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 ) May cause hallucinations and psychotic-like behaviors ( 5.4 ) May cause or exacerbate dyskinesia ( 5.5 ) May cause problems with impulse control or compulsive behaviors ( 5.6 ) 5.1 Falling Asleep during Activities of Daily Living and Somnolence Patients treated with ropinirole hydrochloride 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 hydrochloride, 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. In controlled clinical trials, somnolence was commonly reported in patients receiving ropinirole hydrochloride and was more frequent in Parkinson's disease (up to 40% ropinirole hydrochloride, 6% placebo) than in Restless Legs Syndrome (12% ropinirole hydrochloride, 6% placebo) [see Adverse Reactions ( 6.1 )] . It has been reported that 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. 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 ropinirole hydrochloride, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole hydrochloride such as concomitant sedating medications, the presence of sleep disorders (other than RLS), 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), ropinirole hydrochloride should ordinarily be discontinued [see Dosage and Administration ( 2.2 , 2.3 )] . If a decision is made to continue ropinirole hydrochloride, 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 ropinirole in both patients with Parkinson’s disease and patients with RLS. In controlled clinical trials in patients with Parkinson’s disease, syncope was observed more frequently in patients receiving ropinirole hydrochloride than in patients receiving placebo (early Parkinson’s disease without L-dopa: ropinirole hydrochloride 12%, placebo 1%; advanced Parkinson’s disease: ropinirole hydrochloride 3%, placebo 2%). Syncope was reported in 1% of patients treated with ropinirole hydrochloride for RLS in 12-week, placebo-controlled clinical trials compared with 0.2% of patients treated with placebo [see Adverse Reactions ( 6.1 )] . Most cases occurred more than 4 weeks after initiation of therapy with ropinirole hydrochloride, and were usually associated with a recent increase in dose. Because the trials of ropinirole hydrochloride excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution. Approximately 4% of patients with Parkinson's disease enrolled in Phase 1 trials had syncope following a 1-mg dose of ropinirole. In two trials in patients with RLS that used a forced-titration regimen and orthostatic challenge with intensive blood pressure monitoring, 2% of RLS patients treated with ropinirole hydrochloride compared with 0% of patients receiving placebo reported syncope. In Phase 1 trials including healthy volunteers, the incidence of syncope was 2%. Of note, 1 subject with syncope developed hypotension, bradycardia, and sinus arrest; the subject recovered spontaneously without intervention. 5.3 Hypotension/Orthostatic Hypotension Dopamine agonists in clinical trials and clinical experience appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. In addition, patients with Parkinson's disease appear to have an impaired capacity to respond to a postural challenge. For these reasons, patients should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and patients should be informed of the risk for syncope and hypotension [see Patient Counseling Information ( 17 )] . Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of orthostatic hypotension in early Parkinson's disease (without L-dopa) in patients treated with ropinirole hydrochloride. Most of these cases occurred more than 4 weeks after initiation of therapy with ropinirole hydrochloride and were usually associated with a recent increase in dose. In 12-week, placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension was reported by 4 of 496 patients (0.8%) treated with ropinirole hydrochloride compared with 2 of 500 patients (0.4%) receiving placebo. In two Phase 2 studies in patients with RLS, 14 of 55 patients (25%) receiving ropinirole hydrochloride experienced an adverse event of hypotension or orthostatic hypotension compared with none of the 27 patients receiving placebo. In these studies, 11 of the 55 patients (20%) receiving ropinirole hydrochloride and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic. In Phase 1 trials of ropinirole hydrochloride with healthy volunteers who received single doses on more than one occasion without titration, 7% had documented symptomatic orthostatic hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for patients with either Parkinson's disease or with RLS. In most of these individuals, the hypotension was accompanied by bradycardia but did not develop into syncope [see Warnings and Precautions ( 5.2 )] . Although dizziness is not a specific manifestation of hypotension or orthostatic hypotension, patients with hypotension or orthostatic hypotension frequently reported dizziness. In controlled clinical trials, dizziness was a common adverse reaction in patients receiving ropinirole hydrochloride and was more frequent in patients with Parkinson's disease or with RLS receiving ropinirole hydrochloride than in patients receiving placebo (early Parkinson's disease without L-dopa: ropinirole hydrochloride 40%, placebo 22%; advanced Parkinson's disease: ropinirole hydrochloride 26%, placebo 16%; RLS: ropinirole hydrochloride 11%, placebo 5%). Dizziness of sufficient severity to cause trial discontinuation of ropinirole hydrochloride was 4% in patients with early Parkinson's disease without L-dopa, 3% in patients with advanced Parkinson's disease, and 1% in patients with RLS. [See Adverse Reactions ( 6.1 ).] 5.4 Hallucinations/Psychotic-like Behavior In double-blind, placebo-controlled, early-therapy trials in patients with Parkinson's disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with ropinirole hydrochloride reported hallucinations, compared with 1.4% of patients on placebo (2 of 147). Among those patients receiving both ropinirole hydrochloride and L-dopa in advanced Parkinson's disease studies, 10.1% (21 of 208) were reported to experience hallucinations, compared with 4.2% (5 of 120) of patients treated with placebo and L-dopa. The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with extended-release ropinirole hydrochloride [see Use in Specific Populations ( 8.5 )] . Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole hydrochloride or after starting or increasing the dose of ropinirole hydrochloride. 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. Patients with a major psychotic disorder should ordinarily not be treated with ropinirole hydrochloride 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 ropinirole hydrochloride [see Drug Interactions ( 7.3 )]. 5.5 Dyskinesia Ropinirole hydrochloride may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease. In double-blind, placebo-controlled trials in advanced Parkinson’s disease, dyskinesia was much more common in patients treated with ropinirole hydrochloride than in those treated with placebo. Among those patients receiving both ropinirole hydrochloride and L-dopa in advanced Parkinson’s disease trials, 34% were reported to experience dyskinesia, compared with 13% of patients treated with placebo [see Adverse Reactions ( 6.1 )]. Decreasing the dose of the dopaminergic drug may ameliorate this adverse reaction. 5.6 Impulse Control/Compulsive Behaviors Case 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 ropinirole hydrochloride, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease and RLS. 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 ropinirole hydrochloride. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole hydrochloride. 5.7 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, withdrawal of, or changes in dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with ropinirole hydrochloride for Parkinson's disease as a prophylactic measure [see Dosage and Administration ( 2.2 )] . 5.8 Melanoma Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to 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 ropinirole hydrochloride for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). 5.9 Augmentation and Early-morning Rebound in Restless Legs Syndrome Reports in the literature indicate treatment of RLS with dopaminergic medications can result in recurrence of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Rebound refers to new onset of symptoms in the early morning hours. Augmentation and/or early-morning rebound have been observed in a postmarketing trial. If augmentation or early-morning rebound occurs, the use of ropinirole hydrochloride should be reviewed and dosage adjustment or discontinuation of treatment should 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. 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 (equivalent to 0.6 to 20 times the maximum recommended human dose [MRHD] for Parkinson's disease [24 mg/day] on a mg/m 2 basis), but was statistically significant at the highest dose (50 mg/kg/day). 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 (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa–controlled clinical trial of ropinirole in patients with Parkinson's disease; 156 patients (78 on 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 (i.e., 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.