Rotigotine transdermal system for the treatment of Parkinson's disease

Background: Levodopa has been the cornerstone of the treatment of Parkinson's disease (PD) for >30 years, but long-term levodopa therapy is associated with development of such motor complications as motor fluctuations, dyskinesias, and drug-induced involuntary movements. Rotigotine is a dopamine agonist with high affinity for the D2 receptor. Rotigotine transdermal system, the first such system approved by the US Food and Drug Administration for the management of PD, has been formulated to deliver a consistent concentration of drug to the bloodstream with the goal of minimizing the complications associated with pulsatile dosing. Objective: This article reviews the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, tolerability, and efficacy of rotigotine transdermal system in the treatment of PD. Methods: MEDLINE (1966-April 2008) and International Pharmaceutical Abstracts (1971-April 2008) were searched using the term rotigotine. All prospective, randomized clinical efficacy trials in humans were included. The reference lists of the identified articles were reviewed for additional publications. Results: In clinical trials, rotigotine transdermal system at doses ranging from 4.5 to 67 mg/d was associated with significant clinical benefit in patients with early and advanced PD. In 4 randomized, doubleblind, placebo-controlled trials of 6 months' duration, patients receiving rotigotine transdermal system had significant improvements on the Unified Parkinson's Disease Rating Scale (UPDRS) part II (activities of daily living) that ranged from -0.3 to -4.2, compared with +0.92 to -2 for placebo (P < 0.001, rotigotine transdermal system vs placebo). In one trial that included pramipexole as an active comparator, the change in UPDRS II at 6 months was -4.2 in the rotigotine transdermal system group and -4.6 in the pramipexole group (P = NS, rotigotine transdermal system vs pramipexole). Changes on the UPDRS III (motor examination) at 6 months ranged from -3.58 to -8.7 with rotigotine transdermal system, compared with +0.38 to -4.3 in the placebo group and -10.3 in the pramipexole group (P < 0.001 vs placebo; P = NS vs pramipexole). The change in “off” time at 6 months ranged from -2.1 to -2.7 hours with rotigotine transdermal system, compared with -0.9 hour with placebo and -2.8 hours with pramipexole (P < 0.001 vs placebo; P = NS vs pramipexole). The proportion of patients achieving a >30% reduction in “off” time ranged from 55.1% to 59.7% of patients receiving rotigotine transdermal system, compared with 34.5% to 35.0% of patients receiving placebo and 67.0% of patients receiving pramipexole (P<0.001 vs placebo; P = NS vs pramipexole). The most commonly reported adverse event was application-site reaction, occurring in 9% to 46% of patients receiving rotigotine transdermal system, compared with 5% to 13% of patients receiving placebo. Other adverse events occurring in >20% of patients receiving rotigotine transdermal systemweresomnolence(8%\2-33%)and nausea(12%-49%). Less than 5% of patients assigned to rotigotine transdermal system discontinued study medication because of an adverse drug event. Conclusions: The available evidence suggests that rotigotine transdermal system was effective compared with placebo in decreasing morbidity in patients with early and advanced PD. The most commonly reported adverse events associated with rotigotine transdermal system were application-site reaction, nausea, and somnolence. Additional clinical trials are needed to determine the long-term tolerability profile of rotigotine transdermal system and its clinical efficacy and tolerability compared with oral dopamine agonists.