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Neupro

"Jan. 8, 2013 -- Parkinson's disease itself doesn't seem to raise a person's risk for compulsive addictions to things like gambling, shopping, or sex, a new study shows.

Compulsive behaviors affect about 14% of Parkinson's patients tre"...

Neupro

Discontinued Warning IconPlease Note: This Brand Name drug is no longer available in the US.
(Generic versions may still be available.)

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Patients should be monitored for developing adverse reactions described in this section. If any of these adverse reactions develop, lowering or discontinuing the dose of Neupro may be beneficial.

Sulfite Sensitivity

Neupro contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Falling Asleep During Activities of Daily Living and Somnolence

Patients with early and advanced 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 trials of Restless Legs Syndrome, 2 % of patients treated with the highest recommended Neupro dose (3 mg/24 hours) reported sleep attacks vs 0 % of placebo patients.

Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually 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. For the highest recommended Neupro dose, the treatment different incidence (Neupro % - Placebo %) for somnolence was 16% for early Parkinson's disease, 4 % for advanced Parkinson's disease, and 6 % for Restless Legs Syndrome. 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 during treatment with 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]

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.

Hallucinations / Psychotic-Like Behavior

There was an increased risk for hallucinations in patients with advanced-stage Parkinson's disease treated with Neupro. For the highest recommended Neupro dose, the incidence of the treatment difference (Neupro % - Placebo %) for hallucinations was 4% for patients with advanced-stage Parkinson's disease, and this 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 highest 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 may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during Neupro treatment or after starting or increasing the dose of Neupro. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. These various manifestations of psychotic-like 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].

Symptomatic Hypotension

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 RLS 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.

Mild-moderate decreases in systolic blood pressure ( ≥ 20 mm Hg) and in diastolic blood pressure ( ≥ 10 mm Hg) occurred more frequently (Neupro % ≥ 5 % greater than placebo %) in all patients (i.e., early and advanced-stage Parkinson's disease and Restless Legs Syndrome) with the highest recommended Neupro dose. These decreases in systolic and diastolic blood pressure were observed when supine, standing, and changing from supine to standing position. More severe decreases in systolic blood pressure (> 40 mm Hg) and in diastolic blood pressure ( ≥ 20 mm Hg) also occurred more frequently (Neupro % ≥ 2 % greater than placebo %) in patients with early and advanced-stage Parkinson's disease during measurements when supine, standing and/or changing from supine to standing position. Some threshold decreases in blood pressure described earlier appeared to be dependent on the dose of Neupro and were also observed at the final study 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 highest recommended Neupro dose, the treatment different incidence (Neupro % - Placebo %) for adverse reactions suggestive of hypotension/orthostatic hypotension was 18 % for early Parkinson's disease, 4 %for advanced Parkinson's disease, and 1 % for 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.

Syncope

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 treated with caution.

Impulse Control / Compulsive Behaviors

Case reports suggest that patients can 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 and that are generally used for the treatment of Parkinson's disease. 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. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Neupro [see PATIENT INFORMATION].

Elevation of Blood Pressure and Heart Rate

Some patients treated with Neupro exhibited moderately severe increases in systolic blood pressure (> 180 mm Hg) and/or in diastolic blood pressure (> 105 mm Hg) while supine and/or standing. In patients with advanced-stage Parkinson's disease, there was an increased risk (treatment difference = highest recommended Neupro dose % - placebo %) of 2 % for systolic blood pressure > 180 mm Hg and of 4 % for diastolic blood pressure > 105 mm Hg. In patients with Restless Legs Syndrome, there was an increased risk (treatment difference = highest recommended Neupro dose % - placebo %) of 4 % for diastolic blood pressure > 105 mm Hg.

Mild-moderate increases in systolic blood pressure ( ≥ 20 mm Hg) and in diastolic blood pressure ( ≥ 10 mm Hg) occurred more frequently (Neupro % ≥ 5 % greater than placebo %) in all patients (i.e., early and advanced-stage Parkinson's disease and Restless Legs Syndrome) with the highest 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) and in diastolic blood pressure ( ≥ 20 mm Hg) also occurred more frequently (Neupro % ≥ 2 % greater than placebo %) in 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. Some threshold increases in blood pressure described earlier appeared to be dependent on the dose of Neupro and were also observed at the final study visit.

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

Some patients treated with Neupro exhibited moderately increased pulse (> 100 beats per minute) while supine and/or standing. In patients with advanced-stage Parkinson's disease, there was an increased risk (treatment difference = highest recommended Neupro dose % - placebo %) of 2 % for increased pulse. In patients with Restless Legs Syndrome, there was an increased risk (treatment difference = highest recommended Neupro dose % - placebo %) of 5 % for increased pulse.

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

Weight Gain and Fluid Retention

Patients taking the highest 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 subjects taking placebo (0 %). In advanced-stage Parkinson's disease, the incidence of weight gain more than 10 % of baseline weight was 9 % Neupro (for highest recommended dose) and 1 % placebo. This weight gain was frequently associated with the development of peripheral edema in patients with Parkinson's disease, suggesting that Neupro may cause substantial fluid retention in some Parkinson's patients. Although the weight gain was usually well-tolerated in subjects observed in the Parkinson's clinical studies, it could cause greater difficulty in patients who may be especially vulnerable to negative clinical consequences from fluid retention such as those with significant congestive heart failure or renal insufficiency.

For the highest recommended Neupro dose, the treatment different incidence (Neupro % - Placebo %) for peripheral edema was 1% for early Parkinson's disease, and 8% for advanced Parkinson's disease. These treatment differences increased further with treatment at Neupro dosing above the highest recommended doses.

Dyskinesia

Neupro may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate pre-existing dyskinesia. For the highest recommended Neupro dose, the treatment different incidence (Neupro % - Placebo %) for dyskinesia was 7 % for patients with advanced-stage Parkinson's disease, and this incidence increased with increasing dose. There was also an increased risk (Neupro 3 % vs placebo 0 %) for discontinuation from the study because of dyskinesia for the highest recommended Neupro dose in these same patients.

Application Site Reactions

Application site reactions (ASRs) were reported at a greater frequency in the Neupro-treated patients than in placebo patients in the double-blind, placebo-controlled dose-response studies with Neupro. For the highest recommended Neupro dose, the treatment different incidence (Neupro % - Placebo %) for various ASRs was 15 % for early-stage Parkinson's disease, 23% for advanced-stage Parkinson's disease, and 39 % for 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 Parkinsons's disease (Neupro 2 % vs placebo 0 %, and Restless Legs Syndrome (Neupro 12 % vs placebo 0 %) who were treated with the highest recommended Neupro dose.

Of ASRs in Neupro-treated patients, most were mild or moderate in intensity. 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.

Melanoma

Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Neupro for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Augmentation and Rebound in RLS

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. Dopaminergic medicinal products, including rotigotine, 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.

Magnetic Resonance Imaging and Cardioversion

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

Heat Application

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.

Withdrawal-Emergent-Hyperpyrexia and Confusion

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 as a prophylactic measure [see DOSAGE AND ADMINISTRATION]

Fibrotic Complications

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.

Binding to Melanin

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.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

Sulfite Sensitivity

Advise patients about potential for sulfite sensitivity. Neupro contains sodium metabisulfite, which may cause allergic-type reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people. An allergy to sulfites is not the same as an allergy to sulfa.

Falling Asleep During Activities of Daily Living and Somnolence

Advise and alert patients about the potential for sedating effects associated with Neupro, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with Neupro to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of Neupro.

Because of the possible additive effects, caution should also be used when patients are taking alcohol, sedating medications, or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with Neupro.

Hallucinations / Psychotic-Like Behavior

Inform patients that hallucinations and other psychotic-like behavior can occur while taking Neupro and that the elderly are at a higher risk than younger patients with Parkinson's disease.

Symptomatic Hypotension

Advise patients that they may develop symptomatic (or asymptomatic) hypotension while taking Neupro. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with Neupro.

Syncope

Advise patients about the potential for syncope in patients using dopamine agonists. For this reason, patients should be alerted to the possibility of syncope while taking Neupro.

Impulse Control / Compulsive Behaviors

Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications generally used for the treatment of Parkinson's disease, including Neupro. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Neupro. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Neupro. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Neupro.

Elevation of Blood Pressure and Heart Rate

Advise patients that Neupro can increase blood pressure and heart rate,

Weight Gain and Fluid Retention

Advise patients that Neupro can cause increased weight and fluid retention manifesting itself as peripheral edema.

Dyskinesias

Inform patients that Neupro may cause and/or exacerbate pre-existing dyskinesias.

Application Site Reactions

Inform patients that application site reactions can occur and that the Neupro transdermal system application site should be rotated on a daily basis. Neupro should not be applied to the same application site more than once every 14 days. Patients should report persistent application site reaction (of more than a few days), increases in severity, or skin reactions that spread outside the application site

If there is a skin rash or irritation from the transdermal system, direct sunlight on the area should be avoided until the skin heals. Exposure could lead to changes in the skin color.

Melanoma

Advise patients with Parkinson's disease that they have a higher risk of developing melanoma. Advise patients to monitor for melanomas frequently and on a regular basis when using Neupro for any indication.

Augmentation and Rebound in RLS

Inform patients that Neupro may cause RLS symptoms to have an earlier onset during the day or become worse.

Magnetic Resonance Imaging and Cardioversion

Inform patients to remove Neupro before undergoing magnetic resonance imaging (MRI) or cardioversion. These procedures could cause a burn to the site where Neupro is applied.

Heat Application

Advise patients about the potential for heat application to increase drug absorption. Because applying external heat (e.g., a heating pad, sauna, or hot bath) to the transdermal system may increase the amount of drug absorbed, patients should be instructed not to apply heating pads or other sources of heat to the area of the transdermal system. Direct sun exposure of the transdermal system should be avoided.

Nausea, Vomiting, and Dyspepsia

Inform patients that Neupro causes nausea, vomiting, and general gastrointestinal distress (i.e., dyspepsia/abdominal discomfort). Nausea and vomiting may occur more frequently during initial therapy and may require dose adjustment.

Instructions for Use

Instruct patients to wear Neupro continuously for 24 hours. After 24 hours, the patch should be removed and a new one applied immediately. Patients can choose the most convenient time of day or night to apply Neupro but should be advised to apply the patch at approximately the same time each day. If a patient forgets to change a patch, a new patch should be applied as soon as possible and replaced at the usual time the following day.

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.

Neupro 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.

Neupro should be applied once daily to clean, dry, and intact skin on the abdomen, thigh, hip, flank, shoulder, or upper arm. Shave hairy areas at least 3 days prior to applying the patch. Do not apply to areas that could be rubbed by tight clothing, or under a waistband, to skin folds, or to skin that is red or irritated. Creams, lotions, ointments, oils, and powders should not be applied to the skin area where Neupro will be placed. Patients should wash their hands to remove any drug and should be careful not to touch their eyes or any objects.

Instruct patients not to cut or damage Neupro.

Care should be used to avoid dislodging the patch while showering, bathing or during physical activity. If the edges of the patch lift, Neupro may be taped down with bandage tape. If the patch detaches, a new one may be applied immediately to a different site. The patient should then change the patch according to their regular schedule.

Removal of the patch: Neupro should always be removed slowly and carefully to avoid irritation. After removal the patch should be folded over so that it sticks to itself and should be discarded so that children and pets cannot reach it. Wash the site with soap and water to remove any drug or adhesive. Baby or mineral oil may be used to remove any excess residue. Alcohol and other solvents (such as nail polish remover) may cause skin irritation and should not be used.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

In rats, there were increases in Leydig cell tumors and in uterine tumors (adenocarcinomas, squamous cell carcinomas) at all doses. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans. Therefore, there were no tumor findings considered relevant to humans at plasma exposures (AUC) up to 4-6 times that in humans at the MRHD.

Mutagenesis

Rotigotine was negative in the in vitro bacterial reverse mutation (Ames) and in the in vivo micronucleus assays. Rotigotine was mutagenic and clastogenic in the in vivo mouse lymphoma tk assay.

Infertility

When rotigotine was administered subcutaneously (1.5, 5, or 15 mg/kg/day) to female rats prior to and during mating and continuing through gestation day 7, an absence of implantation was observed at all doses. The lowest dose tested is 2 times the MRHD on a mg/m² basis. In male rats treated from 70 days prior to and during mating, there was no effect on fertility; however, a decrease in epididymal sperm motility was observed at the highest dose tested. The no-effect dose (5 mg/kg/day) is 6 times the MRHD on a mg/m² basis. When rotigotine was administered subcutaneously to female mice at doses of 10, 30, and 90 mg/kg/day from 2 weeks until 4 days before mating and then at a dose of 6 mg/kg/day (all groups) (approximately 4 times the MRHD on a mg/m² basis) from 3 days before mating until gestation day 7, a markedly reduced (low dose) or complete absence of implantation (mid and high doses) was observed. The effects on implantation in rodents are thought to be due to the prolactin-lowering effect of rotigotine. In humans, chorionic gonadotropin, not prolactin, is essential for implantation.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In studies conducted in mice, rats, and rabbits, rotigotine was shown to have adverse effects on embryo-fetal development when administered during pregnancy at doses similar to or lower than those used clinically. Neupro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Rotigotine administered subcutaneously (10, 30, or 90 mg/kg/day) to pregnant mice during organogenesis (gestation days 6 through 15) resulted in increased incidences of delayed skeletal ossification and decreased fetal body weights at the two highest doses and an increase in embryo-fetal death at the high dose. The no-effect dose for embryo-fetal developmental toxicity in mice is approximately 6 times the maximum recommended human dose (MRHD) for Parkinson's disease (8 mg/24 hours) on a body surface area (mg/m2) basis. Rotigotine administered subcutaneously (0.5, 1.5, or 5 mg/kg/day) to pregnant rats during organogenesis (gestation days 6 through 17) resulted in increased embryo-fetal death at all doses. The lowest effect dose is less than the MRHD on a mg/m² basis. This effect in rats is thought to be due to the prolactin-lowering effect of rotigotine. When rotigotine was administered subcutaneously (5, 10, or 30 mg/kg/day) to pregnant rabbits during organogenesis (gestation days 7 through 19), an increase in embryo-fetal death occurred at the two highest doses tested. The no-effect dose is 12 times the MRHD on a mg/m² basis.

In a study in which rotigotine was administered subcutaneously (0.1, 0.3, or 1 mg/kg/day) to rats throughout pregnancy and lactation (gestation day 6 through postnatal day 21), impaired growth and development during lactation and long-term neurobehavioral abnormalities were observed in the offspring at the highest dose tested; when those offspring were mated, growth and survival of the next generation were adversely affected. The no-effect dose for pre- and postnatal developmental toxicity (0.3 mg/kg/day) is less than the MRHD on a mg/m² basis.

Nursing Mothers

Rotigotine decreases prolactin secretion in humans and could potentially inhibit lactation.

Studies have shown that rotigotine and/or its metabolite(s) are excreted in rat milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when NEUPRO is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Of subjects treated with Neupro in clinical studies for the treatment of Parkinson's disease, approximately 50% were 65 years old and over, and approximately 11% were 75 and over. Among subjects treated with Neupro in clinical studies for the treatment of RLS, 26% were 65 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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.

Renal Impairment

The effect of renal function on rotigotine pharmacokinetics has been studied in subjects with mild to severe impairment of renal function including subjects requiring dialysis compared to healthy subjects. There were no relevant changes in rotigotine plasma concentrations. In subjects with severe renal impairment not on dialysis, (i.e., creatinine clearance 15 to <30 ml/min), exposure to rotigotine conjugates was doubled. No dosage adjustment is recommended.

Hepatic Impairment

The effect of impaired hepatic function on the pharmacokinetics of rotigotine has been studied in subjects with moderate impairment of hepatic function (Child Pugh classification – Grade B). There were no relevant changes in rotigotine plasma concentrations. No dose adjustment is necessary in subjects with moderate impairment of hepatic function. No information is available on subjects with severe impairment of hepatic function.

Last reviewed on RxList: 4/13/2012
This monograph has been modified to include the generic and brand name in many instances.

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