Drugs

, Volume 60, Issue 1, pp 115–137 | Cite as

Ropinirole

A Review of its Use in the Management of Parkinson’s Disease
Adis Drug Evaluation

Summary

Abstract

Ropinirole, a non-ergoline dopamine agonist, has selective affinity for dopamine D2-like receptors and little or no affinity for non-dopaminergic brain receptors. Ropinirole is indicated as adjunct therapy to levodopa in patients with advanced Parkinson’s disease. It is also indicated, and recent clinical trials have focused on its use, as monotherapy in patients with early Parkinson’s disease.

In the symptomatic treatment of early Parkinson’s disease ropinirole monotherapy was significantly more effective than placebo in 2 multicentre, randomised, double-blind trials of 3 to 12 months duration as assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and Clinical Global Impression/Clinical Global Evaluation Scales. In a similarly designed 3-year comparative study with bromocriptine, ropinirole recipients showed a significant improvement in UPDRS-activities of daily living (ADL) scores; however, motor scores were similar between the 2 groups. Ropinirole and levodopa treatments were similar in efficacy as measured by UPDRS ADL scores, although ropinirole recipients showed significantly less improvement on UPDRS motor scores at the 5-year study end-point in a multicentre, randomised double-blind trial.

As an adjunct therapy to levodopa in patients with more advanced Parkinson’s disease, ropinirole was reported to be as effective as bromocriptine and significantly more effective than placebo. In general in the comparisons with placebo ropinirole allowed a ≥20% reduction in the concomitant dose of levodopa without compromising efficacy in a significant proportion of patients and, in some trials decreased the amount of awake time spent in the ‘off’ state (‘off’ state is defined as a gradual return to parkinsonism despite adequate medication).

Ropinirole was well tolerated either as monotherapy or as an adjunct to levodopa treatment. Nausea, dizziness and somnolence were the most commonly reported adverse events and were reported at a higher incidence by patients receiving ropinirole than by those receiving placebo. In patients with early Parkinson’s disease, ropinirole generally showed a similar overall tolerability profile to bromocriptine although, over a 3-year period nausea was more commonly reported with ropinirole recipients. In a 5-year study, the incidence of dyskinesia was significantly lower with ropinirole than with levodopa regardless of levodopa supplementation. Prior to the addition of supplementary levodopa 5% of ropinirole recipients had experienced dyskinesia compared with 36% of those receiving levodopa.

Conclusions: In patients with early Parkinson’s disease, ropinirole monotherapy was more efficacious than bromocriptine with regard to improvement in activities of daily living, and need for supplemental levodopa. Ropinirole recipients had a higher requirement for levodopa supplementation than levodopa recipients in a 5-year study, but the incidence of dyskinesia was significantly lower with ropinirole than with levodopa (markedly so in the one third of ropinirole recipients who were able to remain on monotherapy with no levodopa supplementation). Thus available data suggest that ropinirole may provide a means of treating early Parkinson’s disease while minimising the risk of dyskinesia and delaying the need for supplemental levodopa in some patients. In addition, ropinirole is also efficacious in the management of more advanced Parkinson’s disease in patients who are experiencing motor complications after long term levodopa use.

Pharmacodynamic Profile

Ropinirole is a non-ergoline dopamine agonist with selective affinity for dopamine D2-like receptors and negligible affinity for non-dopaminergic brain receptors [including β-adrenoceptors and adrenergic (α1-, α2-), serotoninergic (5-HT1), γ-aminobutyric acid and benzodiazepine receptors].

Ropinirole effectively produced a reversal of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian deficits in marmosets and caused less dyskinesia than levodopa. In addition, it caused biphasic changes in spontaneous locomotor activity in mice; in rats it significantly inhibited dyskinesia induced by the administration of the mixed dopamine agonist tetralin. Ropinirole reduced parkinsonian akinesia and disability in MPTP-treated marmosets given levodopa/carbidopa 8 to 10 months previously. However, dyskinesia similar to that produced by the earlier administration of levodopa was induced suggesting a priming effect of levodopa.

In healthy male volunteers, ropinirole (0.4, 0.8 and 1mg) produced changes compatible with peripheral D2 dopaminergic effects: it reduced venous plasma noradrenaline responses to the 5-minute isometric handgrip and 3-minute immobile standing tests, and the dopamine response to the 3-minute cold pressor test. However, in 1 study a low dose regimen of ropinirole (6 mg/day, ≥1 week) had no significant effect on blood pressure or heart rate in patients with Parkinson’s disease.

Ropinirole has demonstrated neuroprotective effects in vitro and a tendency to preserve dopaminergic function in vivo. In a preliminary 5-year positron emission tomography study, patients with Parkinson’s disease were given either ropinirole or levodopa therapy. However, after 5 years there were no significant differences in the intention-to-treat groups between patients receiving either ropinirole or levodopa therapy. Those patients who remained on ropinirole monotherapy (dosage not given) until study completion had a significantly smaller mean percentage reduction in putamen Ki∘ than those ropinirole recipients who required supplemental levodopa (dosage not given). Ropinirole has also shown free radical scavenging and antioxidant activity in ex vivo studies.

Pharmacokinetic Profile

Ropinirole displays approximately linear pharmacokinetics after single and multiple doses in patients with Parkinson’s disease. It is rapidly absorbed after oral administration and reached maximum peak plasma concentrations (Cmax) of 5.27 to 26.9 μg/L after 3 daily doses of 1 to 6mg. Ropinirole is widely distributed throughout the body with a volume of distribution of approximately 7.5 L/kg and up to approximately 40% is plasma-protein bound with a blood to plasma ratio of 1: 1.

In patients with Parkinson’s disease, ropinirole has a terminal elimination half-life of approximately 6 hours. It is extensively metabolised by the liver predominantly via the cytochrome P450 1A2 isoenzyme to form 2 inactive metabolites, and less than 5 to 10% is excreted unchanged in the urine. The total clearance of ropinirole after oral administration is approximately 47 L/h. In patients ≥65 years of age oral clearance is reduced by 15 to 30%; however, because ropinirole is individually titrated to clinical response, dosage adjustment is unnecessary. Ropinirole can be coadministered with levodopa and theophylline without any clinically significant effects on the pharmacokinetics of either drug. In addition, in patients with Parkinson’s disease plus a cardiac condition, digoxin can be coadministered without any clinically significant effect on its pharmacokinetics. Estrogen replacement therapy in women decreased the oral clearance of ropinirole by approximately 33% in comparison with values in other women with Parkinson’s disease who were not taking the hormone supplement.

Therapeutic Efficacy

Ropinirole has been compared with placebo, levodopa and bromocriptine as monotherapy in patients with early Parkinson’s disease in multicentre, randomised, double-blind and parallel-group trials. In similarly designed trials ropinirole has also been compared with bromocriptine and placebo (including 1 nonblind trial) as an adjunctive therapy to levodopa in patients with advanced Parkinson’s disease.

Ropinirole monotherapy was more effective than bromocriptine and as effective as levodopa with regard to Unified Parkinson’s Disease Rating Scale (UPDRS) activities of daily living (ADL) scores in 2 long term clinical trials. In a 3-year trial there was a tendency for fewer ropinirole recipients (mean dosage 12 mg/day) to require supplemental levodopa treatment, and ADL scores were significantly improved and UPDRS motor scores were slightly improved when compared with those in bromocriptine recipients (mean dosage 24 mg/day). In another trial, in patients who completed the 5-year study motor scores were significantly improved with levodopa (mean dosage including supplemental levodopa 753 mg/day) compared with those for ropinirole (mean dosage 16.5 mg/day). However, this was not considered clinically significant, at least partially because this difference was not reflected in the ADL scores, which were slightly although not significantly worse with ropinirole therapy.

As was expected, when compared with placebo, ropinirole (maximum dosage ranged from 10 to 24 mg/day) showed a significant improvement in motor scores and a significantly higher proportion were classified as responders (≥30% reduction from baseline UPDRS motor score). In addition, in 2 randomised double-blind studies fewer ropinirole recipients required supplemental levodopa.

As adjunct therapy to levodopa ropinirole was reported to be as effective as bromocriptine with a tendency for a greater proportion of ropinirole recipients to be classed as responders (classification included a reduction in levodopa dose, other criteria not reported) in a large 6-month trial. In comparison with placebo recipients, a significantly greater proportion of patients receiving ropinirole showed a ≥20% reduction in levodopa dose with either a decrease in awake time spent in the ‘off’ state or an improvement in clinical global impression scores.

Tolerability

Commonly reported adverse events associated with ropinirole monotherapy were nausea, dizziness and somnolence which occurred in at least 10% of patients (≥5% in 1 study). Less commonly reported adverse events included vomiting, headache, insomnia and hallucinations. In a 6-month comparative trial a higher incidence of these events occurred in ropinirole versus placebo recipients. However, this incidence declined over a 6-month extension of this trial and arthralgia replaced nausea as one of the most commonly reported adverse events.

Ropinirole showed a similar tolerability profile to both bromocriptine and levodopa with few exceptions. In patients receiving ropinirole monotherapy, nausea was more common than in bromocriptine recipients and hallucinations were more common than in levodopa recipients. The incidence of dyskinesia was relatively low and did not differ between ropinirole and bromocriptine recipients. In contrast, significantly fewer ropinirole than levodopa recipients experienced dyskinesia in a 5-year trial, an effect that was particularly striking prior to the addition of supplemental levodopa (5% ropinirole vs 36% levodopa).

Nausea, dyskinesia, dizziness and somnolence were also the most commonly reported adverse events in patients receiving ropinirole as adjunct therapy to levodopa. In a comparative trial with placebo, ropinirole was associated with a significantly higher incidence of dizziness, dyskinesia, nausea, somnolence and headache, but in another trial only the incidence of dyskinesia was significantly higher. The increased incidence of dyskinesia was usually associated with the ropinirole titration phase of the trial, during which a decrease in levodopa dose was not permitted.

Pooled data from studies indicate that ropinirole and bromocriptine have a similar tolerability profile when administered as adjunct therapy to levodopa. However, nausea is more commonly experienced with ropinirole therapy, albeit with approximately half the incidence seen in patients with early Parkinson’s disease.

Dosage and Administration

Ropinirole therapy has been approved for the treatment of idiopathic Parkinson’s disease, either as monotherapy in patients with early disease or as an adjunct to levodopa in patients with more advanced disease.

Ropinirole is initiated at a low dose (0.25mg 3 times daily) and titrated over 4 weeks to a dose of 1mg 3 times daily. If sufficient symptomatic control is not achieved or maintained the dose of ropinirole should be increased (to a maximum therapeutic dose of 24 mg/day) until an acceptable therapeutic response is established. The mean effective ropinirole dose in patients with early Parkinson’s disease who were supplemented with levodopa was 16.5 mg/day at the completion of a 5 year double-blind study. Doses above 24 mg/day have not been investigated in clinical trials. When administered as an adjunct to levodopa, the concurrent levodopa dose may be reduced according to tolerability.

Ropinirole is contraindicated for patients known to have hypersensitivity to the product. Patients should be cautioned that they may develop postural hypotension with or without dizziness, nausea, syncope and sweating (usually associated with initiation of treatment or changes in dosage).

Elderly patients may be at higher risk of experiencing hallucinations than younger patients; this leads to withdrawal in a small percentage of patients. No dosage adjustment is necessary in patients with mild to moderate renal impairment; as yet there have been no studies in patients with severe renal impairment and ropinirole should be administered with caution. Patients should be warned of the potential sedative effects of ropinirole, including somnolence, and if affected should be advised against driving or operating complex machinery. In addition, caution should be used when patients are taking alcohol or other CNS depressants in combination with ropinirole.

Ropinirole is well tolerated in combination with commonly administered drugs such as selegiline, amantidine, tricyclic antidepressants, benzodiazepines, ibuprofen, diuretics, antihistamines and anticholinergics. Dosage adjustment of ropinirole may be required with coadministration of hormone replacement therapy, drugs known to be potent inhibitors of the cytochrome P450 1A2 isoenzyme and levodopa.

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© Adis International Limited 2000

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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