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Mechanism Of Action
Ropinirole is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.
Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D1, 5-HT1, 5-HT2, benzodiazepine, GABA, muscarinic, alpha1-, alpha2-, and beta-adrenoreceptors.
The precise mechanism of action of ropinirole as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D2-type receptors within the caudate-putamen in the brain. This conclusion is supported by studies that show that ropinirole improves motor function in various animal models of Parkinson's disease. In particular, ropinirole attenuates the motor deficits induced by lesioning the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates. The relevance of D3 receptor binding in Parkinson's disease is unknown.
Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure with resulting postural 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.
The mechanism of postural 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.
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 QT intervals at higher exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been systematically evaluated.
In clinical studies with immediate-release ropinirole, over 88% of a radiolabeled dose was recovered in urine, and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.
Ropinirole displayed linear kinetics up to doses of 24 mg/day (8 mg immediate-release, 3 times a day). Increase in systemic exposure of ropinirole following oral administration of 2 to 12 mg of REQUIP XL (ropinirole extended release tablets) was approximately dose-proportional. For REQUIP XL, steady-state concentrations of ropinirole are expected to be achieved within 4 days of dosing.
Relative bioavailability of REQUIP XL (ropinirole extended release tablets) Extended-Release Tablets compared with immediate-release tablets was approximately 100%. In a repeat-dose study in patients with Parkinson's disease using REQUIP XL (ropinirole extended release tablets) 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 (ropinirole extended release tablets) than for the immediate-release formulation and the median time-to-peak concentration was 6 to 10 hours. In a single-dose study, administration of REQUIP XL (ropinirole extended release tablets) 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 study 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 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 isozyme 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 to patients is 47 L/hr (cv = 45%) 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%).
Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with immediate-release ropinirole (2 mg 3 times daily) increased ropinirole AUC by 84% on average and Cmax by 60% (n = 12 patients).
Coadministration of immediate-release ropinirole (2 mg 3 times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.
Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of immediate-release ropinirole (2 mg 3 times daily) in 12 patients with Parkinson's disease. Immediate-release ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson's disease.
Coadministration of carbidopa + L-dopa (SINEMET 10/100 mg twice daily) with immediate-release ropinirole (2 mg 3 times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of immediate-release ropinirole 2 mg 3 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 oral clearance of ropinirole.
Because therapy with REQUIP XL (ropinirole extended release tablets) 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.
Oral clearance of ropinirole is reduced by approximately 15% in patients above 65 years of age compared with younger patients. Dosage adjustment is not necessary in the elderly (above 65 years), as the dose of ropinirole is individually titrated to clinical response.
Female and male patients showed similar oral clearance.
The influence of race on the pharmacokinetics of ropinirole has not been evaluated.
Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in patients 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. The use of ropinirole in patients with severe renal impairment has not been studied.
The effect of hemodialysis on ropinirole clearance is not known, but because of the relatively high apparent volume of distribution of ropinirole (7.5 L/kg), significant removal of ropinirole by hemodialysis is unlikely.
The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. These patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function. REQUIP XL (ropinirole extended release tablets) should be titrated with caution in this population.
Population pharmacokinetic analysis revealed no change in the oral clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients who had Parkinson's disease only.
The effectiveness of the immediate-release formulation of ropinirole (REQUIP Tablets) in the treatment of early and advanced Parkinson's disease was initially established in 3 randomized, double-blind, placebo-controlled trials.
The effectiveness of REQUIP XL (ropinirole extended release tablets) in the treatment of Parkinson's disease was supported by 2 randomized, double-blind, multicenter clinical trials and clinical pharmacokinetic considerations. One trial conducted in advanced Parkinson's disease patients compared REQUIP XL (ropinirole extended release tablets) with placebo as adjunctive therapy to L-dopa. A second trial compared REQUIP XL (ropinirole extended release tablets) with REQUIP Tablets in early phase Parkinson's disease patients not receiving L-dopa.
In these studies a variety of measures were used to assess the effects of treatment (e.g., patient diaries recording time “on” and “off,” tolerability of L-dopa dose reductions, and the Unified Parkinson's Disease Rating Scale [UPDRS] scores). The UPDRS is a multi-item rating scale evaluating 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, etc.) scored for different body regions and has a maximum (worst) score of 108.
Study in Patients With Advanced Parkinson's Disease (With L-dopa)
The effectiveness of REQUIP XL (ropinirole extended release tablets) as adjunctive therapy to L-dopa in patients with Parkinson's disease was established in a randomized, double-blind, placebo-controlled, parallel group, 24-week 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 study had a mean disease duration of 8.6 years, 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 with similar mean data in each treatment group. The mean baseline dose of L-dopa in the group receiving REQUIP XL (ropinirole extended release tablets) was 824 mg/day 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 REQUIP XL total daily dose 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 maximal allowed daily dosage for REQUIP XL (ropinirole extended release tablets) 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 (ropinirole extended release tablets) and by approximately half an 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 (ANCOVA, p < 0.0001). Results for this endpoint showing the statistical superiority of REQUIP XL (ropinirole extended release tablets) over Placebo are presented in Table 3.
Table 3. Change from Baseline in Total Awake Time Spent "Off"
at Week 24
| REQUIP XL
(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|
The difference between groups in favor of REQUIP XL (ropinirole extended release tablets) , 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 (ropinirole extended release tablets) 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 (ropinirole extended release tablets) and in 72% of patients treated with placebo (p < 0.001).
Study in Patients With Early Parkinson's Disease (Without L-dopa)
A 36-week multicenter, double-blind, titration/3-period maintenance, cross-over study compared the efficacy of REQUIP XL (ropinirole extended release tablets) with the immediate-release formulation of REQUIP (IR) 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 subjects were randomized (1:1:1:1) to 4 treatment sequences (2 were titrated on REQUIP IR and 2 on REQUIP XL (ropinirole extended release tablets) ). The REQUIP IR titration was slower in rate than that of the REQUIP XL (ropinirole extended release tablets) . 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 4 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 REQUIP IR and of about -10 for the groups started on REQUIP XL (ropinirole extended release tablets) . No difference was observed between groups when switches were made between identical formulations or between different formulations. This suggests therapeutic dosage equivalence between REQUIP IR and REQUIP XL (ropinirole extended release tablets) formulations.
The optimal daily dose at the end of the titration period for patients on REQUIP IR was substantially lower (mean 7 mg) compared to the dose at the end of the titration period for patients on REQUIP XL (ropinirole extended release tablets) (mean 18 mg). In this study, the marked difference in the final optimal dosages suggests that the higher doses afforded no additional benefit when compared to the lower doses [see DOSAGE AND ADMINISTRATION].
Last reviewed on RxList: 4/30/2009
This monograph has been modified to include the generic and brand name in many instances.
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