1 INDICATIONS AND USAGE Ropinirole extended-release tablets are indicated for the treatment of Parkinson's disease.

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

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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 )] 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 Elite Laboratories, Inc.

at 1-888-852-6657 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 REQUIP 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 inpatients treated with ropinirole extended-release tablets (incidence at least 5% greater thanplacebo) 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 Body System/Adverse Reaction Ropinirole Extended-Release Tablets (n = 202) % Placebo (n = 191) % 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 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.

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 Ropinirole Extended-Release Tablets Placebo N = 74 % 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 5 4 5 12 11 0 8 Dyskinesia 1 4 4 7 11 4 7 Dizziness 3 8 4 8 5 4 6 Sudden onset of sleep 3 8 5 4 1 0 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 REQUIP 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 Ropinirole Extended-Release Tablets Placebo N = 40 % 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 8 8 15 33 10 15 18 Vomiting 5 0 5 10 0 0 4 Nervous system disorders Somnolence 5 15 12 10 8 8 10 Headache 3 8 10 8 5 15 8 Dizziness 5 0 5 10 8 8 7 Sudden onset of sleep 0 0 5 0 10 8 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 REQUIP 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 REQUIP, 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 REQUIP, 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 )]