Neupro rotigotine 1 mg/24h Patch, Extended Release — NDC 50474-801-17 (Billing 50474-0801-17)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Rotigotine is a non-ergoline dopamine agonist. The precise mechanism of action of rotigotine as a treatment for Parkinson's disease is unknown, although it is thought to be related to its ability to stimulate dopamine receptors within the caudate-putamen in the brain. The precise mechanism of action of rotigotine as a treatment for Restless Legs Syndrome is unknown but is thought to be related to its ability to stimulate dopamine receptors.

12.2Pharmacodynamics Cardiac Electrophysiology There is no indication of a QT/QTc prolonging effect of NEUPRO in doses up to 24 mg/24 hours. The effects of NEUPRO at doses up to 24 mg/24 hours (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg IV, single dose), parallel-group trial with an overall treatment period of 52 days in male and female patients with advanced-stage Parkinson's disease. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.

12.3Pharmacokinetics On average, approximately 45% of the rotigotine from the patch is released within 24 hours (0.2 mg/cm 2 ). Rotigotine is primarily eliminated in the urine as inactive conjugates. After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours.

The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours. Absorption and Bioavailability When single doses of 8 mg/24 hours are applied to the trunk, there is an average lag time of approximately 3 hours until drug is detected in plasma (range 1 to 8 hours). T max typically occurs between 15 to 18 hours post dose but can occur from 4 to 27 hours post dose.

However, there is no characteristic peak concentration observed. Rotigotine displays dose-proportionality over a daily dose range of 1 mg/24 hours to 24 mg/24 hours. In the clinical studies of rotigotine effectiveness, the transdermal system application site was rotated from day to day (abdomen, thigh, hip, flank, shoulder, or upper arm) and the mean measured plasma concentrations of rotigotine were stable over the 6 months of maintenance treatment.

Relative bioavailability for the different application sites at steady-state was evaluated in subjects with Parkinson's disease. In a single trial conducted in patients with early-stage Parkinson's disease, differences in bioavailability ranged from less than 1% (abdomen vs. hip) to 46% (shoulder vs. thigh) with shoulder application showing higher bioavailability. Because rotigotine is administered transdermally, food should not affect absorption.

In a 14-day clinical study with rotigotine administered to healthy subjects, steady-state plasma concentrations were achieved within 2 to 3 days of daily dosing. Average NEUPRO plasma concentrations (±95% CI) in patients with early-stage Parkinson's disease are shown in Figure 2 after application of a 8 mg/24 hours transdermal system to 1 of 6 application sites (shoulder, upper arm, flank, hip, abdomen, or thigh) on 2 different days during the maintenance phase. Figure 2 Average NEUPRO Plasma Concentrations in Patients with Early-Stage Parkinson's Disease Figure 2 Distribution The weight normalized apparent volume of distribution (Vd/F) in humans is approximately 84 L/kg after repeated dose administration.

The binding of rotigotine to human plasma proteins is approximately 92% in vitro and 89.5% in vivo . Metabolism and Elimination Rotigotine is extensively metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl-rotigotine.

Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine. After removal of the patch, plasma levels decreased wi… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Rotigotine is a non-ergoline dopamine agonist. The precise mechanism of action of rotigotine as a treatment for Parkinson's disease is unknown, although it is thought to be related to its ability to stimulate dopamine receptors within the caudate-putamen in the brain. The precise mechanism of action of rotigotine as a treatment for Restless Legs Syndrome is unknown but is thought to be related to its ability to stimulate dopamine receptors.

12.3Pharmacokinetics On average, approximately 45% of the rotigotine from the patch is released within 24 hours (0.2 mg/cm 2 ). Rotigotine is primarily eliminated in the urine as inactive conjugates. After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours.

The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours. Absorption and Bioavailability When single doses of 8 mg/24 hours are applied to the trunk, there is an average lag time of approximately 3 hours until drug is detected in plasma (range 1 to 8 hours). T max typically occurs between 15 to 18 hours post dose but can occur from 4 to 27 hours post dose.

However, there is no characteristic peak concentration observed. Rotigotine displays dose-proportionality over a daily dose range of 1 mg/24 hours to 24 mg/24 hours. In the clinical studies of rotigotine effectiveness, the transdermal system application site was rotated from day to day (abdomen, thigh, hip, flank, shoulder, or upper arm) and the mean measured plasma concentrations of rotigotine were stable over the 6 months of maintenance treatment.

Relative bioavailability for the different application sites at steady-state was evaluated in subjects with Parkinson's disease. In a single trial conducted in patients with early-stage Parkinson's disease, differences in bioavailability ranged from less than 1% (abdomen vs. hip) to 46% (shoulder vs. thigh) with shoulder application showing higher bioavailability. Because rotigotine is administered transdermally, food should not affect absorption.

In a 14-day clinical study with rotigotine administered to healthy subjects, steady-state plasma concentrations were achieved within 2 to 3 days of daily dosing. Average NEUPRO plasma concentrations (±95% CI) in patients with early-stage Parkinson's disease are shown in Figure 2 after application of a 8 mg/24 hours transdermal system to 1 of 6 application sites (shoulder, upper arm, flank, hip, abdomen, or thigh) on 2 different days during the maintenance phase. Figure 2 Average NEUPRO Plasma Concentrations in Patients with Early-Stage Parkinson's Disease Figure 2 Distribution The weight normalized apparent volume of distribution (Vd/F) in humans is approximately 84 L/kg after repeated dose administration.

The binding of rotigotine to human plasma proteins is approximately 92% in vitro and 89.5% in vivo . Metabolism and Elimination Rotigotine is extensively metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl-rotigotine.

Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine. After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours.

Rotigotine is primarily excreted in urine (approximately 71%) as inactive conjugates of the parent compound and N-desalkyl metabolites. A smaller proportion is excreted in feces (approximately 23%). The major metabolites found in urine were rotigotine sulfate (16% to 22% of the absorbed dose), rotigotine glucuronide (11% to 15%), and N-despropyl-rotigotine sulfate metabolite (14% to 20%) and N-desthienylethyl-rotigotine sulfate metabolite (10% to 21%).

Approximately 11% is renally eliminated as other metabolites. A small amount of unconjugated rotigotine is renally eliminated (less than 1% of the absorbed dose). Drug Interaction Studies CYP Interactions In vitro studies indicate that multiple CYP-isoforms are capable of catalyzing the metabolism of rotigotine.

In human liver microsomes, no extensive inhibition of the metabolism of rotigotine was observed when co-incubated with CYP isoform specific inhibitors. If an ind… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology There is no indication of a QT/QTc prolonging effect of NEUPRO in doses up to 24 mg/24 hours. The effects of NEUPRO at doses up to 24 mg/24 hours (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg IV, single dose), parallel-group trial with an overall treatment period of 52 days in male and female patients with advanced-stage Parkinson's disease. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.

14 CLINICAL STUDIES

14.1Parkinson's Disease The effectiveness of NEUPRO in the treatment of the signs and symptoms of idiopathic Parkinson's disease was established in five parallel-group, randomized, double-blind, placebo-controlled trials conducted in the U.S. and abroad. Three of these five trials enrolled patients with early-stage Parkinson's disease (not receiving levodopa), and two enrolled patients with advanced-stage Parkinson's disease who were receiving levodopa. Depending on trial design, patients underwent a weekly titration of NEUPRO in 2 mg/24 hours increments to either the randomized dose or optimal dose.

Back titrations by 2 mg/24 hours decrement of NEUPRO were permitted for intolerable adverse events. Patch application sites were changed on a daily basis. Change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS), Parts II + III, served as the primary outcome assessment measure in the early-stage studies.

The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (Part I), Activities of Daily Living (ADL) (Part II), motor performance (Part III), and complications of therapy (Part IV). Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for Part II.

Part III is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108. Change from baseline in time spent "off" (hours) based on daily diaries was the primary outcome assessment in the two trials of advanced-stage Parkinson's disease (with levodopa). Studies in Patients with Early-Stage Parkinson's Disease Patients (N=649) in the three trials of early-stage Parkinson's disease had limited or no prior exposure to levodopa (off levodopa for at least 28 days prior to baseline or levodopa use for no more than 6 months).

Patients were excluded from the studies if they had a history of pallidotomy, thalamotomy, deep brain stimulation, or fetal tissue transplant. Patients receiving selegiline, anticholinergic agents, or amantadine must have been on a stable dose and able to maintain that dose for the duration of the study. PD-1 This trial was a multicenter, multinational, dose-response study in which 316 early-stage Parkinson's disease patients were titrated over 4 weeks to their randomized treatment with either placebo or one of four fixed doses of NEUPRO (2 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, or 8 mg/24 hours).

The patches were applied to the upper abdomen and the sites of application were rotated on a daily basis. Patients underwent a weekly titration (increasing the number of 2 mg/24 hours patches or placebo patches at weekly intervals) over 4 weeks such that the target doses of NEUPRO were achieved for all groups by the end of 3 weeks and were administered over the fourth week of the titration phase. Patients then continued on treatment for a 7-week maintenance phase followed by a down titration during the last week.

Two back titrations by a single patch (i.e., 2 mg/24 hours decrement of NEUPRO or placebo) at a time were permitted for intolerable adverse events. The mean age of patients was approximately 60 years (range 33-83 years; approximately 36% were 65 years or older) and the study enrolled more men (62%) than women (39%). Most patients (85%) were Caucasian and most randomized patients (≥88%) completed the full treatment period.

Mean baseline combined UPDRS (Parts II + III) scores were similar among all treatment groups, between 27.1 and 28.5 for all groups. The mean change from baseline and difference from placebo for each treatment group is shown in Table 5. Statistically significant mean changes reflecting dose-related improvement were observed at th… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies of rotigotine were conducted in mice at doses of 0, 3, 10, and 30 mg/kg and in rats at doses of 0, 0.3, 1, and 3 mg/kg; in both studies rotigotine was administered subcutaneously once every 48 hours. No significant increases in tumors occurred in mice at doses up to 9 times the maximum recommended human dose (MRHD) in Parkinson's disease (8 mg/24 hours). In rats, there were increases in Leydig cell tumors and in uterine tumors (adenocarcinomas, squamous cell carcinomas) at all doses.

The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans. Therefore, there were no tumor findings considered relevant to humans at plasma exposures (AUC) up to 4 to 6 times that in humans at the MRHD. Mutagenesis Rotigotine was negative in the in vitro bacterial reverse mutation (Ames) and in the in vivo micronucleus assays.

Rotigotine was mutagenic and clastogenic in the in vivo mouse lymphoma tk assay. Infertility When rotigotine was administered subcutaneously (0, 1.5, 5, or 15 mg/kg/day) to female rats prior to and during mating and continuing through gestation day 7, an absence of implantation was observed at all doses. The lowest dose tested is 2 times the MRHD on a mg/m 2 basis.

In male rats treated from 70 days prior to and during mating, there was no effect on fertility; however, a decrease in epididymal sperm motility was observed at the highest dose tested. The no-effect dose (5 mg/kg/day) is 6 times the MRHD on a mg/m 2 basis. When rotigotine was administered subcutaneously to female mice at doses of 0, 10, 30, and 90 mg/kg/day from 2 weeks until 4 days before mating and then at a dose of 6 mg/kg/day (all groups) (approximately 4 times the MRHD on a mg/m 2 basis) from 3 days before mating until gestation day 7, a markedly reduced (low dose) or complete absence of implantation (mid and high doses) was observed.

The effects on implantation in rodents are thought to be due to the prolactin-lowering effect of rotigotine. In humans, chorionic gonadotropin, not prolactin, is essential for implantation.

13.2Animal Toxicology and/or Pharmacology Retinal Pathology: Albino rats Retinal degeneration was observed in albino rats in a 6-month toxicity study at the highest dose of rotigotine (plasma exposure [AUC] at least 15 times that in humans at the MRHD). Retinal degeneration was not observed in the 2-year carcinogenicity studies in albino rat (plasma AUCs up to 4-6 times that in humans at the MRHD) or albino mouse, or in monkeys treated for 1 year. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.