AHFS Class:

• Nonergot-derivative Dopamine Receptor Agonists 28:36.20.08

Generic Name(s):

• Rotigotine

Chemical Name:

• 5,6,7,8-Tetrahydro-6-[propyl [2-(2-thienyl)ethyl]amino-(6 S )-1-naphthalenol

Molecular Formula:

• C₁₉H₂₅NOS

Rotigotine is a nonergot-derivative dopamine receptor agonist.1,2,12,15

Parkinsonian Syndrome

Transdermal rotigotine is used for the symptomatic management of parkinson disease.1,2,3,4,5,6,7,13,14

Dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine) are used as initial monotherapy in patients with early parkinson disease or as an adjunct to levodopa in patients with advanced disease.101,115,123,157 Levodopa is currently the most effective drug for relieving motor symptoms of parkinson disease.115,123,157 However, the effectiveness of levodopa decreases over time as the disease progresses, and most patients develop motor complications (e.g., end-of-dose failure, “on-off” phenomenon, dyskinesias) with long-term use.101,115,157 Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents such as a dopamine receptor agonist; alternatively, a levodopa-sparing strategy may be used in which other antiparkinsonian agents are initiated first to delay use of levodopa.101,115,116,123,157 This latter approach is often used in younger patients who have a higher risk of developing motor complications and a longer life expectancy.101,116,123,157 The appropriate treatment approach should be individualized based on the patient's age, symptoms, degree of disability, and adverse effects of therapy.101,120,122,123,124,125 (For additional information on treatment options in parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.)

Efficacy of transdermal rotigotine for the management of parkinson disease has been established in 5 multinational, randomized, double-blind, placebo-controlled studies in patients with early parkinson disease not receiving levodopa and in patients with advanced parkinson disease who were receiving concomitant levodopa therapy.1,2,3,4,6,7 In these studies, dosage of rotigotine transdermal system was titrated weekly in increments of 2 mg/24 hours to either the randomized dosage or optimal dosage depending on the individual trial design; dosage reduction was permitted for intolerable adverse effects and in all of the studies, dosage was titrated downwards upon completion of treatment.1,2,3,4,6,7 In the studies in patients with early parkinson disease, response to therapy was assessed principally using the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III, which evaluated activities of daily living (ADL) and motor performance, respectively.1,2,3,4 In the studies in patients with advanced parkinson disease, the primary efficacy end point was time spent in the “off” state (emergence of parkinsonian symptoms) based on 24-hour home diaries.1,6,7

Three of the studies evaluated patients with early parkinson disease; these patients had limited or no prior exposure to levodopa and were permitted to receive selegiline, anticholinergic agents, or amantadine if they were on stable dosages and were able to maintain those dosages for the duration of the study.1,2,3,4 In the first study, patients were randomized to receive one of 4 fixed dosages of transdermal rotigotine (2, 4, 6, or 8 mg/24 hours) or placebo for 12 weeks.1,2 Rotigotine was substantially more effective than placebo in improving motor performance and ADL at the 3 highest dosages evaluated; the 6 and 8 mg/24 hours dosages produced a similar effect.1,2 In the second study, patients were randomized to receive transdermal rotigotine (titrated based on efficacy and tolerability up to a maximum dosage of 6 mg/24 hours) or placebo for 28 weeks.1,3 Clinical response (defined as an improvement of at least 20% in UPDRS scores [parts II and III]) occurred in 48% of patients receiving rotigotine (mean daily dosage: 5.7 mg/24 hours) compared with 19% of those receiving placebo.3,14 The combined UPDRS score decreased by a mean of 4 in patients receiving rotigotine and increased by 1.3 in patients receiving placebo.1,3 Long-term safety and tolerability of transdermal rotigotine were demonstrated in an open-label extension of this trial; patients received an optimal dosage for up to 6 years (mean dosage at the end of treatment was 7.2 mg/24 hours).13 In the third study, patients were randomized to receive transdermal rotigotine, oral ropinirole, or placebo for up to approximately 39 weeks.1,4 Dosage of transdermal rotigotine was titrated based on efficacy and tolerability up to a maximum of 8 mg/24 hours.1,4 The mean decrease from baseline in the combined UPDRS score (parts II and III) was 6.8 in patients receiving rotigotine compared with a mean decrease of 2.3 in those receiving placebo; clinical response (defined as an improvement of at least 20% in UPDRS parts II and III score) was achieved in 52, 68, and 30% of patients receiving rotigotine, ropinirole, and placebo, respectively.1,4

Studies in patients with advanced parkinson disease demonstrated that rotigotine was more effective than placebo in reducing “off time” in patients who were experiencing “on-off” phenomena despite optimal dosages of levodopa.1,6,7 In one of these studies, patients receiving transdermal rotigotine 8 or 12 mg/24 hours experienced a mean decrease in “off” time of 2.7 or 2.1 hours, respectively, compared with 0.9 hours with placebo.1,7 In another study, transdermal rotigotine (mean dosage of 13 mg/24 hours; range: 4-16 mg/24 hours) was more effective than placebo and noninferior to pramipexole in reducing “off” time.1,6 The mean decrease in daily “off” time from baseline to the end of treatment was 2.5 and 2.8 hours for patients receiving rotigotine and pramipexole, respectively, compared with 0.9 hours in patients receiving placebo.1,6 Onset of treatment benefit was noted as early as the first week of treatment.1

Restless Legs Syndrome

Transdermal rotigotine is used for the symptomatic management of moderate-to-severe primary restless legs syndrome (RLS; also known as Willis-Ekbom disease).1,8,9,10,11,12 Experts state that treatment of RLS should be considered if symptoms substantially interfere with sleep or daytime function.40 Nonergot-derivative dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine) are considered one of several drugs of choice for reducing symptoms of RLS; there is moderate to strong evidence supporting the use of any of the currently available drugs in this class.8,11,12,18,35,36,40 Treatment should be individualized based on the patient's symptoms, age, comorbidities, preference, and adverse effects of therapy (e.g., risk of augmentation).40

Efficacy of transdermal rotigotine in the management of RLS has mainly been established in 2 fixed-dose, randomized, double-blind, placebo-controlled trials in patients with moderate-to-severe RLS (defined as a score of at least 15 on the International Restless Legs Syndrome [IRLS] rating scale and score of at least 4 on the Clinical Global Impressions [CGI] Item 1 assessment [severity of symptoms]).1,8,9 Patients in these studies received transdermal rotigotine dosages ranging from 0.5 to 3 mg/24 hours; dosage was titrated over several weeks, followed by a 6-month maintenance period and then a 1 week down-titration period.1 The co-primary efficacy endpoints of the studies were assessed by the IRLS scale and the Clinical Global Impression-Improvement (CGI-I) scale.1,8,9

In the first study, patients were randomized to receive placebo or transdermal rotigotine in one of 4 dosages (0.5, 1, 2, or 3 mg/24 hours) for 6 months.1,9 Patients in all of the dosage groups experienced mean changes in IRLS and CGI scores that were higher than placebo; however, a statistically significant difference was achieved with only the 2 highest dosages; 60 and 67% of patients receiving transdermal rotigotine 2 and 3 mg/24 hours, respectively, were considered responders (defined as 50% or greater score reduction) on the IRLS scale compared with 37.4% of patients receiving placebo.1,9 On the CGI Item 1 scale, 52.6 and 59.7% of patients receiving transdermal rotigotine 2 and 3 mg/24 hours, respectively, were considered responders (defined as 50% or greater score reduction) compared with 30.3% of patients receiving placebo.9 Efficacy of the drug was maintained throughout the 6-month treatment period.1,9

In the second study, patients were randomized to receive transdermal rotigotine (1, 2, or 3 mg/24 hours) or placebo.1,8 The mean changes in IRLS and CGI scores were substantially improved in patients receiving rotigotine compared with those receiving placebo.1,8 In this study, 51.8, 57.8, and 55.4% of patients receiving transdermal rotigotine 1, 2, and 3 mg/24 hours, respectively, were considered responders (defined as 50% or greater score reduction) on the IRLS scale compared with 25.4% of those receiving placebo.8 On the CGI Item 1 scale, 50.9, 53.2, and 61.6% of patients receiving transdermal rotigotine 1, 2, and 3 mg/24 hours, respectively, were considered responders (defined as 50% or greater score reduction) compared with 31.6% of those receiving placebo.8 Improvement was observed within the first week of treatment and was maintained throughout the 6-month treatment period.8

In an open-label extension study in patients with moderate-to-severe RLS, transdermal rotigotine therapy (in dosages up to 4 mg/24 hours) was well tolerated after 1 year of treatment and provided sustained efficacy at a stable dosage for up to 5 years.12

Administration

Rotigotine is administered percutaneously by topical application of a transdermal system (patch).1 The transdermal system should be applied once daily at a convenient time for the patient during the day or night, but should be applied at approximately the same time each day.1

Because rotigotine is administered transdermally, food is not expected to affect absorption of the drug, and the transdermal system may be applied without regard to meals.1

Patients should be carefully instructed in the proper use and disposal of the rotigotine transdermal system.1

The rotigotine transdermal system should be applied immediately after removal from its pouch and removal of the protective liner.1 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 by firmly pressing the system with the palm of the hand for 30 seconds with the adhesive side touching the skin to ensure good contact, particularly around the edges.1 The application site should not be oily, irritated, or damaged.1 In addition, application to areas where the transdermal system could be rubbed by tight clothing or under a waistband and skin folds should be avoided.1

If application of the transdermal system to a hairy area is necessary, the area at the application site should be shaved at least 3 days prior to application.1 Creams, lotions, oils, ointments, or powders should not be applied to the skin where the transdermal system will be placed.1

The application site for the rotigotine transdermal system should be moved on a daily basis (i.e., from the right side to the left side, from the upper body to the lower body).1 The transdermal system should not be applied to the same application site more often than once every 14 days.1

Each rotigotine transdermal system should be worn continuously for 24 hours.1 If a transdermal system should inadvertently come off during the period of use or if a patient forgets to change the patch, a new system should be applied for the remainder of the day; the patient should then change the patch the following day according to their regular time schedule.1 Patients who experience difficulty with patch adhesion should be advised that they may tape the edges of the system in place with bandage tape.1

After handling a rotigotine transdermal system, patients should wash their hands to remove any drug; patients also should avoid touching their eyes or other objects prior to handwashing.1

Because the backing layer of the rotigotine transdermal system contains aluminum, the patch should be removed prior to magnetic resonance imaging (MRI) or cardioversion to avoid skin burns .1

Dosage

The rotigotine transdermal system (Neupro^®) is labeled in terms of the approximate rate of drug delivery per 24 hours.1

The prescribed dosage of transdermal rotigotine may be achieved using either single or multiple patches of the drug.1

Parkinsonian Syndrome

For the management of early parkinson disease in adults, transdermal rotigotine therapy should be initiated at a dosage of 2 mg/24 hours.1 Based on individual patient response and tolerability, dosage may be increased weekly by 2 mg/24 hours if additional therapeutic effect is needed.1 In clinical studies, the lowest effective dosage was 4 mg/24 hours.1 The maximum recommended dosage for patients with early parkinson disease is 6 mg/24 hours.1

For the management of advanced parkinson disease in adults, transdermal rotigotine therapy may be initiated at a dosage of 4 mg/24 hours.1 Based on individual patient response and tolerability, dosage may be increased weekly by 2 mg/24 hours if additional therapeutic effect is needed.1 The maximum recommended dosage for patients with advanced parkinson disease is 8 mg/24 hours.1

When discontinuing treatment with transdermal rotigotine in patients with parkinson disease, the daily dosage should be reduced by a maximum of 2 mg/24 hours with a dosage reduction preferably every other day, until complete withdrawal of the drug is achieved.1

Restless Legs Syndrome

For the management of restless legs syndrome (RLS) in adults, transdermal rotigotine therapy should be initiated at a dosage of 1 mg/24 hours.1 Based on individual patient response and tolerability, the dosage may be increased weekly by 1 mg/24 hours if additional therapeutic effect is needed.1 The lowest effective dosage is 1 mg/24 hours.1 The maximum recommended dosage is 3 mg/24 hours.1

When discontinuing treatment with transdermal rotigotine in patients with RLS, the daily dosage should be reduced by 1 mg/24 hours with a dosage reduction preferably every other day, until complete withdrawal of the drug is achieved.1

Special Populations

Dosage adjustment is not necessary in patients with mild to severe renal impairment, including those receiving hemodialysis.1,17

No dosage adjustment is necessary for patients with moderate hepatic impairment.1 Rotigotine has not been studied in patients with severe hepatic impairment; the manufacturer does not provide specific dosage recommendations for such patients.1

The manufacturer does not provide specific dosage recommendations for geriatric patients.1

Dosage adjustment is not necessary based on race, weight, or gender.1,23

Contraindications

• Rotigotine is contraindicated in patients who are hypersensitive to the drug or to any components in the transdermal administration system.1

Warnings/Precautions

Sulfite Sensitivity

Rotigotine transdermal system (Neupro^®) contains sodium metabisulfite,1 a sulfite that may cause allergic-type reactions (including anaphylactic symptoms and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.1,26,27,28,29,30,31,32,33 The overall prevalence of sulfite sensitivity in the general population is unknown and probably low; however, such sensitivity appears to occur more often in asthmatic than in nonasthmatic individuals.1,32

Falling Asleep During Activities of Daily Living and Somnolence

Falling asleep while engaged in activities of daily living, including operating a motor vehicle, has been reported in patients receiving rotigotine; such events have sometimes resulted in accidents.1,2 Although many patients reported somnolence while receiving transdermal rotigotine, some patients did not perceive warning signs, such as excessive drowsiness, and believed they were alert prior to the episode of falling asleep.1 Some of the cases were reported as late as 1 year after initiation of transdermal rotigotine therapy.1 Falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history.1

Somnolence commonly occurs in patients receiving transdermal rotigotine and appears to be more frequent in patients with parkinson disease than in patients with restless legs syndrome (RLS).1 However, patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.1

Before initiating transdermal rotigotine, patients should be advised of the potential to develop drowsiness and specifically asked about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs, presence of sleep disorders).1 Patients should be continually reassessed for drowsiness or sleepiness during therapy, especially since some of these episodes occur well after starting treatment.1 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), rotigotine generally should be discontinued.1 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.1 There is insufficient information to establish whether dosage reduction will eliminate this adverse event.1

Hallucinations/Psychotic-like Behavior

An increased risk of dose-related hallucinations has been reported in patients with advanced parkinson disease receiving rotigotine.1,30 In controlled studies, hallucinations were reported in 7% of patients receiving the drug compared with 3% of those receiving placebo.1,30

Other new or worsening mental status and behavioral changes, which can be severe and include psychotic-like behavior, have been reported during transdermal rotigotine therapy or after initiating or increasing dosage of the drug in the postmarketing setting.1 Such abnormal thinking and behavior may consist of one or more of the following manifestations: paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.1 Other drugs used in the treatment of parkinson disease can produce similar effects on thinking and behavior.1

Because of the risk of exacerbating psychosis, rotigotine should generally not be used in patients with a major psychotic disorder.1 In addition, concomitant use of rotigotine with antipsychotic agents may exacerbate parkinsonian symptoms and result in decreased efficacy of transdermal rotigotine therapy.1

If hallucinations or psychotic-like behavior occurs, a reduction in transdermal rotigotine dosage or discontinuance of therapy may be beneficial.1

Symptomatic Hypotension and Syncope

Rotigotine and other dopamine agonists appear to impair systemic regulation of blood pressure, resulting in postural/orthostatic hypotension, particularly during dosage escalation.1,123 Orthostatic hypotension can also be a manifestation of parkinson disease.1,123 Syncope also has been reported in patients receiving dopamine agonists.1

In clinical studies, decreases in systolic and diastolic blood pressure occurred more frequently during blood pressure measurements taken in the supine, standing, and/or supine to standing positions in patients receiving rotigotine compared with those receiving placebo.1 Orthostatic decreases in systolic blood pressure (20 mm Hg or greater) occurred in 13-32% of all patients receiving the highest recommended dosage of transdermal rotigotine.1 More severe decreases in systolic blood pressure (greater than 40 mm Hg) and in diastolic blood pressure (20 mm Hg or greater) occurred more frequently in patients with parkinson disease.1 The increased risk for clinically significant decreases in blood pressure or orthostatic hypotension was observed especially during the dosage titration period.1 Patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension were excluded from clinical studies.1

Patients should be monitored for orthostatic hypotension during rotigotine therapy, particularly during dosage escalation.1 Patients, particularly those with severe cardiovascular disease, also should be monitored for signs of syncope or presyncope.1

Impulse Control/Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, uncontrolled spending, binge eating, other intense urges) and inability to control these urges have been reported in some patients receiving dopaminergic agents.1 These urges stopped in some cases when the dosage was reduced or the drug was discontinued.1,21 If a patient develops such urges while receiving rotigotine, consideration should be given to reducing the dosage or discontinuing the drug.1

Elevation of Blood Pressure and Heart Rate

Increases in systolic blood pressure (exceeding 180 mm Hg) and/or diastolic blood pressure (exceeding 105 mm Hg) while supine and/or standing have been reported in patients receiving transdermal rotigotine.1 Patients with advanced parkinson disease had a 5% increased risk for such increases in systolic blood pressure and a 4% increased risk for such increases in diastolic blood pressure.1 Patients with RLS had an 8% increased risk of diastolic blood pressure exceeding 105 mm Hg.1

Mild to moderate increases in blood pressure (increase in systolic or diastolic blood pressure of 20 or 10 mm Hg or more, respectively) occurred more frequently in all patients receiving the maximum recommended dosage of transdermal rotigotine compared with those receiving placebo.1 Such increases were observed when supine, standing, and changing from supine to standing position.1 More severe increases in blood pressure (increase in systolic or diastolic blood pressure of greater than 40 or 20 mm Hg or more, respectively) also were reported in patients receiving rotigotine.1 Patients with advanced parkinson disease or RLS receiving the maximum recommended dosage of transdermal rotigotine had an increased risk of hypertension compared with patients receiving placebo.1

Some patients receiving transdermal rotigotine had a moderately increased heart rate (exceeding 100 beats per minute) while supine and/or standing.1 Patients with advanced parkinson disease or RLS had a 2 or 5% increased risk of elevated heart rate, respectively.1

The possibility of blood pressure and heart rate elevations should be considered when administering transdermal rotigotine in patients with cardiovascular disease.1

Weight Gain and Fluid Retention

Patients receiving the maximum recommended transdermal rotigotine dosage for early or advanced parkinson disease had a higher incidence of substantial weight gain (more than 10% of baseline weight) than patients receiving placebo.1 Weight gain was frequently associated with the development of peripheral edema in patients with parkinson disease, suggesting that the drug may cause substantial fluid retention in such patients.1 Peripheral edema was reported with higher frequency in patients receiving transdermal rotigotine than those receiving placebo in parkinson disease studies; the risk of peripheral edema was increased when the drug was administered at higher than recommended dosages.1

Patients with risk factors (e.g., congestive heart failure, renal insufficiency) should be monitored for weight gain and fluid retention during rotigotine therapy.1

Dyskinesia

Transdermal rotigotine may potentiate the adverse dopaminergic effects of levodopa and may cause and/or exacerbate preexisting dyskinesia.1 In a clinical study in patients with advanced parkinson disease who were receiving levodopa therapy, dyskinesia was reported in 14% of patients receiving the maximum recommended dosage of transdermal rotigotine compared with 7% of those receiving placebo and was found to be dose related.1

Application Site Reactions

Dose-dependent application site reactions (e.g., localized erythema, edema, or pruritus limited to the patch area) have been reported in patients receiving transdermal rotigotine.1,6,7 Across all patient populations studied, application site reactions occurred in 32-43% of the patients receiving the maximum recommended rotigotine dosage compared with 4-19% of those receiving placebo.1 Application site reactions were severe enough to result in drug discontinuance in 2-12% of patients receiving the maximum recommended transdermal rotigotine dosage.1

Generalized (nonapplication site) skin reactions (e.g., allergic rash [including erythematous, maculopapular rash or pruritus]) also have been reported, but less frequently than application site reactions.1

Daily rotation of transdermal rotigotine application sites has been shown to reduce the incidence of application site reactions.1,10 (See Dosage and Administration: Administration.) If a patient reports a persistent application site reaction (i.e., lasting for more than a few days), an increase in severity, or a skin reaction spreading outside the application site, the risks versus benefits of continued therapy should be evaluated in the individual patient.1 If a generalized skin reaction associated with the use of transdermal rotigotine is observed, therapy should be discontinued.1

Augmentation and Rebound in Restless Legs Syndrome

Long-term use of dopaminergic agents in patients with RLS has been associated with augmentation (i.e., worsening of symptoms during treatment); augmentation can manifest as an increase in overall symptom severity or earlier time of symptom onset each day.1,19,40 A retrospective analysis of data from several clinical trials suggests that the risk of augmentation with transdermal rotigotine is relatively low for up to 18 months; augmentation was observed in 9.7% of the patients treated with transdermal rotigotine and was clinically relevant in 2.9% of the patients.19

Rebound (an exacerbation of RLS symptoms) also has been reported and is considered to be an end-of-dose effect related to the half-life of the drug.1 Discontinuance or wearing off of dopaminergic medications can result in rebound.1

Magnetic Resonance Imaging and Cardioversion

Because the backing layer of the rotigotine transdermal system contains aluminum, the patch should be removed prior to magnetic resonance imaging (MRI) or cardioversion to avoid skin burns.1

Heat Application

Although the effect of heat application to the rotigotine transdermal system has not been specifically studied, heat application has been shown to increase drug absorption several fold with transdermal formulations of other drugs.1 Clinicians should advise patients to avoid exposing the application site to external sources of direct heat, such as heating pads or electric blankets, heat lamps, saunas, hot baths, hot tubs, heated water beds, hair dryers, and prolonged direct sunlight.1

Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (NMS; characterized by elevated temperature, muscular rigidity, altered consciousness, rhabdomyolysis, and/or autonomic instability) has been reported in association with rapid dosage reduction, withdrawal of, or changes in dopaminergic therapy.1 The manufacturer therefore recommends that the dosage of transdermal rotigotine be tapered when discontinuing therapy.1

Fibrotic Complications

Fibrotic complications, including retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and/or cardiac valvulopathy (which may be accompanied by clinically important regurgitation), have been reported in some patients treated with ergot-derivative dopamine agonists, presumably related to the ergoline structure of these compounds.1,24,25 It is not known whether nonergot-derivative dopamine agonists can also cause such fibrotic reactions.1,25

Binding to Melanin

Binding to melanin-containing tissues (e.g., eyes) was noted in the pigmented rat and monkey after a single dose of rotigotine.1 However, the binding to melanin slowly cleared over a 14-day observation period.1 Similar binding to melanin has been reported with other dopamine agonists.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of transdermal rotigotine in pregnant women.1 In animal studies, adverse developmental effects (e.g., delayed skeletal ossification, decreased fetal body weight, embryofetal death) were observed with subcutaneous administration of rotigotine at dosages similar to or lower than those used clinically.1

Lactation

Because rotigotine decreases prolactin secretion, the drug is expected to inhibit lactation.1,23

Rotigotine and/or its metabolites are distributed into milk in rats; it is not known whether the drug is distributed into human milk.1 The effects of rotigotine on the breast-fed infant or on milk production also are not known.1 The known benefits of breast-feeding should be considered along with the mother's clinical need for rotigotine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of rotigotine in pediatric patients have not been established.1

Geriatric Use

Of the patients with parkinson disease receiving transdermal rotigotine in clinical studies, approximately 50% were 65 years of age or older and approximately 11% were 75 years of age or older.1 Of the patients with restless legs syndrome receiving transdermal rotigotine in clinical studies, 26% were 65 years of age or older.1 No overall differences in safety or efficacy were observed between these geriatric patients and younger individuals.1 Other clinical experience has not revealed age-related differences in response; however, the possibility of greater sensitivity in some geriatric patients cannot be ruled out.1

Geriatric patients with parkinson disease are at increased risk for hallucinations compared with younger individuals.1

Plasma concentrations of rotigotine in patients 65-80 years of age were similar to those in younger adults (approximately 40-64 years of age).1,20 The manufacturer states that rotigotine exposures in older geriatric patients (exceeding 80 years of age) have not been studied, but may be higher because of the skin changes that occur with aging.1

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh class B), there were no relevant changes in rotigotine plasma concentrations.1

The effects of severe hepatic impairment on the pharmacokinetics of rotigotine have not been evaluated.1

Renal Impairment

There were no relevant changes in rotigotine plasma concentrations in individuals with mild to severe renal impairment (including those with end-stage renal disease requiring hemodialysis) compared with those with normal renal function.1,17 In individuals with severe renal impairment (creatinine clearance of 15 to less than 30 mL/minute) not receiving dialysis, exposure to conjugated rotigotine metabolites was doubled.1,17

Common Adverse Effects

In patients with early parkinson disease (not receiving concomitant levodopa), the most common adverse reactions (incidence at least 5% higher with rotigotine than that reported with placebo) were nausea,1,2,3,4 vomiting,1,2,3,4 somnolence,1,2,3 application site reactions,1,2,3,4 dizziness,1,2,3 anorexia,1,2 hyperhidrosis,1,2 insomnia,1,2,3 headache,2,3 fatigue,2 anxiety,2 peripheral edema,2 and dyspepsia.3

In patients with advanced parkinson disease (receiving concomitant levodopa), the most common adverse reactions (incidence at least 5% higher with rotigotine than that reported with placebo) were application site reactions,1,7 nausea,1,6,7 dyskinesia,1,6,7 dizziness,1,7 peripheral edema,1,7 insomnia,7 and hallucinations.7

In patients with RLS, the most common adverse reactions (incidence at least 5% higher with rotigotine than that reported with placebo) were application site reactions,1,8,9 nausea,1,8,9 somnolence,1,9 headache,1 and insomnia.9

Multiple cytochrome P-450 (CYP) isoenzymes are capable of catalyzing the metabolism of rotigotine.1 If an individual CYP isoenzyme is inhibited, other isoenzymes can catalyze rotigotine metabolism.1 In addition, rotigotine is metabolized by multiple sulfotransferases and uridine diphosphate-glucuronosyltransferases (UGT1A9 and UGT2B15); therefore, it is unlikely that inhibition of any one metabolic pathway would substantially alter rotigotine concentrations.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that there is no risk for rotigotine-induced inhibition of CYP isoenzymes 1A2, 2C9, and 3A4 and a low risk of rotigotine-induced inhibition of CYP2C19 and CYP2D6 at therapeutic concentrations.1 Pharmacokinetic interactions mediated by CYP isoenzymes are unlikely since metabolism of rotigotine does not depend on any single metabolic pathway.1 If an individual CYP isoenzyme is inhibited, other isoenzymes can catalyze rotigotine metabolism.1

In vitro, there is no indication that rotigotine induces CYP isoenzymes 1A2, 2B6, 2C9, 2C19, and 3A4.1

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase (UGT)

Rotigotine is metabolized by UGT enzymes 1A9 and 2B15; because the drug is metabolized by multiple pathways, it is unlikely that inhibition of any one metabolic pathway would substantially alter rotigotine concentrations.1

Alcohol and other CNS Depressants

Alcohol and other CNS depressants (e.g., sedatives, anxiolytics, antidepressants, antipsychotics, opiate analgesics) may increase the risk of additive effects, including somnolence and falling asleep during activities of daily living, in patients receiving transdermal rotigotine, and should therefore be used concomitantly with caution.1,23

Cimetidine

Concurrent administration of transdermal rotigotine (up to 4 mg/24 hours) and cimetidine (400 mg twice daily), an inhibitor of CYP1A2, CYP2C19, CYP2D6, and CYP3A4, in healthy individuals did not alter the steady-state pharmacokinetics of rotigotine.1

Digoxin

Rotigotine did not influence P-glycoprotein-mediated transport of digoxin; therefore, rotigotine is not expected to alter the pharmacokinetics of digoxin.1

Dopamine Agonists

Transdermal rotigotine may potentiate the therapeutic and/or adverse dopaminergic effects (including dyskinesia) of other dopamine agonists.1

Dopamine Antagonists

Dopamine antagonists (e.g., antipsychotic agents, metoclopramide) may diminish the effectiveness of rotigotine.1

Hormonal Contraceptives

Concurrent administration of transdermal rotigotine (3 mg/24 hours) did not substantially affect the pharmacodynamics or pharmacokinetics of an oral estrogen-progestin combination contraceptive (ethinyl estradiol 0.03 mg with 0.15 mg levonorgestrel) in healthy females.1,22 Possible interactions with rotigotine and other forms of hormonal contraceptives have not been evaluated to date.23

Levodopa/Carbidopa

Concurrent administration of levodopa/carbidopa (100/25 mg twice daily) and transdermal rotigotine (4 mg/24 hours) in patients with restless legs syndrome had no effect on the steady-state pharmacokinetics of any of the drugs.1,34 Rotigotine may potentiate the therapeutic effects of levodopa as well as its adverse dopaminergic effects (including dyskinesia).1 (See Dyskinesia under Cautions: Warnings/Precautions.)

Omeprazole

Concurrent administration of oral omeprazole (40 mg daily), a selective CYP2C19 inhibitor, and transdermal rotigotine (4 mg/24 hours) had no effect on the steady-state pharmacokinetics of rotigotine in healthy individuals.1,23

Warfarin

No potential for displacement of warfarin by rotigotine (and vice versa) from their respective human serum albumin binding sites was detected in vitro.1

Description

Rotigotine is a nonergot-derivative dopamine receptor agonist.1,2,12,15 In in vitro studies, rotigotine demonstrated binding specificity for and intrinsic activity at dopamine D₁, D₂, D₃, D₄, and D₅ receptors, with the highest affinity for the D₃ dopamine receptor subtype.15,23 Rotigotine has antagonistic effects at α_2B-adrenergic receptors and agonistic effects at serotonin type 1A (5-hydroxytryptamine [5-HT_1A]) receptors, but no activity on 5-HT_2B receptors.15,23

The exact mechanism(s) of action of rotigotine in the management of parkinson disease has not been fully elucidated.1 However, the drug appears to act by stimulating dopamine receptors (D₃, D₂, and D₁) in the caudate putamen of the brain.1,23

The precise mechanism(s) of action of rotigotine in the management of restless legs syndrome is unknown, but appears to be related to its ability to stimulate dopamine receptors.1,23

Following topical application, the rotigotine transdermal system releases an average of approximately 45% of the rotigotine from the system within 24 hours.1 When single doses of 8 mg/24 hours were applied to the trunk, there was an average lag time of approximately 3 hours (range: 1-8 hours) until the drug was detected in plasma.1 Peak rotigotine concentrations typically occur 15-18 hours postdose, but can occur from 4-27 hours postdose.1 However, there is no characteristic peak concentration observed.1 Steady-state plasma concentrations of rotigotine were observed within 2-3 days of daily dosing when administered to healthy individuals in a 14-day study.1 Because rotigotine is administered transdermally, food should not affect absorption.1 In a study in patients with early parkinson disease receiving transdermal rotigotine, relative bioavailability at steady state by application site ranged from less than 1% (abdomen versus hip) to 46% (shoulder versus thigh), with shoulder application showing higher bioavailability.1,20 In a study in healthy males, absolute bioavailability of the drug when applied as a transdermal system was 37%.16 Rotigotine is approximately 92% bound to human plasma proteins in vitro and 89.5% bound in vivo.1 Rotigotine is extensively metabolized by conjugation and N -dealkylation.1,16 Multiple cytochrome P-450 (CYP) isoenzymes, sulfotransferases, and 2 uridine diphosphate-glucuronosyltransferases (UGT1A9 and UGT2B15) are capable of catalyzing the metabolism of rotigotine.1 Approximately 71 and 23% of a single IV dose of rotigotine is excreted in urine and feces, respectively, as metabolites over 9 days; less than 1% of the dose is excreted as unchanged drug in urine.1,16 The major metabolites found in urine include rotigotine sulfate, rotigotine glucuronide, N -despropyl-rotigotine sulfate, and N -desthienylethyl-rotigotine sulfate.1,16 Following removal of the transdermal system, elimination of the drug was biphasic with an initial half-life of 3 hours and a terminal half-life of 5-7 hours.1

Advice to Patients

• Importance of reading the manufacturer's patient information.1
• Importance of using the rotigotine transdermal system (patch) as prescribed.1 Importance of instructing patients to wear the system continuously for 24 hours.1 Advise patients to remove the patch after 24 hours and immediately apply a new one.1 If a patient forgets to change a patch, they should be advised to apply a new patch as soon as possible and then replace it at the usual time the following day.1
• Advise patients that rotigotine transdermal system (Neupro^®) contains sodium metabisulfite, which is a sulfite that can cause severe allergic-type reactions (including anaphylactic symptoms and life-threatening or less severe asthmatic episodes) in certain susceptible individuals.1 An allergy to sulfites is not the same as an allergy to sulfa drugs.1 Patients should be advised to immediately remove the patch and seek immediate medical attention if they experience swelling of the lips or tongue, chest pain, and/or difficulty breathing or swallowing.1
• Importance of advising patients of the potential for sedating effects, including somnolence and the possibility of falling asleep without feeling drowsy or without warning while engaged in activities of daily living.1 Patients should avoid driving, operating machinery, or participating in other potentially dangerous activities until effects on the individual are known.1 Importance of advising patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving) occur at any time during therapy, they should not drive or participate in potentially dangerous activities until they have contacted their clinician.1
• Importance of informing patients that hallucinations or other psychotic-like behavior can occur during therapy, particularly in geriatric patients with parkinson disease.1
• Risk of symptomatic (e.g., dizziness, nausea, sweating) or asymptomatic orthostatic hypotension and syncope during therapy, particularly during initial therapy and following an increase in dosage.1 Patients should avoid rising rapidly after sitting or lying down, especially if they have been in a seated or recumbent position for prolonged periods and/or if they are just beginning transdermal rotigotine therapy.1 Patients should be advised to contact their clinician if they experience any signs or symptoms of lowered blood pressure during therapy.1
• Risk of increased blood pressure or exacerbation of hypertension and increased heart rate.1
• Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending, binge eating) while receiving transdermal rotigotine and of advising them of the importance of reporting such urges.1,21
• Risk of weight gain and fluid retention, which may manifest as peripheral edema.1 Patients should be advised to contact their clinician if they experience swelling or fluid retention, especially in the ankles or legs, or have an unusually fast increase in weight.1
• Risk of new onset or exacerbation of dyskinesia.1
• Importance of informing patients that application site reactions can occur with transdermal rotigotine and that the application site should be rotated on a daily basis.1 The patch should not be applied to the same application site more often than once every 14 days.1 Patients should report persistent application site reactions (lasting more than a few days), increases in severity, or skin reactions that spread outside the application site.1 If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be avoided until the skin heals; such exposure may lead to changes in skin color.1
• Importance of informing patients that transdermal rotigotine may cause restless legs symptoms to have an earlier onset during the day or become worse.1
• Importance of informing patients to remove the rotigotine patch before undergoing magnetic resonance imaging (MRI) or cardioversion to avoid possible skin burns.1
• Importance of advising patients about the potential for heat application to increase rotigotine absorption from the patch.1 Patients should be instructed to avoid applying external heat sources (e.g., heating pads, electric blankets, heat lamps, saunas, hot baths, hot tubs, heated water beds, hair dryers) to the transdermal system and to avoid direct sun exposure of the transdermal system.1
• Importance of informing patients that transdermal rotigotine may cause nausea, vomiting, and general GI distress (i.e., dyspepsia, abdominal discomfort).1
• Importance of following recommended procedures for administration, removal, and disposal of rotigotine transdermal systems and of reviewing the instruction sheet provided by the manufacturer.1
• Importance of patient (or individual assisting the patient) thoroughly washing hands with soap and water after handling the rotigotine transdermal system (e.g., initial application, removal) and to wash the application site thoroughly after removing the system.1
• Importance of proper transdermal system disposal, including keeping it out of the reach of children or pets.1
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., CNS depressants including sedatives, antidepressants, and antipsychotics) and OTC drugs and herbal supplements, as well as any concomitant illnesses.1
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. UCB, Inc. Neupro^® (rotigotine transdermal system) prescribing information. Smyrna, GA; 2019 Jan.

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