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ATC Code: N04BC04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Ropinirole is a potent, non-ergoline D2/D3 dopamine agonist.
Parkinson's disease is characterised by a marked dopamine deficiency in the nigral striatal system. Ropinirole alleviates this deficiency by stimulating striatal dopamine receptors.
Although not fully understood, the pathophysiology of Restless Legs Syndrome is thought to be a result of a dopaminergic deficiency, such as a reduction in the synthesis of dopamine and/or D2 receptor density in the striatum. Neuropharmacological evidence suggests primary dopaminergic system involvement and possibly other neurotransmitter systems. Furthermore, evidence from Positron Emission Tomography (PET) studies show that a mild striatal pre-synaptic dopaminergic dysfunction may be involved.
Pharmacodynamic Effects: Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
Clinical Studies: Parkinson's Disease: A double-blind 5-year study in 268 patients compared ropinirole and L-dopa in the treatment of early Parkinson's disease. The incidence of dyskinesias in patients receiving ropinirole (either alone or following subsequent L-dopa supplementation) was markedly lower than for patients receiving L-dopa (with or without additional L-dopa supplementation). Patients randomised to ropinirole were 4 times less likely to develop dyskinesias than those on L-dopa (odds ratio 3.8: 95% CI [2.1, 6.9]; p<0.0001); the incidence of dyskinesia was 20% and 46% for ropinirole and L-dopa patients, respectively. In those patients who completed the study without the need for supplemental L-dopa, ropinirole patients were 15-times less likely to develop dyskinesia than L-dopa patients (odds ratio 15.2: 95% CI [6.2, 36.9]; p<0.0001); the incidence of dyskinesia was 5% and 36% for ropinirole and L-dopa patients, respectively.
In the patients who completed the 5-year study, there was no significant difference in efficacy between those who received either ropinirole or L-dopa. A difference of 1.5 (95%CI [-0.1, 3.2] from baseline to completion in the Activities of Daily Living (ADL) score on the Unified Parkinson's Disease Rating Scale (UPDRS), was observed. Thirty-four percent (34%) of ropinirole patients who completed the 5-year study remained on monotherapy at study endpoint. The mean dose of ropinirole at study endpoint was 16.5 mg for all patients and 15.0 mg for those on monotherapy.
Restless Legs Syndrome: Restless Legs Syndrome is classed as a neurological condition that has a profound impact on sleep and is characterised by distressing sensations deep in the lower limbs and an urge to move the affected limbs in order to relieve symptoms. Approximately 80% of patients with Restless Legs Syndrome experience periodic leg movements of sleep, which are repetitive stereotypic movements that affect one or both legs and may wake the patient several times during the night. As these movements frequently disrupt sleep they contribute significantly to the morbidity of Restless Legs Syndrome.
In the three pivotal, 12-week efficacy studies, Restless Legs Syndrome patients were randomised to ropinirole or placebo, and the effects on the International Restless Legs Syndrome (IRLS) scale and Clinical Global Impression (CGI) scores at Week-12 were compared to baseline. The mean dose of ropinirole at Week 12 was 2.0 mg/day. At week 12, statistically significant differences between ropinirole and placebo were seen in all three studies. In addition, statistically significant differences in IRLS total score and CGI score between ropinirole and placebo were seen as early as 1-week of treatment in all three studies.
Short and long-term efficacy study: Short (12-week) and longer term (26-week) efficacy was evaluated in a randomized, double-blind, placebo-controlled clinical trial; this trial was designed to evaluate efficacy in a moderate-to-severe RLS patient population (baseline IRLS ≥24) as well as explore longer-term safety. Patients were randomised to ropinirole (N=197) or placebo (N=207), and efficacy was evaluated using the IRLS scale total score at weeks 12 and 26. The primary efficacy end point for the ITT population in adjusted mean change from baseline to Week 12 showed a treatment difference (95% CI) of -2.1 (-4.0, -0.1) in favour of ropinirole (p=0.039). Similarly, the secondary efficacy end point for ITT population in adjusted mean change from baseline to Week 26 showed a treatment difference (95% CI) of -2.5 (-4.6, -0.3) in favour of ropinirole (p=0.023). The magnitude of change observed on the IRLS scale is lower than expected, based on three previous 12-week clinical efficacy trials (SK&F-101468190, SK&F-101468194, SK&F-101468249) of ropinirole that evaluated patients with a baseline IRLS score ≥15. There were considerable variations in treatment effects across centre groups in this trial. The treatment differences (95% CI) observed at week 12 ranged from 2.8 (-3.8, 9.3) to -11.0 (-17.4, -4.5); those at week 26 ranged from 0.8 (-7.1, 8.6) to -15.9 (-22.0, -9.9). The proportion of subjects who were withdrawn prematurely from the trial at the conclusion of the double-blind treatment period was 39% in the group receiving ropinirole versus 29% in the placebo group. The adverse events across the trial were consistent with the known safety profile of ropinirole; the rates of confirmed augmentation, confirmed 'clinically meaningful' augmentation and early morning rebound as assessed by an independent Adjudication Board were 4%, 3% and 2%, respectively, during the 66-week duration of study.
A 12-week placebo-controlled polysomnography study in Restless Legs Syndrome patients examined the effect of treatment with ropinirole on periodic leg movements of sleep and periodic leg movements of sleep that lead to arousal from sleep. Statistically significant differences in both the periodic leg movements of sleep (p=<0.001) and the periodic leg movements leading to arousal index (p=0.0096) were seen between ropinirole and placebo from baseline to Week 12.
Long-term maintenance of efficacy was demonstrated in a 36-week study. Patients continued on ropinirole demonstrated a significantly lower relapse rate compared with patients randomised to placebo (33% Vs 58%, p=0.0156).
Ropinirole patients reported significant improvements compared to placebo in sleep disturbance, sleep quantity, sleep adequacy and daytime somnolence.
Pharmacokinetics: The pharmacokinetics of ropinirole are consistent between healthy volunteers, Parkinson's disease patients and patients with Restless Legs Syndrome.
Wide inter-individual variability in the pharmacokinetic parameters has been seen. Bioavailability of ropinirole is approximately 50% (36 to 57%).
Absorption: Oral absorption of ropinirole is rapid with peak concentrations of the drug achieved at a median time of 1.5 hours post dose.
The bioavailability of ropinirole was similar in both the fed and fasted state. However, a high fat meal decreases the rate of absorption of ropinirole, as shown by a delay in median Tmax by 2.6 hours and an average 25% decrease in Cmax.
As expected for a drug being administered approximately every half-life, there is, on average, two-fold higher steady-state plasma concentrations of ropinirole following the recommended t.i.d. regimen compared to those observed following a single oral dose.
Distribution: Plasma protein binding of the drug is low (10 to 40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 7 L/kg).
Metabolism: Ropinirole is primarily cleared by CYP1A2 metabolism and its metabolites are mainly excreted in the urine. The major metabolite is at least 100 times less potent than ropinirole in animal models of dopaminergic function.
Elimination: Ropinirole is cleared from the systemic circulation with an average elimination half-life of about 6 hours.
The increase in systemic exposure (Cmax and AUC) to ropinirole is approximately proportional over the therapeutic dose range. No change in the oral clearance of ropinirole is observed following single and repeated oral administration.
Pharmacokinetic/Pharmacodynamic relationships: In Parkinson's disease patients treated with ropinirole there was a trend for slightly higher average plasma concentrations of ropinirole in responders compared to non-responders.
Special Patient Populations: Elderly: Oral clearance of ropinirole is reduced by approximately 15% in elderly patients (65 years or above) compared to younger patients. Dosing adjustment is not necessary in the elderly.
Renal Impairment: There was no change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with mild to moderate renal impairment.
In patients with end stage renal disease receiving regular dialysis, oral clearance of ropinirole is reduced by approximately 30%. The recommended maximum dose of REQUIP is limited to 18 mg/day in patients with Parkinson's disease (see Renal impairment under Dosage & Administration).
The recommended maximum dose is limited to 3 mg/day in patients with Restless Legs Syndrome (immediate release tablets) (see Renal impairment under Dosage & Administration).
Pregnancy: Physiological changes in pregnancy (including decreased CYP1A2 activity) are predicted to gradually lead to an increased maternal systemic exposure of ropinirole (reaching an approximate 2-fold increase by the third trimester based on physiologically based pharmacokinetic modelling).
Toxicology: Non-Clinical Information: Carcinogenesis, mutagenesis: Two-year studies have been conducted in the mouse and rat at dosages up to 50 mg/kg. The mouse study did not reveal any carcinogenic effect. In the rat, the only drug-related lesions were Leydig cell hyperplasia/adenoma in the testis resulting from the hypoprolactinaemic effect of ropinirole. These lesions are considered to be a species-specific phenomenon and do not constitute a hazard with regard to the clinical use of ropinirole.
Genotoxicity was not observed in a battery of in vitro and in vivo tests.
Reproductive toxicology: In fertility studies in rats, effects were seen on implantation due to the prolactin-lowering effect of ropinirole. In humans, chorionic gonadotropin, not prolactin, is essential for implantation in females. No effects were seen on male fertility.
Parkinson's Disease: Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg, increased foetal death at 90 mg/kg and digit malformations at 150 mg/kg (3.4, 5.1 and 8.5 times the mean human AUC at the Maximum Recommended Human Dose (MRHD)). There was no teratogenic effect in the rat at 120 mg/kg (6.8 times the mean human AUC at the MRHD) and no indication of an effect during organogenesis in the rabbit when given alone at 20 mg/kg (9.5 times the mean human Cmax at the MRHD). However, ropinirole at 10 mg/kg (4.8 times the mean human Cmax at the MRHD) administered to rabbits in combination with oral L-dopa produced a higher incidence and severity of digit malformations than L-dopa alone.
Restless Legs Syndrome: Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg, increased foetal death at 90 mg/kg and digit malformations at 150 mg/kg (33, 49 and 81 times the mean human AUC at the Maximum Recommended Human Dose (MRHD). There was no teratogenic effect in the rat at 120 mg/kg (65 times the mean human AUC at the MRHD and no indication of an effect during organogenesis in the rabbit when given alone at 20 mg/kg (60 times the mean human Cmax at the MRHD). However, ropinirole at 10 mg/kg (30 times the mean human Cmax at the MRHD) administered to rabbits in combination with oral L-dopa produced a higher incidence and severity of digit malformations than L-dopa alone.
Ropinirole-related material was shown to transfer into the milk of lactating rats in small amounts (approximately 0.01% of the dose per pup).
Animal toxicology and/or pharmacology: Ropinirole caused no serious or irreversible toxicity in laboratory animals at 15 mg/kg (monkey), 20 mg/kg (mouse) or 50 mg/kg (rat); 0.9, 0.4 and 2.8 times (for PD) or 8.8, 3.5, and 27 times (for RLS) the mean human AUC at the MRHD. The toxicology profile is principally determined by the pharmacological activity of the drug (behavioural changes, hypoprolactinaemia, and decrease in blood pressure and heart rate, ptosis and salivation).
