Pharmacology Update
Rivastigmine Transdermal System (Exelon® ®Patch)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco.Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The fda has approved a higher dose of the rivastigmine transdermal system (13.3 mg/24 hours) for the treatment of Alzheimer's disease (AD). Lower-dose patches were previously approved for mild-to-moderate disease. Rivastigamine is a reversible acetylcholinesterase inhibitor. The transdermal system is marketed by Novartis as Exelon.
Indications
Rivastigmine transdermal system is indicated for treatment of mild, moderate, and severe dementia of the Alzheimer's type as well as mild-to-moderate dementia associated with Parkinson's disease.
Dosage
The recommended initial dose is 4.6 mg/24 hours. If tolerated, the dose may be increased after a minimum of 4 weeks to 9.5 mg/24 hours. After an additional 4 weeks, the dose may be increased to 13.3 mg/24 hours. The recommended dose for mild-to-moderate disease is 9.5 mg or 13.3 mg/24 hours. For severe AD, the dose is 13.3 mg/24 hours.
Rivastigmine transdermal system is available as patches delivering 4.6 mg/24 hours, 9.5 mg/24 hours, and 13.3 mg/24 hours.
Potential Advantages
The transdermal system provides an alternative to oral cholinesterase inhibitors with good tolerability, particularly GI symptoms, and effectiveness. In a small study (n = 164) in patients with poor response to oral agents, with a decline in global function with oral agents, or those who were unable to tolerate oral agents, 82% showed improvement or no decline at 24 weeks after switching to transdermal rivastigmine.3
Potential Disadvantages
The most frequent adverse events are nausea, vomiting, application site erythema, and agitation.
Comments
The safety and efficacy of the 13.3 mg/24 hour patch was evaluated in a 48-week randomized, double-blind, study in patients with mild-to-moderate AD showing functional and cognitive decline. 1,4 In the open-label phase, subjects (n = 1584) were started on 4.6 mg/day followed by 9.5 mg/day from week 4 up to week 48. The mean age was 76 years (range 50-85 years), 65% women, and 97% Caucasian. Subjects were patients with functional decline (determined by investigator) and cognitive decline (decrease in MMSE score of 2 or higher from the previous visit or a decrease of 3 or more from baseline). Those with decline (n = 567) were randomized to rivastigmine (13.3 mg/day; n = 280) or 9.5 mg/day (n = 287) for 48 weeks. The primary efficacy outcomes were change from baseline in Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cog) Subscale and Alzheimer's Disease Cooperative Study-Instrument Activities of Daily Living (ADCS-IADL), assessed by caregiver, at week 48. Data were analyzed based on intent-to-treat last observation carried forward. Mean changes in ADAS-Cog declined for both strengths of rivastigmine but at a slower rate initially with the higher strength. Statistical difference was seen at week 24 (P = 0.027), but the benefit was no longer statistically different at week 48 (P = 0.227). A similar pattern occurred with mean changes in ADCS-IADL; however, statistical significance in favor of the 13.3 mg/day was maintained for 48 weeks. In a 24-week study, rivastigmine 13.3 mg/day was significantly more effective than 4.6 mg/day in patients with severe AD1. The overall rate of discontinuation was numerically lower with the higher strength (9.6% vs 12.7%).1
Clinical Implications
AD is a progressive disease with no cure. Currently available drug treatments include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and a NMDA receptor antagonist (memantine). These drugs can improve symptoms and/or temporarily slow the progression of the disease in some patients. The new strength of rivastigmine provides an option for patients with more severe disease and may produce a measurable slowing of progression in some patients who have shown decline at the lower dose. The wholesale cost for the 13.3 mg/24 hour patch is $9.88 per day compared to $8.85 for memantine (10 mg twice daily) and $10.50 for donepezil (23 mg once daily).
References
1. Exelon Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; June 2013.
2. Dhillon S. Rivastigmine transdermal patch: A review of its use in the management of dementia of the Alzheimer's type. Drugs 2011;7:1209-1231.
3. Han HJ, et al. Efficacy and safety of switching from oral cholinesterase inhibitors to the rivastigmine transdermal patch in patients with probable Alzheimer's disease. J Clin Neurol 2011;7:137-142.
4. Cummings J, et al. Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10 cm²) in Alzheimer's disease. Dement Geriatr Cogn Disord 2012;33:341-353.
