New FDA Actions: UCB's Neupro
JULY 10, 2012
Jocelyn Thomas, PharmD, and Kevin Joseph, PharmD Candidate
The FDA approved Neupro (Rotigotine Transdermal System) for the treatment of Parkinson's disease and restless leg syndrome.
Neupro (Rotigotine Transdermal System), manufactured by UCB, is the first approved nonergotderived dopamine agonist that is delivered continuously through a transdermal system. It was approved by the FDA April 3, 2012, for the treatment of Parkinson’s disease (PD) and restless legs syndrome (RLS).
Neupro is a nonergoline dopamine agonist. Approximately 45% of the rotigotine from the patch is released over 24 hours. It is primarily eliminated in the urine as inactive conjugates.1
Rotigotine displays dose-proportionality over a daily dose range of 1 mg/24 hours to 24 mg/24 hours. Steady-state plasma concentration is achieved within 2 to 3 days of daily dosing. Rotigotine has a volume of distribution of 84 L/kg and is 89.5% plasma proteins bound.2
Dosing and Administration
Neupro is a transdermal patch that is applied once a day. It is manufactured in 1, 2, 3, 4, 6, and 8 mg per 24-hour patches. For earlystage PD, Neupro should be started at 2 mg/24 hours and may be titrated weekly by 2 mg/24 hours to a maximum dosage of 6 mg/24 hours. For advanced-stage PD, the recommended starting dose is 4 mg/24 hours titrated weekly by 2 mg/24 hours to 8 mg/24 hours.2
For RLS, Neupro should be started at 1 mg/24 hours and titrated weekly by 1 mg/24 hours. The max recommended dose is 3 mg/24 hours. When discontinuing Neupro, the daily dose should not be reduced by more than 2 mg/24 hours, with a dose reduction preferably every other day.
Mechanism of Action
Rotigotine is a nonergoline dopamine agonist, but the precise mechanism of action of rotigotine as a treatment for PD and RLS is unknown.3
Neupro was approved based on 5 parallel, randomized, double-blind, placebo-controlled trials.
PD-1 was a trial that enrolled 316 patients with early-stage PD. This trial was conducted over a 4-week period with a 7-week maintenance phase. Significant mean changes showed that dose-related improvements were observed with the highest doses.
PD-2 enrolled 277 early-stage PD patients and was conducted over a 28-week period followed by a 24-week maintenance period. Primary efficacy was shown after a treatment period of about 27 weeks. Patients treated with Neupro experienced an overall mean change on the Unified Parkinson’s Disease Rating Scale (UPDRS) II and III of -4.0, and the placebo group showed a change of +1.3.
PD trial 3 enrolled 561 early-stage PD patients. This trial was conducted over a 39-week period with a 24-week maintenance phase. Neupro-treated patients had a change in the combined UPDRS II and III from the start to the end of -6.8, and the placebo group showed a statistically significant change of -2.3.
For PD trials 4 and 5, which enrolled patients with advancedstage PD, Neupro-treated patients showed benefits as early as the first week of the treatment. It is important to note that patients received concurrent treatment with levodopa during the trial.
Neupro is contraindicated in patients who have hypersensitivity to Rotigotine or any component of the formulation. Dose-dependent application site reactions have been observed; daily rotation of application sites has been shown to decrease incidence of reactions. Weight gain and fluid retention have been reported, therefore Neupro must be used with caution in patients with heart failure or renal insufficiency.
Neupro may cause hallucinations and other psychotic-like behaviors, so avoid use in patients with preexisting major psychotic disorders. Risk for melanoma development is increased in PD patients; therefore periodic skin examinations are recommended. Patients must be cautioned about performing tasks that require mental alertness, as Neupro may cause somnolence.
PD and RLS patients being treated with dopaminergic agonists ordinarily require careful monitoring for postural hypotension. Use caution in patients with pre-existing cardiovascular disease, because therapy has been associated with increases in blood pressure as well as orthostatic hypotension. Rotigotine may cause or exacerbate preexisting dyskinesia, therefore caution is advised.
Remove the patch prior to MRIs or cardioversion to avoid skin burns. Also avoid exposure of the application site to any direct external heat sources. Neupro patches contain sodium metabisulfite, which may cause allergic reactions in some patients.
Dopamine antagonists, antipsychotics, and metoclopramide could diminish the effectiveness of Neupro.2
Dr. Thomas is a clinical pharmacist, primary care in the Harris County Hospital District at Gulfgate Health Center in Houston, Texas. Mr. Joseph is a doctor of pharmacy candidate currently on rotation from Texas Southern University.
1. Talati R, White M, Coleman C. Rotigotine; The first transdermal nonergot-derived dopamine agonist for the treatment of Parkinson disease. FormularyJournal. November 2007.
2. Neupro complete prescribing information. www.neupro.com/pdf/Neupro-PI.pdf. Accessed May 2012.
3. Giladi N, Fichtner A, Poewe W, et al. Rotigotine transdermal system for control of early morning motor impairment and sleep disturbances in patients with Parkinson's disease. JNeural Transm. 2010. Dec; Epub 2010 (12):1395-1399.