Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Each capsule shaped, film coated tablet contains ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows: 2 mg: pink tablets debossed with 'L191' NDC 46708-262-30 bottle of 30 tablets NDC 46708-262-90 bottle of 90 tablets NDC 46708-262-31 bottle of 100 tablets NDC 46708-262-71 bottle of 500 tablets NDC 46708-262-91 bottle of 1000 tablets NDC 46708-262-10 carton of 100 (10X10) unit dose tablets 4 mg: light brown tablets debossed with 'L193' NDC 46708-263-30 bottle of 30 tablets NDC 46708-263-90 bottle of 90 tablets NDC 46708-263-31 bottle of 100 tablets NDC 46708-263-71 bottle of 500 tablets NDC 46708-263-91 bottle of 1000 tablets NDC 46708-263-10 carton of 100 (10X10) unit dose tablets 6 mg: white to off white tablets debossed with 'L321' NDC 46708-264-30 bottle of 30 tablets NDC 46708-264-90 bottle of 90 tablets NDC 46708-264-31 bottle of 100 tablets NDC 46708-264-71 bottle of 500 tablets NDC 46708-264-91 bottle of 1000 tablets NDC 46708-264-10 carton of 100 (10X10) unit dose tablets 8 mg: dark brown to red tablets debossed with 'L194' NDC 46708-265-30 bottle of 30 tablets NDC 46708-265-90 bottle of 90 tablets NDC 46708-265-31 bottle of 100 tablets NDC 46708-265-71 bottle of 500 tablets NDC 46708-265-91 bottle of 1000 tablets NDC 46708-265-10 carton of 100 (10X10) unit dose tablets 12 mg: light green tablets debossed with 'L195' NDC 46708-266-30 bottle of 30 tablets NDC 46708-266-90 bottle of 90 tablets NDC 46708-266-31 bottle of 100 tablets NDC 46708-266-71 bottle of 500 tablets NDC 46708-266-91 bottle of 1000 tablets NDC 46708-266-10 carton of 100 (10X10) unit dose tablets Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP.; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 2mg rOPINIRole Extended-Release Tablets 2 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 2.28 mg ropinirole hydrochloride equivalent to 2 mg ropinirole 46708-262-30 2 mg 30's HDPE Bottle Pack; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 4mg rOPINIRole Extended-Release Tablets 4 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 4.56 mg ropinirole hydrochloride equivalent to 4 mg ropinirole 46708-263-30 4 mg 30's HDPE Bottle Pack; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 6mg rOPINIRole Extended-Release Tablets 6 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 6.84 mg ropinirole hydrochloride equivalent to 6 mg ropinirole 46708-264-30 6 mg 30's HDPE Bottle Pack; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 8mg rOPINIRole Extended-Release Tablets 8 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 9.12 mg ropinirole hydrochloride equivalent to 8 mg ropinirole 46708-265-30 8 mg 30's HDPE Bottle Pack; PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 12mg rOPINIRole Extended-Release Tablets 12 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 13.68 mg ropinirole hydrochloride equivalent to 12 mg ropinirole 46708-266-30 12 mg 30's HDPE Bottle Pack
- 16 HOW SUPPLIED/STORAGE AND HANDLING Each capsule shaped, film coated tablet contains ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows: 2 mg: pink tablets debossed with 'L191' NDC 46708-262-30 bottle of 30 tablets NDC 46708-262-90 bottle of 90 tablets NDC 46708-262-31 bottle of 100 tablets NDC 46708-262-71 bottle of 500 tablets NDC 46708-262-91 bottle of 1000 tablets NDC 46708-262-10 carton of 100 (10X10) unit dose tablets 4 mg: light brown tablets debossed with 'L193' NDC 46708-263-30 bottle of 30 tablets NDC 46708-263-90 bottle of 90 tablets NDC 46708-263-31 bottle of 100 tablets NDC 46708-263-71 bottle of 500 tablets NDC 46708-263-91 bottle of 1000 tablets NDC 46708-263-10 carton of 100 (10X10) unit dose tablets 6 mg: white to off white tablets debossed with 'L321' NDC 46708-264-30 bottle of 30 tablets NDC 46708-264-90 bottle of 90 tablets NDC 46708-264-31 bottle of 100 tablets NDC 46708-264-71 bottle of 500 tablets NDC 46708-264-91 bottle of 1000 tablets NDC 46708-264-10 carton of 100 (10X10) unit dose tablets 8 mg: dark brown to red tablets debossed with 'L194' NDC 46708-265-30 bottle of 30 tablets NDC 46708-265-90 bottle of 90 tablets NDC 46708-265-31 bottle of 100 tablets NDC 46708-265-71 bottle of 500 tablets NDC 46708-265-91 bottle of 1000 tablets NDC 46708-265-10 carton of 100 (10X10) unit dose tablets 12 mg: light green tablets debossed with 'L195' NDC 46708-266-30 bottle of 30 tablets NDC 46708-266-90 bottle of 90 tablets NDC 46708-266-31 bottle of 100 tablets NDC 46708-266-71 bottle of 500 tablets NDC 46708-266-91 bottle of 1000 tablets NDC 46708-266-10 carton of 100 (10X10) unit dose tablets Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP.
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 2mg rOPINIRole Extended-Release Tablets 2 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 2.28 mg ropinirole hydrochloride equivalent to 2 mg ropinirole 46708-262-30 2 mg 30's HDPE Bottle Pack
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 4mg rOPINIRole Extended-Release Tablets 4 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 4.56 mg ropinirole hydrochloride equivalent to 4 mg ropinirole 46708-263-30 4 mg 30's HDPE Bottle Pack
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 6mg rOPINIRole Extended-Release Tablets 6 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 6.84 mg ropinirole hydrochloride equivalent to 6 mg ropinirole 46708-264-30 6 mg 30's HDPE Bottle Pack
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 8mg rOPINIRole Extended-Release Tablets 8 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 9.12 mg ropinirole hydrochloride equivalent to 8 mg ropinirole 46708-265-30 8 mg 30's HDPE Bottle Pack
- PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 12mg rOPINIRole Extended-Release Tablets 12 mg* (30 Tablets in 1 Bottle) *Each extended-release tablet contains 13.68 mg ropinirole hydrochloride equivalent to 12 mg ropinirole 46708-266-30 12 mg 30's HDPE Bottle Pack
Overview
Ropinirole extended-release tablets contains ropinirole, a non-ergoline dopamine agonist as the hydrochloride salt. The chemical name of ropinirole hydrochloride 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 is a white to yellow solid with a melting range of 243° to 250°C and a solubility of 133 mg/mL in water. Each capsule shaped, film coated tablet contains 2.28 mg, 4.56 mg, 6.84 mg, 9.12 mg, or 13.68 mg ropinirole hydrochloride equivalent to ropinirole 2 mg, 4 mg, 6 mg, 8 mg, or 12 mg, respectively. Inactive ingredients consist of carboxymethylcellulose sodium, colloidal silicon dioxide, hydrogenated castor oil, hypromellose, magnesium stearate, povidone, pregelatinized starch, ethylcellulose and one or more of the following: FD&C Blue No. 2 aluminum lake, ferric oxides (black, red, yellow), polyethylene glycol 6000, polyethylene glycol 8000, titanium dioxide, talc. Structure
Indications & Usage
Ropinirole extended-release tablets are non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease (1.1) 1.1 Parkinson's Disease Ropinirole extended-release tablets are indicated for the treatment of Parkinson’s disease.
Dosage & Administration
•Ropinirole extended-release tablets are taken once daily, with or without food; tablets must be swallowed whole and must 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 dose 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 most closely 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 starting dose is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at 1-week or longer intervals as appropriate, based on therapeutic response and tolerability. The maximum recommended dose of ropinirole extended-release tablets is 24 mg/day. In clinical trials, dosage was initiated at 2 mg/day and gradually titrated based on individual patient therapeutic response and tolerability. Doses greater than 24 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 1 week or longer after each dose increment. Monitor patients during dose titration because too rapid a rate of titration may lead to dose selection that may not provide additional benefit, but that may increase the risk of adverse reactions [see Clinical Studies (14.2)] . Due to the flexible dosing design used in clinical trials, specific dose-response information could not be determined. Ropinirole extended-release tablets should be discontinued gradually over a 7-day period. 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 Extended-Release Ropinirole Tablets Patients may be switched directly from immediate-release ropinirole to extended-release ropinirole tablets. The initial dose of ropinirole extended-release tablets should most closely match the total daily dose of the immediate-release formulation of ropinirole tablets, as shown in Table 1. Table 1. Conversion from Immediate-Release Ropinirole Tablets to Extended-Release Ropinirole Tablets Immediate-Release Ropinirole Tablets Total Daily Dose (mg) Extended-Release Ropinirole Tablets 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.
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) •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) 5.1 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 machinary, 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 tablets in clinical trials, there were 5 cases of sudden onset of sleep and 2 cases of motor vehicle accident in which it is not known if falling asleep was a contributing factor. During the 6-month trial in advanced Parkinson’s disease, somnolence was reported in 7% of patients receiving ropinirole extended-release tablets compared with 4% of patients receiving placebo. During the 36-week trial in early Parkinson’s disease, somnolence was reported in 11% of patients receiving ropinirole extended-release tablets compared with 15% of patients receiving the immediate-release formulation of ropinirole tablets [see Adverse Reactions (6.1)]. However, because dose-response was not systematically studied with ropinirole extended-release tablets, the occurrence of somnolence at the highest recommended doses may be higher than these reported frequencies [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 preexisting 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, 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. 5.2 Syncope Syncope, sometimes associated with bradycardia, was observed in association with ropinirole extended-release tablets in Parkinson’s disease patients. In a placebo-controlled trial involving patients with advanced Parkinson’s disease, syncope occurred in 2 of the 202 patients (1%) who received ropinirole extended-release tablets, and in none of the 191 patients who received placebo [see Adverse Reactions (6.1)] . Because the trial of ropinirole extended-release tablets excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution. 5.3 Hypotension/Orthostatic Hypotension Dopamine agonists, in clinical trials and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. In addition, patients with Parkinson’s disease appear to have an impaired capacity to respond to a postural challenge. For these reasons, patients should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and patients should be informed of the risk for syncope and hypotension [see Patient Counseling Information (17)]. In a placebo-controlled trial involving patients with advanced Parkinson’s disease, hypotension was reported as an adverse event in 5 of 202 patients (2%) receiving ropinirole extended-release tablets and in none of the 191 patients receiving placebo. Orthostatic hypotension was reported as an adverse event in 5% of patients receiving ropinirole extended-release tablets, and in 1% of placebo recipients [see Adverse Reactions (6.1)] . An analysis of the randomized, double-blinded, placebo-controlled trial in advanced Parkinson’s disease was conducted using a variety of adverse event terms possibly suggestive of hypotension, including hypotension, orthostatic hypotension, dizziness, vertigo, and blood pressure decreased. This analysis showed a higher incidence of these events with ropinirole extended-release tablets (7%, 15 of 202) vs. placebo (3%, 6 of 191). The increased incidence with ropinirole extended-release tablets 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. Orthostatic vital signs (semi-supine to standing) were monitored throughout the advanced Parkinson’s disease trial and changes related to ropinirole extended-release tablets (compared with placebo) from baseline were assessed. The frequency of orthostatic hypotension at any time during the trial was 38% for ropinirole extended-release tablets vs. 31% for placebo for mild to moderate systolic blood pressure decrements (≥20 mm Hg), 63% for ropinirole extended-release tablets vs. 58% for placebo for mild-to-moderate diastolic blood pressure decrements (≥10 mm Hg), 10% for ropinirole extended-release tablets vs. 7% for placebo for severe diastolic blood pressure decrements (≥20 mm Hg), and 23% for ropinirole extended-release tablets vs. 19% for placebo for mild-to-moderate combined systolic and diastolic blood pressure decrements. Significant decrements in blood pressure unrelated to standing were also reported in some patients taking ropinirole extended-release tablets. In the semi-supine position, the frequency was 10% for ropinirole extended-release tablets vs. 8% for placebo for severe systolic blood pressure decrease (≥40 mm Hg), and was 25% for ropinirole extended-release tablets vs. 21% for placebo for severe diastolic blood pressure decrease (≥20 mm Hg). The increased incidence for hypotension and/or orthostatic hypotension was observed in both the titration and maintenance phases and in some cases persisted into the maintenance period after developing in the titration phase. 5.4 Elevation of Blood Pressure and Changes in Heart Rate In the placebo-controlled trial in advanced Parkinson’s disease, there were no clear effects of ropinirole extended-release tablets on average changes in blood pressure or heart rate compared with placebo. In the semi-supine position, the frequency was 8% for ropinirole extended-release tablets vs. 5% for placebo for severe systolic blood pressure increase (≥40 mm Hg). In the standing position, the frequency was 9% for ropinirole extended-release tablets vs. 6% for placebo for severe systolic blood pressure increase ≥40 mm Hg). In the semi-supine position, the frequency was 23% for ropinirole extended-release tablets vs. 18% for placebo for moderate pulse increase (≥15 beats/ minute), and 19% for ropinirole extended-release tablets vs. 17% for placebo for moderate pulse decrease (≥15 beats/minute). In the standing position, the frequency was 2% for ropinirole extended-release tablets vs. <1% for placebo for severe pulse increase (≥30 beats/minute), and 24% for ropinirole extended-release tablets vs. 19% for placebo for moderate pulse decrease (≥15 beats/minute). The increased incidence for various elevations of systolic and/or diastolic blood pressure and/or changes in pulse was observed in both the titration and maintenance phases as well as persisting into the maintenance period after developing in the titration phase. Elevation of blood pressure and/or changes in heart rate in patients taking ropinirole extended-release tablets should be considered when treating patients with cardiovascular disease. 5.5 Hallucinations/Psychotic-like Behavior In the double-blind, placebo-controlled, advanced Parkinson’s disease trial 8% (17 of 202) of patients receiving ropinirole extended-release tablets reported hallucination compared with 2% (4 of 191) patients receiving placebo [see Adverse Reactions (6.1)] . Hallucination led to discontinuation of treatment in 2% (4 of 202) of patients on ropinirole extended-release tablets and 1% (2 of 191) of patients on placebo. The incidence of hallucination is increased in elderly patients (i.e., older than 65 years) treated with ropinirole extended-release tablets [see Use in Specific Populations (8.5)] . Postmarketing reports indicate that patients 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 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, disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with ropinirole extended-release tablets 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 extended-release tablets [see Drug Interactions (7.3)] . 5.6 Dyskinesia Ropinirole extended-release tablets may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease. In the double-blind, placebo-controlled trial in patients with advanced Parkinson’s disease dyskinesia was reported as an adverse event in 13% of patients taking ropinirole extended-release tablets and 3% of patients on placebo [see Adverse Reactions (6.1)] . Decreasing the dose of a dopaminergic drug may ameliorate this side effect. 5.7 Impulse Control/Compulsive Behaviors Case 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 extended-release tablets, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. 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 extended-release tablets. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole extended-release tablets. 5.8 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, withdrawal of, or changes in dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with ropinirole extended-release tablets as a prophylactic measure [see Dosage and Administration (2.2)] . 5.9 Melanoma Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2 to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. In the clinical development program (N = 613), one patient treated with ropinirole extended-release tablets and also levodopa/carbidopa developed melanoma. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using ropinirole extended-release tablets. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). 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. In the clinical development program (N = 613), 2 patients treated with ropinirole extended-release tablets had pleural effusion. 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 (equivalent to 0.6 to 20 times the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m 2 basis), but was statistically significant at the highest dose (50 mg/kg/day). 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 (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible-dose, L-dopa-controlled clinical trial of immediate-release ropinirole in patients with Parkinson’s disease; 156 patients (78 on immediate-release 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 (i.e., 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 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)
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)] · Melanoma [see Warnings and Precautions (5.9)] · Fibrotic Complications [see Warnings and Precautions (5.10)] · Most common adverse reactions (incidence for ropinirole extended-release tablets at least 5% greater than placebo) in advanced Parkinson’s disease with concomitant L-dopa were dyskinesia, nausea, dizziness, hallucination. (6.1) · Most common adverse reactions (incidence incidence for ropinirole extended-release tablets at least 5%) in early Parkinson’s disease without L-dopa were nausea, somnolence, abdominal pain/discomfort, dizziness, headache, and constipation (6.1) To report SUSPECTED ADVERSE REACTIONS, contact 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 in 1 clinical trial. In a second trial, patients with early Parkinson’s disease were treated with ropinirole extended-release tablets or the immediate-release formulation of ropinirole tablets without L-dopa. Advanced Parkinson’s Disease (with L-dopa) In the 24-week, double-blind, placebo-controlled trial for the treatment of advanced Parkinson’s disease, 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 hallucination. 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 was hallucination (2%) Table 2 lists treatment-emergent 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 the 26-week, double-blind, placebo-controlled trial. In this trial, either ropinirole extended-release tablets or placebo was used as an adjunct to L-dopa. Table 2. Treatment-Emergent Adverse Reaction Incidence in a Double-Blind, Placebo-Controlled Trial in Advanced Stage Parkinson’s Disease (With L-dopa) (Events ≥ 2% of Patients Treated with Ropinirole Extended-Release Tabletsand >% with 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 Constipation 4 2 Abdominal pain/discomfort 6 3 Diarrhea 3 2 Dry mouth 2 <1 General disorders Edema peripheral 4 1 Injury, poisoning, and procedural complication Fall* 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 Hypotension 2 0 Hypertension b 3 2 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. The incidence for many adverse reactions with ropinirole extended-release tablets treatment was increased relative to placebo (i.e., the incidence in the group receiving ropinirole extended-release tablets was 2% or greater than placebo in either the titration or maintenance phases of the trial. During the titration phase, an increased incidence (shown in descending order of % treatment difference) was observed for dyskinesia, nausea, abdominal pain/discomfort, orthostatic hypotension, dizziness, vertigo, hypertension, peripheral edema, and dry mouth. During the maintenance phase, an increased incidence was observed for dyskinesia, nausea, dizziness, hallucination, somnolence, fall, hypertension, abnormal dreams, constipation, chest pain, bronchitis, and nasopharyngitis. Some adverse reactions developing in the titration phase persisted (³7 days) into the maintenance phase. These “persistent” adverse reactions included dyskinesia, hallucination, orthostatic hypotension, and dry mouth. The incidence of adverse reactions was not clearly different between women and men. Early Parkinson’s Disease (without L-dopa) In the 36–week early Parkinson’s disease trial the most commonly observed adverse reactions in patients treated with ropinirole extended-release tablets (≥5%) were nausea (19%), somnolence (11%), abdominal pain/discomfort (7%), dizziness (6%), headache (6%), and constipation (5%). The type of adverse reactions and the frequency (i.e. incidence) with which they occurred were generally similar over the whole treatment period in this trial of early Parkinson’s disease patients who were initially treated with ropinirole extended-release tablets or the immediate-release formulation of ropinirole tablets and subsequently crossed over to treatment with the other formulation. During the titration phase, an increased incidence with ropinirole extended-release tablets compared with the immediate-release formulation of ropinirole tablets (i.e., the incidence in ropinirole extended-release tablets was 2% or greater than immediate-release ropinirole tablets), shown in descending order of % treatment difference, was observed for: constipation, hallucination, vertigo, abdominal pain/discomfort, nausea, vomiting, fall, headache, diarrhea, pyrexia, and flatulence. During the maintenance phase, an increased incidence was observed for fall, myalgia, and sleep disorder. Several adverse reactions developing in the titration phase persisted (³7 days) into the maintenance phase. These “persistent” adverse reactions included: constipation, hallucination, muscle spasms, flatulence, insomnia, sleep disorder, abdominal pain/discomfort, cough, and nasopharyngitis. 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 (³5% 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 (³5% 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%).
Drug Interactions
•Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole;dose adjustment 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 CYP1A2 Inhibitors and Inducers In vitro metabolism studies showed that 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 [HRT]) reduced the clearance of ropinirole. Starting or stopping HRT 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.
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