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 fixed-dose combination of memantine (MEM) and donepezil (DON) for the treatment of Alzheimer’s disease. Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist, while donepezil is an acetylcholinesterase inhibitor. This fixed-combination formulation of the two drugs is marketed by Forest Pharmaceuticals as Namzaric.
INDICATIONS
MEM/DON is indicated for the treatment of moderate to severe dementia of the Alzheimer’s type in patients already stabilized on MEM 10 mg twice daily or 28 mg once daily of extended-release formulation, and donepezil 10 mg or 5 mg and 10 mg, respectively.
DOSAGE
The starting dose is 28 mg/10 mg once daily in the evening.1 The dose may be swallowed whole or sprinkled on applesauce and may be taken without regard for meals. MEN/DON is supplied as 14 mg or 28 mg extended-release memantine HCl and donepezil HCl 10 mg.
POTENTIAL ADVANTAGES
The addition of MEM to a stable dose of an acetylcholinesterase inhibitor may improve cognitive performance.1 The once-daily oral capsule is intended for patients currently taking memantine (10 mg twice daily or 28 mg extended-release once-daily) and donepezil 10 mg. In addition, the capsules can be opened to allow the contents to be sprinkled on food to facilitate dosing for patients who may have difficulty swallowing.1
POTENTIAL DISADVANTAGES
The combination as Namzaric has not been studied in a clinical trial. It is not indicated for initial therapy.
COMMENTS
The approval of this fixed combination was based on a single randomized, double-blind, 24-week study in participants with moderate-to-severe Alzheimer’s disease (DSM-IV and NINCIDS-ADRDA criteria) on a stable dose of an anticholinesterase inhibitor for 3 months prior to screening.1
The participants (n = 677) had a Mini Mental State Examination score ≥ 3 and ≤ 14 and were randomized to memantine extended-release tablets, 28 mg or placebo. Sixty-eight percent were on donepezil.
The co-primary efficacy endpoint was the Severe Impairment Battery (SIB) and the Clinician’s Interview-Based Impression of Change (CIBIC-Plus). SIB assesses key elements of cognitive performance (attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction with a range of 0-100). CIBIC-Plus assesses four domains (overall clinical status, functional [i.e., daily living], cognitive, and behavioral). Each domain is scored from 1 to 7.
At 24 weeks, the difference between MEM/AChEI was 2.6 units compared to placebo/AChEI. The responses for both groups were wide ranging but favored MEM/AChEI in terms of showing an improvement or a smaller decline. The mean difference for CIBIC-Plus was 0.3 units. Both endpoints were statistically significant.
Similar to SIB, a greater percentage of participants showed marked to minimal improvement with MEM/AChEI while placebo/AChEI showed more moderate to marked worsening. Roughly 40% showed no change with each group.
CLINICAL IMPLICATIONS
Alzheimer’s disease is the most common cause of dementia. Current evidence suggests that cholinesterase inhibitors have modest overall benefit for slowing disease decline.2 The benefit of memantine alone is less impressive.
The addition of memantine in patients stabilized on donepezil may provide benefit to some patients, at least in the short-term. A randomized, controlled, 24-week study also showed the benefit of adding memantine 20 mg to 10 mg donepezil.3 In a much longer study, 52 weeks, the addition of 20 mg of memantine to donepezil in patients with moderate-to-severe Alzheimer’s disease showed no benefit.4
Authors of a systemic review and a meta-analysis suggest that the clinical benefit of combination therapy is not clear.5 Finally, an APA practice guideline for the treatment of patients with Alzheimer’s disease and other dementias indicated that for cognitive symptoms, the benefits of adding memantine to cholinesterase inhibitors are, at best, slight or of unclear clinical significance.6
The cost of MEM/DON was not available at the time of this review.
REFERENCES
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Namzaric Prescribing Information. Forest Laboratories. December 2014.
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Tan CC et al. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis 2014;41:615-631.
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Tariot PN, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: A randomized controlled trial. JAMA 2004;297:317-324.
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Howard R et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med 2012;366:893-903.
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Muayqui T, Camiciloi R. Systematic review and meta-analysis of combination therapy with cholinesterase inhibitors and memantine in Alzheimer’s disease and other dementias. Dement Geriatr Cogn Dis Extra 2012;2:546-572.
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American Psychiatric Association. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients with Alzheimer’s Disease and Other Dementias. Available at: http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/alzheimerwatch.pdf. Accessed Feb. 21, 2015.
