Ropinirole Hydrochloride Tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.
The effectiveness of Ropinirole Hydrochloride Tablets were demonstrated in randomized, controlled trials in patients with early Parkinson’s disease who were not receiving concomitant L-dopa therapy as well as in patients with advanced disease on concomitant L-dopa (see CLINICAL PHARMACOLOGY: Clinical Trials).
Restless Legs Syndrome
Ropinirole Hydrochloride Tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).
Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with moderate-to-severe RLS.
Ropinirole Hydrochloride Tablets are contraindicated for patients known to have hypersensitivity to the product.
Falling Asleep During Activities of Daily Living
Patients treated with Ropinirole Hydrochloride Tablets 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 Ropinirole Hydrochloride Tablets, some perceived that they had no 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 1 year after initiation of treatment.
In controlled clinical trials, somnolence was a common occurrence in patients receiving Ropinirole Hydrochloride Tablets and is more frequent in Parkinson’s disease (up to 40% Ropinirole Hydrochloride Tablets, 6% placebo) than in Restless Legs Syndrome (12% Ropinirole Hydrochloride Tablets, 6% placebo). 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. 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 Tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Ropinirole Hydrochloride Tablets such as concomitant sedating medications, the presence of sleep disorders (other than Restless Legs Syndrome), and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin — see PRECAUTIONS: Drug Interactions). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Ropinirole Hydrochloride Tablets should ordinarily be discontinued. (See DOSAGE AND ADMINISTRATION for guidance in discontinuing Ropinirole Hydrochloride Tablets.) If a decision is made to continue Ropinirole Hydrochloride Tablets, 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.
Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in both Parkinson’s disease patients and RLS patients. In the 2 double-blind, placebo-controlled studies of Ropinirole Hydrochloride Tablets in patients with Parkinson’s disease who were not being treated with L-dopa, 11.5% (18 of 157) of patients on Ropinirole Hydrochloride Tablets had syncope compared to 1.4% (2 of 147) of patients on placebo. Most of these cases occurred more than 4 weeks after initiation of therapy with Ropinirole Hydrochloride Tablets, and were usually associated with a recent increase in dose.
Of 208 patients being treated with both L-dopa and Ropinirole Hydrochloride Tablets in placebo-controlled advanced Parkinson’s disease trials, there were reports of syncope in 6 (2.9%) compared to 2 of 120 (1.7%) of placebo/L-dopa patients.
In patients with RLS, of 496 patients treated with Ropinirole Hydrochloride Tablets in 12-week placebo-controlled trials, there were reports of syncope in 5 (1.0%) compared with 1 of 500 (0.2%) patients treated with placebo.
Because the studies of Ropinirole Hydrochloride Tablets excluded patients with significant cardiovascular disease, it is not known to what extent the estimated incidence figures apply to either Parkinson’s disease or RLS patients in clinical practice. Therefore, patients with severe cardiovascular disease should be treated with caution.
Two of 47 Parkinson’s disease patient volunteers enrolled in phase 1 studies had syncope following a 1-mg dose. In 2 studies in RLS patients that used a forced titration regimen and orthostatic challenge with intensive blood pressure monitoring, 1 of 55 RLS patients treated with Ropinirole Hydrochloride Tablets compared with 0 of 27 patients receiving placebo reported syncope. In phase 1 studies including 110 healthy volunteers, 1 patient developed hypotension, bradycardia, and sinus arrest of 26 seconds accompanied by syncope; the patient recovered spontaneously without intervention. One other healthy volunteer reported syncope.
Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting postural 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, Parkinson’s 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 (see PRECAUTIONS: Information for Patients).
Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of postural hypotension in early Parkinson’s disease (without L-dopa) in patients treated with Ropinirole Hydrochloride Tablets. Most of these cases occurred more than 4 weeks after initiation of therapy with Ropinirole Hydrochloride 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 Hydrochloride Tablets compared with 2 of 500 patients (0.4%) receiving placebo.
In two phase 2 studies in patients with RLS that used a forced-titration regimen and orthostatic challenges with intensive blood pressure monitoring, 14 of 55 patients (25%) receiving Ropinirole Hydrochloride Tablets experienced an adverse event of hypotension or postural hypotension. As described above, one additional patient was noted to have an episode of vasovagal syncope (although no blood pressure recording was documented). None of the 27 patients receiving placebo had a similar adverse event. In these studies, 11 of the 55 patients (20%) receiving Ropinirole Hydrochloride 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; not all of these changes were associated with clinical symptoms. Except for its forced nature these studies used a similar titration schedule as those in the phase 3 efficacy trials.
In phase 1 studies of Ropinirole Hydrochloride Tablets that included 110 healthy volunteers, 9 subjects had documented symptomatic postural hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for either Parkinson’s disease patients or RLS patients. In 8 of these 9 individuals, the hypotension was accompanied by bradycardia, but did not develop into syncope (see Syncope subsection). None of these events resulted in death or hospitalization.
One of 47 Parkinson’s disease patient volunteers enrolled in phase 1 studies had documented hypotension following a 2-mg dose on 2 occasions.
In double-blind, placebo-controlled, early-therapy studies in patients with Parkinson’s disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with Ropinirole Hydrochloride Tablets reported hallucinations, compared to 1.4% of patients on placebo (2 of 147). Among those patients receiving both Ropinirole Hydrochloride Tablets and L-dopa in advanced Parkinson’s disease (with L-dopa) studies, 10.1% (21 of 208) were reported to experience hallucinations, compared to 4.2% (5 of 120) of patients treated with placebo and L-dopa.
Hallucinations were of sufficient severity to cause discontinuation of treatment in 1.3% of the early Parkinson’s disease (without L-dopa) patients and 1.9% of the advanced Parkinson’s disease (with L-dopa) patients, compared to 0% and 1.7% of placebo patients, respectively.
In patients with RLS, hallucinations were reported by 0% of patients treated with Ropinirole Hydrochloride Tablets (0 of 496) compared with 0.2% of patients who received placebo (1 of 500) in the 12-week placebo-controlled trials; in premarketing long-term open-label studies, 0.5% of patients reported hallucinations during therapy with Ropinirole Hydrochloride Tablets (2 of 390) but did not discontinue treatment and symptoms resolved.
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