ROPINIROLE HYDROCHLORIDE (Page 2 of 9)

5.2 Syncope

Syncope, sometimes associated with bradycardia, was observed in association with treatment 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 tablets than in patients receiving placebo (early Parkinson’s disease without levodopa [L-dopa]: ropinirole tablets 12%, placebo 1%; advanced Parkinson’s disease: ropinirole tablets 3%, placebo 2%). Syncope was reported in 1% of patients treated with ropinirole tablets 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 tablets, and were usually associated with a recent increase in dose.

Because the trials conducted with ropinirole tablets 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 tablets. 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 tablets 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

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 ropinirole tablets 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)].

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 tablets. Most of these cases occurred more than 4 weeks after initiation of therapy with ropinirole tablets 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 tablets 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 tablets 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 tablets 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 tablets 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 tablets and was more frequent in patients with Parkinson’s disease or with RLS receiving ropinirole tablets than in patients receiving placebo (early Parkinson’s disease without L-dopa: ropinirole tablets 40%, placebo 22%; advanced Parkinson’s disease: ropinirole tablets 26%, placebo 16%; RLS: ropinirole tablets 11%, placebo 5%). Dizziness of sufficient severity to cause trial discontinuation of ropinirole tablets 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 tablets reported hallucinations, compared with 1.4% of patients on placebo (2 of 147). Among those patients receiving both ropinirole tablets 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 tablets [see Use in Specific Populations (8.5)].

Postmarketing 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-like behavior during treatment with ropinirole tablets or after starting or increasing the dose of ropinirole tablets. 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 can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, mania, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with ropinirole tablets 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 tablets [see Drug Interactions (7.3)].

5.5 Dyskinesia

Ropinirole tablets may cause 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 tablets than in those treated with placebo. Among those patients receiving both ropinirole tablets 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 dopaminergic medications may ameliorate this adverse reaction.

5.6 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 ropinirole tablets, 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 ropinirole tablets for Parkinson’s disease and RLS. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole tablets.

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 of, withdrawal of, or changes in, dopaminergic therapy. It is recommended that the dose be tapered at the end of treatment with ropinirole tablets as a prophylactic measure [see Dosage and Administration (2.2, 2.3)].

5.8 Withdrawal Symptoms

Symptoms including insomnia, apathy, anxiety, depression, fatigue, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including ropinirole tablets. These symptoms generally do not respond to levodopa.

Prior to discontinuation of ropinirole tablets, 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.

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