Ropinirole extended-release tablets are non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease. ( 1) Ropinirole extended-release tablets are indicated for the treatment of Parkinson’s disease.
Contraindications
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)
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) Elevation of blood pressure and changes in heart rate may occur (5.4) May cause hallucinations and psychotic-like behaviors (5.5) May cause or exacerbate dyskinesia (5.6) May cause problems with impulse control or compulsive behaviors (5.7 )
5.1Falling Asleep during Activities of Daily Living and Somnolence
Patients treated with ropinirole extended-release tablets 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. Among the 613 patients who received ropinirole extended-release in flexible-dose clinical trials (Study 1 and Study 3), <1% of patients reported sudden onset of sleep and < 1% of patients reported a motor vehicle accident in which it is not known if falling asleep was a contributing factor. In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), sudden onset of sleep was reported in 4% of 276 patients on ropinirole extended-release compared with 3% of 74 patients on placebo.
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In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), sudden onset of sleep was reported in 5% of 146 patients on ropinirole extended-release compared with 0% of 40 patients on placebo [see AdverseReactions ( 6.1 ) ]. The incidence of sudden onset of sleep was not dose-related in either trial. During a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), somnolence was reported in 7% of 202 patients on ropinirole extended-release compared with 4% of 191 patients on placebo.
During a flexible-dose, active-control, crossover trial in early Parkinson’s disease (Study 3), somnolence was reported in 11% of 140 patients on ropinirole extended-release compared with 15% of 149 patients on an immediate-release formulation of ropinirole [see Adverse Reactions ( 6.1 ) ]. In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), somnolence was reported in 8% of 276 patients on ropinirole extended-release compared with 5% of 74 patients on placebo.
In a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), somnolence was reported in 10% of 146 patients on ropinirole extended-release compared with 5% of 40 patients on placebo [see Adverse Reactions ( 6.1 ) ]. The frequency of reported somnolence was not dose-related. 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 extended-release tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole extended-release tablets such as concomitant sedating medications or alcohol, the presence of sleep disorders, 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 extended-release tablets should ordinarily be discontinued [see Dosage and Administration ( 2.2 ) ]. If a decision is made to continue ropinirole extended-release tablets, 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 extended-release tablets in patients with Parkinson’s disease. In a placebo-controlled flexible-dose trial in patients with advanced Parkinson's disease (Study 1), syncope occurred in 1% of patients on ropinirole extended-release compared with 0% of patients on placebo [see Adverse Reactions ( 6.1 ) ]. In the placebo-controlled fixed-dose trials (Study 2 and Study 4), one patient on ropinirole extended-release with advanced Parkinson's disease) and one patient on ropinirole extended-release with early Parkinson's disease experienced syncope during the titration period for ropinirole extended-release.
Both patients discontinued prematurely from the respective trials. Because the trials conducted with ropinirole extended-release excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.
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 extended-release tablets 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 ) ].
In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), hypotension was reported as an adverse reaction in 2% of patients on ropinirole extended-release, compared with 0% of patients on placebo. In this study, orthostatic hypotension was reported as an adverse reaction in 5% of patients on ropinirole extended-release, and 1% of patients on placebo [see Adverse Reactions ( 6.1 ) ].
Some patients experienced hypotension or orthostatic hypotension that started in the titration and persisted into the maintenance period. There was also a higher incidence for the combined adverse reaction terms of “hypotension”, “orthostatic hypotension”, “dizziness”, “vertigo”, and “blood pressure decreased” in 7% of patients on ropinirole extended-release compared with 3% of patients on placebo. The increased incidence of those events with ropinirole extended-release was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this trial.
The frequency of orthostatic hypotension (systolic blood pressure decrements ≥20 mm Hg) at any time during the trial was 38% for ropinirole extended-release vs. 31% for placebo. In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), a decrease in standing systolic blood pressure of ≥20 mm Hg was observed in 26% of patients on ropinirole extended-release compared with 18% of patients on placebo.
In a placebo-controlled fixed-dose trial of patients with early Parkinson's disease (Study 4), a decrease in standing systolic blood pressure of ≥20 mm Hg was observed in 14% of patients on ropinirole extended-release compared with 10% of patients on placebo. Significant decrements in blood pressure unrelated to standing were also reported in some patients taking ropinirole extended-release tablets.
5.4Elevation of Blood Pressure and Changes in Heart Rate
The potential for elevation
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Interactions
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 )
7.1Cytochrome 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 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 ) ].
7.2Estrogens
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 extended-release tablets [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 extended-release tablets.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
There are no adequate data on the developmental risk associated with the use of ropinirole extended-release tablets 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.
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 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 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) were nausea, somnolence, abdominal pain/discomfort, dizziness, headache, and constipation.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc. at 1-888-375-3784 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. During the premarketing development of ropinirole extended-release, patients with advanced Parkinson’s disease received ropinirole extended-release 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 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 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 (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 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 causing discontinuation of treatment with ropinirole extended-release 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 who participated in Study 1. In this trial, either ropinirole extended-release 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 and More Common than on Placebo) a Body System/Adverse Reaction Ropinirole Extended-Release (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 and placebo) that the incidence for dyskinesia, hypertension, and fall was dose-related to ropinirole extended-release. 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 discontinued prematurely during the titration phase becauseof 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 4 mg, 9% for ropinirole extended-release 8 mg, 8% for ropinirole extended-release 12 mg, 8% for ropinirole extended-release 16 mg, and 0% for ropinirole extended-release 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 and numerically higher than on placebo in Study 2. The most common adverse reaction (incidence for ropinirole extended-release 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 and More Common than on Placebo) Adverse Reaction Ropinirole Extended-Release 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-d
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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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