Long-term tolerability of ropinirole treatment in Restless Legs Syndrome

D Lee,1 K Tucci-Herron,1 C Chiang 2 1Sleep Disorder Center, East Carolina Neurology Inc., NC, USA; 2GlaxoSmithKline, Research Triangle Park, NC, USA

Introduction

Restless Legs Syndrome (RLS) is a chronic condition, which may require ongoing treatment and can have long-term impact on sleep and quality of life. The clinical diagnosis of RLS is based on four criteria: (1) an urge to move the legs usually accompanied by uncomfortable sensations in the legs, (2) that begin or worsen at rest, (3) are partially or totally relieved by movement (at least as long as it continues), and (4) are worse in the evening or at night than during the day. Although the exact cause is unclear, imaging studies1-6 and clinical observations7 suggest that RLS may be related to dopaminergic dysfunction. A recent treatment algorithm reported dopamine agonists as the treatment of choice in patients with daily RLS.8 Treatment with ropinirole has been shown to be efficacious and well tolerated in patients with RLS in randomized trials of up to 36 weeks.9-12 In addition, two extension studies were performed to assess the safety and tolerability of ropinirole during 52 weeks of treatment. REQUIP (ropinirole hydrochloride) is the first and only FDA-approved treatment for moderate-to-severe primary RLS.

Methods

• Two 52-week, open-label, continuation studies were conducted: protocols 101468/192 (worldwide) and 101468/243 (USA). The studies had the same design.
• Patients were eligible for inclusion if they had completed one of the six predefined ‘parent’ studies from the extensive ropinirole in RLS clinical trial program. The criteria for inclusion into the parent studies included a diagnosis of primary RLS, at least 15 nights of RLS symptoms during the previous month, and a baseline score of at least 15 points on the International Restless Legs Syndrome Study Group’s rating scale – the International Restless Legs Scale (IRLS; 0-40 [absence of RLS – most severe RLS]). If the period between finishing the first study and starting the continuation study was longer than 30 days, patients had a second screening and baseline visit to re-assess eligibility.
• In these continuation studies, patients received ropinirole once daily, 1-3 hours before bedtime, at a starting dose of 0.25 mg/ day, followed by flexible dose titration, as needed and tolerated, up to a maximum of 4.0 mg/day.
• The incidence and severity of adverse events (AEs) were assessed. Additionally, in Study 243, orthostatic blood pressure was evaluated at baseline and on days of dose increases.
• Efficacy assessments included the change in baseline in IRLS total score at Week 52 last observation carried forward (LOCF).

• The safety analysis included 390 patients for the two studies combined – see Table 1 for demographic and baseline characteristics.
• The mean (SD) daily dose of ropinirole, over the course of the two 52-week studies combined, was 1.66 (0.988) mg/day, and 1.92 (1.164) mg/day at Week 52 LOCF.
• The AEs observed in these long-term studies were consistent with those reported in shorter studies.
• Nausea was the most commonly reported AE (Table 2).
• Most AEs were mild or moderate in severity. The number of patients reporting on-treatment AEs by intensity were: mild, 282 (72.3%); moderate, 267 (68.5%); severe, 122 (31.3%). Most AEs occurred within the first 12 weeks of therapy.
• A total of 20% of patients reported an AE that led to dose reduction.
• The rate of withdrawals due to AEs was low (34/390 patients, 8.7%).
• Augmentation is commonly defined as worsening and/or earlier onset of RLS symptoms attributable to a specific therapeutic intervention for RLS. Although these studies were not designed to specifically assess augmentation, augmentation was reported by investigators as an AE of worsening RLS in 15/390 patients (3.8%).
• There were 6 reports of syncope, one of which led to discontinuation.
• In Study 243, 1 patient (1/81, 1.2%) reported orthostatic hypotension as an AE, which resolved on the same day and was not associated with orthostatic blood pressure values of potential clinical concern.  There were no reports of orthostatic hypotension in Study 192.
• There were 39 serious AEs reported; of these, one (benign intracranial hypertension) was considered related or possibly related to study medication.
  

Efficacy

• Improvements (decreases) in IRLS total cores were observed overall, and in both studies individually, at Week 52 LOCF (Figure 1).

• Ropinirole was generally well tolerated during the long-term treatment of patients with moderate-to-severe RLS.
• The majority of AEs were mild or moderate in intensity and were not treatment-limiting.
• These studies provide important information about the general tolerability and long-term safety profile of ropinirole in the treatment of RLS.
• Increasing awareness of this disorder and its treatment will help practitioners to recognize and treat RLS early, and thus improve the quality of life of these patients.

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