Ropinirole

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the label: • Hypersensitivity [ see Contraindications (4) ] • Falling asleep during activities of daily living and somnolence [ see Warnings and Precautions (5.1) ] • Syncope [ see Warnings and Precautions (5.2) ] • Hypotension/orthostatic hypotension [ see Warnings and Precautions (5.3) ] • Hallucinations/psychotic-like behavior [ see Warnings and Precautions (5.4) ] • Dyskinesia [ see Warnings and Precautions (5.5) ] • Impulse control/compulsive behaviors [ see Warnings and Precautions (5.6) ] • Withdrawal-emergent hyperpyrexia and confusion [ see Warnings and Precautions (5.7) ] • Withdrawal Symptoms [ see Warnings and Precautions (5.8) ] • Augmentation and early-morning rebound in RLS [ see Warnings and Precautions (5.9) ] • Fibrotic complications [ see Warnings and Precautions (5.10) ] • Retinal pathology [ see Warnings and Precautions (5.11) ] Most common adverse reactions (incidence with ropinirole at least 5% greater than placebo) in the respective indications were: Early PD: Nausea, somnolence, dizziness, syncope, asthenic condition, viral infection, leg edema, vomiting, and dyspepsia. (6.1) Advanced PD: Dyskinesia, somnolence, nausea, dizziness, confusion, hallucinations, sweating, and headache. (6.1) RLS: Nausea, vomiting, somnolence, dizziness, and asthenic condition. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice. Parkinson's Disease During the premarketing development of ropinirole, patients received ropinirole either without L-dopa (early Parkinson's disease trials) or as concomitant therapy with L-dopa (advanced Parkinson's disease trials). Because these 2 populations may have differential risks for various adverse reactions, this section will in general present adverse reaction data for these 2 populations separately. Early Parkinson's Disease (without L-dopa): In the double-blind, placebo-controlled trials in patients with early-stage Parkinson's disease, the most commonly observed adverse reactions in patients treated with ropinirole (incidence at least 5% greater than placebo) were nausea, somnolence, dizziness, syncope, asthenic condition (i.e., asthenia, fatigue, and/or malaise), viral infection, leg edema, vomiting, and dyspepsia. Approximately 24% of patients treated with ropinirole who participated in the double-blind, placebo-controlled early Parkinson's disease (without L-dopa) trials discontinued treatment due to adverse reactions compared with 13% of patients who received placebo. The most common adverse reactions in patients treated with ropinirole (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation were nausea and dizziness. Table 3 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with early Parkinson's disease (without L-dopa) treated with ropinirole participating in the double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. In these trials, either ropinirole or placebo was used as early therapy (i.e., without L-dopa). Table 3. Treatment-Emergent Adverse Reaction Incidence in Double-blind, Placebo-Controlled Early Parkinson's Disease (without L-dopa) Trials (Events ≥2% of Patients Treated with Ropinirole and Numerically More Frequent than the Placebo Group) a Body System/Adverse Reaction Ropinirole (n = 157) (%) Placebo (n = 147) (% Autonomic nervous system Flushing Dry mouth Increased sweating 3 5 6 1 3 4 Body as a whole Asthenic condition b Chest pain Dependent edema Leg edema Pain 16 4 6 7 8 5 2 3 1 4 Cardiovascular general Hypertension Hypotension Orthostatic symptoms Syncope 5 2 6 12 3 0 5 1 Central/peripheral nervous system Dizziness Hyperkinesia Hypesthesia Vertigo 40 2 4 2 22 1 2 0 Gastrointestinal Abdominal pain Anorexia Dyspepsia Flatulence Nausea Vomiting 6 4 10 3 60 12 3 1 5 1 22 7 Heart rate/rhythm Extrasystoles Atrial fibrillation Palpitation Tachycardia 2 2 3 2 1 0 2 0 Metabolic/nutritional Increased alkaline phosphatase 3 1 Psychiatric Amnesia Impaired concentration Confusion Hallucination Somnolence Yawning 3 2 5 5 40 3 1 0 1 1 6 0 Reproductive male Impotence 3 1 Resistance mechanism Viral infection 11 3 Respiratory Bronchitis Dyspnea Pharyngitis Rhinitis Sinusitis 3 3 6 4 4 1 0 4 3 3 Urinary Urinary tract infection 5 4 Vascular extracardiac Peripheral ischemia 3 0 Vision Eye abnormality Abnormal vision Xerophthalmia 3 6 2 1 3 0 a Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category. b Asthenic condition (i.e., asthenia, fatigue, and/or malaise). Advanced Parkinson's Disease (with L-dopa): In the double-blind, placebo-controlled trials in patients with advanced-stage Parkinson's disease, the most commonly observed adverse reactions in patients treated with ropinirole (incidence at least 5 % greater than placebo) were dyskinesia, somnolence, nausea, dizziness, confusion, hallucinations, increased sweating, and headache. Approximately 24% of patients who received ropinirole in the double-blind, placebo-controlled advanced Parkinson's disease (with L-dopa) trials discontinued treatment due to adverse reactions compared with 18% of patients who received placebo. The most common adverse reaction in patients treated with ropinirole (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation was dizziness. Table 4 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with advanced Parkinson's disease (with L-dopa) treated with ropinirole who participated in the double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. In these trials, either ropinirole or placebo was used as an adjunct to L-dopa. Table 4. Treatment-Emergent Adverse Reaction Incidence in Double-blind, Placebo-Controlled Advanced Parkinson's Disease (with L-dopa) Trials (Events ≥2% of Patients Treated with Ropinirole and Numerically More Frequent than the Placebo Group) a Body System/Adverse Reaction Ropinirole (n = 208) (%) Placebo (n = 120) (%) Autonomic nervous system Dry mouth Increased sweating 5 7 1 2 Body as a whole Increased drug level Pain 7 5 3 3 Cardiovascular general Hypotension Syncope 2 3 1 2 Central/peripheral nervous system Dizziness Dyskinesia Falls Headache Hypokinesia Paresis Paresthesia Tremor 26 34 10 17 5 3 5 6 16 13 7 12 4 0 3 3 Gastrointestinal Abdominal pain Constipation Diarrhea Dysphagia Flatulence Nausea Increased saliva Vomiting 9 6 5 2 2 30 2 7 8 3 3 1 1 18 1 4 Metabolic/nutritional Weight decrease 2 1 Musculoskeletal Arthralgia Arthritis 7 3 5 1 Psychiatric Amnesia Anxiety Confusion Abnormal dreaming Hallucination Nervousness Somnolence 5 6 9 3 10 5 20 1 3 2 2 4 3 8 Red blood cell Anemia 2 0 Resistance mechanism Upper respiratory tract infection 9 8 Respiratory Dyspnea 3 2 Urinary Pyuria Urinary incontinence Urinary tract infection 2 2 6 1 1 3 Vision Diplopia 2 1 a Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category. Restless Legs Syndrome In the double-blind, placebo-controlled trials in patients with RLS, the most commonly observed adverse reactions in patients treated with ropinirole (incidence at least 5% greater than placebo) were nausea, vomiting, somnolence, dizziness, and asthenic condition (i.e., asthenia, fatigue, and/or malaise). Approximately 5% of patients treated with ropinirole who participated in the double-blind, placebo-controlled trials in the treatment of RLS discontinued treatment due to adverse reactions compared with 4% of patients who received placebo. The most common adverse reaction in patients treated with ropinirole (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation was nausea. Table 5 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with RLS treated with ropinirole participating in the 12 week, double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. Table 5. Treatment-Emergent Adverse Reaction Incidence in Double-blind, Placebo-Controlled Restless Legs Syndrome Trials (Events ≥2% of Patients Treated with Ropinirole and Numerically More Frequent than the Placebo Group) a Body System/Adverse Reaction Ropinirole (n = 496) (%) Placebo (n = 500) (%) Ear and labyrinth Vertigo 2 1 Gastrointestinal Nausea Vomiting Diarrhea Dyspepsia Dry mouth Abdominal pain upper 40 11 5 4 3 3 8 2 3 3 2 1 General disorders and administration site conditions Asthenic condition b Edema peripheral 9 2 4 1 Infections and infestations Nasopharyngitis Influenza 9 3 8 2 Musculoskeletal and connective tissue Arthralgia Muscle cramps Pain in extremity 4 3 3 3 2 2 Nervous system Somnolence Dizziness Paresthesia 12 11 3 6 5 1 Respiratory, thoracic, and mediastinal Cough Nasal congestion 3 2 2 1 Skin and subcutaneous tissue Hyperhidrosis 3 1 a Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category. b Asthenic condition (i.e., asthenia, fatigue, and/or malaise). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ropinirole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General Disorders and Administration Site Conditions Withdrawal symptoms [ see Warnings and Precautions (5.8) ]

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

11 DESCRIPTION Ropinirole tablets, USP contains ropinirole, a non-ergoline dopamine agonist, as the hydrochloride salt. The chemical name of ropinirole hydrochloride, USP is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one and the empirical formula is C 16 H 24 N 2 O•HCl. The molecular weight is 296.84 (260.38 as the free base). The structural formula is: Ropinirole hydrochloride, USP is a pale cream to yellow powder with a melting range of 243°C to 250°C and a solubility of 133 mg/mL in water. Each modified oval shaped, biconvex film-coated tablet contains 0.29 mg, 0.57 mg, 1.14 mg, 2.28 mg, 3.42 mg, 4.56 mg, or 5.70 mg ropinirole hydrochloride, USP equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. Inactive ingredients consist of microcrystalline cellulose, lactose monohydrate, citric acid monohydrate, croscarmellose sodium, magnesium stearate. 0.25 mg tablet contains opadry white. The components of opadry white are hypromellose, titanium dioxide, polyethylene glycol 6000 and polysorbate 80. 0.5 mg tablet contains opadry yellow. The components of opadry yellow are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide yellow and polysorbate 80. 1 mg tablet contains opadry green. The components of opadry green are hypromellose, titanium dioxide, triacetin, iron oxide yellow and FD&C Blue No. 2. 2 mg tablet contains opadry pink. The components of opadry pink are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide red and polysorbate 80. 3 mg tablet contains opadry purple. The components of opadry purple are hypromellose, titanium dioxide, carmine, polyethylene glycol 400, polysorbate 80 and FD&C Blue No. 1. 4 mg tablet contains opadry brown. The components of opadry brown are hypromellose, titanium dioxide, iron oxide red, polyethylene glycol 400, FD&C Blue No. 2, polysorbate 80 and iron oxide black. Also contains FD&C yellow No. 6 as a color additive. 5 mg tablet contains opadry blue. The components of opadry blue are hypromellose, titanium dioxide, polyethylene glycol 400, FD&C Blue No. 2 and polysorbate 80. molecular structure

2 DOSAGE AND ADMINISTRATION Ropinirole tablets can be taken with or without food. (2.1) Retitration of ropinirole may be warranted if therapy is interrupted. (2.1) Parkinson’s Disease : The recommended starting dose is 0.25 mg taken three times daily; titrate to a maximum daily dose of 24 mg. (2.2) Renal Impairment: The maximum recommended dose is 18 mg/day in patients with end-stage renal disease on hemodialysis. (2.2) Restless Legs Syndrome: The recommended starting dose is 0.25 mg once daily, 1 to 3 hours before bedtime, titrate to a maximum recommended dose of 4 mg daily. (2.3) Renal Impairment: The maximum recommended dose is 3 mg/day in patients with end-stage renal disease on hemodialysis. (2.3) 2.1 General Dosing Recommendations Ropinirole can be taken with or without food [see Clinical Pharmacology (12.3)]. If a significant interruption in therapy with ropinirole has occurred, retitration of therapy may be warranted. 2.2 Dosing for Parkinson’s Disease The recommended starting dose of ropinirole for Parkinson's disease is 0.25 mg 3 times daily. Based on individual patient therapeutic response and tolerability, if necessary, the dose should then be titrated with weekly increments as described in Table 1. After Week 4, if necessary, the daily dose may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly up to a maximum recommended total daily dose of 24 mg/day (8 mg 3 times daily). Doses greater than 24 mg/day have not been tested in clinical trials. Table 1. Ascending-Dose Schedule of Ropinirole for Parkinson's Disease Week Dosage Total Daily Dose 1 0.25 mg 3 times daily 0.75 mg 2 0.5 mg 3 times daily 1.5 mg 3 0.75 mg 3 times daily 2.25 mg 4 1 mg 3 times daily 3 mg Ropinirole should be discontinued gradually over a 7 day period in patients with Parkinson’s disease [ see Warnings and Precautions (5.8) ]. The frequency of administration should be reduced from 3 times daily to twice daily for 4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of ropinirole. 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 for patients with end-stage renal disease on hemodialysis is 0.25 mg 3 times a day. 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 in patients with severe renal impairment without regular dialysis has not been studied. 2.3 Dosing for Restless Legs Syndrome The recommended adult starting dose for RLS is 0.25 mg once daily 1 to 3 hours before bedtime. After 2 days, if necessary, the dose can be increased to 0.5 mg once daily, and to 1 mg once daily at the end of the first week of dosing, then as shown in Table 2 as needed to achieve efficacy. Titration should be based on individual patient therapeutic response and tolerability, up to a maximum recommended dose of 4 mg daily. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established. Table 2. Dose Titration Schedule of Ropinirole for Restless Legs Syndrome Day/Week Dose to be taken once daily 1 to 3 hours before bedtime Days 1 and 2 0.25 mg Days 3 to 7 0.5 mg Week 2 1 mg Week 3 1.5 mg Week 4 2 mg Week 5 2.5 mg Week 6 3 mg Week 7 4 mg When discontinuing ropinirole in patients with RLS, gradual reduction of the daily dose is recommended [see Warnings and Precautions (5.8, 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 for patients with end-stage renal disease on hemodialysis is 0.25 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 3 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of ropinirole in patients with severe renal impairment without regular dialysis has not been studied.

1 INDICATIONS AND USAGE Ropinirole tablets are a non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease (PD) and moderate-to-severe primary Restless Legs Syndrome (RLS). (1.1, 1.2) 1.1 Parkinson’s Disease Ropinirole tablets are indicated for the treatment of Parkinson’s disease. 1.2 Restless Legs Syndrome Ropinirole tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).

10 OVERDOSAGE The symptoms of overdose with ropinirole are related to its dopaminergic activity. General supportive measures are recommended. Vital signs should be maintained, if necessary. In clinical trials, there have been patients who accidentally or intentionally took more than their prescribed dose of ropinirole. The largest overdose reported with ropinirole in clinical trials was 435 mg taken over a 7 day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported in cases of overdose included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.

7 DRUG INTERACTIONS Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole; dose adjustment of ropinirole may be required. (7.1, 12.3) Hormone replacement therapy (HRT): Starting or stopping HRT may require dose adjustment of ropinirole. (7.2, 12.3) Dopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole. (7.3) 7.1 Cytochrome P450 1A2 Inhibitors and Inducers In vitro metabolism studies showed that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with ropinirole, adjustment of the dose of ropinirole may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, increases the AUC and C max of ropinirole [see Clinical Pharmacology (12.3)] . Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking [see Clinical Pharmacology (12.3)] . 7.2 Estrogens Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy) reduced the clearance of ropinirole. Starting or stopping hormone replacement therapy may require adjustment of dosage of ropinirole [ see Clinical Pharmacology (12.3) ]. 7.3 Dopamine Antagonists Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of ropinirole.

12 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. The precise mechanism of action of ropinirole as a treatment for RLS is unknown, although it is thought to be related to its ability to stimulate dopamine receptors. 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 patients 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 D2-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. 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. 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 Ropinirole displayed linear kinetics over the dosing range of 1 to 8 mg 3 times daily. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing. Absorption Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours. In clinical trials, 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. Relative bioavailability from a tablet compared with an oral solution is 85%. Food does not affect the extent of absorption of ropinirole, although its Tmax is increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal. 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 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 CYP1A 2 is known to be induced by smoking. In a trial in patients with RLS, smokers (n = 7) had an approximately 30% lower Cmax 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 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, 2.3) ]. 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 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 steadystate 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 intravenously) in 12 patients with Parkinson’s disease. Ciprofloxacin: Coadministration 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 ethinylestradiol: intake 0.6 to 3 mg over 4 month to 23 year period) reduced the oral clearance of ropinirole by 36% in 16 patients. L-dopa: Coadministration of carbidopa + L-dopa (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 2 mg 3 times daily increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients). Commonly Administered Drugs: Population analysis showed that commonly administered drugs (e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, anticholinergics) did not affect the clearance of ropinirole. An in vitro study indicates that ropinirole is not a substrate for P-glycoprotein. Ropinirole and its circulating metabolites do not inhibit or induce P450 enzymes; therefore, ropinirole is unlikely to affect the pharmacokinetics of other drugs by a P450 mechanism.

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. The precise mechanism of action of ropinirole as a treatment for RLS is unknown, although it is thought to be related to its ability to stimulate dopamine receptors.

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 patients 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 D2-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. 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. 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 Ropinirole displayed linear kinetics over the dosing range of 1 to 8 mg 3 times daily. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing. Absorption Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours. In clinical trials, 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. Relative bioavailability from a tablet compared with an oral solution is 85%. Food does not affect the extent of absorption of ropinirole, although its Tmax is increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal. 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 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 CYP1A 2 is known to be induced by smoking. In a trial in patients with RLS, smokers (n = 7) had an approximately 30% lower Cmax 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 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, 2.3) ]. 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 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 steadystate 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 intravenously) in 12 patients with Parkinson’s disease. Ciprofloxacin: Coadministration 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 ethinylestradiol: intake 0.6 to 3 mg over 4 month to 23 year period) reduced the oral clearance of ropinirole by 36% in 16 patients. L-dopa: Coadministration of carbidopa + L-dopa (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 2 mg 3 times daily increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients). Commonly Administered Drugs: Population analysis showed that commonly administered drugs (e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, anticholinergics) did not affect the clearance of ropinirole. An in vitro study indicates that ropinirole is not a substrate for P-glycoprotein. Ropinirole and its circulating metabolites do not inhibit or induce P450 enzymes; therefore, ropinirole is unlikely to affect the pharmacokinetics of other drugs by a P450 mechanism.

20231211

3

3 DOSAGE FORMS AND STRENGTHS 0.25 mg, white to off white coloured, modified oval shaped, biconvex, film-coated tablet debossed with “105” on one side and “RH” on the other side 0.5 mg, pale yellow coloured, modified oval shaped, biconvex, film-coated tablet debossed with “106” on one side and “RH” on the other side 1 mg, pale green coloured, modified oval shaped, biconvex, film-coated tablet debossed with “107” on one side and “RH” on the other side 2 mg, pink coloured, modified oval shaped, biconvex, film-coated tablet debossed with “110” on one side and “RH” on the other side 3 mg, purple coloured, modified oval shaped, biconvex, film-coated tablet debossed with “112” on one side and “RH” on the other side 4 mg, brown coloured, modified oval shaped, biconvex, film-coated tablet debossed with “114” on one side and “RH” on the other side 5 mg, pale blue coloured, modified oval shaped, biconvex, film-coated tablet debossed with “115” on one side and “RH” on the other side Tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg (3)

Ropinirole Ropinirole ROPINIROLE HYDROCHLORIDE ROPINIROLE CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE POLYETHYLENE GLYCOL 6000 POLYSORBATE 80 white to off white modified oval, biconvex 105;RH Ropinirole Ropinirole ROPINIROLE HYDROCHLORIDE ROPINIROLE CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE POLYETHYLENE GLYCOL 6000 FERRIC OXIDE YELLOW POLYSORBATE 80 Pale yellow Modified oval, biconvex 106;RH Ropinirole Ropinirole ROPINIROLE HYDROCHLORIDE ROPINIROLE CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE TRIACETIN FERRIC OXIDE YELLOW FD&C BLUE NO. 2 Pale green Modified oval, biconvex 107;RH Ropinirole Ropinirole ROPINIROLE HYDROCHLORIDE ROPINIROLE CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE POLYETHYLENE GLYCOL 6000 FERRIC OXIDE RED POLYSORBATE 80 modified oval, biconvex 110;RH Ropinirole Ropinirole ROPINIROLE HYDROCHLORIDE ROPINIROLE CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE POLYETHYLENE GLYCOL 400 POLYSORBATE 80 FD&C BLUE NO. 1 modified oval,biconvex 112;RH Ropinirole Ropinirole ROPINIROLE HYDROCHLORIDE ROPINIROLE CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) HYPROMELLOSE 2910 (3 MPA.S) TITANIUM DIOXIDE FERRIC OXIDE RED POLYETHYLENE GLYCOL 400 FD&C BLUE NO. 2 POLYSORBATE 80 FERROSOFERRIC OXIDE FD&C YELLOW NO. 6 modified oval,biconvex 114;RH Ropinirole Ropinirole ROPINIROLE HYDROCHLORIDE ROPINIROLE CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE POLYETHYLENE GLYCOL 400 FD&C BLUE NO. 2 POLYSORBATE 80 Pale blue modified oval, biconvex 115;RH

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year carcinogenicity studies of ropinirole were conducted in mice at oral doses of 0, 5, 15, and 50 mg/kg/day and in rats at oral doses of 0, 1.5, 15, and 50 mg/kg/day. In rats, there was an increase in testicular Leydig cell adenomas at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the MRHD for Parkinson’s disease (24 mg/day) on a mg/m 2 basis. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans. In mice, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day. The highest dose not associated with this finding (15 mg/kg/day) is 3 times the MRHD on a mg/m 2 basis. Mutagenesis Ropinirole was not mutagenic or clastogenic in in vitro (Ames, chromosomal aberration in human lymphocytes, mouse lymphoma tk) assays, or in the in vivo mouse micronucleus test. Impairment of Fertility When administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on a mg/m 2 basis) or greater. This effect in rats is thought to be due to the prolactin-lowering effect of ropinirole. In rat studies using a low oral dose (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days 0 to 8), ropinirole did not affect female fertility at oral doses up to 100 mg/kg/day (40 times the MRHD on a mg/m 2 basis). No effect on male fertility was observed in rats at oral doses up to 125 mg/kg/day (50 times the MRHD on a mg/m 2 basis).

ANDA079229

Ropinirole

Ropinirole

69452-357

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL NDC 69452- 356 -20 rOPINIRole Tablets, USP 0.25 mg PHARMACIST: Dispense the pateint information leaflet with the drug product. RX Only 100 Tablets BIONPHARMA NDC 69452- 357 -20 rOPINIRole Tablets, USP 0.5 mg PHARMACIST: Dispense the pateint information leaflet with the drug product. RX Only 100 Tablets BIONPHARMA NDC 69452- 358 -20 rOPINIRole Tablets, USP 1 mg PHARMACIST: Dispense the pateint information leaflet with the drug product. RX Only 100 Tablets BIONPHARMA NDC 69452-359-20 rOPINIRole Tablets, USP 2 mg PHARMACIST: Dispense the pateint information leaflet with the drug product. RX Only 100 Tablets BIONPHARMA NDC 69452- 360 -20 rOPINIRole Tablets, USP 3 mg PHARMACIST: Dispense the pateint information leaflet with the drug product. RX Only 100 Tablets BIONPHARMA NDC 69452- 361 -20 rOPINIRole Tablets, USP 4 mg PHARMACIST: Dispense the pateint information leaflet with the drug product. RX Only 100 Tablets BIONPHARMA NDC 69452- 362 -20 rOPINIRole Tablets, USP 5 mg PHARMACIST: Dispense the pateint information leaflet with the drug product. RX Only 100 Tablets BIONPHARMA label 0.25 mg_100s label 0.5 mg_100s label 1 mg_100s label 2 mg_100s label 3 mg_100s label 4 mg_100s label 5 mg_100s

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Dosing Instructions Instruct patients to take ropinirole tablets only as prescribed. If a dose is missed, advise patients not to double their next dose. Ropinirole tablets can be taken with or without food [see Dosage and Administration (2.1)]. Ropinirole is the active ingredient in ropinirole tablets (the immediate-release formulation). Ask your patients if they are taking another medication containing ropinirole. Hypersensitivity/Allergic Reactions Advise patients about the potential for developing a hypersensitivity/allergic reaction including manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product. Inform patients who experience these or similar reactions to immediately contact their healthcare professional [see Contraindications (4)]. Falling Asleep during Activities of Daily Living and Somnolence Alert patients to the potential sedating effects caused by ropinirole tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence is a frequent adverse reaction with potentially serious consequences, patients should not drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with ropinirole tablets to gauge whether or not it adversely affects their mental and/or motor performance. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) in combination with ropinirole tablets or when taking a concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole [see Warnings and Precautions (5.1)] . Syncope and Hypotension/Orthostatic Hypotension Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking ropinirole tablets, especially if they are elderly. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment). Postural/orthostatic symptoms may be related to sitting up or standing. Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with ropinirole tablets [see Warnings and Precautions (5.2, 5.3)] . Hallucinations/Psychotic-Like Behavior Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations), and that other psychotic-like behavior can occur while taking ropinirole tablets. In patients with Parkinson’s disease, the elderly are at greater risk than younger patients. This risk is greater in patients who are taking ropinirole tablets with L-dopa or taking higher doses of ropinirole tablets and may also be further increased in patients taking any other drugs that increase dopaminergic tone. Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop [ see Warnings and Precautions (5.4) ]. Dyskinesia Inform patients that ropinirole tablets may cause and/or exacerbate pre-existing dyskinesias [ see Warnings and Precautions (5.5) ]. Impulse Control/Compulsive Behaviors Advise patients that they may experience impulse control and/or compulsive behaviors while taking ropinirole tablets. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with ropinirole tablets. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole tablets [ see Warnings and Precautions (5.6) ]. Withdrawal-Emergent Hyperpyrexia and Confusion Advise patients to contact their healthcare provider if they wish to discontinue ropinirole tablets or decrease the dose of ropinirole tablets. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they present with fever, muscular rigidity, or altered consciousness [ see Warnings and Precautions (5.7) ]. Withdrawal Symptoms Advise patients that withdrawal symptoms may occur during or after discontinuation or dose reduction of ropinirole tablets. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as apathy, anxiety, depression, fatigue, insomnia, sweating, or pain. Notify patients that in case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered [ see Warnings and Precautions (5.8) ]. Augmentation and Rebound Inform patients with RLS that augmentation and/or rebound may occur after starting treatment with ropinirole tablets [ see Warnings and Precautions (5.9) ]. Nursing Mothers Because of the possibility that ropinirole may be excreted in breast milk, discuss the developmental and health benefits of breastfeeding along with the mother’s clinical need for ropinirole tablets and any potential adverse effects on the breastfed child from ropinirole or from the underlying maternal condition [ see Use in Specific Populations (8.2) ]. Advise patients that ropinirole tablets could inhibit lactation because ropinirole inhibits prolactin secretion. Pregnancy Because experience with ropinirole in pregnant women is limited and ropinirole has been shown to have adverse effects on embryofetal development in animals, including teratogenic effects, advise patients of this potential risk. Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy [ see Use in Specific Populations (8.1) ]. Distributed by: Bionpharma Inc. Princeton, NJ 08540 MADE IN INDIA Revised: 5/2023 948026791

14 CLINICAL STUDIES 14.1 Parkinson’s Disease The effectiveness of ropinirole in the treatment of Parkinsons disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials. Four trials were conducted in patients with early Parkinsons disease and no concomitant L-dopa and 7 trials were conducted in patients with advanced Parkinsons disease with concomitant L-dopa. Three placebo-controlled trials provide evidence of effectiveness of ropinirole in the management of patients with Parkinsons disease who were and were not receiving concomitant L-dopa. Two of these 3 trials enrolled patients with early Parkinsons disease (without L-dopa) and 1 enrolled patients receiving L-dopa. In these trials a variety of measures were used to assess the effects of treatment (e.g., Unified Parkinsons Disease Rating Scale [UPDRS], Clinical Global Impression [CGI] scores, patient diaries recording time "on" and "off", tolerability of L-dopa dose reductions). In both trials of patients with early Parkinsons disease (without L-dopa), the motor component (Part III) of the UPDRS was the primary outcome assessment. The UPDRS is a multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinsons disease (e.g., tremor, rigidity, bradykinesia, postural instability) scored for different body regions and has a maximum (worst) score of 108. In the trial of patients with advanced Parkinsons disease (with L-dopa), both reduction in percent awake time spent off and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually. Trials in Patients with Early Parkinsons Disease (without L-dopa) Trial 1 was a 12 week multicenter trial in which 63 patients with idiopathic Parkinsons disease receiving concomitant anti-Parkinson medication (but not L-dopa) were enrolled and 41 were randomized to ropinirole and 22 to placebo. Patients had a mean disease duration of approximately 2 years. Patients were eligible for enrollment if they presented with bradykinesia and at least tremor, rigidity, or postural instability. In addition, they must have been classified as Hoehn & Yahr Stage I-IV. This scale, ranging from I = unilateral involvement with minimal impairment to V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinsons disease. The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared with baseline) of at least 30% in the UPDRS motor score. Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of 0.5 mg twice daily to a maximum of 5 mg twice daily. Once patients reached their maximally tolerated dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks. The mean dose achieved by patients at trial endpoint was 7.4 mg/day. Mean baseline UPDRS motor score was 18.6 for patients treated with ropinirole and 19.9 for patients treated with placebo. At the end of 12 weeks, the percentage of responders was greater on ropinirole than on placebo and the difference was statistically significant (Table 6). Table 6. Percent Responders for Unified Parkinsons Disease Rating Scale Motor Score in Trial 1 (Intent-to-Treat Population) Responders Difference from Placebo Placebo 41% NA Ropinirole 71% 30% Trial 2 in patients with early Parkinsons disease (without L-dopa) was a double-blind, randomized, placebo-controlled, 6 month trial. In this trial, 241 patients were enrolled and 116 were randomized to ropinirole and 125 to placebo. Patients were essentially similar to those in the trial described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the trial. Patients had a mean disease duration of 2 years and limited (not more than a 6 week period) or no prior exposure to L-dopa. The starting dosage of ropinirole in this trial was 0.25 mg 3 times daily. The dosage was titrated at weekly intervals by increments of 0.25 mg 3 times daily to a dosage of 1 mg 3 times daily. Further titrations at weekly intervals were at increments of 0.5 mg 3 times daily up to a dosage of 3 mg 3 times daily, and then weekly at increments of 1 mg 3times daily. Patients were to be titrated to a dosage of at least 1.5 mg 3 times daily and then to their maximally tolerated dosage, up to a maximum of 8 mg 3 times daily. The mean dose attained in patients at trial endpoint was 15.7 mg/day. The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS motor score. At the end of the 6 month trial, patients treated with ropinirole showed improvement in motor score compared with placebo and the difference was statistically significant (Table 7). Table 7. Mean Percentage Change from Baseline in Unified Parkinson’s Disease Motor Score at End of Treatment in Trial 2 (Intent-to-Treat Population) Treatment Baseline UPDRS Motor Score Mean Change from Baseline Difference from Placebo Placebo 17.7 +4% NA Ropinirole 17.9 -22% -26% Trial in Patients with Advanced Parkinsons Disease (with L-dopa) Trial 3 was a double-blind, randomized, placebo-controlled, 6 month trial that randomized 149 patients (Hoehn & Yahr II-IV) who were not adequately controlled on L-dopa. Ninety-five patients were randomized to ropinirole and 54 were randomized to placebo. Patients in this trial had a mean disease duration of approximately 9 years, had been exposed to L-dopa for approximately 7 years, and had experienced on-off periods with L-dopa therapy. Patients previously receiving stable doses of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the trial. Patients were started at a dosage of 0.25 mg 3 times daily of ropinirole and titrated upward by weekly intervals until an optimal therapeutic response was achieved. The maximum dosage of trial medication was 8 mg 3 times daily. All patients had to be titrated to at least a dosage of 2.5 mg 3 times daily. Patients could then be maintained on this dosage level or higher for the remainder of the trial. Once a dosage of 2.5 mg 3 times daily was achieved, patients underwent a mandatory reduction in their L-dopa dosage, to be followed by additional mandatory reductions with continued escalation of the dosage of ropinirole. Reductions in the dosage of L-dopa were also allowed if patients experienced adverse reactions that the investigator considered related to dopaminergic therapy. The mean dose attained at trial endpoint was 16.3 mg/day. The primary outcome was the proportion of responders, defined as patients who were able both to achieve a decrease (compared with baseline) of at least 20% in their L-dopa dosage and a decrease of at least 20% in the proportion of the time awake in the off condition (a period of time during the day when patients are particularly immobile), as determined by subject diary. In addition, the mean change in off time from baseline and the percent change from baseline in daily L-dopa dosage were examined. At the end of 6 months, the percentage of responders was greater on ropinirole than on placebo and the difference was statistically significant (Table 8). Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of ropinirole, patients treated with ropinirole had a 19.4% mean reduction in L-dopa dosage while patients treated with placebo had a 3% reduction. Mean daily L-dopa dosage at baseline was 759 mg for patients treated with ropinirole and 843 mg for patients treated with placebo. The mean number of daily off hours at baseline was 6.4 hours for patients treated with ropinirole and 7.3 hours for patients treated with placebo. At the end of the 6 month trial, there was a mean reduction of 1.5 hours of off time in patients treated with ropinirole and a mean reduction of 0.9 hours of off time in patients treated with placebo, resulting in a treatment difference of 0.6 hours of off time. Table 8. Mean Responder Percentage of Patients Reducing Daily L-Dopa Dosage by at Least 20% and Daily Proportion of "Off" Time by at Least 20% at End of Treatment in Trial 3 (Intent-to-Treat Population) Treatment Responders Difference from Placebo Placebo 11% NA Ropinirole 28% 17% 14.2 Restless Legs Syndrome The effectiveness of ropinirole in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria. Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, anemia) were excluded. All trials employed flexible dosing, with patients initiating therapy at 0.25 mg of ropinirole once daily. Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily. All doses were taken between 1 and 3 hours before bedtime. A variety of measures were used to assess the effects of treatment, including the IRLS scale and Clinical Global Impression-Global Improvement (CGI-I) scores. The IRLS scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. Three of the controlled trials utilized the change from baseline in the IRLS scale at the Week 12 endpoint as the primary efficacy outcome. Three hundred eighty patients were randomized to receive ropinirole (n = 187) or placebo (n = 193) in a U.S. trial (RLS-1); 284 were randomized to receive either ropinirole (n = 146) or placebo (n = 138) in a multinational trial (excluding U.S.) (RLS-2); and 267 patients were randomized to ropinirole (n = 131) or placebo (n = 136) in a multinational trial (including U.S.) (RLS-3). Across the 3 trials, the mean duration of RLS was 16 to 22 years (range: 0 to 65 years), mean age was approximately 54 years (range: 18 to 79 years), and approximately 61% were women. The mean dose at Week 12 was approximately 2 mg/day for the 3 trials. At baseline, mean total IRLS score was 22 for ropinirole and 21.6 for placebo in RLS-1, 24.4 for ropinirole and 25.2 for placebo in RLS-2, and 23.6 for ropinirole and 24.8 for placebo in RLS-3. In all 3 trials, a statistically significant difference between the treatment group receiving ropinirole and the treatment group receiving placebo was observed at Week 12 for both the mean change from baseline in the IRLS scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I (see Table 9). Table 9. Mean Change in Total IRLS Rating Scale Score and Percent Responders on CGI-I Ropinirole Placebo Difference from Placebo Mean change in total IRLS scale score at Week 12 RLS-1 -13.5 -9.8 -3.7 RLS-2 -11 -8 -3 RLS-3 -11.2 -8.7 -2.5 Percent responders on CGI-I at Week 12 RLS-1 73.3% 56.5% 16.8% RLS-2 53.4% 40.9% 12.5% RLS-3 59.5% 39.6% 19.9% IRLS = International Restless Legs Syndrome, CGI-I = Clinical Global Impression-Global Improvement, RLS = Restless Legs Syndrome. Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36 week trial. Following a 24 week, single-blind treatment phase (flexible dosages of ropinirole of 0.25 to 4 mg once daily), patients who were responders (defined as a decrease of >6 points on the IRLS scale total score relative to baseline) were randomized in double-blind fashion to placebo or continuation of ropinirole for an additional 12 weeks. Relapse was defined as an increase of at least 6 points on the IRLS scale total score to a total score of at least 15, or withdrawal due to lack of efficacy. For patients who were responders at Week 24, the mean dose of ropinirole was 2 mg (range: 0.25 to 4 mg). Patients continued on ropinirole demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% versus 57.8%, P = 0.0156).

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. (8.1) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of ropinirole in pregnant women. In animal studies, ropinirole had adverse effects on development when administered to pregnant rats at doses similar to (neurobehavioral impairment) or greater than (teratogenicity and embryolethality at >36 times) the MRHD for Parkinson’s disease. Ropinirole doses associated with teratogenicity and embryolethality in pregnant rats were associated with maternal toxicity. In pregnant rabbits, ropinirole potentiated the teratogenic effects of L-dopa when these drugs were administered in combination [ see Data ]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated populations is unknown. Data Animal Data: Oral administration of ropinirole (0, 20, 60, 90, 120, or 150 mg/kg/day) to pregnant rats during organogenesis resulted in embryolethality, increased incidence of fetal malformations (digit, cardiovascular, and neural tube defects) and variations, and decreased fetal weight at the 2 highest doses. These doses were also associated with maternal toxicity. The highest no-effect dose for adverse effects on embryofetal development (90 mg/kg/day) is approximately 36 times the MRHD for Parkinson’s disease (24 mg/day) on a body surface area (mg/m 2 ) basis. No effect on embryofetal development was observed in rabbits when ropinirole was administered alone during organogenesis at oral doses of 0, 1, 5, or 20 mg/kg/day (up to 16 times the MRHD on a mg/m 2 basis). In pregnant rabbits, there was a greater incidence and severity of fetal malformations (primarily digit defects) when ropinirole (10 mg/kg/day) was administered orally during gestation in combination with L-dopa (250 mg/kg/day) than when L-dopa was administered alone. This drug combination was also associated with maternal toxicity. Oral administration of ropinirole (0, 0.1, 1, or 10 mg/kg/day) to rats during late gestation and continuing throughout lactation resulted in neurobehavioral impairment (decreased startle response) and decreased body weight in offspring at the highest dose. The no-effect dose of 1 mg/kg/day is less than the MRHD on a mg/m 2 basis. 8.2 Lactation Risk Summary There are no data on the presence of ropinirole in human milk, the effects of ropinirole on the breastfed infant, or the effects of ropinirole on milk production. However, inhibition of lactation is expected because ropinirole inhibits secretion of prolactin in humans. Ropinirole or metabolites, or both, are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ropinirole and any potential adverse effects on the breastfed infant from ropinirole or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of ropinirole is individually titrated to clinical therapeutic response and tolerability. Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients [ see Clinical Pharmacology (12.3) ]. In flexible-dose clinical trials of extended-release ropinirole for Parkinson’s disease, 387 patients were 65 years and older and 107 patients were 75 years and older. Among patients receiving extended-release ropinirole, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%). In these trials, the incidence of overall adverse reactions increased with increasing age for both patients receiving extended-release ropinirole and placebo. In the fixed-dose clinical trials of extended-release ropinirole, 176 patients were 65 years and older and 73 were 75 and older. Among patients with advanced Parkinson’s disease receiving extended-release ropinirole, vomiting and nausea were more common in patients greater than 65 years (5% and 9%, respectively) compared with patients less than 65 (1% and 7%, respectively). 8.6 Renal Impairment No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). For patients with end-stage renal disease on hemodialysis, a reduced maximum dose is recommended [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)] . The use of ropinirole in patients with severe renal impairment (creatinine clearance 30 mL/min) without regular dialysis has not been studied. 8.7 Hepatic Impairment The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING Each modified oval shaped, biconvex film-coated tablet contains ropinirole hydrochloride, USP equivalent to the labeled amount of ropinirole as follows: 0.25 mg: white to off white coloured, modified oval shaped, biconvex, film-coated tablet debossed with “105” on one side and “RH” on the other side in bottles of 100 (NDC 69452-356-20), with a child-resistant closure. 0.5 mg: pale yellow coloured, modified oval shaped, biconvex, film-coated tablet debossed with “106” on one side and “RH” on the other side in bottles of 100 (NDC 69452-357-20), with a child-resistant closure. 1 mg: pale green coloured, modified oval shaped, biconvex, film-coated tablet debossed with “107” on one sideand “RH” on the other side in bottles of 100 (NDC 69452-358-20), with a child-resistant closure. 2 mg: pink coloured, modified oval shaped, biconvex, film-coated tablet debossed with “110” on one side and “RH” on the other side in bottles of 100 (NDC 69452-359-20), with a child-resistant closure. 3 mg: purple coloured, modified oval shaped, biconvex, film-coated tablet debossed with “112” on one side and “RH” on the other side in bottles of 100 (NDC 69452-360-20), with a child-resistant closure. 4 mg: brown coloured, modified oval shaped, biconvex, film-coated tablet debossed with “114” on one side and “RH” on the other side in bottles of 100 (NDC 69452-361-20), with a child-resistant closure. 5 mg: pale blue coloured, modified oval shaped, biconvex, film-coated tablet debossed with “115” on one side and“RH” on the other side in bottles of 100 (NDC 69452-362-20), with a child-resistant closure. Storage Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Close container tightly after each use.