24 HR ropinirole 6 MG Extended Release Oral Tablet

INDICATIONS & USAGE Parkinson’s Disease Ropinirole Tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease. The effectiveness of Ropinirole 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 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.

DOSAGE AND ADMINISTRATION • Ropinirole extended-release tablets are taken once daily, with or without food; tablets must be swallowed whole and not be chewed, crushed, or divided. ( 2.1 ) • The recommended starting dose is 2 mg taken once daily for 1 to 2 weeks; the dose should be increased by 2 mg/day at 1 week or longer intervals. The maximum recommended dose of ropinirole extended-release tablets is 24 mg/day. ( 2.2 , 14.2 ) • Renal Impairment: In patients with end-stage renal disease on hemodialysis, the maximum recommended dose is 18 mg/day. ( 2.2 ) • If ropinirole extended-release tablets must be discontinued, it should be tapered gradually over a 7-day period; retitration of ropinirole extended-release tablets may be warranted if therapy is interrupted. ( 2.1 , 2.2 ) • Patients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets; the initial switching dose of ropinirole extended-release tablets should approximately match the total daily dose of immediate-release ropinirole. ( 2.3 ) 2.1 General Dosing Recommendations • Ropinirole extended-release tablets are taken once daily, with or without food [see Clinical Pharmacology ( 12.3 )] . • Tablets must be swallowed whole and must not be chewed, crushed, or divided. • If a significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted. 2.2 Dosing for Parkinson’s Disease The recommended starting dose of ropinirole extended-release tablets is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals, based on therapeutic response and tolerability. Monitor patients at least weekly during dose titration. Too rapid a rate of titration may lead to the selection of a dose that does not provide additional benefit, but increases the risk of adverse reactions. In fixed-dose studies designed to characterize the dose response to ropinirole extended-release tablets, there was no additional therapeutic benefit shown in patients with advanced stage Parkinson’s disease taking daily doses greater than 8 mg/day, or with early stage Parkinson’s disease taking doses greater than 12 mg/day [see Clinical Studies ( 14.1 and 14.2 )] . Although the maximum recommended dose of ropinirole extended-release tablets is 24 mg, patients with advanced Parkinson’s disease should generally be maintained at daily doses of 8 mg or lower and patients with early Parkinson’s disease should generally be maintained at daily doses 12 mg or lower. Ropinirole extended-release tablets should be discontinued gradually over a 7-day period [see Warnings and Precautions (5.9)] . Renal Impairment No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole extended-release tablets for patients with end-stage renal disease on hemodialysis is 2 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole extended-release tablets in patients with severe renal impairment without regular dialysis has not been studied. 2.3 Switching from Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets Patients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets. The initial dose of ropinirole extended-release tablets should approximately match the total daily dose of the immediate-release formulation of ropinirole, as shown in Table 1. Table 1. Conversion from Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets Immediate-Release Ropinirole Tablets Total Daily Dose (mg) Ropinirole Extended-Release Tablets Total Daily Dose (mg) 0.75 to 2.25 2 3 to 4.5 4 6 6 7.5 to 9 8 12 12 15 16 18 18 21 20 24 24 Following conversion to ropinirole extended-release tablets, the dose may be adjusted depending on therapeutic response and tolerability [see Dosage and Administration ( 2.2 )] . 2.4 Effect of Gastrointestinal Transit Time on Medication Release Ropinirole extended-release tablets are designed to release medication over a 24-hour period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication and medication residue being passed in the stool.

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 tablets 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 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 have reported these events more than 1 year after initiation of treatment. In controlled clinical trials, somnolence was commonly reported in patients receiving ropinirole tablets and was more frequent in Parkinson's disease (up to 40% ropinirole tablets, 6% placebo) than in Restless Legs Syndrome (12% ropinirole tablets, 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 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 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 or alcohol, 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 tablets should ordinarily be discontinued [see Dosage and Administration (2.2, 2.3)] . 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 . 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

CONTRAINDICATIONS Ropinirole extended-release tablets are contraindicated in patients known to have a hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or any of the excipients. History of hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ropinirole is a non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to stimulate dopamine D 2 receptors within the caudate-putamen in the brain. 12.2 Pharmacodynamics Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure resulting in orthostatic hypotension, especially during dose escalation. In some subjects in clinical trials, blood pressure changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest with syncope [see Warnings and Precautions (5.2, 5.3) ]. The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to a D 2 -mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant symptom of orthostatic signs and symptoms. At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers. Immediate-release ropinirole had no dose-related effect on electrocardiogram wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg. Immediate-release ropinirole had no dose- or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been systematically evaluated. 12.3 Pharmacokinetics Increase in systemic exposure of ropinirole following oral administration of 2 to 12 mg of ropinirole extended-release tablets was approximately dose proportional. For ropinirole extended-release tablets, steady-state concentrations of ropinirole are expected to be achieved within 4 days of dosing. Absorption In clinical trials with immediate-release ropinirole, more than 88% of a radiolabeled dose was recovered in urine, and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect. The bioavailability of ropinirole extended-release tablets is similar to that of immediate-release ropinirole tablets. In a repeat-dose trial in subjects with Parkinson’s disease using ropinirole extended-release tablets 8 mg, the dose-normalized AUC (0-24) and C min for ropinirole extended-release tablets and immediate-release ropinirole were similar. Dose-normalized C max was, on average, 12% lower for ropinirole extended-release tablets than for the immediate-release formulation and the median time to peak concentration was 6 to 10 hours. In a single-dose trial, administration of ropinirole extended-release tablets to healthy volunteers with food (i.e., high-fat meal) increased AUC by approximately 30% and C max by approximately 44% compared with dosing under fasted conditions. In a repeat-dose trial in patients with Parkinson’s disease, food (i.e., high-fat meal) increased AUC by approximately 20% and C max by approximately 44%; T max was prolonged by 3 hours (median prolongation) compared with dosing under fasted conditions [see Dosage and Administration (2) ] . Distribution Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg. It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1. Metabolism Ropinirole is extensively metabolized by the liver. The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl metabolite and hydroxy metabolites. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated. In vitro studies indicate that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be induced by smoking and omeprazole and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin. Elimination The clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 6 hours. Less than 10% of the administered dose is excreted as unchanged drug in urine. N-despropyl ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic acid metabolite (10%) and the glucuronide of the hydroxy metabolite (10%). Specific Populations Because therapy with ropinirole extended-release tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary. Geriatric Patients: Oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients. Dosage adjustment is not necessary in the elderly (older than 65 years), as the dose of ropinirole is to be individually titrated to clinical response. Male and Female Patients: Male and female patients showed similar clearance. Racial or Ethnic Groups: The influence of race on the pharmacokinetics of ropinirole has not been evaluated. Cigarette Smoking: Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. In a trial in patients with Restless Legs Syndrome, smokers (n = 7) had an approximately 30% lower C max and a 38% lower AUC than did nonsmokers (n = 11) when those parameters were normalized for dose. Patients with Renal Impairment: Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in subjects with moderate renal impairment (creatinine clearance between 30 to 50 mL/min) compared with an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in patients with moderate renal impairment. A trial of immediate-release ropinirole in subjects with end-stage renal disease on hemodialysis has shown that clearance of ropinirole was reduced by approximately 30%. The recommended maximum dose is lower in these patients [see Dosage and Administration (2.2) ] . The use of ropinirole in subjects with severe renal impairment (creatinine clearance <30 mL/min) without regular dialysis has not been studied. Patients with Hepatic Impairment: The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Because ropinirole is extensively metabolized by the liver, these patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function. Other Diseases: Population pharmacokinetic analysis revealed no change in the clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients with Parkinson’s disease only. Drug Interaction Studies Digoxin: Coadministration of immediate-release ropinirole (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 immediate-release ropinirole (2 mg 3 times daily) in 12 patients with Parkinson’s disease. Immediate-release ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg intravenously) in 12 patients with Parkinson’s disease. Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with immediate-release ropinirole (2 mg 3 times daily) increased ropinirole AUC by 84% on average and C max by 60% (n = 12 patients). Estrogens: Population pharmacokinetic analysis reve