Ropinirole hydrochloride is used for the symptomatic management of idiopathic parkinsonian syndrome.
Dopamine receptor agonists (bromocriptine mesylate, pramipexole dihydrochloride, pergolide mesylate, ropinirole hydrochloride) are used as adjuncts to levodopa for the symptomatic management of parkinsonian syndrome in patients with advanced disease. Dopamine receptor agonists also are used as monotherapy for the initial symptomatic management of parkinsonian syndrome. Levodopa currently is the most effective drug for relieving the symptoms of parkinsonian syndrome and traditionally has been considered the drug of choice for the initial symptomatic management of idiopathic parkinsonian syndrome. However, long-term administration of levodopa is associated with motor complications. One strategy to reduce the risk of motor complications and to improve long-term outcome is to initiate symptomatic therapy with a dopamine receptor agonist and to add levodopa as supplemental therapy when dopamine receptor agonist monotherapy no longer provides adequate symptom control. However, clinical studies evaluating this strategy are limited both in number and duration, and it remains to be determined whether initiating therapy with a dopamine receptor agonist rather than levodopa results in a more favorable long-term outcome. Factors to consider when choosing an agent for the initial symptomatic management of idiopathic parkinsonian syndrome include patient age, cognitive status, disease severity, and cost. Most clinicians would use levodopa for initial therapy in individuals older than 70 years of age (since these individuals are less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction), in patients with cognitive impairment, and in those with severe disease. A dopamine receptor agonist may be preferred for initial therapy in patients 70 years of age or younger.
Efficacy of ropinirole for the management of parkinsonian syndrome has been established in several placebo-controlled studies of up to 6 months' duration in patients with early (approximately 2 years' duration) parkinsonian syndrome receiving no concomitant levodopa therapy, and in patients with advanced parkinsonian syndrome who were receiving levodopa therapy concomitantly. In these studies, improvement in manifestations of parkinsonian syndrome was assessed principally using the Unified Parkinson's Disease Rating Scale (UPDRS), a 4-part rating scale intended to evaluate mentation, activities of daily living, motor performance, and complications of therapy.
Ropinirole appears to improve activities of daily living as well as motor manifestations of parkinsonian syndrome, such as tremor, rigidity, bradykinesia, and postural stability. In clinical studies in patients with early parkinsonian syndrome, ropinirole was more effective than placebo in reducing the severity of symptoms associated with this disorder. In a study in patients with early parkinsonian syndrome, clinical response (defined as improvement of at least 30% in UPDRS motor score) occurred in 71% of patients receiving ropinirole (mean daily dosage: 7.4 mg) compared with 41% of patients receiving placebo for 12 weeks. In addition, improvement from baseline in the UPDRS motor score averaged 43% in ropinirole-treated patients versus 21% with placebo. In this study, concomitant therapy with amantadine, selegiline, or anticholinergic drugs, but not levodopa or other dopamine receptor agonists, was allowed. In another placebo-controlled study in patients with early parkinsonian syndrome, 47% of patients receiving ropinirole (mean daily dosage: 15.7 mg on an intent-to-treat basis) responded to therapy (defined as improvement of at least 30% in UPDRS motor score) compared with 20% of those receiving placebo; average UPDRS motor score improved by 22-24% with ropinirole therapy and worsened by 3-4% in the placebo group. In this study, addition of levodopa therapy for symptomatic relief was required in 29% of patients treated with placebo versus 11% of those receiving ropinirole.
In placebo-controlled clinical studies in patients with advanced parkinsonian syndrome who were receiving concomitant levodopa therapy, ropinirole reduced the severity of symptoms associated with this disorder and allowed a reduction in levodopa dosage. In patients with advanced parkinsonian syndrome who were experiencing ''on-off'' phenomena (i.e., a deteriorating response to levodopa therapy), ropinirole was more effective than placebo in reducing ''off'' time. In a study in patients with advanced (mean disease duration: 9 years) parkinsonian syndrome, average daily ''off'' time was reduced from a baseline value of 6.4 hours to 4.9 hours following 6 months of therapy with ropinirole, while ''off'' time with placebo averaged 7.3 hours at baseline and 6.4 hours after 6 months. In another study in patients with advanced parkinsonian syndrome not optimally controlled with levodopa therapy, ''off'' time was reduced by at least 30% in 65 versus 39% of patients (on an intent-to-treat basis) treated with ropinirole versus placebo, respectively, for 12 weeks.
A preliminary report of a long-term (approximately 3 years' duration), comparative study in patients with early parkinsonian syndrome receiving ropinirole or bromocriptine (with supplemental levodopa therapy in some patients) indicated clinically important improvements in UPDRS motor score and activities of daily living (ADL) score with either therapy, although functional status (as measured by the ADL score) was more improved in ropinirole-treated patients at the end of the study. Further study is required to establish safety and efficacy of ropinirole during long-term administration and to determine the long-term effect of the drug on disability in parkinsonian syndrome.
Patients receiving a dopamine receptor agonist (e.g., pramipexole, ropinirole) have reported falling asleep while engaged in activities of daily living, including business meetings, telephone calls, and operating a motor vehicle, which occasionally resulted in accidents. Although many of these patients reported somnolence while receiving pramipexole or ropinirole, some perceived no warning signs (e.g., excessive drowsiness) and believed that they were alert immediately prior to the event. Some of these events have been reported as late as 1 year after initiation of therapy with the drug.
Many experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. Therefore, it is recommended that clinicians continually reassess patients for drowsiness or sleepiness especially since some incidents of sudden sleep onset occurred well after the start of dopamine receptor agonist therapy. Clinicians also should be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities. In addition, patients should be asked about any factors that may increase the risk of somnolence during ropinirole therapy (e.g., concomitant sedating drugs, the presence of sleep disorders [other than restless legs syndrome], concomitant drugs that increase ropinirole plasma concentrations [e.g., ciprofloxacin]). If a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), ropinirole generally should be discontinued. If a decision is made to continue the drug, patients should be advised not to drive and to avoid other potentially dangerous activities. The manufacturers state that there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
Patients should be informed that hallucinations can occur with ropinirole therapy; geriatric patients are at increased risk for this adverse effect. Patients also should be advised that ropinirole may cause somnolence and that they should not drive a car or operate other complex machinery until they have gained sufficient experience with the drug to determine whether it has adverse effects on their mental and/or motor performance. In addition, the possibility of additive sedative effects should be considered in patients receiving other CNS depressants concomitantly with ropinirole.
Restless Legs Syndrome
Ropinirole is used for the symptomatic management of moderate-to-severe primary restless legs syndrome (Ekbom syndrome). Restless legs syndrome is a sensorimotor disorder characterized by a distressing urge to move the legs accompanied by sensations deep in the limbs that have been described as twitching, pulling, and sometimes painful. These symptoms are present at rest, especially in the evening and at night, and are relieved by movement. Some clinicians consider a dopamine receptor agonist (e.g., ropinirole) the drug of choice for patients with symptoms that occur nightly.
Efficacy of ropinirole for this indication has been established in 3 randomized, placebo-controlled studies in patients with moderate-to-severe restless legs syndrome (score of at least 15 on the International Restless Legs Syndrome [IRLS] scale and a history of symptoms of restless legs syndrome on at least 15 nights per month). Patients were excluded from these studies if they had restless legs syndrome associated with end-stage renal failure, anemia, or pregnancy. Ropinirole was initiated at a dosage of 0.25 mg once daily (given 1-3 hours before bedtime) and increased over 7 weeks to a maximum dosage of 4 mg once daily; the average dosage after 7 weeks of therapy was 2 mg once daily. The primary end point of these studies was the mean change in IRLS score from baseline to week 12. The Clinical Global Impression-Global Improvement (CGI-I) scale was used to assess general improvement. At week 12, the mean improvement in IRLS score in patients receiving ropinirole was greater than that in patients receiving placebo. In addition, 73.3, 53.4, and 59.5% of patients receiving ropinirole in the 3 studies were described as responders (defined as being much improved or very much improved) on the CGI-I scale compared with 56.5, 40.9, and 39.6%, respectively, of patients receiving placebo. Ropinirole therapy was associated with greater improvement in sleep and quality-of-life scores than placebo. Improvement was observed in ropinirole-treated patients as early as week 1. Efficacy has been maintained over 36 weeks in patients who continued to receive ropinirole.
Use of dopamine receptor agonists in patients with restless legs syndrome can result in end-of-dose rebound (i.e., worsening of symptoms in the early morning hours). Long-term use of dopamine receptor agonists in patients with restless legs syndrome has been associated with augmentation of the symptoms of restless legs syndrome; augmentation can take the form of onset of symptoms earlier in the day, increase in symptoms, or extension of symptoms from the legs to the arms or trunk. Because patients with rebound restless legs syndrome or augmentation were excluded from clinical studies that evaluated efficacy of ropinirole and the duration of these studies was not long enough to evaluate the incidence of these events, the incidence and appropriate management of rebound and/or augmentation in patients receiving long-term therapy with ropinirole have not been evaluated in controlled clinical studies.
The reported incidence of somnolence is lower in patients receiving ropinirole for restless legs syndrome (12%) than in those receiving the drug for parkinsonian syndrome (up to 40%).
(See Uses: Parkinsonian Syndrome.)