Ropinirole

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 D2 receptors within the caudate-putamen in the brain. The precise mechanism of action of ropinirole as a treatment for Restless Legs Syndrome is unknown, although it is thought to be related to its ability to stimulate dopamine receptors.

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).

2 DOSAGE AND ADMINISTRATION · Ropinirole tablets can be taken with or without food. (2.1) · Retitration of ropinirole tablets 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 tablets can be taken with or without food [see Clinical Pharmacology (12.3)] . If a significant interruption in therapy with ropinirole tablets have occurred, retitration of therapy may be warranted. 2.2 Dosing 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 tablets 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 three 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 tablets. 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 three 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 tablets 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 tablets 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 tablets 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 tablets in patients with severe renal impairment without regular dialysis has not been studied.

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 tablets 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 Alembic Pharmaceuticals Limited at 1-866-210-9797 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 tablets, patients received ropinirole tablets either without L-dopa (early Parkinson’s disease trials) or as concomitant therapy with L-dopa (advanced Parkinson’s disease trials). Because these two populations may have differential risks for various adverse reactions, this section will in general present adverse reaction data for these two 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 tablets (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 tablets 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 tablets (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 tablets 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 tablets 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 tablets and Numerically More Frequent than the Placebo Group) a Body System/ Adverse Reaction 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 Asthenic condition b 16 5 Chest pain 4 2 Dependent edema 6 3 Leg edema 7 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 Abdominal pain 6 3 Anorexia 4 1 Dyspepsia 10 5 Flatulence 3 1 Nausea 60 22 Vomiting 12 7 Heart rate/rhythm Extrasystoles 2 1 Atrial fibrillation 2 0 Palpitation 3 2 Tachycardia 2 0 Metabolic/nutritional Increased alkaline phosphatase 3 1 Psychiatric Amnesia 3 1 Impaired concentration 2 0 Confusion 5 1 Hallucination 5 1 Somnolence 40 6 Yawning 3 0 Reproductive male Impotence 3 1 Resistance mechanism Viral infection 11 3 Respiratory Bronchitis 3 1 Dyspnea 3 0 Pharyngitis 6 4 Rhinitis 4 3 Sinusitis 4 3 Urinary Urinary tract infection 5 4 Vascular extracardiac Peripheral ischemia 3 0 Vision Eye abnormality 3 1 Abnormal vision 6

7 DRUG INTERACTIONS · Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole tablets; dose adjustment of ropinirole tablets may be required (7.1, 12.3) · Hormone replacement therapy(HRT): Starting or stopping HRT may require dose adjustment of ropinirole tablets (7.2, 12.3) · Dopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole tablets (7.3) 7.1 Cytochrome P450 1A2 Inhibitors and Inducers In vitro metabolism studies showed that 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 tablets, adjustment of the dose of ropinirole tablets 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 [HRT]) reduced the clearance of ropinirole. Starting or stopping HRT may require adjustment of dosage of ropinirole tablets [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 tablets.