These Highlights Do Not Include All The Information Needed To Use Neupro Safely And Effectively. See Full Prescribing Information For Neupro.

If you have Parkinson's disease, read this side. If you have Restless Legs Syndrome (also known as Willis-Ekbom disease), read the other side.

Rx Only

What is NEUPRO?

NEUPRO is a prescription medicine used to treat Parkinson's disease (PD). NEUPRO is a patch worn on the skin.

It is not known if NEUPRO is safe and effective in children.

Who should not use NEUPRO?

Do notuse NEUPRO if you are allergic to rotigotine or any of the ingredients in NEUPRO. See the end of this leaflet for a complete list of ingredients in NEUPRO.

What should I tell my doctor before using NEUPRO?

Before you start using NEUPRO, tell your doctor if you:

• have breathing problems including asthma.
• have daytime sleepiness from a sleep disorder or have unexpected or unpredictable sleepiness or periods of sleep.
• have mental problems such as schizophrenia, bipolar disorder, or psychosis.
• feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down.
• drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while using NEUPRO.
• have high or low blood pressure.
• have or have had heart problems.
• are pregnant or plan to become pregnant. It is not known if NEUPRO will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if NEUPRO passes into your breastmilk. The amount of breast milk you make may be decreased while taking NEUPRO. Talk to your doctor about the best way to feed your baby if you take NEUPRO.

Tell your doctor about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements.

NEUPRO and other medicines may affect each other causing side effects. NEUPRO may affect the way other medicines work, and other medicines may affect how NEUPRO works.

Especially tell your doctor if you take other medicines that can make you sleepy such as sleep medicines, antidepressants, or antipsychotics.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I use NEUPRO for Parkinson's disease?

• Read the Instructions for Use at the end of this leaflet for specific information about the right way to apply the NEUPRO patch.
• Use NEUPRO exactly as your doctor tells you to use it.
• NEUPRO comes in 4 different size (dose) patches for Parkinson's disease. Your doctor should start you on a low dose of NEUPRO. Your doctor will change the dose weekly until you are taking the right amount of medicine to control your symptoms. It may take several weeks before you reach the dose that controls your symptoms best.
• Apply NEUPRO 1 time each day at the same time each day.
• You may bathe, shower, or swim while wearing a NEUPRO patch. Water may loosen your NEUPRO patch.
• If the edges of the patch lift, you may tape them down with bandaging tape.
• If your NEUPRO patch falls off, apply a new NEUPRO patch for the rest of the day. The next day, apply a new patch at your regular time.
• If you miss a dose or forget to change your NEUPRO patch, apply a new NEUPRO patch as soon as you remember. Replace the NEUPRO patch at your normal time the next day.
• Do notstop using NEUPRO without talking to your doctor first. If your doctor tells you to stop using NEUPRO, you should ask your doctor for specific instructions on how to slowly and safely discontinue using NEUPRO. If you stop using NEUPRO, you may have withdrawal symptoms (see " What are the possible side effects of NEUPRO?" ).

What should I avoid while using NEUPRO?

• Do notdrive, operate machinery, or do other dangerous activities until you know how NEUPRO affects you.
• Avoid exposing the site where you have applied your NEUPRO patch to heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds, and direct sunlight. Too much medicine could be absorbed into your body.
• Do notuse NEUPRO during certain medical procedures called magnetic resonance imaging (MRI) or cardioversion. Using NEUPRO during these procedures could cause a burn to the site where you applied your NEUPRO patch.
• Avoid direct sunlight if you get a skin rash or irritation from NEUPRO until your skin heals. Sun exposure could lead to skin color changes.

What are the possible side effects of NEUPRO?

NEUPRO can cause serious side effects, including:

• severe allergic reactions.NEUPRO contains a sulfite called sodium metabisulfite. Sulfites can cause severe allergic reactions that are life threatening to some people who are sensitive to sulfites. An allergy to sulfites is not the same as an allergy to sulfa. People with asthma are more likely to be allergic to sulfites. Remove your NEUPRO patch right away and call your doctor if you have swelling of the lips or tongue, chest pain, trouble breathing or swallowing.
• falling asleep during normal activities.You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking NEUPRO. You may suddenly fall asleep without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while using NEUPRO are greater if you take other medicines that cause drowsiness. Tell your doctor right away if this happens. Before starting NEUPRO, be sure to tell your doctor if you take any medicines that make you drowsy.
• hallucinations and other psychosis.NEUPRO can cause or worsen psychotic symptoms including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkinson's disease who are elderly, taking NEUPRO, or taking higher doses of NEUPRO. If you have hallucinations or any of these other psychotic-like changes, talk with your doctor.
• changes in blood pressure.NEUPRO can decrease or increase your blood pressure. Lowering of your blood pressure is of special concern. If you faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down, this may mean that your blood pressure is decreased. If you notice this, you should contact your doctor. Also, when changing position from lying down or sitting to standing up, you should do it carefully and slowly. Lowering of your blood pressure can happen, especially when you start taking NEUPRO or when your dose is increased.
• fainting.Fainting can occur, and sometimes your heart rate may be decreased. This can happen especially when you start using NEUPRO or your dose is increased. Tell your doctor if you faint or feel dizzy.
• unusual urges.Some patients using NEUPRO get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, strong urges to spend money, binge eating, or increased sexual urges and behaviors. Some patients may want to use more NEUPRO than prescribed for their symptoms (dopamine dysregulation syndrome). If you notice or your family notices that you are developing any unusual behaviors, talk to your doctor.
• changes in heart rate. NEUPRO can increase your heart rate.
• increased weight and fluid retentioncan occur in patients using NEUPRO. NEUPRO can cause your body to keep extra fluid which leads to swelling and weight gain. Tell your doctor if you have swelling or fluid retention, especially in the ankles or legs, or have an unusually fast increase in weight.
• uncontrolled, sudden movements.NEUPRO may cause uncontrolled, sudden movements or make such movements you already have worse or more frequent. Tell your doctor if this happens. The doses of your anti-Parkinson's medicine may need to be changed.
• skin site reactions.Skin reactions may occur at the site where you apply NEUPRO. Tell your doctor if you get a rash, redness, swelling, or itching that will not go away at the skin site where you have applied NEUPRO.
• withdrawal symptoms.NEUPRO is a dopamine agonist medicine. Dopamine agonist medicines, including NEUPRO, can cause withdrawal symptoms as your dose is slowly lowered (tapered) or when treatment with NEUPRO is stopped. Tell your doctor right away if you get any of the following withdrawal symptoms:
  • fever
  • confusion
  • severe muscle stiffness
  • feeling like you do not care things you usually care about (apathy)
  • anxiety
  • depression
  • fatigue
  • insomnia
  • sweating
  • pain

The most common side effects of NEUPRO for Parkinson's disease are nausea, vomiting, sleepiness, application site reactions, dizziness, loss of appetite, difficulty falling asleep and staying asleep, increased sweating, vision problems, leg swelling, and uncontrolled, sudden movements of arms or legs.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of NEUPRO. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store NEUPRO?

• Store NEUPRO at 68°F to 77°F (20°C to 25°C).
• Store NEUPRO in its original sealed pouch until use. Do notstore NEUPRO outside of the pouch.

Keep NEUPRO and all medicines out of reach of children and away from pets.

General information about the safe and effective use of NEUPRO.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NEUPRO for a condition for which it was not prescribed. Do not give NEUPRO to other people even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about NEUPRO. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about NEUPRO that was written for health professionals.

For more information, go to www.neupro.com or call 1-844-599-2273.

What are the ingredients in NEUPRO?

Active ingredient:rotigotine

Inactive ingredients:ascorbyl palmitate, povidone, silicone adhesive, sodium metabisulfite, and dl-alpha-tocopherol.

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.

Store at 20º - 25ºC (68º - 77ºF); excursions permitted between 15º - 30ºC (59º - 86ºF). [See USP Controlled Room Temperature]

NEUPRO should be stored in the original pouch. Do not store outside of pouch.

Apply the transdermal system immediately upon removal from the pouch. Discard used systems in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.

INSTRUCTIONS FOR USE

NEUPRO ^®[NU pro]

(rotigotine transdermal system)

When to apply NEUPRO:

Each NEUPRO patch is sealed in a pouch that protects it until you are ready to apply it. See Figure A.

• NEUPRO should be applied right away after removing it from the protective pouch. Do notdamage or cut your NEUPRO patch into smaller pieces.
• Choose the time of day or night that works best for you to apply your NEUPRO patch. Apply your NEUPRO patch at the same time each day.
• Wear your NEUPRO patch for 24 hours.
• After 24 hours, remove your NEUPRO patch and apply a new one right away to a different area of your skin.

Where to apply NEUPRO:

• Choose an area of clean, dry, and healthy skin on the stomach, thigh, hip, side of the body between the ribs and the pelvis (flank), shoulder, or upper arm. See Figure B.
• Apply your NEUPRO patch to a different place on your skin each day, for example, from the right side to the left side and from the upper body to the lower body. Your NEUPRO patch should not be applied to the same area of your skin more than 1 time every 14 days. Apply NEUPRO to a different area of skin (only one of the shaded areas in Figure B)each day to reduce the chance of getting skin irritation.
• If you need to apply your NEUPRO patch to a hairy area, the area should be shaved at least 3 days before applying the patch.
• Avoid applying your NEUPRO patch to areas where it could be rubbed by tight clothing or under a waistband.
• Avoid applying your NEUPRO patch on skin folds.
• Do notapply your NEUPRO patch to skin that is red, irritated, or injured.
• Avoid applying creams, lotions, ointments, oils, and powders to the skin area where your NEUPRO patch will be placed.

How to apply NEUPRO:

How to remove NEUPRO:

• Slowly and carefully peel off your used NEUPRO patch. Carefully fold it in half (sticky sides together) and throw away the folded patch so that children and pets cannot reach it. Your NEUPRO patch still contains some medicine and could harm a child or pet.
• Gently wash the area with warm water and mild soap to remove any sticky material (adhesive) that stays on your skin.
• Baby or mineral oil may also be used to remove any adhesive. Avoid using alcohol or other solvents, such as nail polish remover. They may cause your skin to become irritated.
• Wash your hands with soap and water.
• You may see mild redness at the site when a patch is removed like when you remove an adhesive bandage. This redness should go away over time. If irritation or itchiness continues, tell your doctor.

This Patient Package Insert and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for: UCB, Inc., Smyrna, GA 30080

Neupro ^®is a registered trademark of the UCB Group of Companies.

©2021 UCB, Inc., Smyrna, GA 30080. All rights reserved.

Rev. 7/2021

Syncope has been reported in patients using dopamine agonists, and for this reason patients should be alerted to the possibility of syncope. Because the studies of NEUPRO excluded patients with clinically relevant cardiovascular disease, patients with severe cardiovascular disease should be asked about symptoms of syncope and pre-syncope.

NEUPRO is a transdermal system that provides continuous delivery of rotigotine, a non-ergoline dopamine agonist, for 24 hours following application to intact skin.

NEUPRO is available in six strengths as shown in Table 4.

The chemical name of rotigotine is (6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol. The empirical formula is C ₁₉H ₂₅NOS. The molecular weight is 315.48. The structural formula for rotigotine is:

NEUPRO may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. For the maximum recommended NEUPRO dose, the incidence of dyskinesia was increased for NEUPRO (NEUPRO 14% vs. placebo 7%) in patients with advanced-stage Parkinson's disease, and this incidence increased with increasing dose. Patients treated with the maximum recommended dose of NEUPRO also had an increased risk (NEUPRO 3% vs. placebo 0%) for early discontinuation from the study because of dyskinesia.

Safety and effectiveness in pediatric patients for any indication have not been established.

Of patients receiving NEUPRO in clinical studies for the treatment of Parkinson's disease, approximately 50% were age 65 and over, and approximately 11% were age 75 and over. Among patients receiving NEUPRO in clinical studies for the treatment of RLS, 26% were age 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No overall differences in plasma levels of rotigotine were observed between patients who were 65 to 80 years old compared with younger patients receiving the same rotigotine doses.

NEUPRO is contraindicated in patients who have demonstrated hypersensitivity to rotigotine or the components of the transdermal system.

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)]

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.

The effect of application of heat to the transdermal system has not been studied. However, heat application has been shown to increase absorption several fold with other transdermal products. Patients should be advised to avoid exposing the NEUPRO application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.

The most likely symptoms of overdose would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions, and other signs of excessive dopaminergic stimulation.

Some clinical laboratory analytes were abnormal in patients treated with the maximum recommended NEUPRO dose in the fixed-dose, placebo-controlled, dose-response trials for patients with early- and advanced-stage Parkinson's disease and with RLS.

Patients with early-stage Parkinson's disease receiving NEUPRO had an increased risk for low hemoglobin below the normal reference range (NEUPRO 8% vs. placebo 2%) and for decreased hematocrit below the normal reference range (NEUPRO 8% vs. placebo 5%). Patients with advanced-stage Parkinson's disease receiving NEUPRO had an increased risk for a low hemoglobin below the normal reference range (NEUPRO 15% vs. placebo 11%) and for decreased hematocrit below the normal reference range (NEUPRO 17% vs. placebo 14%). Patients with RLS receiving NEUPRO had an increased risk for a decreased hemoglobin below the normal reference range (NEUPRO 15% vs. placebo 12%). There was also an increased risk for markedly decreased hemoglobin and hematocrit (NEUPRO 2% vs. placebo 0%) in patients with advanced-stage Parkinson's disease receiving NEUPRO and for markedly decreased hematocrit (NEUPRO 1% vs. placebo 0%) in patients with RLS receiving NEUPRO.

Patients with early-stage Parkinson's disease receiving NEUPRO had an increased risk for elevated serum blood urea nitrogen (BUN) above the normal reference range (NEUPRO 11% vs. placebo 2%). There was also an increased risk for markedly elevated serum BUN (NEUPRO 3% vs. placebo 2%) in patients with advanced-stage Parkinson's disease receiving NEUPRO.

There was an increased risk for low serum glucose below the normal reference range in patients with early- stage Parkinson's disease receiving NEUPRO (NEUPRO 15% vs. placebo 6%) and in patients with advanced-stage Parkinson's disease (NEUPRO 10% vs. placebo 7%). There was also an increased risk for markedly decreased serum glucose (NEUPRO 1% vs. placebo 0%) in patients with advanced-stage Parkinson's disease receiving NEUPRO.

Serum creatine phosphokinase (CPK) was elevated in Japanese patients taking NEUPRO for early- or advanced-stage Parkinson's disease in placebo-controlled, flexible-dose studies conducted in Japan. The frequency of CPK elevation observed in patients receiving NEUPRO for early-stage Parkinson's disease was 40% (35/88) in the NEUPRO group compared to 17% (15/89) in the placebo group. The frequency of CPK elevation observed in patients receiving NEUPRO for advanced-stage Parkinson's disease was 39% (99/253) in the NEUPRO group compared to 20% (34/171) in the placebo group using pooled data from two studies.

Increased CPK occurred at any time during the respective studies, and in some instances increased CPK was observed at two or more consecutive visits. The total daily dose of NEUPRO taken by patients with early- and advanced-stage Parkinson's disease ranged between 2 mg/24 hours to 16 mg/24 hours. Studies of NEUPRO conducted outside of Japan did not include assessments of serum CPK in patients treated for Parkinson's disease .Increased CPK was also reported in postmarketing data.

NEUPRO is a dopamine agonist indicated for the treatment of:

• Parkinson's disease ( 1.1)
• Moderate-to-severe primary Restless Legs Syndrome ( 1.2)

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.

As has been reported with other dopamine agonists, binding to melanin-containing tissues (i.e., eyes) in the pigmented rat and monkey was evident after a single dose of rotigotine, but was slowly cleared over the 14-day observation period.

There is no known antidote for overdosage of dopamine agonists. In case of suspected overdose, the excess transdermal system(s) should immediately be removed from the patient. Concentrations of rotigotine decrease after patch removal. The terminal half-life of rotigotine is 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours. The patient's heart rate, heart rhythm, and blood pressure should be monitored. As shown in a study of renally impaired patients, dialysis is not expected to be beneficial. Treatment of overdose may require general supportive measures to maintain vital signs. If it is necessary to discontinue use of rotigotine after overdose, it should be discontinued gradually to prevent hyperpyrexia and confusion [see Dosage and Administration (2.4)and Warnings and Precautions (5.14)].

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.

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).

Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating and pain have been reported during taper or after discontinuation of dopamine agonists, including NEUPRO. These symptoms generally do not respond to levodopa.

Prior to discontinuation, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

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

• 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)

The clinical program included 1309 patients with moderate-to-severe RLS. The efficacy of NEUPRO in the treatment of Restless Legs Syndrome (RLS) was primarily evaluated in two randomized, double-blind, placebo-controlled, fixed-dose trials with maintenance periods of 6 months duration. Patients received NEUPRO doses ranging from 0.5 mg/24 hours to 3 mg/24 hours or placebo once daily. In these two trials, the mean duration of RLS was 2.1 to 3.1 years, mean age was approximately 55 years (range 19-78 years), approximately 68% were women, and 97% were Caucasian. In both trials, patches were applied to different application sites including the abdomen, thigh, hip, flank, shoulder, and/or upper arm and patch application sites were rotated on a daily basis.

The two outcome measures used to assess the effect of treatment as co-primary efficacy endpoints were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.

• 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)

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.

Dopaminergic agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, resulting in postural/orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to a postural challenge. For these reasons, both Parkinson's and Restless Legs Syndrome patients being treated with dopaminergic agonists ordinarily (1) require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and (2) should be informed of this risk.

An increased risk for decreases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position in patients treated with NEUPRO. In patients taking the maximum recommended NEUPRO dose, orthostatic (change from supine to standing) decreases in systolic blood pressure (at least 20 mm Hg or greater) was 16% for NEUPRO and 14% for placebo in patients with early-stage Parkinson's disease, 32% for NEUPRO and 27% for placebo in patients with advanced-stage Parkinson's disease, and 13% for NEUPRO and 11% for placebo in patients with Restless Legs Syndrome.

More severe decreases in systolic blood pressure (40 mm Hg or greater) and in diastolic blood pressure (20 mm Hg or greater) also occurred more frequently (NEUPRO incidence at least 2% greater than placebo) in patients with early- and advanced-stage Parkinson's disease during measurements when supine, standing, or changing from supine to standing position. Patients experienced dose-related decreases in blood pressure at different times throughout the trial including the final visit.

An analysis using a variety of adverse reaction terms suggestive of orthostatic hypotension, including dizziness/postural dizziness and others, showed an increased risk for all patients treated with NEUPRO. For the maximum recommended NEUPRO dose, the incidence of adverse reactions suggestive of hypotension/orthostatic hypotension was 29% for NEUPRO and 11% for placebo in early-stage Parkinson's disease, 27% for NEUPRO and 23% for placebo in advanced-stage Parkinson's disease, and 8% for NEUPRO and 7% for placebo in Restless Legs Syndrome.

This increased risk for symptomatic hypotension and decreases in blood pressure was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this study. The increased risk for significant decreases in blood pressure or orthostatic hypotension occurred especially in the dose escalation/titration period.

NEUPRO is indicated for the treatment of Parkinson's disease.

Transdermal System: 1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, and 8 mg/24 hours of rotigotine.

There was an increased risk for hallucinations in patients with advanced-stage Parkinson's disease treated with NEUPRO. In patients taking the maximum recommended NEUPRO dose, the incidence of hallucinations was 7% for NEUPRO and 3% for placebo, and this treatment difference increased with increasing dose.

Hallucinations were of sufficient severity to cause discontinuation of treatment (mainly during the dose escalation/titration period) in 3% of advanced-stage Parkinson's disease patients treated with the maximum recommended dose of NEUPRO compared with 1% of placebo-treated patients. Hallucinations have also been reported in post-marketing reports.

Post-marketing reports indicate that patients with Parkinson's disease or RLS may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic behavior during NEUPRO treatment or after starting or increasing the dose of NEUPRO. Other drugs prescribed to improve the symptoms of Parkinson's disease or RLS can have similar effects on thinking and behavior. This abnormal thinking and behavior may consist of one or more of the following: paranoid ideation, delusions, hallucinations, confusion, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium. These various manifestations of psychotic behavior were also observed during the clinical development of NEUPRO for early- and advanced-stage Parkinson's disease and Restless Legs Syndrome.

Patients with a major psychotic disorder should ordinarily not be treated with NEUPRO because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of NEUPRO [see Drug Interactions (7.1)].

The following adverse reaction has been identified during post-approval use of NEUPRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General Disorders and Administration Site Conditions: withdrawal symptoms [see Warnings and Precautions (5.15)]

Nervous System Disorders: Dropped head syndrome

Musculoskeletal and connective tissue disorders:Rhabdomyolysis

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 withdrawal of NEUPRO is achieved.

Pregnancy: Based on animal data, may cause fetal harm. ( 8.1)

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)].

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.

Application site reactions (ASRs) occurred at a greater frequency in the NEUPRO-treated patients than in placebo-treated patients in the double-blind, placebo-controlled, dose-response studies with NEUPRO. For the maximum recommended NEUPRO dose, the incidence of application site reactions was 32% for NEUPRO and 19% for placebo in patients with early-stage Parkinson's disease, 36% for NEUPRO and 13% for placebo in patients with advanced-stage Parkinson's disease, and 43% for NEUPRO and 4% for placebo in patients with Restless Legs Syndrome. ASRs exhibited a dose-dependent relationship for all doses for patients with early- and advanced-stage Parkinson's disease and Restless Legs Syndrome. ASRs were also of sufficient severity to cause study discontinuation for patients with early-stage Parkinson's disease (NEUPRO 3% vs. placebo 0%), advanced-stage Parkinson's disease (NEUPRO 2% vs. placebo 0%), and Restless Legs Syndrome (NEUPRO 12% vs. placebo 0%) who were treated with the maximum recommended NEUPRO dose.

The signs and symptoms of these reactions generally were localized erythema, edema, or pruritus limited to the patch area and usually did not lead to dose reduction. Generalized skin reactions (e.g., allergic rash, including erythematous, macular-papular rash, or pruritus) have been reported at lower rates than ASRs during the development of NEUPRO.

In a clinical study designed to investigate the cumulative skin irritation of NEUPRO, daily rotation of NEUPRO application sites has been shown to reduce the incidence of ASRs in comparison to repetitive application to the same site. In a clinical study investigating the skin sensitizing potential of NEUPRO in 221 healthy subjects, no case of contact sensitization was observed. Localized sensitization reactions were observed in a study with healthy subjects by continuously rotating a 0.5 mg/24 hours transdermal system, after induction of maximal irritational stress was achieved by repetitive transdermal system application to the same site.

If a patient reports a persistent application site reaction (of more than a few days), reports an increase in severity, or reports a skin reaction spreading outside the application site, an assessment of the risk and benefits for the individual patient should be conducted. If a generalized skin reaction associated with the use of NEUPRO is observed, NEUPRO should be discontinued.

A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, rhabdomyolysis, and/or autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti- Parkinsonian therapy. Therefore, it is recommended that the dose be tapered at the end of NEUPRO treatment [see Dosage and Administration (2.4)].

NEUPRO is indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients taking the maximum recommended NEUPRO dose for early-stage Parkinson's disease had a higher incidence (2%) of substantial weight gain (more than 10% of baseline weight) than patients taking placebo (0%). In advanced-stage Parkinson's disease, the incidence of weight gain more than 10% of baseline weight was 9% in NEUPRO-treated patients (for the maximum recommended dose) and 1% in placebo-treated patients. This weight gain was frequently associated with the development of peripheral edema in patients with Parkinson's disease, suggesting that NEUPRO may cause fluid retention in some Parkinson's patients. In patients taking the maximum recommended NEUPRO dose, the incidence of peripheral edema was 3% for NEUPRO and 2% for placebo in early-stage Parkinson's disease and 9% for NEUPRO and 1% for placebo in advanced-stage Parkinson's disease. These treatment differences increased further with treatment at NEUPRO dosing above the maximum recommended doses. Monitor for weight gain and fluid retention when treating patients with concomitant illnesses such as congestive heart failure or renal insufficiency.

Each transdermal system is packaged in a separate pouch.

Each strength is available in cartons of 30 transdermal systems.

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.

Augmentation is a worsening of RLS symptoms during treatment, leading to an increase in overall symptom severity or earlier time of symptom onset each day compared to before initiation of treatment. Use of dopaminergic medications, including NEUPRO, may result in augmentation.

Rebound, an exacerbation of RLS symptoms, is considered to be an end of dose effect, related to the half-life of the therapeutic agent. Reports in the published literature indicate discontinuation or wearing off of dopaminergic medications can result in rebound.

Treatment for Parkinson's disease.

NDC 50474-808-11

Neupro ^®

(rotigotine transdermal system)

Includes:

• 7 systems that deliver 2 mg/24 hours each
• 7 systems that deliver 4 mg/24 hours each

Titration kit for

Parkinson's disease

Please see Important Safety Information on back of carton

and full Prescribing Information inside.

Your step-by-step guide to beginning therapy

with the NEUPRO transdermal system

This package also contains:

• Full Prescribing Information

Professional samples—Rx only

Not for sale

For transdermal use only

Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including NEUPRO, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with NEUPRO for Parkinson's disease or RLS. Dopamine dysregulation syndrome, the repeated use of more NEUPRO than as prescribed to manage their symptoms of Parkinson's disease or RLS, was observed in some patients during treatment with NEUPRO. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking NEUPRO .

Some patients treated with NEUPRO exhibited increases in systolic blood pressure (greater than 180 mm Hg) and/or diastolic blood pressure (greater than 105 mm Hg) while supine or standing. In patients with advanced-stage Parkinson's disease, this increased risk for systolic blood pressure greater than 180 mm Hg was 5% for NEUPRO and 3% for placebo and for diastolic blood pressure greater than 105 mm Hg was 4% for NEUPRO and 0% for placebo. In patients with Restless Legs Syndrome, this increased risk for diastolic blood pressure greater than 105 mm Hg was 8% for NEUPRO and 4% for placebo.

Increases in systolic blood pressure (at least 20 mm Hg or more) and in diastolic blood pressure (at least 10 mm Hg or more) occurred more frequently (incidence at least 5% greater than placebo) in all patients (i.e., early- and advanced-stage Parkinson's disease and Restless Legs Syndrome) taking the maximum recommended NEUPRO dose. These increases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position. More severe increases in systolic blood pressure (40 mm Hg or more) and in diastolic blood pressure (20 mm Hg or more) also occurred more frequently (incidence at least 2% greater than placebo) in NEUPRO-treated patients with early- and advanced-stage Parkinson's disease and with Restless Legs Syndrome during measurements when supine, standing, and/or changing from supine to standing position.

In the placebo-controlled trials, there was an increased risk for hypertension as an adverse reaction with the maximum recommended NEUPRO dose in patients with advanced-stage Parkinson's disease (NEUPRO 3% vs. placebo 0%) and Restless Legs Syndrome (NEUPRO 4% vs. placebo 0%).

Some patients treated with NEUPRO exhibited increased pulse (greater than 100 beats per minute) while supine and/or standing. In patients with advanced-stage Parkinson's disease, there was an increased risk (at least 2% greater than placebo) of increased pulse for patients taking the maximum recommended NEUPRO dose. In patients with Restless Legs Syndrome, there was an increased risk (at least 5% greater than placebo) of increased pulse for patients taking the maximum recommended NEUPRO dose.

These findings of blood pressure and heart rate elevations should be considered when treating patients with cardiovascular disease.

The backing layer of NEUPRO contains aluminum. To avoid skin burns, NEUPRO should be removed prior to magnetic resonance imaging or cardioversion.

NDC 50474-801-03

30 systems

Neupro ^®

(rotigotine transdermal system)

1 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-802-03

30 systems

Neupro ^®

(rotigotine transdermal system)

2 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-803-03

30 systems

Neupro ^®

(rotigotine transdermal system)

3 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-804-03

30 systems

Neupro ^®

(rotigotine transdermal system)

4 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-805-03

30 systems

Neupro ^®

(rotigotine transdermal system)

6 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-806-03

30 systems

Neupro ^®

(rotigotine transdermal system)

8 mg/24 hours

For transdermal use only

Rx Only

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.

NDC 50474-801-17

7 systems

Neupro ^®

(rotigotine transdermal system)

1 mg/24 hours

This package contains:

• 7 systems that deliver 1 mg/24 hours each
• Full Prescribing Information

Treatment for moderate-to-severe primary

Restless Legs Syndrome (RLS)

Please see Important Safety Information on back of carton

and full Prescribing Information inside

Sample Kit for

Restless Legs Syndrome

Professional samples – not for sale

For transdermal use only – Rx only

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.

Store at 20º - 25ºC (68º - 77ºF); excursions permitted between 15º - 30ºC (59º - 86ºF). [See USP Controlled Room Temperature]

NEUPRO should be stored in the original pouch. Do not store outside of pouch.

Apply the transdermal system immediately upon removal from the pouch. Discard used systems in household trash in a manner that prevents accidental application or ingestion by children, pets, or others.

INSTRUCTIONS FOR USE

NEUPRO ^®[NU pro]

(rotigotine transdermal system)

When to apply NEUPRO:

Each NEUPRO patch is sealed in a pouch that protects it until you are ready to apply it. See Figure A.

• NEUPRO should be applied right away after removing it from the protective pouch. Do notdamage or cut your NEUPRO patch into smaller pieces.
• Choose the time of day or night that works best for you to apply your NEUPRO patch. Apply your NEUPRO patch at the same time each day.
• Wear your NEUPRO patch for 24 hours.
• After 24 hours, remove your NEUPRO patch and apply a new one right away to a different area of your skin.

Where to apply NEUPRO:

• Choose an area of clean, dry, and healthy skin on the stomach, thigh, hip, side of the body between the ribs and the pelvis (flank), shoulder, or upper arm. See Figure B.
• Apply your NEUPRO patch to a different place on your skin each day, for example, from the right side to the left side and from the upper body to the lower body. Your NEUPRO patch should not be applied to the same area of your skin more than 1 time every 14 days. Apply NEUPRO to a different area of skin (only one of the shaded areas in Figure B)each day to reduce the chance of getting skin irritation.
• If you need to apply your NEUPRO patch to a hairy area, the area should be shaved at least 3 days before applying the patch.
• Avoid applying your NEUPRO patch to areas where it could be rubbed by tight clothing or under a waistband.
• Avoid applying your NEUPRO patch on skin folds.
• Do notapply your NEUPRO patch to skin that is red, irritated, or injured.
• Avoid applying creams, lotions, ointments, oils, and powders to the skin area where your NEUPRO patch will be placed.

How to apply NEUPRO:

How to remove NEUPRO:

• Slowly and carefully peel off your used NEUPRO patch. Carefully fold it in half (sticky sides together) and throw away the folded patch so that children and pets cannot reach it. Your NEUPRO patch still contains some medicine and could harm a child or pet.
• Gently wash the area with warm water and mild soap to remove any sticky material (adhesive) that stays on your skin.
• Baby or mineral oil may also be used to remove any adhesive. Avoid using alcohol or other solvents, such as nail polish remover. They may cause your skin to become irritated.
• Wash your hands with soap and water.
• You may see mild redness at the site when a patch is removed like when you remove an adhesive bandage. This redness should go away over time. If irritation or itchiness continues, tell your doctor.

This Patient Package Insert and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Manufactured for: UCB, Inc., Smyrna, GA 30080

Neupro ^®is a registered trademark of the UCB Group of Companies.

©2021 UCB, Inc., Smyrna, GA 30080. All rights reserved.

Rev. 7/2021

Syncope has been reported in patients using dopamine agonists, and for this reason patients should be alerted to the possibility of syncope. Because the studies of NEUPRO excluded patients with clinically relevant cardiovascular disease, patients with severe cardiovascular disease should be asked about symptoms of syncope and pre-syncope.

NEUPRO is a transdermal system that provides continuous delivery of rotigotine, a non-ergoline dopamine agonist, for 24 hours following application to intact skin.

NEUPRO is available in six strengths as shown in Table 4.

The chemical name of rotigotine is (6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol. The empirical formula is C ₁₉H ₂₅NOS. The molecular weight is 315.48. The structural formula for rotigotine is:

NEUPRO may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. For the maximum recommended NEUPRO dose, the incidence of dyskinesia was increased for NEUPRO (NEUPRO 14% vs. placebo 7%) in patients with advanced-stage Parkinson's disease, and this incidence increased with increasing dose. Patients treated with the maximum recommended dose of NEUPRO also had an increased risk (NEUPRO 3% vs. placebo 0%) for early discontinuation from the study because of dyskinesia.

Safety and effectiveness in pediatric patients for any indication have not been established.

Of patients receiving NEUPRO in clinical studies for the treatment of Parkinson's disease, approximately 50% were age 65 and over, and approximately 11% were age 75 and over. Among patients receiving NEUPRO in clinical studies for the treatment of RLS, 26% were age 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No overall differences in plasma levels of rotigotine were observed between patients who were 65 to 80 years old compared with younger patients receiving the same rotigotine doses.

NEUPRO is contraindicated in patients who have demonstrated hypersensitivity to rotigotine or the components of the transdermal system.

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)]

If you have Parkinson's disease, read this side. If you have Restless Legs Syndrome (also known as Willis-Ekbom disease), read the other side.

Rx Only

What is NEUPRO?

NEUPRO is a prescription medicine used to treat Parkinson's disease (PD). NEUPRO is a patch worn on the skin.

It is not known if NEUPRO is safe and effective in children.

Who should not use NEUPRO?

Do notuse NEUPRO if you are allergic to rotigotine or any of the ingredients in NEUPRO. See the end of this leaflet for a complete list of ingredients in NEUPRO.

What should I tell my doctor before using NEUPRO?

Before you start using NEUPRO, tell your doctor if you:

• have breathing problems including asthma.
• have daytime sleepiness from a sleep disorder or have unexpected or unpredictable sleepiness or periods of sleep.
• have mental problems such as schizophrenia, bipolar disorder, or psychosis.
• feel dizzy, nauseated, sweaty, or faint when you stand up from sitting or lying down.
• drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while using NEUPRO.
• have high or low blood pressure.
• have or have had heart problems.
• are pregnant or plan to become pregnant. It is not known if NEUPRO will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if NEUPRO passes into your breastmilk. The amount of breast milk you make may be decreased while taking NEUPRO. Talk to your doctor about the best way to feed your baby if you take NEUPRO.

Tell your doctor about all the medicines you take,including prescription and over-the-counter medicines, vitamins, and herbal supplements.

NEUPRO and other medicines may affect each other causing side effects. NEUPRO may affect the way other medicines work, and other medicines may affect how NEUPRO works.

Especially tell your doctor if you take other medicines that can make you sleepy such as sleep medicines, antidepressants, or antipsychotics.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I use NEUPRO for Parkinson's disease?

• Read the Instructions for Use at the end of this leaflet for specific information about the right way to apply the NEUPRO patch.
• Use NEUPRO exactly as your doctor tells you to use it.
• NEUPRO comes in 4 different size (dose) patches for Parkinson's disease. Your doctor should start you on a low dose of NEUPRO. Your doctor will change the dose weekly until you are taking the right amount of medicine to control your symptoms. It may take several weeks before you reach the dose that controls your symptoms best.
• Apply NEUPRO 1 time each day at the same time each day.
• You may bathe, shower, or swim while wearing a NEUPRO patch. Water may loosen your NEUPRO patch.
• If the edges of the patch lift, you may tape them down with bandaging tape.
• If your NEUPRO patch falls off, apply a new NEUPRO patch for the rest of the day. The next day, apply a new patch at your regular time.
• If you miss a dose or forget to change your NEUPRO patch, apply a new NEUPRO patch as soon as you remember. Replace the NEUPRO patch at your normal time the next day.
• Do notstop using NEUPRO without talking to your doctor first. If your doctor tells you to stop using NEUPRO, you should ask your doctor for specific instructions on how to slowly and safely discontinue using NEUPRO. If you stop using NEUPRO, you may have withdrawal symptoms (see " What are the possible side effects of NEUPRO?" ).

What should I avoid while using NEUPRO?

• Do notdrive, operate machinery, or do other dangerous activities until you know how NEUPRO affects you.
• Avoid exposing the site where you have applied your NEUPRO patch to heating pads, electric blankets, heat lamps, saunas, hot tubs, heated water beds, and direct sunlight. Too much medicine could be absorbed into your body.
• Do notuse NEUPRO during certain medical procedures called magnetic resonance imaging (MRI) or cardioversion. Using NEUPRO during these procedures could cause a burn to the site where you applied your NEUPRO patch.
• Avoid direct sunlight if you get a skin rash or irritation from NEUPRO until your skin heals. Sun exposure could lead to skin color changes.

What are the possible side effects of NEUPRO?

NEUPRO can cause serious side effects, including:

• severe allergic reactions.NEUPRO contains a sulfite called sodium metabisulfite. Sulfites can cause severe allergic reactions that are life threatening to some people who are sensitive to sulfites. An allergy to sulfites is not the same as an allergy to sulfa. People with asthma are more likely to be allergic to sulfites. Remove your NEUPRO patch right away and call your doctor if you have swelling of the lips or tongue, chest pain, trouble breathing or swallowing.
• falling asleep during normal activities.You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking NEUPRO. You may suddenly fall asleep without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while using NEUPRO are greater if you take other medicines that cause drowsiness. Tell your doctor right away if this happens. Before starting NEUPRO, be sure to tell your doctor if you take any medicines that make you drowsy.
• hallucinations and other psychosis.NEUPRO can cause or worsen psychotic symptoms including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkinson's disease who are elderly, taking NEUPRO, or taking higher doses of NEUPRO. If you have hallucinations or any of these other psychotic-like changes, talk with your doctor.
• changes in blood pressure.NEUPRO can decrease or increase your blood pressure. Lowering of your blood pressure is of special concern. If you faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down, this may mean that your blood pressure is decreased. If you notice this, you should contact your doctor. Also, when changing position from lying down or sitting to standing up, you should do it carefully and slowly. Lowering of your blood pressure can happen, especially when you start taking NEUPRO or when your dose is increased.
• fainting.Fainting can occur, and sometimes your heart rate may be decreased. This can happen especially when you start using NEUPRO or your dose is increased. Tell your doctor if you faint or feel dizzy.
• unusual urges.Some patients using NEUPRO get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble, strong urges to spend money, binge eating, or increased sexual urges and behaviors. Some patients may want to use more NEUPRO than prescribed for their symptoms (dopamine dysregulation syndrome). If you notice or your family notices that you are developing any unusual behaviors, talk to your doctor.
• changes in heart rate. NEUPRO can increase your heart rate.
• increased weight and fluid retentioncan occur in patients using NEUPRO. NEUPRO can cause your body to keep extra fluid which leads to swelling and weight gain. Tell your doctor if you have swelling or fluid retention, especially in the ankles or legs, or have an unusually fast increase in weight.
• uncontrolled, sudden movements.NEUPRO may cause uncontrolled, sudden movements or make such movements you already have worse or more frequent. Tell your doctor if this happens. The doses of your anti-Parkinson's medicine may need to be changed.
• skin site reactions.Skin reactions may occur at the site where you apply NEUPRO. Tell your doctor if you get a rash, redness, swelling, or itching that will not go away at the skin site where you have applied NEUPRO.
• withdrawal symptoms.NEUPRO is a dopamine agonist medicine. Dopamine agonist medicines, including NEUPRO, can cause withdrawal symptoms as your dose is slowly lowered (tapered) or when treatment with NEUPRO is stopped. Tell your doctor right away if you get any of the following withdrawal symptoms:
  • fever
  • confusion
  • severe muscle stiffness
  • feeling like you do not care things you usually care about (apathy)
  • anxiety
  • depression
  • fatigue
  • insomnia
  • sweating
  • pain

The most common side effects of NEUPRO for Parkinson's disease are nausea, vomiting, sleepiness, application site reactions, dizziness, loss of appetite, difficulty falling asleep and staying asleep, increased sweating, vision problems, leg swelling, and uncontrolled, sudden movements of arms or legs.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of NEUPRO. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store NEUPRO?

• Store NEUPRO at 68°F to 77°F (20°C to 25°C).
• Store NEUPRO in its original sealed pouch until use. Do notstore NEUPRO outside of the pouch.

Keep NEUPRO and all medicines out of reach of children and away from pets.

General information about the safe and effective use of NEUPRO.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use NEUPRO for a condition for which it was not prescribed. Do not give NEUPRO to other people even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet summarizes the most important information about NEUPRO. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about NEUPRO that was written for health professionals.

For more information, go to www.neupro.com or call 1-844-599-2273.

What are the ingredients in NEUPRO?

Active ingredient:rotigotine

Inactive ingredients:ascorbyl palmitate, povidone, silicone adhesive, sodium metabisulfite, and dl-alpha-tocopherol.

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.

The effect of application of heat to the transdermal system has not been studied. However, heat application has been shown to increase absorption several fold with other transdermal products. Patients should be advised to avoid exposing the NEUPRO application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot tubs, heated water beds, and prolonged direct sunlight.

The most likely symptoms of overdose would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions, and other signs of excessive dopaminergic stimulation.

Some clinical laboratory analytes were abnormal in patients treated with the maximum recommended NEUPRO dose in the fixed-dose, placebo-controlled, dose-response trials for patients with early- and advanced-stage Parkinson's disease and with RLS.

Patients with early-stage Parkinson's disease receiving NEUPRO had an increased risk for low hemoglobin below the normal reference range (NEUPRO 8% vs. placebo 2%) and for decreased hematocrit below the normal reference range (NEUPRO 8% vs. placebo 5%). Patients with advanced-stage Parkinson's disease receiving NEUPRO had an increased risk for a low hemoglobin below the normal reference range (NEUPRO 15% vs. placebo 11%) and for decreased hematocrit below the normal reference range (NEUPRO 17% vs. placebo 14%). Patients with RLS receiving NEUPRO had an increased risk for a decreased hemoglobin below the normal reference range (NEUPRO 15% vs. placebo 12%). There was also an increased risk for markedly decreased hemoglobin and hematocrit (NEUPRO 2% vs. placebo 0%) in patients with advanced-stage Parkinson's disease receiving NEUPRO and for markedly decreased hematocrit (NEUPRO 1% vs. placebo 0%) in patients with RLS receiving NEUPRO.

Patients with early-stage Parkinson's disease receiving NEUPRO had an increased risk for elevated serum blood urea nitrogen (BUN) above the normal reference range (NEUPRO 11% vs. placebo 2%). There was also an increased risk for markedly elevated serum BUN (NEUPRO 3% vs. placebo 2%) in patients with advanced-stage Parkinson's disease receiving NEUPRO.

There was an increased risk for low serum glucose below the normal reference range in patients with early- stage Parkinson's disease receiving NEUPRO (NEUPRO 15% vs. placebo 6%) and in patients with advanced-stage Parkinson's disease (NEUPRO 10% vs. placebo 7%). There was also an increased risk for markedly decreased serum glucose (NEUPRO 1% vs. placebo 0%) in patients with advanced-stage Parkinson's disease receiving NEUPRO.

Serum creatine phosphokinase (CPK) was elevated in Japanese patients taking NEUPRO for early- or advanced-stage Parkinson's disease in placebo-controlled, flexible-dose studies conducted in Japan. The frequency of CPK elevation observed in patients receiving NEUPRO for early-stage Parkinson's disease was 40% (35/88) in the NEUPRO group compared to 17% (15/89) in the placebo group. The frequency of CPK elevation observed in patients receiving NEUPRO for advanced-stage Parkinson's disease was 39% (99/253) in the NEUPRO group compared to 20% (34/171) in the placebo group using pooled data from two studies.

Increased CPK occurred at any time during the respective studies, and in some instances increased CPK was observed at two or more consecutive visits. The total daily dose of NEUPRO taken by patients with early- and advanced-stage Parkinson's disease ranged between 2 mg/24 hours to 16 mg/24 hours. Studies of NEUPRO conducted outside of Japan did not include assessments of serum CPK in patients treated for Parkinson's disease .Increased CPK was also reported in postmarketing data.

NEUPRO is a dopamine agonist indicated for the treatment of:

• Parkinson's disease ( 1.1)
• Moderate-to-severe primary Restless Legs Syndrome ( 1.2)

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.

As has been reported with other dopamine agonists, binding to melanin-containing tissues (i.e., eyes) in the pigmented rat and monkey was evident after a single dose of rotigotine, but was slowly cleared over the 14-day observation period.

There is no known antidote for overdosage of dopamine agonists. In case of suspected overdose, the excess transdermal system(s) should immediately be removed from the patient. Concentrations of rotigotine decrease after patch removal. The terminal half-life of rotigotine is 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours. The patient's heart rate, heart rhythm, and blood pressure should be monitored. As shown in a study of renally impaired patients, dialysis is not expected to be beneficial. Treatment of overdose may require general supportive measures to maintain vital signs. If it is necessary to discontinue use of rotigotine after overdose, it should be discontinued gradually to prevent hyperpyrexia and confusion [see Dosage and Administration (2.4)and Warnings and Precautions (5.14)].

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.

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).

Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating and pain have been reported during taper or after discontinuation of dopamine agonists, including NEUPRO. These symptoms generally do not respond to levodopa.

Prior to discontinuation, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

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

• 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)

The clinical program included 1309 patients with moderate-to-severe RLS. The efficacy of NEUPRO in the treatment of Restless Legs Syndrome (RLS) was primarily evaluated in two randomized, double-blind, placebo-controlled, fixed-dose trials with maintenance periods of 6 months duration. Patients received NEUPRO doses ranging from 0.5 mg/24 hours to 3 mg/24 hours or placebo once daily. In these two trials, the mean duration of RLS was 2.1 to 3.1 years, mean age was approximately 55 years (range 19-78 years), approximately 68% were women, and 97% were Caucasian. In both trials, patches were applied to different application sites including the abdomen, thigh, hip, flank, shoulder, and/or upper arm and patch application sites were rotated on a daily basis.

The two outcome measures used to assess the effect of treatment as co-primary efficacy endpoints were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.

• 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)

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.

Dopaminergic agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, resulting in postural/orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to a postural challenge. For these reasons, both Parkinson's and Restless Legs Syndrome patients being treated with dopaminergic agonists ordinarily (1) require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and (2) should be informed of this risk.

An increased risk for decreases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position in patients treated with NEUPRO. In patients taking the maximum recommended NEUPRO dose, orthostatic (change from supine to standing) decreases in systolic blood pressure (at least 20 mm Hg or greater) was 16% for NEUPRO and 14% for placebo in patients with early-stage Parkinson's disease, 32% for NEUPRO and 27% for placebo in patients with advanced-stage Parkinson's disease, and 13% for NEUPRO and 11% for placebo in patients with Restless Legs Syndrome.

More severe decreases in systolic blood pressure (40 mm Hg or greater) and in diastolic blood pressure (20 mm Hg or greater) also occurred more frequently (NEUPRO incidence at least 2% greater than placebo) in patients with early- and advanced-stage Parkinson's disease during measurements when supine, standing, or changing from supine to standing position. Patients experienced dose-related decreases in blood pressure at different times throughout the trial including the final visit.

An analysis using a variety of adverse reaction terms suggestive of orthostatic hypotension, including dizziness/postural dizziness and others, showed an increased risk for all patients treated with NEUPRO. For the maximum recommended NEUPRO dose, the incidence of adverse reactions suggestive of hypotension/orthostatic hypotension was 29% for NEUPRO and 11% for placebo in early-stage Parkinson's disease, 27% for NEUPRO and 23% for placebo in advanced-stage Parkinson's disease, and 8% for NEUPRO and 7% for placebo in Restless Legs Syndrome.

This increased risk for symptomatic hypotension and decreases in blood pressure was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this study. The increased risk for significant decreases in blood pressure or orthostatic hypotension occurred especially in the dose escalation/titration period.

NEUPRO is indicated for the treatment of Parkinson's disease.

Transdermal System: 1 mg/24 hours, 2 mg/24 hours, 3 mg/24 hours, 4 mg/24 hours, 6 mg/24 hours, and 8 mg/24 hours of rotigotine.

There was an increased risk for hallucinations in patients with advanced-stage Parkinson's disease treated with NEUPRO. In patients taking the maximum recommended NEUPRO dose, the incidence of hallucinations was 7% for NEUPRO and 3% for placebo, and this treatment difference increased with increasing dose.

Hallucinations were of sufficient severity to cause discontinuation of treatment (mainly during the dose escalation/titration period) in 3% of advanced-stage Parkinson's disease patients treated with the maximum recommended dose of NEUPRO compared with 1% of placebo-treated patients. Hallucinations have also been reported in post-marketing reports.

Post-marketing reports indicate that patients with Parkinson's disease or RLS may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic behavior during NEUPRO treatment or after starting or increasing the dose of NEUPRO. Other drugs prescribed to improve the symptoms of Parkinson's disease or RLS can have similar effects on thinking and behavior. This abnormal thinking and behavior may consist of one or more of the following: paranoid ideation, delusions, hallucinations, confusion, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium. These various manifestations of psychotic behavior were also observed during the clinical development of NEUPRO for early- and advanced-stage Parkinson's disease and Restless Legs Syndrome.

Patients with a major psychotic disorder should ordinarily not be treated with NEUPRO because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of NEUPRO [see Drug Interactions (7.1)].

The following adverse reaction has been identified during post-approval use of NEUPRO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General Disorders and Administration Site Conditions: withdrawal symptoms [see Warnings and Precautions (5.15)]

Nervous System Disorders: Dropped head syndrome

Musculoskeletal and connective tissue disorders:Rhabdomyolysis

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 withdrawal of NEUPRO is achieved.

Pregnancy: Based on animal data, may cause fetal harm. ( 8.1)

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)].

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.

Application site reactions (ASRs) occurred at a greater frequency in the NEUPRO-treated patients than in placebo-treated patients in the double-blind, placebo-controlled, dose-response studies with NEUPRO. For the maximum recommended NEUPRO dose, the incidence of application site reactions was 32% for NEUPRO and 19% for placebo in patients with early-stage Parkinson's disease, 36% for NEUPRO and 13% for placebo in patients with advanced-stage Parkinson's disease, and 43% for NEUPRO and 4% for placebo in patients with Restless Legs Syndrome. ASRs exhibited a dose-dependent relationship for all doses for patients with early- and advanced-stage Parkinson's disease and Restless Legs Syndrome. ASRs were also of sufficient severity to cause study discontinuation for patients with early-stage Parkinson's disease (NEUPRO 3% vs. placebo 0%), advanced-stage Parkinson's disease (NEUPRO 2% vs. placebo 0%), and Restless Legs Syndrome (NEUPRO 12% vs. placebo 0%) who were treated with the maximum recommended NEUPRO dose.

The signs and symptoms of these reactions generally were localized erythema, edema, or pruritus limited to the patch area and usually did not lead to dose reduction. Generalized skin reactions (e.g., allergic rash, including erythematous, macular-papular rash, or pruritus) have been reported at lower rates than ASRs during the development of NEUPRO.

In a clinical study designed to investigate the cumulative skin irritation of NEUPRO, daily rotation of NEUPRO application sites has been shown to reduce the incidence of ASRs in comparison to repetitive application to the same site. In a clinical study investigating the skin sensitizing potential of NEUPRO in 221 healthy subjects, no case of contact sensitization was observed. Localized sensitization reactions were observed in a study with healthy subjects by continuously rotating a 0.5 mg/24 hours transdermal system, after induction of maximal irritational stress was achieved by repetitive transdermal system application to the same site.

If a patient reports a persistent application site reaction (of more than a few days), reports an increase in severity, or reports a skin reaction spreading outside the application site, an assessment of the risk and benefits for the individual patient should be conducted. If a generalized skin reaction associated with the use of NEUPRO is observed, NEUPRO should be discontinued.

A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, rhabdomyolysis, and/or autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti- Parkinsonian therapy. Therefore, it is recommended that the dose be tapered at the end of NEUPRO treatment [see Dosage and Administration (2.4)].

NEUPRO is indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients taking the maximum recommended NEUPRO dose for early-stage Parkinson's disease had a higher incidence (2%) of substantial weight gain (more than 10% of baseline weight) than patients taking placebo (0%). In advanced-stage Parkinson's disease, the incidence of weight gain more than 10% of baseline weight was 9% in NEUPRO-treated patients (for the maximum recommended dose) and 1% in placebo-treated patients. This weight gain was frequently associated with the development of peripheral edema in patients with Parkinson's disease, suggesting that NEUPRO may cause fluid retention in some Parkinson's patients. In patients taking the maximum recommended NEUPRO dose, the incidence of peripheral edema was 3% for NEUPRO and 2% for placebo in early-stage Parkinson's disease and 9% for NEUPRO and 1% for placebo in advanced-stage Parkinson's disease. These treatment differences increased further with treatment at NEUPRO dosing above the maximum recommended doses. Monitor for weight gain and fluid retention when treating patients with concomitant illnesses such as congestive heart failure or renal insufficiency.

Each transdermal system is packaged in a separate pouch.

Each strength is available in cartons of 30 transdermal systems.

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.

Augmentation is a worsening of RLS symptoms during treatment, leading to an increase in overall symptom severity or earlier time of symptom onset each day compared to before initiation of treatment. Use of dopaminergic medications, including NEUPRO, may result in augmentation.

Rebound, an exacerbation of RLS symptoms, is considered to be an end of dose effect, related to the half-life of the therapeutic agent. Reports in the published literature indicate discontinuation or wearing off of dopaminergic medications can result in rebound.

Treatment for Parkinson's disease.

NDC 50474-808-11

Neupro ^®

(rotigotine transdermal system)

Includes:

• 7 systems that deliver 2 mg/24 hours each
• 7 systems that deliver 4 mg/24 hours each

Titration kit for

Parkinson's disease

Please see Important Safety Information on back of carton

and full Prescribing Information inside.

Your step-by-step guide to beginning therapy

with the NEUPRO transdermal system

This package also contains:

• Full Prescribing Information

Professional samples—Rx only

Not for sale

For transdermal use only

Patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including NEUPRO, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, or other urges while being treated with NEUPRO for Parkinson's disease or RLS. Dopamine dysregulation syndrome, the repeated use of more NEUPRO than as prescribed to manage their symptoms of Parkinson's disease or RLS, was observed in some patients during treatment with NEUPRO. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking NEUPRO .

Some patients treated with NEUPRO exhibited increases in systolic blood pressure (greater than 180 mm Hg) and/or diastolic blood pressure (greater than 105 mm Hg) while supine or standing. In patients with advanced-stage Parkinson's disease, this increased risk for systolic blood pressure greater than 180 mm Hg was 5% for NEUPRO and 3% for placebo and for diastolic blood pressure greater than 105 mm Hg was 4% for NEUPRO and 0% for placebo. In patients with Restless Legs Syndrome, this increased risk for diastolic blood pressure greater than 105 mm Hg was 8% for NEUPRO and 4% for placebo.

Increases in systolic blood pressure (at least 20 mm Hg or more) and in diastolic blood pressure (at least 10 mm Hg or more) occurred more frequently (incidence at least 5% greater than placebo) in all patients (i.e., early- and advanced-stage Parkinson's disease and Restless Legs Syndrome) taking the maximum recommended NEUPRO dose. These increases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position. More severe increases in systolic blood pressure (40 mm Hg or more) and in diastolic blood pressure (20 mm Hg or more) also occurred more frequently (incidence at least 2% greater than placebo) in NEUPRO-treated patients with early- and advanced-stage Parkinson's disease and with Restless Legs Syndrome during measurements when supine, standing, and/or changing from supine to standing position.

In the placebo-controlled trials, there was an increased risk for hypertension as an adverse reaction with the maximum recommended NEUPRO dose in patients with advanced-stage Parkinson's disease (NEUPRO 3% vs. placebo 0%) and Restless Legs Syndrome (NEUPRO 4% vs. placebo 0%).

Some patients treated with NEUPRO exhibited increased pulse (greater than 100 beats per minute) while supine and/or standing. In patients with advanced-stage Parkinson's disease, there was an increased risk (at least 2% greater than placebo) of increased pulse for patients taking the maximum recommended NEUPRO dose. In patients with Restless Legs Syndrome, there was an increased risk (at least 5% greater than placebo) of increased pulse for patients taking the maximum recommended NEUPRO dose.

These findings of blood pressure and heart rate elevations should be considered when treating patients with cardiovascular disease.

The backing layer of NEUPRO contains aluminum. To avoid skin burns, NEUPRO should be removed prior to magnetic resonance imaging or cardioversion.

NDC 50474-801-03

30 systems

Neupro ^®

(rotigotine transdermal system)

1 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-802-03

30 systems

Neupro ^®

(rotigotine transdermal system)

2 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-803-03

30 systems

Neupro ^®

(rotigotine transdermal system)

3 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-804-03

30 systems

Neupro ^®

(rotigotine transdermal system)

4 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-805-03

30 systems

Neupro ^®

(rotigotine transdermal system)

6 mg/24 hours

For transdermal use only

Rx Only

NDC 50474-806-03

30 systems

Neupro ^®

(rotigotine transdermal system)

8 mg/24 hours

For transdermal use only

Rx Only

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.

NDC 50474-801-17

7 systems

Neupro ^®

(rotigotine transdermal system)

1 mg/24 hours

This package contains:

• 7 systems that deliver 1 mg/24 hours each
• Full Prescribing Information

Treatment for moderate-to-severe primary

Restless Legs Syndrome (RLS)

Please see Important Safety Information on back of carton

and full Prescribing Information inside

Sample Kit for

Restless Legs Syndrome

Professional samples – not for sale

For transdermal use only – Rx only