Drug Facts
Composition & Profile
Identifiers & Packaging
Each modified oval shaped, biconvex film-coated tablet contains ropinirole hydrochloride, USP equivalent to 0.5 mg: pale yellow coloured, modified oval shaped, biconvex, film-coated tablet debossed with “106” on one side and “RH” on the other side in NDC: 70518-4318-00 PACKAGING: 30 in 1 BLISTER PACK Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Close container tightly after each use. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762; DRUG: Ropinirole GENERIC: Ropinirole DOSAGE: TABLET, FILM COATED ADMINSTRATION: ORAL NDC: 70518-4318-0 COLOR: yellow SHAPE: OVAL SCORE: No score SIZE: 9 mm IMPRINT: 106;RH PACKAGING: 30 in 1 BLISTER PACK ACTIVE INGREDIENT(S): ROPINIROLE HYDROCHLORIDE 0.5mg in 1 INACTIVE INGREDIENT(S): CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE POLYETHYLENE GLYCOL 6000 FERRIC OXIDE YELLOW POLYSORBATE 80 MM1
- Each modified oval shaped, biconvex film-coated tablet contains ropinirole hydrochloride, USP equivalent to 0.5 mg: pale yellow coloured, modified oval shaped, biconvex, film-coated tablet debossed with “106” on one side and “RH” on the other side in NDC: 70518-4318-00 PACKAGING: 30 in 1 BLISTER PACK Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Close container tightly after each use. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762
- DRUG: Ropinirole GENERIC: Ropinirole DOSAGE: TABLET, FILM COATED ADMINSTRATION: ORAL NDC: 70518-4318-0 COLOR: yellow SHAPE: OVAL SCORE: No score SIZE: 9 mm IMPRINT: 106;RH PACKAGING: 30 in 1 BLISTER PACK ACTIVE INGREDIENT(S): ROPINIROLE HYDROCHLORIDE 0.5mg in 1 INACTIVE INGREDIENT(S): CELLULOSE, MICROCRYSTALLINE LACTOSE MONOHYDRATE CITRIC ACID MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE POLYETHYLENE GLYCOL 6000 FERRIC OXIDE YELLOW POLYSORBATE 80 MM1
Overview
Ropinirole tablets, USP contains 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 the empirical formula is 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 pale cream to yellow powder with a melting range of 243°C to 250°C and a solubility of 133 mg/mL in water. Each modified oval shaped, biconvex film-coated tablet contains 0.29 mg, 0.57 mg, 1.14 mg, 2.28 mg, 3.42 mg, 4.56 mg, or 5.70 mg ropinirole hydrochloride, USP equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. Inactive ingredients consist of microcrystalline cellulose, lactose monohydrate, citric acid monohydrate, croscarmellose sodium, magnesium stearate. 0.25 mg tablet contains opadry white. The components of opadry white are hypromellose, titanium dioxide, polyethylene glycol 6000 and polysorbate 80. 0.5 mg tablet contains opadry yellow. The components of opadry yellow are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide yellow and polysorbate 80. 1 mg tablet contains opadry green. The components of opadry green are hypromellose, titanium dioxide, triacetin, iron oxide yellow and FD&C Blue No. 2. 2 mg tablet contains opadry pink. The components of opadry pink are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide red and polysorbate 80. 3 mg tablet contains opadry purple. The components of opadry purple are hypromellose, titanium dioxide, carmine, polyethylene glycol 400, polysorbate 80 and FD&C Blue No. 1. 4 mg tablet contains opadry brown. The components of opadry brown are hypromellose, titanium dioxide, iron oxide red, polyethylene glycol 400, FD&C Blue No. 2, polysorbate 80 and iron oxide black. Also contains FD&C yellow No. 6 as a color additive. 5 mg tablet contains opadry blue. The components of opadry blue are hypromellose, titanium dioxide, polyethylene glycol 400, FD&C Blue No. 2 and polysorbate 80. molecular structure
Indications & 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).
Dosage & Administration
Ropinirole tablets can be taken with or without food. (2.1) Retitration of ropinirole 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 can be taken with or without food [see Clinical Pharmacology (12.3)]. If a significant interruption in therapy with ropinirole has occurred, retitration of therapy may be warranted. 2.2 Dosing for Parkinson’s Disease The recommended starting dose of ropinirole for Parkinson's disease is 0.25 mg 3 times daily. Based on individual patient therapeutic response and tolerability, if necessary, the dose should then be titrated with weekly increments as described in Table 1. After Week 4, if necessary, the daily dose may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly up to a maximum recommended total daily dose of 24 mg/day (8 mg 3 times daily). Doses greater than 24 mg/day have not been tested in clinical trials. Table 1. Ascending-Dose Schedule of Ropinirole 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 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 3 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. 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 3 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 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 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 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 in patients with severe renal impairment without regular dialysis has not been studied.
Warnings & 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) 5.1 Falling 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. 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. 5.2 Syncope 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)]. 5.4 Hallucinations/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 behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole or after starting or increasing the dose of ropinirole. Other drugs prescribed to improve the symptoms of Parkinson’s disease or RLS can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with ropinirole because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of ropinirole [ see Drug Interactions (7.3) ]. 5.5 Dyskinesia Ropinirole may cause or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease. In double-blind, placebo-controlled trials in advanced Parkinson’s disease, dyskinesia was much more common in patients treated with ropinirole than in those treated with placebo. Among those patients receiving both ropinirole and L-dopa in advanced Parkinson’s disease trials, 34% were reported to experience dyskinesia, compared with 13% of patients treated with placebo [see Adverse Reactions (6.1)] . Decreasing the dose of dopaminergic medications may ameliorate this adverse reaction. 5.6 Impulse Control/Compulsive Behaviors Reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ropinirole, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with ropinirole for Parkinson’s disease or RLS. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole. 5.7 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction of, withdrawal of, or changes in, dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with ropinirole as a prophylactic measure [see Dosage and Administration (2.2, 2.3)] . 5.8 Withdrawal Symptoms Symptoms including insomnia, apathy, anxiety, depression, fatigue, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including ropinirole. These symptoms generally do not respond to levodopa. Prior to discontinuation of ropinirole, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered. 5.9 Augmentation and Early-Morning Rebound in Restless Legs Syndrome Augmentation is a phenomenon in which dopaminergic medication causes a worsening of symptom severity above and beyond the level at the time the medication was started. The symptoms of augmentation may include the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Augmentation has been described during therapy for RLS. Rebound refers to new onset of symptoms in the early morning hours. Augmentation and/or early-morning rebound have been observed in a postmarketing trial of ropinirole. If augmentation or early-morning rebound occurs, the use of ropinirole should be reviewed and dosage adjustment or discontinuation of treatment should be considered. When discontinuing ropinirole in patients with RLS, gradual reduction of the daily dose is recommended whenever possible [see Dosage and Administration 2.3] . 5.10 Fibrotic Complications Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, non-ergot-derived dopamine agonists such as ropinirole can cause them is unknown. Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded. 5.11 Retinal Pathology Retinal degeneration was observed in albino rats in the 2 year carcinogenicity study at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the maximum recommended human dose (MRHD) for Parkinson’s disease (24 mg/day) on a mg/m 2 basis. Retinal degeneration was not observed in a 3 month study in pigmented rats, in a 2 year carcinogenicity study in albino mice, or in 1 year studies in monkeys or albino rats. The significance of this effect for humans has not been established, but involves disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding). Ocular electroretinogram assessments were conducted during a 2 year, double-blind, multicenter, flexible dose, L-dopa-controlled clinical trial of ropinirole in patients with Parkinson’s disease; 156 patients (78 on ropinirole, mean dose: 11.9 mg/day, and 78 on L-dopa, mean dose: 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the trial. 5.12 Binding to Melanin Ropinirole binds to melanin-containing tissues (e.g., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days.
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
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. 6.1 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, 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 asthenic condition (i.e., asthenia, fatigue, and/or malaise). Approximately 5% of patients treated with ropinirole who participated in the double-blind, placebo-controlled trials in the treatment of RLS discontinued treatment due to adverse reactions compared with 4% 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 nausea. Table 5 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with RLS treated with ropinirole participating in the 12 week, double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. Table 5. Treatment-Emergent Adverse Reaction Incidence in Double-blind, Placebo-Controlled Restless Legs Syndrome Trials (Events ≥2% of Patients Treated with Ropinirole and Numerically More Frequent than the Placebo Group) a Body System/Adverse Reaction Ropinirole (n = 496) (%) Placebo (n = 500) (%) Ear and labyrinth Vertigo 2 1 Gastrointestinal Nausea Vomiting Diarrhea Dyspepsia Dry mouth Abdominal pain upper 40 11 5 4 3 3 8 2 3 3 2 1 General disorders and administration site conditions Asthenic condition b Edema peripheral 9 2 4 1 Infections and infestations Nasopharyngitis Influenza 9 3 8 2 Musculoskeletal and connective tissue Arthralgia Muscle cramps Pain in extremity 4 3 3 3 2 2 Nervous system Somnolence Dizziness Paresthesia 12 11 3 6 5 1 Respiratory, thoracic, and mediastinal Cough Nasal congestion 3 2 2 1 Skin and subcutaneous tissue Hyperhidrosis 3 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. b Asthenic condition (i.e., asthenia, fatigue, and/or malaise). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ropinirole. 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 (5.8) ]
Drug 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) 7.1 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, 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)] . 7.2 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 [ 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.
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