Neupro

1 INDICATIONS AND USAGE NEUPRO is a dopamine agonist indicated for the treatment of: Parkinson's disease ( 1.1 ) Moderate-to-severe primary Restless Legs Syndrome ( 1.2 ) 1.1 Parkinson's Disease (PD) NEUPRO is indicated for the treatment of Parkinson's disease. 1.2 Restless Legs Syndrome (RLS) NEUPRO is indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome.

2 DOSAGE AND ADMINISTRATION Parkinson's disease: Initially, 2 mg/24 hours for early-stage disease or 4 mg/24 hours for advanced-stage disease. The dose may be increased as needed by 2 mg/24 hours at weekly intervals, up to 6 mg/24 hours for early-stage disease and up to 8 mg/24 hours for advanced-stage disease. ( 2.1 ) Restless Legs Syndrome: Initially, 1 mg/24 hours, increased as needed by 1 mg/24 hours at weekly intervals, up to 3 mg/24 hours. ( 2.2 ) Apply once a day to the skin; press firmly in place for 30 seconds. Do not place NEUPRO on oily, irritated, or damaged skin, or where it will be rubbed by tight clothing. Do not use the same site more than once every 14 days. The prescribed dose may be achieved using single or multiple patches. ( 2.3 ) To discontinue treatment, reduce the dose gradually until complete withdrawal of NEUPRO. ( 2.4 ) 2.1 Dosage in Parkinson's Disease Early-Stage Parkinson's Disease In patients with early-stage Parkinson's disease, the recommended starting dose for NEUPRO is 2 mg/24 hours. Based upon individual patient clinical response and tolerability, NEUPRO dosage may be increased weekly by 2 mg/24 hours if additional therapeutic effect is needed. The lowest effective dose is 4 mg/24 hours. The maximum recommended dose for early-stage Parkinson's disease is 6 mg/24 hours. Advanced-Stage Parkinson's Disease In patients with advanced-stage Parkinson's disease, the recommended starting dose for NEUPRO is 4 mg/24 hours. Based upon individual patient clinical response and tolerability, NEUPRO dosage may be increased weekly by 2 mg/24 hours if additional therapeutic effect is needed. The maximum recommended dose for advanced-stage Parkinson's disease is 8 mg/24 hours. 2.2 Dosage in Restless Legs Syndrome In patients with Restless Legs Syndrome, the recommended starting dose for NEUPRO is 1 mg/24 hours. Based upon individual patient clinical response and tolerability, NEUPRO dosage may be increased weekly by 1 mg/24 hours if additional therapeutic effect is needed. The lowest effective dose is 1 mg/24 hours. The maximum recommended dose is 3 mg/24 hours. 2.3 Administration Information NEUPRO is applied once a day. The adhesive side of the transdermal system should be applied to clean, dry, intact healthy skin on the front of the abdomen, thigh, hip, flank, shoulder, or upper arm. The transdermal system should be applied at approximately the same time every day, at a convenient time for the patient. Because NEUPRO is administered transdermally, food is not expected to affect absorption and it can be applied irrespective of the timing of meals. The application site for NEUPRO should be moved on a daily basis (for example, from the right side to the left side and from the upper body to the lower body). NEUPRO should not be applied to the same application site more than once every 14 days and should not be placed on skin that is oily, irritated, or damaged, or where it will be rubbed by tight clothing. If it is necessary to apply NEUPRO to a hairy area, the area should be shaved at least 3 days prior to NEUPRO application. The system should be applied immediately after opening the pouch and removing the protective liner. The system should be pressed firmly in place for 30 seconds, making sure there is good contact, especially around the edges. If the patient forgets to replace NEUPRO, or if the transdermal system becomes dislodged, another transdermal system should be applied for the remainder of the day. The prescribed dose may be achieved using single or multiple patches [see Patient Counseling Information (17) ]. 2.4 Discontinuation of NEUPRO For discontinuation of NEUPRO in patients with Parkinson's disease, reduce the daily dose by a maximum of 2 mg every 24 hours preferably every other day, until complete withdrawal of NEUPRO is achieved. For discontinuation of NEUPRO in patients with Restless Legs Syndrome, reduce the daily dose by 1 mg every 24 hours preferably every other day, until complete with…

5 WARNINGS AND PRECAUTIONS Contains sodium metabisulfite that may cause allergic-type reactions in those with sulfite sensitivity. ( 5.1 ) Falling asleep during activities of daily living, including the operation of motor vehicles, and somnolence may occur. ( 5.2 ) Hallucinations/psychosis and dyskinesia may occur. ( 5.3 , 5.9 ) Symptomatic postural hypotension and syncope may occur, especially during dose escalation. ( 5.4 , 5.5 ) Consider dose reduction or stopping NEUPRO if patient develops compulsive behaviors. ( 5.6 ) Elevation of blood pressure and heart rate may occur. ( 5.7 ) Application site reactions can occur and may be severe. ( 5.10 ) Hyperpyrexia and confusion may occur with sudden discontinuation or dose reduction. ( 5.14 ) 5.1 Sulfite Sensitivity NEUPRO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. 5.2 Falling Asleep During Activities of Daily Living and Somnolence Patients with early- and advanced-stage Parkinson's disease and with Restless Legs Syndrome treated with NEUPRO have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on NEUPRO, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment. In clinical trials in patients with Restless Legs Syndrome, 2% of patients treated with the maximum recommended NEUPRO dose (3 mg/24 hours) reported sleep attacks compared to 0% of placebo-treated patients. It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Somnolence is a common occurrence in patients receiving NEUPRO. In patients taking the maximum recommended NEUPRO dose, there was an increased risk of somnolence for early-stage Parkinson's disease (NEUPRO 19%, placebo 3%), for advanced-stage Parkinson's disease (NEUPRO 32%, placebo 28%), and for Restless Legs Syndrome (NEUPRO 10%, placebo 4%). Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with NEUPRO. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities while taking NEUPRO. Before initiating treatment with NEUPRO, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase this risk with NEUPRO such as concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), NEUPRO should ordinarily be discontinued [see Dosage and Administration (2.4) ] . If a decision is made to continue NEUPRO, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 5.3 Hallucinations/Psychosis There was an increased risk for h…

4 CONTRAINDICATIONS NEUPRO is contraindicated in patients who have demonstrated hypersensitivity to rotigotine or the components of the transdermal system. History of hypersensitivity to rotigotine or components of the transdermal patch. ( 4 )

7 DRUG INTERACTIONS 7.1 Dopamine Antagonists Dopamine antagonists, such as antipsychotics or metoclopramide, may diminish the effectiveness of NEUPRO [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of NEUPRO in pregnant women. In animal studies, rotigotine was shown to have adverse effects on embryofetal development when administered during pregnancy at doses similar to or lower than those used clinically [ see Data ]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated population is unknown. Data Animal Data Rotigotine administered subcutaneously (0, 10, 30, or 90 mg/kg/day) to pregnant mice during organogenesis (gestation days 6 through 15) resulted in increased incidences of delayed skeletal ossification and decreased fetal body weights at the two highest doses and an increase in embryofetal death at the high dose. The no-effect dose for embryofetal developmental toxicity in mice is approximately 6 times the maximum recommended human dose (MRHD) for Parkinson's disease (8 mg/24 hours) on a body surface area (mg/m 2 ) basis. Rotigotine administered subcutaneously (0, 0.5, 1.5, or 5 mg/kg/day) to pregnant rats during organogenesis (gestation days 6 through 17) resulted in increased embryofetal death at all doses. The lowest effect dose is less than the MRHD on a mg/m 2 basis. This effect in rats is thought to be due to the prolactin-lowering effect of rotigotine. When rotigotine was administered subcutaneously (0, 5, 10, or 30 mg/kg/day) to pregnant rabbits during organogenesis (gestation days 7 through 19), an increase in embryofetal death occurred at the two highest doses tested. The no-effect dose is 12 times the MRHD on a mg/m 2 basis. In a study in which rotigotine was administered subcutaneously (0, 0.1, 0.3, or 1 mg/kg/day) to rats throughout pregnancy and lactation (gestation day 6 through postnatal day 21), impaired growth and development during lactation and long-term neurobehavioral abnormalities were observed in the offspring at the highest dose tested; when those offspring were mated, growth and survival of the next generation were adversely affected. The no- effect dose for pre- and postnatal developmental toxicity (0.3 mg/kg/day) is less than the MRHD on a mg/m 2 basis.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in the labeling: Sulfite Sensitivity [see Warnings and Precautions (5.1) ] Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.2) ] Hallucinations/Psychosis [see Warnings and Precautions (5.3) ] Symptomatic Hypotension [see Warnings and Precautions (5.4) ] Syncope [see Warnings and Precautions (5.5) ] Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.6) ] Elevation of Blood Pressure and Heart Rate [see Warnings and Precautions (5.7) ] Weight Gain and Fluid Retention [see Warnings and Precautions (5.8) ] Dyskinesia [see Warnings and Precautions (5.9) ] Application Site Reactions [see Warnings and Precautions (5.10) ] Augmentation and Rebound in RLS [see Warnings and Precautions (5.11) ] Hyperpyrexia and Confusion [see Warnings and Precautions (5.14) ] Withdrawal Symptoms [see Warnings and Precautions (5.15) ] Fibrotic Complications [see Warnings and Precautions (5.16) ] Parkinson's disease: Most common adverse reactions (at least 5% greater than placebo) were nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, disturbances in initiating and maintaining sleep, hyperhidrosis, visual disturbance, peripheral edema, and dyskinesia. ( 6.1 ) Restless Legs Syndrome: Most common adverse reactions (at least 5% greater than placebo) were application site reactions, nausea, disturbances in initiating and maintaining sleep, somnolence, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 1-844-599-2273 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions (number of unique patients experiencing an adverse reaction associated with treatment/total number of patients treated) observed in the clinical trials of a drug cannot be directly compared to incidence of adverse reactions in the clinical trials of another drug and may not reflect the incidence of adverse reactions observed in practice. Adverse Reactions in Early-Stage Parkinson's Disease The safety of NEUPRO was evaluated in a total of 649 early-stage Parkinson's disease patients who participated in three double-blind, placebo-controlled studies with durations of 3 to 9 months. Additional safety information was collected in short-term studies and two open-label extension studies in patients with early-stage Parkinson's disease. In the double-blind, placebo-controlled, dose-response study in patients with early-stage Parkinson's disease, the most common adverse reactions (at least 5% greater than placebo) for the maximum recommended dose of NEUPRO (6 mg/24 hours) were nausea, vomiting, somnolence, application site reactions, dizziness, anorexia, disturbances in initiating and maintaining sleep, hyperhidrosis, and visual disturbance. In this trial, 12% of patients treated with the maximum recommended NEUPRO dose (6 mg/24 hours) discontinued treatment because of adverse reactions, compared with 6% of patients who received placebo. Table 1 summarizes the adverse reactions that occurred in greater than 2% of NEUPRO-treated patients and more frequent than in placebo-treated patients in a double-blind, placebo-controlled, fixed-dose trial in patients with early-stage Parkinson's disease. Incidences for the non-recommended 8 mg/24 hours dose are also shown. Table 1 Adverse Reactions in a Placebo-Controlled, Fixed-Dose Trial in Patients with Early-Stage Parkinson's Disease Adverse Reaction Placebo N=64 % NEUPRO Dose 2 mg/24h N=67 % 4 mg/24h N=63 % 6 mg/24h N=65 % 8 mg/24h N=70 % Nausea 13 34 38 48 41 Vomiting 3 10 16 20 11 Somnolence 3 12 14 19 20 Application and instillation site reactions 19 21 19 32 43 Dizziness 11 21 14 22 20 Anorexia 0 2 2 9 4 Disturbances in initiating and maintaining sleep 6 6 11 14 11 Hyperhidrosis 3 3 3 11 3 Visual disturbance 0 …