warnings and cautions
5 WARNINGS AND PRECAUTIONS • Sudden onset of sleep and somnolence may occur ( 5.1 ) • Syncope may occur ( 5.2 ) • Hypotension, including orthostatic hypotension may occur ( 5.3 ) • Elevation of blood pressure and changes in heart rate may occur ( 5.4 ) • May cause hallucinations and psychotic-like behaviors ( 5.5 ) • May cause or exacerbate dyskinesia ( 5.6 ) • May cause problems with impulse control or compulsive behaviors ( 5.7 ) 5.1 Falling Asleep during Activities of Daily Living and Somnolence Patients treated with REQUIP XL have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents. Although many of these patients reported somnolence while on ropinirole, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some have reported these events more than 1 year after initiation of treatment. Among the 613 patients who received REQUIP XL in flexible-dose clinical trials (Study 1 and Study 3), <1% of patients reported sudden onset of sleep and <1% of patients reported a motor vehicle accident in which it is not known if falling asleep was a contributing factor. In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), sudden onset of sleep was reported in 4% of 276 patients on REQUIP XL compared with 3% of 74 patients on placebo. In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), sudden onset of sleep was reported in 5% of 146 patients on REQUIP XL compared with 0% of 40 patients on placebo [see Adverse Reactions ( 6.1 )] . The incidence of sudden onset of sleep was not dose-related in either trial. During a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), somnolence was reported in 7% of 202 patients on REQUIP XL compared with 4% of 191 patients on placebo. During a flexible-dose, active-control, crossover trial in early Parkinson’s disease (Study 3), somnolence was reported in 11% of 140 patients on REQUIP XL compared with 15% of 149 patients on an immediate-release formulation of REQUIP [see Adverse Reactions ( 6.1 )] . In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), somnolence was reported in 8% of 276 patients on REQUIP XL compared with 5% of 74 patients on placebo. In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), somnolence was reported in 10% of 146 patients on REQUIP XL compared with 5% of 40 patients on placebo [see Adverse Reactions ( 6.1 )] . The frequency of reported somnolence was not dose-related. It has been reported that falling asleep while engaged in activities of daily living usually 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. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with REQUIP XL, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with REQUIP XL such as concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin) [see Drug Interactions ( 7.1 )] . If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), REQUIP XL should ordinarily be discontinued [see Dosage and Administration ( 2.2 )] . If a decision is made to continue REQUIP XL, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 5.2 Syncope Syncope, sometimes associated with bradycardia, was observed in association with treatment with REQUIP XL in patients with Parkinson’s disease. In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), syncope occurred in 1% of patients on REQUIP XL compared with 0% of patients on placebo [see Adverse Reactions ( 6.1 )] . In the placebo-controlled fixed-dose trials (Study 2 and Study 4), one patient on REQUIP XL with advanced Parkinson’s disease) and one patient on REQUIP XL with early Parkinson’s disease experienced syncope during the titration period for REQUIP XL. Both patients discontinued prematurely from the respective trials. Because the trials conducted with REQUIP XL excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution. 5.3 Hypotension/Orthostatic Hypotension Patients with Parkinson’s disease may have impaired ability to respond normally to a fall in blood pressure after standing from lying down or seated position. Patients on REQUIP XL should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of the risk for syncope and hypotension [see Patient Counseling Information ( 17 )]. In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), hypotension was reported as an adverse reaction in 2% of patients on REQUIP XL, compared with 0% of patients on placebo. In this study, orthostatic hypotension was reported as an adverse reaction in 5% of patients on REQUIP XL and 1% of patients on placebo [see Adverse Reactions ( 6.1 )] . Some patients experienced hypotension or orthostatic hypotension that started in the titration and persisted into the maintenance period. There was also a higher incidence for the combined adverse reaction terms of “hypotension”, “orthostatic hypotension”, “dizziness”, “vertigo”, and “blood pressure decreased” in 7% of patients on REQUIP XL compared with 3% of patients on placebo. The increased incidence of those events with REQUIP XL 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 trial. The frequency of orthostatic hypotension (systolic blood pressure decrements ≥20 mm Hg) at any time during the trial was 38% for REQUIP XL vs. 31% for placebo. In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), a decrease in standing systolic blood pressure of ≥20 mm Hg was observed in 26% of patients on REQUIP XL compared with 18% of patients on placebo. In a placebo-controlled fixed-dose trial of patients with early Parkinson’s disease (Study 4), a decrease in standing systolic blood pressure of ≥20 mm Hg was observed in 14% of patients on REQUIP XL compared with 10% of patients on placebo. Significant decrements in blood pressure unrelated to standing were also reported in some patients taking REQUIP XL. 5.4 Elevation of Blood Pressure and Changes in Heart Rate The potential for elevation in blood pressure and changes in heart rate should be considered when treating patients with cardiovascular disease with REQUIP XL. In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), the frequency of systolic blood pressure increase (≥40 mm Hg) in the semi-supine position was 8% of patients on REQUIP XL vs. 5% of patients on placebo. In the standing position, the frequency of systolic blood pressure increase (≥40 mm Hg) was 9% for REQUIP XL vs. 6% for placebo. There was no clear effect of REQUIP XL on average heart rate. In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), hypertension was reported as an adverse reaction in 3% of patients on REQUIP XL, compared with 1% of patients on placebo [see Adverse Reactions ( 6.1 )] . In a placebo‑controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), hypertension was reported as an adverse reaction in 5% of patients on REQUIP XL, compared with 0% of patients on placebo [see Adverse Reactions ( 6.1 )] . 5.5 Hallucinations/Psychotic-Like Behavior In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), 8% of patients on REQUIP XL reported hallucination, compared with 2% of patients on placebo [see Adverse Reactions ( 6.1 )] . Hallucinations led to discontinuation of treatment in 2% of patients on REQUIP XL and 1% of patients on placebo. The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with REQUIP XL [see Use in Specific Populations ( 8.5 )] . In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of hallucination was 3% in patients on REQUIP XL compared with 0% in patients on placebo [see Adverse Reactions ( 6.1 )] . The most common adverse reaction associated with study discontinuation for any dose of REQUIP XL was hallucination (2%). Postmarketing reports indicate that patients with Parkinson’s disease may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with REQUIP XL or after starting or increasing the dose of REQUIP XL. 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, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with REQUIP XL because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of REQUIP XL [see Drug Interactions ( 7.3 )] . 5.6 Dyskinesia REQUIP XL may cause or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease. In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), the incidence of dyskinesia was 13% in patients on REQUIP XL and 3% in patients on placebo [see Adverse Reactions ( 6.1 )] . In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of dyskinesia was 7% in patients on REQUIP XL compared with 1% in patients on placebo [see Adverse Reactions ( 6.1 )] . Decreasing the dose of dopaminergic medications may ameliorate this adverse reaction. 5.7 Impulse Control/Compulsive Behaviors Reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including REQUIP XL, 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, binge or compulsive eating, or other urges while being treated with REQUIP XL for Parkinson’s disease. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP XL. 5.8 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction of, withdrawal of, or changes in, dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with REQUIP XL as a prophylactic measure [see Dosage and Administration ( 2.2 )] . 5.9 Withdrawal Symptoms Symptoms including insomnia, apathy, anxiety, depression, fatigue, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including REQUIP XL. These symptoms generally do not respond to levodopa. Prior to discontinuation of REQUIP XL, patients should be informed about the 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. 5.10 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 reactions are believed to be related to the ergoline structure of these compounds, whether other, non–ergot-derived dopamine agonists, such as ropinirole, can cause them is unknown. Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole. In the clinical development program (N = 613), 2 patients treated with REQUIP XL had pleural effusion. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded. 5.11 Retinal Pathology Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m 2 basis. Retinal degeneration was not observed in a 3-month study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys or albino rats. The significance of this effect for humans has not been established, but involves disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding). Ocular electroretinogram assessments were conducted during a 2-year, double-blind, multicenter, flexible-dose, L–dopa-controlled clinical trial of immediate‑release ropinirole in patients with Parkinson’s disease; 156 patients (78 on immediate-release ropinirole, mean dose: 11.9 mg/day and 78 on L-dopa, mean dose: 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the trial. 5.12 Binding to Melanin Ropinirole binds to melanin-containing tissues (e.g., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days.