs were in line with expectations for the disease and age strata. There was no peculiar finding in this set of data that could raise concern.

The post-market safety profile of Neupro is similar to that seen in clinical trials. Aggression and pruritus generalized are two AEs that have been identified in the post-market safety database. With the exception of application site skin reactions, the observed AEs are consistent with those seen with other dopaminergic agents in the same drug class.

In conclusion, the safety profile for Neupro appears to be consistent with its dopaminergic activity and associated mechanism of action, with the exception of its tendency to cause application site irritations. Neupro may result in SAEs such as hallucination, orthostatic hypotension, tachycardia, and hypertension. In addition, other potential SAEs include sudden onset of sleep, peripheral edema, impulse-control disorders, melanoma, fall, fibrotic complications, hyperglycaemia, heart failure, urinary retention and infection, constipation, and augmentation of RLS. Risk management wording, commensurate with the likelihood of the adverse reactions and their potential seriousness, has been included in the Product Monograph for Neupro.

For more information, refer to the Neupro Product Monograph, approved by Health Canada and available through the Drug Product Database.