ROPINIROLE 2 mg Tablet, Film Coated, 30-count

WARNINGS Falling Asleep During Activities of Daily Living Patients treated with Ropinirole 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 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 Tablets and is more frequent in Parkinson's disease (up to 40% Ropinirole Tablets, 6% placebo) than in Restless Legs Syndrome (12% Ropinirole 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 Tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Ropinirole 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 Tablets should ordinarily be discontinued. (See DOSAGE AND ADMINISTRATION for guidance in discontinuing Ropinirole Tablets.) If a decision is made to continue Ropinirole 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 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 Tablets in patients with Parkinson’s disease who were not being treated with L-dopa, 11.5% (18 of 157) of patients on Ropinirole 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 Tablets, and were usually associated with a recent increase in dose.

Of 208 patients being treated with both L-dopa and Ropinirole 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 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 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 pre…

ADVERSE REACTIONS Parkinson’s Disease During the premarketing development of Ropinirole Tablets, patients received Ropinirole Tablets either without L-dopa (early Parkinson’s disease studies) or as concomitant therapy with L-dopa (advanced Parkinson’s disease studies). Because these 2 populations may have differential risks for various adverse events, this section will, in general, present adverse event data for these 2 populations separately. Early Parkinson’s Disease (Without L-dopa) The most commonly observed adverse events (>5%) in the double-blind, placebo-controlled early Parkinson’s disease trials associated with the use of Ropinirole Tablets (n = 157) not seen at an equivalent frequency among the placebo-treated patients (n = 147) were, in order of decreasing incidence: nausea, dizziness, somnolence, headache, vomiting, syncope, fatigue, dyspepsia, viral infection, constipation, pain, increased sweating, asthenia, dependent/leg edema, orthostatic symptoms, abdominal pain, pharyngitis, confusion, hallucinations, urinary tract infections, and abnormal vision.

Approximately 24% of 157 patients treated with Ropinirole Tablets who participated in the double-blind, placebo-controlled early Parkinson’s disease (without L-dopa) trials discontinued treatment due to adverse events compared to 13% of 147 patients who received placebo. The adverse events most commonly causing discontinuation of treatment by patients treated with Ropinirole Tablets were: nausea (6.4%), dizziness (3.8%), aggravated Parkinson’s disease (1.3%), hallucinations (1.3%), somnolence (1.3%), vomiting (1.3%), and headache (1.3%).

Of these, hallucinations appear to be dose-related. While other adverse events leading to discontinuation may be dose-related, the titration design utilized in these trials precluded an adequate assessment of the dose response. For example, in the larger of the 2 trials described in CLINICAL PHARMACOLOGY: Clinical Trials, the difference in the rate of discontinuations emerged only after 10 weeks of treatment, suggesting, although not proving, that the effect could be related to dose.

Adverse Event Incidence in Controlled Clinical Studies Table 2 lists treatment-emergent adverse events that occurred in ≥2% of patients with early Parkinson’s disease (without L-dopa) treated with Ropinirole Tablets participating in the double-blind, placebo-controlled studies and were numerically more common in the group treated with Ropinirole Tablets. In these studies, either Ropinirole Tablets or placebo was used as early therapy (i.e., without L-dopa). The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies.

Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse-events incidence rate in the population studied. Table 2.

Treatment-Emergent Adverse Event * Incidence in Double-Blind, Placebo-Controlled Early Parkinson’s Disease (Without L-dopa) Trials (Events ≥2% of Patients Treated With Ropinirole Tablets and Numerically More Frequent Than the Placebo Group) Adverse Experience Ropinirole Tablets (n = 157) (%) Placebo (n = 147) (%) Autonomic nervous system Flushing 3 1 Dry mouth 5 3 Increased sweating 6 4 Body as a whole Asthenia 6 1 Chest pain 4 2 Dependent edema 6 3 Leg edema 7 1 Fatigue 11 4 Malaise 3 1 Pain 8 4 Cardiovascular general Hypertension 5 3 Hypotension 2 0 Orthostatic symptoms 6 5 Syncope 12 1 Central/peripheral nervous system Dizziness 40 22 Hyperkinesia 2 1 Hypesthesia 4 2 Vertigo 2 0 Gastrointestinal system Abdominal pain 6 3 Anorexia 4 1 Dyspepsia 10 5 Flatulence 3 1 Nau…

DRUG INTERACTIONS P 450 Interaction In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for substrates or inhibitors of this enzyme when coadministered with ropinirole to alter its clearance. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with Ropinirole Tablets, adjustment of the dose of Ropinirole Tablets may be required.

L-dopa Co-administration of carbidopa + L-dopa (SINEMET® 10/100 mg twice daily) with ropinirole (2 mg 3 times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of Ropinirole Tablets 2 mg 3 times daily increased mean steady state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients). Digoxin Co-administration of Ropinirole Tablets (2 mg 3 times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.

Theophylline Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of ropinirole (2 mg 3 times daily) in 12 patients with Parkinson’s disease. Ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson’s disease. Ciprofloxacin Co-administration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with ropinirole (2 mg 3 times daily) increased ropinirole AUC by 84% on average and Cmax by 60% (n = 12 patients).

Estrogens Population pharmacokinetic analysis revealed that estrogens (mainly ethinyl estradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients. Dosage adjustment may not be needed for Ropinirole Tablets in patients on estrogen therapy because patients must be carefully titrated with ropinirole to tolerance or adequate effect. However, if estrogen therapy is stopped or started during treatment with Ropinirole Tablets, then adjustment of the dose of Ropinirole Tablets may be required.

Dopamine Antagonists Since ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may diminish the effectiveness of Ropinirole Tablets. Patients with major psychotic disorders treated with neuroleptics should only be treated with dopamine agonists if the potential benefits outweigh the risks. Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the oral clearance of ropinirole.