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)
1.1Parkinson’s Disease
Ropinirole tablets are indicated for the treatment of Parkinson’s disease.
1.2Restless Legs Syndrome
Ropinirole tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).
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
Warnings and precautions
Sudden onset of sleep and somnolence may occur (5.1) Syncope may occur (5.2) Hypotension, including orthostatic hypotension may occur (5.3) May cause hallucinations and psychotic-like behaviors (5.4) May cause or exacerbate dyskinesia (5.5) May cause problems with impulse control or compulsive behaviors (5.6)
5.1Falling Asleep during Activities of Daily Living and Somnolence
Patients treated with ropinirole have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents. Although many of these patients reported somnolence while on ropinirole, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some have reported these events more than 1 year after initiation of treatment.
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In controlled clinical trials, somnolence was commonly reported in patients receiving ropinirole and was more frequent in Parkinson's disease (up to 40% ropinirole, 6% placebo) than in RLS (12% ropinirole, 6% placebo) [see Adverse Reactions (6.1)] . It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing somnolence, although patients may not give such a history.
For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with ropinirole, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole such as concomitant sedating medications or alcohol, the presence of sleep disorders (other than RLS), and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin) [see Drug Interactions (7.1)] .
If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), ropinirole should ordinarily be discontinued [see Dosage and Administration (2.2, 2.3)] . If a decision is made to continue ropinirole, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
5.2Syncope
Syncope, sometimes associated with bradycardia, was observed in association with treatment with ropinirole in both patients with Parkinson’s disease and patients with RLS. In controlled clinical trials in patients with Parkinson’s disease, syncope was observed more frequently in patients receiving ropinirole than in patients receiving placebo (early Parkinson’s disease without levodopa [L-dopa]: ropinirole 12%, placebo 1%; advanced Parkinson’s disease: ropinirole 3%, placebo 2%).
Syncope was reported in 1% of patients treated with ropinirole for RLS in 12 week, placebo-controlled clinical trials compared with 0.2% of patients treated with placebo [see Adverse Reactions (6.1)]. Most cases occurred more than 4 weeks after initiation of therapy with ropinirole, and were usually associated with a recent increase in dose. Because the trials conducted with ropinirole excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.
Approximately 4% of patients with Parkinson’s disease enrolled in Phase 1 trials had syncope following a 1 mg dose of ropinirole. In 2 trials in patients with RLS that used a forced-titration regimen and orthostatic challenge with intensive blood pressure monitoring, 2% of RLS patients treated with ropinirole compared with 0% of patients receiving placebo reported syncope. In Phase 1 trials including healthy volunteers, the incidence of syncope was 2%.
Of note, 1 subject with syncope developed hypotension, bradycardia, and sinus arrest; the subject recovered spontaneously without intervention.
5.3 Hypotension/Orthostatic Hypotension Patients with Parkinson’s disease may have impaired ability to respond normally to a fall in blood pressure after standing from lying down or seated position. Patients on ropinirole should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of the risk for syncope and hypotension [see Patient Counseling Information (17)] .
Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of orthostatic hypotension in early Parkinson’s disease (without L-dopa) in patients treated with ropinirole. Most of these cases occurred more than 4 weeks after initiation of therapy with ropinirole and were usually associated with a recent increase in dose. In 12 week, placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension was reported by 4 of 496 patients (0.8%) treated with ropinirole compared with 2 of 500 patients (0.4%) receiving placebo.
In 2 Phase 2 trials in patients with RLS, 14 of 55 patients (25%) receiving ropinirole experienced an adverse event of hypotension or orthostatic hypotension compared with none of the 27 patients receiving placebo. In these trials, 11 of the 55 patients (20%) receiving ropinirole and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic.
In Phase 1 trials of ropinirole with healthy volunteers who received single doses on more than one occasion without titration, 7% had documented symptomatic orthostatic hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for patients with either Parkinson’s disease or with RLS. In most of these individuals, the hypotension was accompanied by bradycardia but did not develop into syncope [see Warnings and Precautions (5.2)] .
Although dizziness is not a specific manifestation of hypotension or orthostatic hypotension, patients with hypotension or orthostatic hypotension frequently reported dizziness. In controlled clinical trials, dizziness was a common adverse reaction in patients receiving ropinirole and was more frequent in patients with Parkinson’s disease or with RLS receiving ropinirole than in patients receiving placebo (early Parkinson’s disease without L-dopa: ropinirole 40%, placebo 22%; advanced Parkinson’s disease: ropinirole 26%, placebo 16%; RLS: ropinirole 11%, placebo 5%).
Dizziness of sufficient severity to cause trial discontinuation of ropinirole was 4% in patients with early Parkinson’s disease without L-dopa, 3% in patients with advanced Parkinson’s disease, and 1% in patients with RLS [see Adverse Reactions (6.1)].
5.4Hallucinations/Psychotic-Like Behavior
In double-blind, placebo-controlled, early-therapy trials in patients with Parkinson’s disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with ropinirole reported hallucinations, compared with 1.4% of patients on placebo (2 of 147). Among those patients receiving both ropinirole and L-dopa in advanced Parkinson’s disease trials, 10.1% (21 of 208) were reported to experience hallucinations, compared with 4.2% (5 of 120) of patients treated with placebo and L-dopa.
The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with extended-release ropinirole [see Use in Specific Populations (8.5)] . Postmarketing reports indicate that patients with Parkinson’s disease or RLS may experience new or worsening mental status and behav
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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)
7.1Cytochrome 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)] .
7.2Estrogens
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) ].
7.3Dopamine 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.
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.
6.1Clinical 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
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
ROPINIROLE HYDROCHLORIDE EQ 4MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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