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Mechanism Of Action
Ropinirole is a non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as a treatment for Parkinson's disease is unknown, although it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen in the brain.
Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure resulting in orthostatic hypotension, especially during dose escalation. In some subjects in clinical trials, blood pressure changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest with syncope [see WARNINGS AND PRECAUTIONS].
The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to a D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant symptom of orthostatic signs and symptoms.
At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers.
Immediate-release ropinirole had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg.
Immediate-release ropinirole had no dose- or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been systematically evaluated.
Increase in systemic exposure of ropinirole following oral administration of 2 to 12 mg of REQUIP XL was approximately dose-proportional. For REQUIP XL, steady-state concentrations of ropinirole are expected to be achieved within 4 days of dosing.
In clinical trials with immediate-release ropinirole, more than 88% of a radiolabeled dose was recovered in urine, and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.
The bioavailability of REQUIP XL extended-release tablets is similar to that of immediate-release ropinirole tablets. In a repeat-dose trial in subjects with Parkinson's disease using REQUIP XL 8 mg, the dose-normalized AUC(0-24) and Cmin for REQUIP XL and immediate-release ropinirole were similar. Dose-normalized Cmax was, on average, 12% lower for REQUIP XL than for the immediate-release formulation and the median time-to-peak concentration was 6 to 10 hours. In a single-dose trial, administration of REQUIP XL to healthy volunteers with food (i.e., high-fat meal) increased AUC by approximately 30% and Cmax by approximately 44%, compared with dosing under fasted conditions. In a repeat-dose trial in patients with Parkinson's disease, food (i.e., high-fat meal) increased AUC by approximately 20% and Cmax by approximately 44%; Tmax was prolonged by 3 hours (median prolongation) compared with dosing under fasted conditions [see DOSAGE AND ADMINISTRATION].
Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg. It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.
Ropinirole is extensively metabolized by the liver. The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl metabolite and hydroxy metabolites. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated.
In vitro studies indicate that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be induced by smoking and omeprazole and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin.
The clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 6 hours. Less than 10% of the administered dose is excreted as unchanged drug in urine. N-despropyl ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic acid metabolite (10%) and the glucuronide of the hydroxy metabolite (10%).
Digoxin: Coadministration of immediate-release ropinirole (2 mg three times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.
Theophylline: Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of immediate-release ropinirole (2 mg three times daily) in 12 patients with Parkinson's disease. Immediate-release ropinirole (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg intravenously) in 12 patients with Parkinson's disease.
Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with immediate-release ropinirole (2 mg three times daily) increased ropinirole AUC by 84% on average and Cmax by 60% (n = 12 patients).
Estrogens: Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients.
L-dopa: Coadministration of carbidopa + L-dopa (10/100 mg twice daily) with immediate-release ropinirole (2 mg three times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of immediate-release ropinirole 2 mg three times daily increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).
Commonly Administered Drugs: Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the clearance of ropinirole. An in vitro study indicates that ropinirole is not a substrate for P-gp. Ropinirole and its circulating metabolites do not inhibit or induce P450 enzymes; therefore, ropinirole is unlikely to affect the pharmacokinetics of other drugs by a P450 mechanism.
Because therapy with REQUIP XL is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary.
Age: Oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients. Dosage adjustment is not necessary in the elderly (older than 65 years), as the dose of ropinirole is to be individually titrated to clinical response.
Gender: Female and male patients showed similar clearance.
Race: The influence of race on the pharmacokinetics of ropinirole has not been evaluated.
Cigarette Smoking: Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. In a trial in patients with Restless Legs Syndrome, smokers (n = 7) had an approximately 30% lower Cmax and a 38% lower AUC than did nonsmokers (n = 11) when those parameters were normalized for dose.
Renal Impairment: Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in subjects with moderate renal impairment (creatinine clearance between 30 to 50 mL/min) compared with an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in patients with moderate renal impairment.
A trial of immediate-release ropinirole in subjects with end-stage renal disease on hemodialysis has shown that clearance of ropinirole was reduced by approximately 30%. The recommended maximum dose is lower in these patients [see DOSAGE AND ADMINISTRATION].
The use of ropinirole in subjects with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.
Hepatic Impairment: The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Because ropinirole is extensively metabolized by the liver, these patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function.
Other Diseases: Population pharmacokinetic analysis revealed no change in the clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients with Parkinson's disease only.
The effectiveness of ropinirole was initially established with the immediate-release formulation (REQUIP tablets) for the treatment of early and advanced Parkinson's disease in 3 randomized, double-blind, placebo-controlled trials.
The effectiveness of REQUIP XL in the treatment of Parkinson's disease was supported by 2 randomized, double-blind, multicenter, flexible-dose clinical trials and clinical pharmacokinetic considerations. One trial conducted in patients with advanced Parkinson's disease compared REQUIP XL with placebo as adjunctive therapy to L-dopa (Study 1). A second trial compared REQUIP XL with REQUIP tablets in patients with early Parkinson's disease not receiving L-dopa (Study 3). REQUIP XL has also been evaluated in 2 postmarketing, randomized, double-blind, multicenter, fixed-dose, dose-response clinical trials conducted in advanced and early Parkinson's disease patients (Study 2 and Study 4, respectively).
In these trials, a variety of measures were used to assess the effects of treatment (e.g., Unified Parkinson's Disease Rating Scale [UPDRS] scores, and patient diaries recording time “on” and “off,” tolerability of L-dopa dose reductions). The UPDRS is a multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability) scored for different body regions and has a maximum (worst) score of 108.
Trials in Patients With Advanced Parkinson's Disease (with L-dopa)
Study 1 (Flexible-Dose Trial)
The effectiveness of REQUIP XL as adjunctive therapy to L-dopa in patients with Parkinson's disease was established in a 24-week, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose, clinical trial in 393 patients (Hoehn & Yahr criteria Stages II-IV) who were not adequately controlled by L-dopa therapy. Patients were allowed to be on concomitant selegiline, amantadine, anticholinergics, and catechol-O-methyltransferase (COMT) inhibitors provided the doses were stable for at least 4 weeks prior to screening and throughout the trial. The primary efficacy endpoint evaluated was the mean change from baseline in total awake time spent “off”.
Patients in this trial had a mean disease duration of 8.6 years, had a mean duration of exposure to L-dopa of 6.5 years, had experienced a minimum of 3 hours awake time “off” with a baseline average of approximately 7 hours awake time “off”, and had a mean baseline UPDRS motor score of approximately 30 points. The mean baseline dose of L-dopa was 824 mg/day in the group receiving REQUIP XL and 776 mg/day for the placebo group. Patients initiated treatment at 2 mg/day for 1 week, followed by increases of 2 mg/day at weekly intervals, to a minimum dose of 6 mg/day. The following week, the total daily dose of REQUIP XL could be further increased (based upon therapeutic response and tolerability) to 8 mg/day. Once a daily dose of 8 mg/day was reached, the background L-dopa dosage was reduced. Thereafter, the daily dose could be increased by up to 4 mg/day approximately every 2 weeks until an optimal dose was achieved (based upon therapeutic response and tolerability). The mean dose of REQUIP XL at the end of Week 24 was 18.8 mg/day. Dose titrations were based upon the degree of symptom control, planned L-dopa dosage reduction, and/or tolerability. The maximum allowed daily dosage for REQUIP XL was 24 mg/day.
The primary efficacy endpoint was mean change from baseline in total awake time spent “off” at Week 24. At baseline, the mean total awake time spent “off” was approximately 7 hours in each treatment group. At Week 24, the total awake time spent “off”, on average, had decreased by approximately 2 hours in the group receiving REQUIP XL and by approximately one-half hour in the placebo group. The adjusted mean difference in total awake time spent “off” between REQUIP XL and placebo was -1.7 hours, which was statistically significant (analysis of covariance [ANCOVA], P < 0.0001). Results for this endpoint, showing the statistical superiority of REQUIP XL over placebo, are presented in Table 5.
Table 5: Change from Baseline in Total Awake Time
Spent “Off” (Primary Efficacy Endpoint) at Week 24 (Study 1)
(n = 201)
(n = 190)
|Mean “Off’ Time at Baseline (hours)||7.0||7.0|
|Mean Change from Baseline in “Off’ Time (hours)||-2.1||-0.4|
|Treatment Difference (REQUIP XL - PLACEBO)||-1.7|
The difference between groups in favor of REQUIP XL, with regard to a decrease in total “off” hours, was primarily related to an increase in total “on” hours without troublesome dyskinesia. Patients treated with REQUIP XL had a mean reduction in L-dopa dose of 278 mg/day (34%), while patients treated with placebo had a mean reduction of 164 mg/day (21%). In patients who reduced their L-dopa dose, reduction was sustained in 93% of patients treated with REQUIP XL and in 72% of patients treated with placebo (P < 0.001).
Study 2 (Fixed-Dose, Dose-Response Trial)
A double-blind, placebo-controlled, fixed-dose, parallel-group trial evaluated the dose-response of REQUIP XL as adjunctive therapy to L-dopa in 352 randomized patients with advanced Parkinson's disease (Hoehn & Yahr criteria Stages II-IV) over a total dosing period of 18 weeks. Patients initiated treatment with placebo or REQUIP XL at 2 mg/day for 1 week, and increased to a target dose of 4 mg/day, 8 mg/day, 12 mg/day, 16 mg/day, or 24 mg/day over a 13-week uptitration period. The dose remained stable over an additional 4-week maintenance period, followed by a 1-week down-titration period. The L-dopa dose was kept constant during the study, if possible. The primary efficacy endpoint was the mean change from baseline in total awake time spent “off” at Week 4 of the maintenance period with daily doses of 4 mg, 8 mg, 12 mg, 16 mg, and 24 mg compared with placebo. The primary statistical analysis of the primary efficacy endpoint was Mixed Model Repeated Measures (MMRM).
At baseline, the mean “off” time ranged from 5.6 to 6.5 hours across groups on REQUIP XL and placebo. Table 6 shows the results for the primary efficacy endpoint. The greatest treatment difference (REQUIP XL - PLACEBO) for the primary efficacy endpoint was observed with the 8 mg dose; however, higher doses were not shown to provide additional benefit.
Table 6: Change from Baseline in Total Awake Time
Spent “Off” (Primary Efficacy Endpoint) at the End of the Maintenance Period
N = 65
|Daily REQUIP XL Dose|
N = 21
N = 60
N = 61
N = 65
N = 25
|LS Mean Change from Baseline for “Off” Time||-1.91||-2.04||-2.92||-2.34||-2.80||-2.37|
|Treatment Difference (REQUIP XL -PLACEBO)||-0.13||-1.01||-0.43||-0.89||-0.46|
|a P value not adjusted for multiple comparisons. A hierarchical step-down approach for statistical testing was used starting with 16-mg dose.|
Trials In Patients With Early Parkinson's Disease (without l-dopa)
Study 3 (Flexible-Dose Trial)
A 36-week, multicenter, double-blind, titration/3-period maintenance, flexible-dose, crossover trial compared the efficacy of REQUIP XL with the immediate-release formulation of REQUIP in 161 patients with early phase Parkinson's disease (Hoehn & Yahr Stages I-III) with limited prior exposure to L-dopa or dopamine agonists. Eligible patients were randomized (1:1:1:1) to 4 treatment sequences (2 were titrated on immediate-release formulation of REQUIP and 2 on REQUIP XL). Titration rate of immediate-release formulation of REQUIP was slower than that of the REQUIP XL. Patients were titrated during the 12-week titration period to their optimal dosage, based upon tolerance and therapeutic response. This was followed by 3 consecutive 8-week maintenance periods, during which patients were either maintained on the prior formulation or switched to the alternative formulation. All switches were performed overnight by using the approximately equivalent doses of ropinirole. The primary efficacy endpoint was the change of UPDRS motor score within each maintenance period.
Patients in all 4 groups started out with similar UPDRS motor scores (about 21) at baseline. All groups exhibited similar improvement in UPDRS total motor scores from baseline until the completion of the titration phase, with a change in score of about -9 observed for the groups started on immediate-release formulation of REQUIP and of about -10 for the groups started on REQUIP XL. No difference was observed between groups when switches were made between identical formulations or between different formulations. This suggests therapeutic dosage equivalence between the immediate-release formulation of REQUIP and REQUIP XL.
The optimal daily dose at the end of the titration period for patients on immediate-release formulation of REQUIP was substantially lower (mean: 7 mg) compared with the dose at the end of the titration period for patients on REQUIP XL (mean: 18 mg). In this trial, the marked difference in the final optimal dosages suggests that the higher doses afforded no additional benefit when compared with the lower doses [see DOSAGE AND ADMINISTRATION].
Study 4 (Fixed-Dose, Dose-Response Trial)
A double-blind, placebo-controlled, fixed-dose, parallel-group trial evaluated the dose response of REQUIP XL without L-dopa in 186 randomized patients with early Parkinson's disease (Hoehn & Yahr Stages I-III) over a total dosing period of 18 weeks. Patients initiated treatment with placebo or REQUIP XL at 2 mg/day for 1 week and were either maintained at a target dose of 2 mg/day or further increased to a target dose of 4 mg/day, 8 mg/day, 12 mg/day, or 24 mg/day over a 13-week up-titration period. The dose remained stable over an additional 4week maintenance period, followed by a 1-week down-titration period. The primary statistical analysis of the primary efficacy endpoint was Mixed Model Repeated Measures (MMRM).
The primary efficacy endpoint was the change from baseline in UPDRS motor score at Week 4 of the maintenance period with daily doses of 2 mg, 4 mg, 8 mg, 12 mg, and 24 mg compared with placebo. At baseline, the mean UPDRS motor score ranged from approximately 21 to 25 across all groups receiving REQUIP XL and placebo. Table 7 shows results for the primary efficacy endpoint. The greatest treatment difference (REQUIP XL - PLACEBO) for the primary efficacy endpoint occurred with the 12-mg dose. At Week 4 of the maintenance period, the primary efficacy analysis (MMRM) did not show a significant difference between placebo (mean adjusted change: -3.98) and any dose of REQUIP XL (mean adjusted changes ranged from -4.09 to -6.14). Data were also analyzed by nonparametric ANCOVA as pre-specified because of non-normality. This analysis and showed that there was a significant reduction from baseline in the UPDRS motor score for the group receiving REQUIP XL 12 mg/day (P = 0.047); however, higher doses were not shown to provide additional benefit.
Table 7: Change from Baseline in UPDRS Part III Motor
Score (Primary Efficacy Endpoint) at the End of the Maintenance Period (Study
N = 35
|Daily REQUIP XL Dose|
N = 13
N = 35
N = 33
N = 34
N = 10
|LS Mean Change from Baseline in UPDRS Part III Motor Score||-3.98||-4.09||-4.97||-5.90||-6.14||-4.85|
|Treatment Difference (REQUIP XL -PLACEBO)||-0.11||-0.99||-1.92||-2.16||-0.87|
|a P value not adjusted for multiple comparisons. A hierarchical step-down approach for statistical testing was used starting with 12-mg dose.|
Last reviewed on RxList: 4/6/2017
This monograph has been modified to include the generic and brand name in many instances.
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