In 2015, the European Neurological Society and the European Federation of Neurological Societies (now combined into the European Academy of Neurology) found a moderate benefit for using cholinesterase inhibitors to treat problematic behaviors in patients with Alzheimer’s disease.13 They found the evidence weak only when they included consideration of cognitive benefits. For patients with moderate to severe Alzheimer’s disease, the Academy endorsed the combination of cholinesterase inhibitors and memantine.13
The United Kingdom National Institute for Clinical Excellence (NICE) guideline on dementia is updated every 1 to 3 years based on evolving evidence for the treatment of Alzheimer’s disease and related symptoms. In 2016, NICE updated its guideline to recommend the use of a cholinesterase inhibitor for patients with mild to severe Alzheimer’s disease and memantine for those with severe Alzheimer’s disease.14 NICE specifically noted that it could not endorse the use of a cholinesterase inhibitor for severe dementia because that indication is not approved in the United Kingdom, even though there is evidence for this use. The NICE guidelines recommend use of cholinesterase inhibitors for the non-cognitive and/or behavioral symptoms of Alzheimer’s disease, vascular dementia, or mixed dementia after failure or intolerance of an antipsychotic medication. They recommend memantine if there is a failure to respond or intolerance of a cholinesterase inhibitor. The NICE guideline did not address concomitant use of a cholinesterase inhibitor with memantine.
The 2017 guideline published by the British Association for Psychopharmacology states that combination therapy (a cholinesterase inhibitor plus memantine) “may” be beneficial. The group noted that while studies were well-designed, sample sizes were small and not based on clinically representative samples.15
Both available evidence and published guidelines suggest that combination treatment for moderate to severe Alzheimer’s disease may slow the worsening of symptoms or prevent the emergence of NPS better than either medication could accomplish alone. Slowing symptom progression could potentially decrease the cost of in-home care and delay institutionalization.
For a patient prescribed combination therapy, the cost of treatment with generics (as of June 2018) could range from approximately $120 per year for donepezil, 10 mg/d, and approximately $180 per year for memantine, 10 mg twice daily, taken by mouth.16 The cost of a once-daily capsule that contains a combination pill of donepezil and memantine is much more because this product is not available generically.
The Donepezil and Memantine in Moderate to Severe Alzheimer’s disease (DOMINO-AD) trial assessed the effect of combination therapy on cognition, activities of daily living, and health-related quality of life, as well as the cost efficacy of the combined treatment.17 In the 52-week study, researchers found that combined donepezil and memantine was not more cost-effective than donepezil alone. However, a post hoc analysis of the DOMINO-AD data combined with the Memantine Clinical Trial Program data found benefits across multiple clinical domains.18
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