Pharmacology

Pharmacodynamics. Ropinirole is a selective D2-type dopamine agonist with a low affinity for D1-type, 5-HT, benzodiazepine, and GABA receptors. It has a direct and selective stimulant effect on postsynaptic D2 receptors. It likely has a neuroprotective effect in the early as well as late phase of Parkinson disease.

Pharmacokinetics. The important points are as follows:

Alternative formulations. Limited oral bioavailability and frequent dosing limits the use of ropinirole, and efforts are being made to improve formulations and route of delivery. Spray drying of ropinirole hydrochloride using sodium alginate polymer has produced microparticles of suitable characteristics for potential intranasal administration to overcome relativity low oral bioavailability because of its extensive hepatic first-pass metabolism (13). Pharmacokinetic and pharmacodynamic activity of ropinirole loaded solid lipid nanoparticles (RP-SLNs) and nanostructured lipid carriers (RP-NLCs) and containing hydrogel (RP-SLN-C and RP-NLC-C) formulations for improved oral and topical delivery have been evaluated. Results show that lipid nanoparticles and corresponding hydrogel formulations can be considered an alternative delivery approach for the improved oral and topical delivery of ropinirole for neuroprotection and effective treatment of Parkinson disease (03).

Ropinirole hydrochloride nanoemulsion with nigella oil for Parkinson disease in silico study was done to explore interactions of ropinirole and thymoquinone at receptor site TNF-alpha and NFK-beta (21). In vitro release and permeation studies exhibited 2-fold and 3.4-fold enhancement when compared with the drug suspension. Neurobehavioral activity and biochemical parameters corroborated well with the pharmacokinetic results. Thus, nanoemulsion is a promising synergistic approach yielding enticing outcomes for better management of Parkinson disease-related symptoms.

Pharmacogenetics. Profiling of five genes that control dopamine transmission (catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3) can be used to predict impulse control and whether it will improve or worsen with the administration of ropinirole dopamine agonists (17).

Clinical trials

Randomized, double-blind, placebo-controlled trials are shown in Table 1. Long-term trials (3 to 5 years) to determine if postponement of L-dopa therapy with ropinirole administration influences the outcome of Parkinson disease are in progress.

Table 1. Randomized, Double-Blind, Placebo-Controlled Trials of Ropinirole

A systematic review and network metaanalysis of double-blind randomized controlled trials of patients with advanced Parkinson disease with motor fluctuations receiving levodopa shows that adjunctive therapy with slow release ropinirole or pramipexole offers similar efficacy and tolerability based on this indirect comparison (29).

Restless legs syndrome. Several controlled clinical trials have shown the effectiveness of ropinirole in restless legs syndrome on objective measures of motor symptoms and subjective measures of sleep (02).

Pooled data from clinical trials show that ropinirole improves sleep and lessens daytime somnolence in patients with primary restless legs syndrome (10). In a 66-week controlled trial, the incidence of augmentation was approximately 3% higher with ropinirole than with placebo (07).

Results of a randomized, double-blind, placebo-controlled, parallel-group trial on a subset of patients with restless legs syndrome and a baseline International Restless Legs Scale (IRLS) total score equal to or greater than 24 showed that ropinirole was effective as compared with placebo (09).

As of October 2020, 87 clinical trials of ropinirole are listed, including those that have been terminated or are still ongoing or have been completed. These include use of prolonged-release and controlled-release preparations. Some are for the indication of restless legs syndrome. Further information on clinical trials is available at https://clinicaltrials.gov/ct2/results?cond=&term=ropinirole.

Indications

Ropinirole is used for the treatment of signs and symptoms of idiopathic Parkinson disease. Ropinirole is used as a monotherapy in early cases and as an adjunct to L-dopa in advanced cases. Ropinirole is also used for the treatment of restless legs syndrome.

Off-label uses

Contraindications

Patients with known hypersensitivity to ropinirole should not take the drug.

Goals and duration of treatment

The aim is control of the symptoms of Parkinson disease as well as slowing the progression of the disease. As an adjunct to L-dopa in late cases, the aim is to reduce the dose of L-dopa to lessen dyskinesias. Ropinirole seems to be an effective treatment for early Parkinson disease. Although levodopa remains the optimal treatment for Parkinson disease, ropinirole provides similar improvements in functional abilities as it minimizes abnormal involuntary movements. Postmarketing surveillance studies have shown that ropinirole may not only improve motor symptoms, the activity of daily living, and complications of the treatment (dystonia, dyskinesia), but may also alleviate symptoms of depression and anxiety. An open-label multicenter extension study has shown that long-term treatment (up to 73 months) with extended- or prolonged-release ropinirole was not associated with any new or unexpected adverse events in patients with early or advanced Parkinson disease, and the most patients preferred the once-daily dose (18).

Dosing

The dose is increased gradually to achieve maximum therapeutic effect with minimal side effects. The starting dose is 0.25 mg three times a day, and the dose is increased by 0.25 mg weekly to a total daily dose of 3 mg. It is further increased by 1.5 mg per day weekly to a dose of 9 mg per day. Further increase is 3 mg per day weekly to a total dose of 24 mg per day.

Special considerations

Pediatric. Safety and efficacy in the pediatric population has not been demonstrated.

Geriatric. Most of the experience with this drug is in geriatric patients.

Pregnancy. Ropinirole causes adverse effects on embryo-fetal development in experimental animals, including teratogenicity. There are no studies of the use of ropinirole in pregnant women. It should be used during pregnancy only if potential benefits outweigh potential risks.

Anesthesia. Dopaminergic drugs should be stopped 8 to 12 hours prior to anesthesia and surgery and resumed as soon as possible following the procedure.

Interactions

Dopamine antagonists. Because ropinirole is a dopamine agonist, dopamine antagonists such as neuroleptics (phenothiazines, metoclopramide) may diminish its efficacy.

Adverse effects

Nausea and vomiting. A systematic review of clinical trials shows that nausea and vomiting represented approximately 50% of all adverse events reported (15). With increase in use of ropinirole, it should be considered a cause of chronic nausea and vomiting.

Syncope. This is more likely to occur during the dose escalation phase and is usually associated with postural hypotension. Patients normally recover spontaneously without any therapeutic intervention. Syncope has been reported due to ropinirole-induced sinus node dysfunction, and this problem can be resolved by discontinuation of the drug.

Sudden episodes of daytime sleepiness. Sleep attacks have been reported with all dopamine agonists currently used in practice. It can be ameliorated by changing the dosing schedule or discontinuing the agonist.

Dyskinesias. The risk of developing dyskinesias during maintained initial ropinirole monotherapy is low. Early use of ropinirole postpones the onset of dyskinesias, but these benefits decline when levodopa therapy is started.

Pisa syndrome. This is also referred to as "pleurothotonus,” and the characteristic feature is an abnormal lateral flexion of the trunk to the right or left. Reports of ropinirole-induced Pisa syndrome have appeared in the literature, and it occurred after about 1 year on the medication among the cases described (06). The posture usually disappears approximately 3 months after discontinuing the medication, but Pisa syndrome may be irreversible despite discontinuing this medication.

Hallucinations. These are usually dose-related and may occur in 5% to 17% of patients on ropinirole monotherapy. Dosage reduction may be required.

Psychoses. Psychoses have been reported during treatment of Parkinson disease and restless legs syndrome with ropinirole. These may not respond to anti-psychotic therapy and require discontinuation of ropinirole. Ropinirole should be used with caution in patients with affective disorders.

Impulse control disorders. These encompass a wide spectrum of abnormal behavior found in patients with Parkinson disease treated with dopamine agonists. Impulse control disorders are significantly associated with the use of ropinirole as compared with transdermal rotigotine (08). An epidemiologic study has confirmed the association of ropinirole with impulse control disorder and gambling disorder (05).