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Mechanism of Action
REQUIP (ropinirole hcl) 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 REQUIP (ropinirole hcl) 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.
Restless Legs Syndrome (RLS)
The precise mechanism of action of REQUIP (ropinirole hcl) as a treatment for Restless Legs Syndrome (also known as Ekbom Syndrome) is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.
Clinical Pharmacology Studies
In healthy normotensive subjects, single oral doses of REQUIP (ropinirole hcl) in the range 0.01 to 2.5 mg had little or no effect on supine blood pressure and pulse rates. Upon standing, REQUIP (ropinirole hcl) caused decreases in systolic and diastolic blood pressure at doses above 0.25 mg. In some subjects, these changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case, transient sinus arrest with syncope. With repeat dosing and slow titration up to 4 mg once daily in healthy volunteers, postural hypotension or hypotension-related adverse events were noted in 13% of subjects on REQUIP (ropinirole hcl) and none of the subjects on placebo.
The mechanism of postural hypotension induced by REQUIP (ropinirole hcl) 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, REQUIP (ropinirole hcl) suppressed serum prolactin concentrations in healthy male volunteers.
REQUIP (ropinirole hcl) 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.
REQUIP (ropinirole hcl) 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 REQUIP (ropinirole hcl) on QT intervals at higher exposures achieved either due to drug interactions or at doses used in Parkinson's disease has not been systematically evaluated.
Absorption, Distribution, Metabolism, and Elimination
The pharmacokinetics of ropinirole are similar in Parkinson's disease patients and patients with Restless Legs Syndrome. Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1-2 hours. In clinical studies, over 88% of a radiolabeled dose was recovered in urine and the absolute bioavailability was 55%, indicating a first-pass effect. Relative bioavailability from a tablet compared to an oral solution is 85%. Food does not affect the extent of absorption of ropinirole, although its T maxis increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal. The clearance of ropinirole after oral administration to patients is 47 L/hr (cv = 45%) and its elimination half-life is approximately 6 hours. Ropinirole is extensively metabolized by the liver to inactive metabolites and displays linear kinetics over the therapeutic dosing range of 1 to 8 mg 3 times daily. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing.
Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg (cv = 32%). It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.
The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl and hydroxy metabolites. In vitro studies indicate that the major cytochrome P450 isozyme involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be stimulated by smoking and omeprazole, and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated. 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%).
In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. Inhibitors or inducers of this enzyme have been shown to alter its clearance when coadministered with ropinirole. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with REQUIP (ropinirole hcl) , adjustment of the dose of REQUIP (ropinirole hcl) may be required.
Because therapy with REQUIP (ropinirole hcl) 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 15% in patients above 65 years of age compared to younger patients. Dosage adjustment is not necessary in the elderly (above 65 years), as the dose of ropinirole is to be 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.
Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. In a study in patients with RLS, smokers (n = 7) had an approximate 30% lower Cmax and a 38% lower AUC than did nonsmokers (n = 11), when those parameters were normalized for dose.
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 to an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in moderately renally impaired patients. The use of REQUIP (ropinirole hcl) in patients with severe renal impairment has not been studied.
The effect of hemodialysis on drug removal is not known, but because of the relatively high apparent volume of distribution of ropinirole (525 L), the removal of the drug by hemodialysis is unlikely.
The pharmacokinetics of ropinirole have not been studied in hepatically impaired patients. These patients may have higher plasma levels and lower clearance of the drug than patients with normal hepatic function. The drug 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 to patients with Parkinson's disease only.
The effectiveness of REQUIP (ropinirole hcl) in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials. Four were conducted in patients with early Parkinson's disease and no concomitant levodopa (L-dopa), and 7 were conducted in patients with advanced Parkinson's disease with concomitant L-dopa.
Among these 11 studies, 3 placebo-controlled studies provide the most persuasive evidence of ropinirole's effectiveness in the management of patients with Parkinson's disease who were and were not receiving concomitant L-dopa. Two of these 3 trials enrolled patients with early Parkinson's disease (without L-dopa) and 1 enrolled patients receiving L-dopa.
In these studies a variety of measures were used to assess the effects of treatment (e.g., the Unified Parkinson's Disease Rating Scale [UPDRS], Clinical Global Impression [CGI] scores, patient diaries recording time “on” and “off,” and tolerability of L-dopa dose reductions).
In both studies of early Parkinson's disease (without L-dopa) patients, the motor component (Part III) of the UPDRS was the primary outcome assessment. The UPDRS is a 4-part 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, etc.) scored for different body regions and has a maximum (worst) score of 108. Responders were defined as patients with at least a 30% reduction in the Part III score.
In the study of advanced Parkinson's disease (with L-dopa) patients, both reduction in percent awake time spent “off” and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually.
Studies in Patients With Early Parkinson's Disease (Without L-dopa)
One early therapy study was a 12-week multicenter study in which 63 patients (41 on REQUIP (ropinirole hcl) ) with idiopathic Parkinson's disease receiving concomitant anti-Parkinson medication (but not L-dopa) were randomized to either REQUIP (ropinirole hcl) or placebo. Patients had a mean disease duration of approximately 2 years. Patients were eligible for enrollment if they presented with bradykinesia and at least tremor, rigidity, or postural instability. In addition, they must have been classified as Hoehn & Yahr Stage I-IV. This scale, ranging from I = unilateral involvement with minimal impairment to V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson's disease. The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared to baseline) of at least 30% in the UPDRS motor score.
Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of 0.5 mg twice daily to a maximum of 5 mg twice daily. Once patients reached their maximally tolerated dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks. The mean dose achieved by patients at study endpoint was 7.4 mg/day. At the end of 12 weeks, 71% of patients treated with REQUIP (ropinirole hcl) were responders, compared with 41% of patients in the placebo group (p = 0.021).
Statistically significant differences between the percentage of responders on REQUIP (ropinirole hcl) compared to placebo were seen after 8 weeks of treatment.
In addition, the mean percentage improvement from baseline in the Total Motor Score was 43% in patients treated with REQUIP (ropinirole hcl) compared with 21% in patients treated with placebo (p = 0.018).
Statistically significant differences in UPDRS motor score between REQUIP (ropinirole hcl) and placebo were seen after 2 weeks of treatment.
The median daily dose at which a 30% reduction in UPDRS motor score was sustained was 4 mg.
The second trial in early Parkinson's disease (without L-dopa) patients was a double-blind, randomized, placebo-controlled, 6-month study. Patients were essentially similar to those in the study described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the study. Patients had a mean disease duration of 2 years and limited (not more than a 6-week period) or no prior exposure to L-dopa. The starting dose of REQUIP (ropinirole hcl) in this trial was 0.25 mg 3 times daily. The dose was titrated at weekly intervals by increments of 0.25 mg 3 times daily to a dose of 1 mg 3 times daily. Further titrations at weekly intervals were at increments of 0.5 mg 3 times daily up to a dose of 3 mg 3 times daily, and then weekly at increments of 1 mg 3 times daily. Patients were to be titrated to a dose of at least 1.5 mg 3 times daily and then to their maximally tolerated dose, up to a maximum of 8 mg 3 times daily. The mean dose attained in patients at study endpoint was 15.7 mg/day.
The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS Motor Score. In this study 241 patients were enrolled. At the end of the 6-month study, patients treated with REQUIP (ropinirole hcl) haD22% improvement in motor score, compared with a 4% worsening in the placebo group (p < 0.001).
Statistically significant differences in UPDRS motor score improvement between REQUIP (ropinirole hcl) and placebo were seen after 12 weeks of treatment.
Study in Patients With Advanced Parkinson's Disease (With L-dopa)
This double-blind, randomized, placebo-controlled, 6-month trial evaluated 148 patients (Hoehn & Yahr II-IV) who were not adequately controlled on L-dopa. Patients in this study had a mean disease duration of approximately 9 years, had been exposed to L-dopa for approximately 7 years, and had experienced “on-off” periods with L-dopa therapy. Patients previously receiving stable doses of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the study. Patients were started at a dose of 0.25 mg 3 times daily of REQUIP (ropinirole hcl) and titrated upward by weekly intervals until an optimal therapeutic response was achieved. The maximum dose of study medication was 8 mg 3 times daily. All patients had to be titrated to at least a dose of 2.5 mg 3 times daily. Patients could then be maintained on this dose level or higher for the remainder of the study. Once a dose of 2.5 mg 3 times daily was achieved, patients underwent a mandatory reduction in their L-dopa dose, to be followed by additional mandatory reductions with continued escalation of the dose of REQUIP (ropinirole hcl) . Reductions in the dosage of L-dopa were also allowed if patients experienced adverse events that the investigator considered related to dopaminergic therapy. The mean dose attained at study endpoint was 16.3 mg/day. The primary outcome was the proportion of responders, defined as patients who were able both to achieve a decrease (compared to baseline) of at least 20% in their L-dopa dose and a decrease of at least 20% in the proportion of the time awake in the “off” condition (a period of time during the day when patients are particularly immobile), as determined by patient diary. In addition, the mean percent change from baseline in daily L-dopa dose was examined.
At the end of 6 months, 28% of patients treated with REQUIP (ropinirole hcl) were classified as responders (based on combined endpoint) while 11% of patients treated with placebo were responders (p = 0.02). Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of REQUIP (ropinirole hcl) , patients treated with REQUIP (ropinirole hcl) had a 19.4% mean reduction in L-dopa dose while patients treated with placebo had a 3% reduction (p < 0.001). L-dopa dosage reduction was also allowed during the study if dyskinesias or other dopaminergic effects occurred. Overall, reduction of L-dopa dose was sustained in 87% of patients treated with REQUIP (ropinirole hcl) and in 57% of patients on placebo. On average, the L-dopa dose was reduced by 31% in patients treated with REQUIP (ropinirole hcl) .
The mean number of “off” hours per day during baseline was 6.4 hours for patients treated with REQUIP (ropinirole hcl) and 7.3 hours for patients treated with placebo. At the end of the 6-month study, patients treated with REQUIP (ropinirole hcl) had a mean of 4.9 hours per day of “off” time, while placebo-treated patients had a mean of 6.4 hours per day of “off” time.
Restless Legs Syndrome (RLS)
The effectiveness of REQUIP (ropinirole hcl) in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled studies in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria (see INDICATIONS AND USAGE). Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥ 15 on the International RLS Rating Scale (IRLS scale) at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, and anemia) were excluded. All studies employed flexible dosing, with patients initiating therapy at 0.25 mg REQUIP (ropinirole hcl) once daily. Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily. All doses were taken between 1 anD3 hours before bedtime.
A variety of measures were used to assess the effects of treatment, including the IRLS Scale and Clinical Global Impression-Global Improvement (CGI-I) scores. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms anD40 the most severe symptoms. Three of the controlled studies utilized the change from baseline in the IRLS Scale at the week 12 endpoint as the primary efficacy outcome.
Three hundred eighty patients were randomized to receive REQUIP (ropinirole hcl) (n = 187) or placebo (n = 193) in a US study; 284 were randomized to receive either REQUIP (ropinirole hcl) (n = 146) or placebo (n = 138) in a multinational study (excluding US); anD267 patients were randomized to REQUIP (ropinirole hcl) (n = 131) or placebo (n = 136) in a multinational study (including US). Across the 3 studies, the mean duration of RLS was 16 to 22 years (range of 0 to 65 years), mean age was approximately 54 years (range of 18 to 79 years), and approximately 61% were women. The mean dose at week 12 was approximately 2 mg/day for the 3 studies.
In all 3 studies, a statistically significant difference between the treatment group receiving REQUIP (ropinirole hcl) and the treatment group receiving placebo was observed at week 12 for both the mean change from baseline in the IRLS Scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I (see Table 1).
Table 1: Mean Change in IRLS Score and Percent Responders
|Mean Change in IRLS score at Week 12|
|US study||-13.5||-9.8||p < 0.0001|
|Multinational study (excluding US)||-11.0||-8.0||p=0.0036|
|Multinational study (including US)||-11.2||-8.7||p=0.0197|
|Percent responders on CGI-I at Week 12|
|Multinational study (excluding US)||53.4%||40.9%||p=0.0416|
|Multinational study (including US)||59.5%||39.6%||p=0.0010|
Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week study. Following a 24-week single-blind treatment phase (flexible doses of REQUIP (ropinirole hcl) of 0.25 to 4 mg once daily), patients who were responders (defined as a decrease of > 6 points on the IRLS Scale total score relative to baseline) were randomized in double-blind fashion to placebo or continuation of REQUIP (ropinirole hcl) for an additional 12 weeks. Relapse was defined as an increase of at least 6 points on the IRLS Scale total score to a total score of at least 15, or withdrawal due to lack of efficacy. For patients who were responders at week 24, the mean dose of ropinirole was 2 mg (range 0.25 to 4 mg). Patients continued on REQUIP (ropinirole hcl) demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% vs 57.8%, p = 0.0156).
Last reviewed on RxList: 11/30/2010
This monograph has been modified to include the generic and brand name in many instances.
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