ROPINIROLE HYDROCHLORIDE

Ropinirole Extended-Release Tablets, USP contain 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 has a molecular formula of 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 white to yellow solid with a melting range of 243º to 250ºC and a solubility of 133 mg/mL in water. Each Ropinirole Extended-Release Tablet, USP for oral administration is oval-shaped and contains 2.28 mg, 4.56 mg, 6.84 mg, 9.12 mg, or 13.68 mg of ropinirole hydrochloride, USP equivalent to ropinirole 2 mg, 4 mg, 6 mg, 8 mg, or 12 mg, respectively. Inactive ingredients consist of colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, and titanium dioxide. In addition the 2 mg tablet also contains iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, polyvinyl-alcohol, and talc. The 4 mg tablet also contains black iron oxide, FD&C Blue #2/Indigo Carmine Aluminum Lake, FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake, polydextrose, polyethylene glycol, and triacetin. The 6 mg tablet also contains polyethylene glycol, polyvinyl-alcohol, and talc. The 8 mg tablet also contains iron oxide red, polyethylene glycol, polyvinyl-alcohol, and talc. The 12 mg tablet also contains iron oxide yellow, polyethylene glycol, polyvinyl-alcohol, and talc. This drug product conforms to USP Dissolution Test 3. Chemical Structure Diagram

Ropinirole extended-release tablets are indicated for the treatment of Parkinson’s disease. Ropinirole extended-release tablets are a non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease. ( 1 )

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 tablets 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 Ropinirole Extended-Release Tablets Total Daily Dose (mg) 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.

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 )

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) ] Elevation of blood pressure and changes in heart rate [see Warnings and Precautions (5.4) ] Hallucinations/psychotic-like behavior [see Warnings and Precautions (5.5) ] Dyskinesia [see Warnings and Precautions (5.6) ] Impulse control/compulsive behaviors [see Warnings and Precautions (5.7) ] Withdrawal-emergent hyperpyrexia and confusion [see Warnings and Precautions (5.8) ] Withdrawal symptoms [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 for ropinirole extended-release tablets all doses at least 5% greater than placebo in either a flexible- or fixed-dose study) in patients with advanced Parkinson’s disease were nausea, dyskinesia, dizziness, and hallucination. ( 6.1 ) Most common adverse reactions (incidence for ropinirole extended-release tablets all doses at least 5% greater than placebo in fixed-dose study) in patients with early Parkinson’s disease not taking L-dopa were nausea, somnolence, sudden onset of sleep, hypertension, and headache. In a flexible-dose study in patients with early Parkinson's, the most common adverse reactions (at least 5% incidence for ropinirole extended-release tablets) were nausea, somnolence, abdominal pain/discomfort, dizziness, headache, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 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. During the premarketing development of ropinirole extended-release tablets, patients with advanced Parkinson’s disease received ropinirole extended-release tablets or placebo as adjunctive therapy with L-dopa in a flexible-dose clinical trial. In a flexible-dose trial, patients with early Parkinson’s disease were treated with ropinirole extended-release tablets or the immediate-release formulation of ropinirole without L-dopa. In addition, placebo-controlled, fixed-dose, postmarketing trials evaluated the dose response of ropinirole extended-release tablets in patients with advanced Parkinson’s disease taking L-dopa and in patients with early Parkinson’s disease without concomitant L-dopa. Advanced Parkinson’s Disease (with L-dopa) Study 1 was a 24-week, double-blind, placebo-controlled, flexible-dose trial in patients with advanced Parkinson’s disease. In Study 1, the most commonly observed adverse reactions in patients treated with ropinirole extended-release tablets (incidence at least 5% greater than placebo) were dyskinesia, nausea, dizziness, and hallucinations. In Study 1, approximately 6% of patients treated with ropinirole extended-release tablets discontinued treatment due to adverse reactions, compared with 5% of patients who received placebo. The most common adverse reaction in patients treated with ropinirole extended-release tablets causing discontinuation of treatment with ropinirole extended-release tablets in Study 1 was hallucination (2%). Table 2 lists adverse reactions that occurred in at least 2% (and were numerically greater than placebo) of patients with advanced Parkinson’s disease treated with ropinirole extended-release tablets who participated in Study 1. In this trial, either ropinirole extended-release tablets or placebo was used as an adjunct to L-dopa. Table 2. Incidence of Adverse Reactions in a Placebo-Controlled Flexible-Dose Trial in Advanced Stage Parkinson’s Disease in Patients Taking L-dopa (Study 1) (Events ≥2% of Patients Treated with Ropinirole Extended-Release Tablets and More Common than on Placebo) a Ropinirole Extended-Release Tablets Placebo (n = 202) (n = 191) Body System/Adverse Reaction % % 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 Dose-related. Ear and labyrinth disorders Vertigo 4 2 Gastrointestinal disorders Nausea 11 4 Abdominal pain/discomfort 6 3 Constipation 4 2 Diarrhea 3 2 Dry mouth 2 <1 General disorders Edema peripheral 4 1 Injury, poisoning, and procedural complications Fall b 2 1 Musculoskeletal and connective tissue disorders Back pain 3 2 Nervous system disorders Dyskinesia b 13 3 Dizziness 8 3 Somnolence 7 4 Psychiatric disorders Hallucination 8 2 Anxiety 2 1 Vascular disorders Orthostatic hypotension 5 1 Hypertension b 3 2 Hypotension 2 0 Although this trial was not designed for optimally characterizing dose-related adverse reactions, there was a suggestion (based upon comparison of incidence of adverse reactions across dose ranges for ropinirole extended-release tablets and placebo) that the incidence for dyskinesia, hypertension, and fall was dose-related to ropinirole extended-release tablets. During the titration phase, the incidence of adverse reactions in descending order of percent treatment difference was dyskinesia, nausea, abdominal pain/discomfort, orthostatic hypotension, dizziness, vertigo, hypertension, peripheral edema, and dry mouth. During the maintenance phase, the most frequently observed adverse reactions were dyskinesia, nausea, dizziness, hallucination, somnolence, fall, hypertension, abnormal dreams, constipation, chest pain, bronchitis, and nasopharyngitis. Some adverse reactions developing in the titration phase persisted (≥7 days) into the maintenance phase. These “persistent” adverse reactions included dyskinesia, hallucination, orthostatic hypotension, and dry mouth. The incidence of adverse reactions was similar in women and men. Study 2 was an 18-week, double-blind, placebo-controlled, fixed-dose, dose-response trial in patients with advanced Parkinson’s disease. In Study 2, approximately 7% of patients treated with any dose of ropinirole extended-release tablets discontinued prematurely during the titration phase because of adverse reactions, compared with 4% of patients on placebo. The percentage of patients who discontinued from the study because of an adverse reaction was 4% for ropinirole extended-release tablets 4 mg, 9% for ropinirole extended-release tablets 8 mg, 8% for ropinirole extended-release tablets 12 mg, 8% for ropinirole extended-release tablets 16 mg, and 0% for ropinirole extended-release tablets 24 mg [see Warnings and Precautions ( 5.2 , 5.5 )] . Table 3 lists adverse reactions with an incidence of at least 5% of patients in any dose group of ropinirole extended-release tablets and numerically higher than on placebo in Study 2. The most common adverse reaction (incidence for ropinirole extended-release tablets all doses at least 5% greater than placebo) was dyskinesia. Table 3. Incidence of Adverse Reactions in a Placebo-Controlled Fixed-Dose Trial in Advanced Stage Parkinson’s Disease in Patients Taking L-dopa (Study 2) (Events ≥5% of Patients Treated with any Dose of Ropinirole Extended-Release Tablets and More Common than on Placebo) Adverse Reaction Placebo N = 74 % Ropinirole Extended-Release Tablets 4 mg N = 25 % 8 mg N = 76 % 12 mg N = 75 % 16 mg N = 75 % 24 mg N = 25 % All Doses N = 276 % Nervous system disorders Somnolence Dyskinesia Dizziness Sudden onset of sleep 5 1 3 3 4 4 8 8 5 4 4 5 12 7 8 4 11 11 5 1 0 4 4 0 8 7 6 4 Vascular disorders Hypertension 1 8 1 1 4 8 3 Infections and infestations Nasopharyngitis 1 0 3 3 0 8 2 Musculoskeletal and connective tissue disorders Arthralgia 0 0 3 0 3 8 2 Psychiatric disorders Insomnia 0 0 0 1 5 0 2 Early Parkinson’s Disease (without L-dopa) Study 3 was a 36-week, flexible-dose crossover trial in patients with early Parkinson's disease who were first treated with ropinirole extended-release tablets or the immediate-release formulation of ropinirole tablets and then crossed over to treatment with the other formulation. In Study 3, the most commonly observed adverse reactions (≥5%) in patients treated with ropinirole extended-release tablets were nausea (19%), somnolence (11%), abdominal pain/discomfort (7%), dizziness (6%), headache (6%), and constipation (5%). Study 4 was an 18-week, double-blind, placebo-controlled, fixed-dose, dose-response trial in patients with early Parkinson’s disease. Overall, 7% of patients treated with any dose of ropinirole extended-release tablets, including 6% during the titration phase, discontinued prematurely from the study because of adverse reactions compared with 5% of patients on placebo. The percentage of patients discontinuing prematurely because of an adverse reaction was 8% for ropinirole extended-release tablets 2 mg, 5% for ropinirole extended-release tablets 4 mg, 8% for ropinirole extended-release tablets 8 mg, 5% for ropinirole extended-release tablets 12 mg, and 15% for ropinirole extended-release tablets 24 mg. Table 4 lists adverse reactions with an incidence of at least 10% of patients in any dose group of ropinirole extended-release tablets and numerically higher than on placebo in Study 4. The most common adverse reactions (incidence for ropinirole extended-release tablets all doses at least 5% greater than placebo) were nausea, somnolence, sudden onset of sleep, hypertension, and headache. Table 4. Incidence of Adverse Reactions in a Double-Blind, Placebo-Controlled, Fixed-Dose Trial in Early Stage Parkinson’s Disease (Study 4) (Events ≥10% of Patients Treated with any Dose of Ropinirole Extended-Release Tablets and Greater Percent than on Placebo) Adverse Reactions Placebo N = 40 % Ropinirole Extended-Release Tablets 2 mg N = 13 % 4 mg N = 41 % 8 mg N = 40 % 12 mg N = 39 % 24 mg N = 13 % All Doses N = 146 % Gastrointestinal disorders Nausea Vomiting 8 5 8 0 15 5 33 10 10 0 15 0 18 4 Nervous system disorders Somnolence Headache Dizziness Sudden onset of sleep 5 3 5 0 15 8 0 0 12 10 5 5 10 8 10 0 8 5 8 10 8 15 8 8 10 8 7 5 Vascular disorders Hypertension 0 0 5 5 3 15 5 Musculoskeletal and connective tissue disorders Back pain 3 0 5 3 3 15 4 Laboratory Abnormalities In the fixed-dose trial in advanced Parkinson's disease (Study 2), 11% of patients on ropinirole extended-release tablets exhibited a shift in serum creatine phosphokinase (CPK) from normal at baseline to above the normal reference range during treatment, compared with 6% of patients on placebo. There was no clear dose response for abnormal shifts in CPK levels in patients with early or advanced stage Parkinson’s disease in either fixed-dose trial. In the fixed-dose trial in early Parkinson's disease patients (Study 4), serum CPK shifted during treatment from normal to above the normal reference range in 10% of patients on ropinirole extended-release tablets and in 5% of patients on placebo. 6.2 Adverse Reactions Observed during the Clinical Development of the Immediate-Release Formulation of Ropinirole Tablets for Parkinson’s Disease (Advanced and Early) 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. In patients with advanced Parkinson's disease who were treated with the immediate-release formulation of ropinirole tablets, the most common adverse reactions (≥5% treatment difference from placebo presented in order of decreasing treatment difference frequency) were dyskinesia (21%), somnolence (12%), nausea (12%), dizziness (10%), confusion (7%), hallucinations (6%), headache (5%), and increased sweating (5%). In patients with early Parkinson's disease who were treated with the immediate-release formulation of ropinirole tablets, the most common adverse reactions (≥5% treatment difference from placebo presented in order of decreasing treatment difference frequency) were nausea (38%), somnolence (34%), dizziness (18%), syncope (11%), asthenic condition (11%), viral infection (8%), leg edema (6%), vomiting (5%), and dyspepsia (5%). 6.3 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ropinirole extended-release tablets. 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 ( 5.9 )]

Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole; dose adjustment of ropinirole extended-release tablets may be required. ( 7.1 , 12.3 ) Hormone replacement therapy (HRT): Starting or stopping HRT treatment may require dose adjustment of ropinirole extended-release tablets. ( 7.2 , 12.3 ) Dopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole extended-release tablets. ( 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 extended-release tablets, adjustment of the dose of ropinirole extended-release tablets may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, with immediate-release ropinirole 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 extended-release 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 extended-release tablets.