Rotigotine

5 WARNINGS AND PRECAUTIONS Contains sodium metabisulfite that may cause allergic-type reactions in those with sulfite sensitivity. ( 5.1 ) Falling asleep during activities of daily living, including the operation of motor vehicles, and somnolence may occur. ( 5.2 ) Hallucinations/psychosis and dyskinesia may occur. ( 5.3 , 5.9 ) Symptomatic postural hypotension and syncope may occur, especially during dose escalation. ( 5.4 , 5.5 ) Consider dose reduction or stopping NEUPRO if patient develops compulsive behaviors. ( 5.6 ) Elevation of blood pressure and heart rate may occur. ( 5.7 ) Application site reactions can occur and may be severe. ( 5.10 ) Hyperpyrexia and confusion may occur with sudden discontinuation or dose reduction. ( 5.14 ) 5.1 Sulfite Sensitivity NEUPRO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. 5.2 Falling Asleep During Activities of Daily Living and Somnolence Patients with early- and advanced-stage Parkinson's disease and with Restless Legs Syndrome treated with NEUPRO have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on NEUPRO, some did not perceive warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported as late as one year after initiation of treatment. In clinical trials in patients with Restless Legs Syndrome, 2% of patients treated with the maximum recommended NEUPRO dose (3 mg/24 hours) reported sleep attacks compared to 0% of placebo-treated patients. It has been reported that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness especially since some of the events occur well after the start of treatment. Somnolence is a common occurrence in patients receiving NEUPRO. In patients taking the maximum recommended NEUPRO dose, there was an increased risk of somnolence for early-stage Parkinson's disease (NEUPRO 19%, placebo 3%), for advanced-stage Parkinson's disease (NEUPRO 32%, placebo 28%), and for Restless Legs Syndrome (NEUPRO 10%, placebo 4%). Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Patients should be advised to exercise caution while driving, operating machines, or working at heights during treatment with NEUPRO. Patients who have already experienced somnolence and/or an episode of sudden sleep onset should not participate in these activities while taking NEUPRO. Before initiating treatment with NEUPRO, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase this risk with NEUPRO such as concomitant sedating medications and the presence of sleep disorders. If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), NEUPRO should ordinarily be discontinued [see Dosage and Administration (2.4) ] . If a decision is made to continue NEUPRO, patients should be advised not to drive and to avoid other potentially dangerous activities. There is insufficient information to establish whether dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 5.3 Hallucinations/Psychosis There was an increased risk for 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) ]. 5.4 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 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. 5.5 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 asked about symptoms of syncope and pre-syncope. 5.6 Impulse Control/Compulsive Behaviors 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 . 5.7 Elevation of Blood Pressure and Heart Rate 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. 5.8 Weight Gain and Fluid Retention 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. 5.9 Dyskinesia 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. 5.10 Application Site Reactions 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. 5.11 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. 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. 5.12 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. 5.13 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. 5.14 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 [see Dosage and Administration (2.4) ]. 5.15 Withdrawal Symptoms 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. 5.16 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. 5.17 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.