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Blog articles are provided as informational purposes only and are not intended to constitute medical advice. Medication protocols are subject to patient’s medical provider’s authorization.

 

There are currently three categories of dementia treatment medications:

Cholinesterase Inhibitors: donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Razadyne®) – These medications increase levels of acetylcholine, a neurotransmitter in the brain, by preventing the enzyme acetylcholinesterase from breaking it down.

N-Methyl-D-Aspartate (NMDA) Receptor Antagonist: memantine (Namenda®) – Memantine blocks the NMDA type of glutamate receptor during periods of overstimulation.

Anti-Amyloid Monoclonal Antibody: aducanumab (Aduhelm®) – Aducanumab reduces the amyloid beta plaque deposits that occur in Alzheimer’s disease. The FDA granted accelerated approval for this medication on June 7, 2021, with continued approval contingent upon whether post-approval trials verify its clinical benefit. At this time, it is recommended for initiation only in the mild stage of dementia or cognitive impairment.

Discontinuation of dementia treatment medications should be considered in the following situations:

When they are no longer demonstrating benefit. The primary goals of therapy for the Cholinesterase Inhibitors and memantine are to maintain cognition and preserve function (e.g., the activities of daily living (ADLs)). In some cases, a secondary goal is the management of psychological/behavioral symptoms. Unfortunately, the improvement in functional and/or cognitive status conferred by Cholinesterase Inhibitors is usually small and of relatively minor clinical significance. In addition, they have not been well studied in patients in advanced stages of dementia and usually become less effective as dementia progresses. As a result, they are typically thought to be of questionable benefit in patients with advanced dementia.

When the risks outweigh the benefits – for example, if they are causing adverse effects. Some of the most common adverse effects for Cholinesterase Inhibitors include anorexia/decreased appetite, weight loss, nausea, vomiting, and diarrhea. Memantine is generally well tolerated in most individuals, although confusion, dizziness, and headache can occur.

To decrease tablet burden. The discontinuation of non-essential medications is a goal for all hospice patients, as a higher tablet burden can be associated with a lower quality of life. Decreasing tablet burden becomes an even more urgent concern when patients are having difficulty swallowing or starting to refuse medications, which often occurs as dementia progresses.

How to discontinue Cholinesterase Inhibitors and/or memantine:

If the patient is taking anything higher than the lowest dose, gradually taper the dose before discontinuation. If these medications are abruptly discontinued at higher doses, a withdrawal syndrome can occur (see below for typical symptoms of withdrawal). At end-of-life, it is typically recommended to reduce the dose of these medications by 25-50% every 1-2 weeks, although more gradual taper methods may be utilized when appropriate.

Taper one medication at a time whenever possible so the patient’s response and reaction to the dose reduction can be more clearly assessed. Consider tapering the Cholinesterase Inhibitor first, and then memantine second. Or if time is short (e.g., patient is expected to stop swallowing soon), you could start tapering the medication with the higher relative dose first.

Monitoring and potential outcomes during the taper and after discontinuation:

It is possible that discontinuation of Cholinesterase Inhibitors and/or memantine may worsen cognitive function, and this decline may not be reversible. In addition, some trials have found that discontinuation of Cholinesterase Inhibitors may result in worsening neuropsychiatric and functional status. However, it is important to note that these trials included patients with all stages of Alzheimer’s (mild to severe), and predominantly involved abrupt discontinuation of the medications rather than a gradual taper. Thus, it is unclear if this decline is a common or clinically significant occurrence for patients who have advanced dementia and who have utilized a gradual taper method before discontinuation.

More importantly for our hospice population, discontinuing Cholinesterase Inhibitors has not been found to affect the patient’s global assessment of change or quality of life when compared with those continuing the medication.

Symptoms of withdrawal syndrome that can occur after abrupt discontinuation: 

Cholinesterase Inhibitors: Agitation, aggression, hallucinations, reduced consciousness, abrupt cognitive decline.

Memantine: Behavioral disturbances.

If behaviors or negative neuropsychiatric symptoms occur after dose reduction or discontinuation of dementia treatment medications, the timing of the symptoms may help to determine whether they are due to the change in medication vs. patient decline or another cause.

If negative symptoms occur in the first week after a dose reduction or discontinuation, it could indicate that the patient is having an adverse drug withdrawal rection. It would typically be recommended to restart the previous dose, and then consider a more gradual taper in the future, when appropriate.

If negative symptoms occur approximately 2 to 6 weeks after a dose reduction or discontinuation, it could indicate that the medication was providing benefit (unless there is another apparent cause of the symptoms, such as UTI, pain, etc.). Hospice may consider restarting the medication, if appropriate.

If negative symptoms occur between 6 and 12 weeks after a dose reduction or discontinuation, it could indicate either of the above or progression of the patient’s underlying condition. Symptom management in this situation would depend on a number of patient-specific factors (e.g., ability to swallow, prognosis). Consider utilizing non-pharmacologic measures and/or other medications, such as antipsychotics or anti-anxiety medications, if appropriate.

 

Written by: Joelle Potts, PharmD, RPh, BCGP

 

 

References:

1.  Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: UpToDate, Inc.; 2021.

2.  Shaw G. FDA narrows Aduhelm label. Pharmacy Practice News, Online First; Jul 12 2021. Available at: https://www.pharmacypracticenews.com/Online-First/Article/07-21/FDA-Narrows-Aduhelm-Label/64066  [accessed 7/22/2021]

3.  Peron EP, Slattum PW, Powers KE, Hobgood SE. Alzheimer Disease. Chapter in: Pharmacotherapy: A Pathophysiologic Approach. DiPiro JT, et al editors. 10th Edition, 2017. McGraw Hill Education, New York. 797-813.

4.  Epperly T, Dunay MA, Boice JL. Alzheimer disease: Pharmacologic and nonpharmacologic therapies for cognitive and functional symptoms. Am Fam Physician. 2017; 95(11): 771-778.

5.  AMDA – The Society for Post-Acute and Long-Term Care Medicine. Recommendation regarding prescribing/continuing acetyl cholinesterase inhibitors or N-Methyl-D-Aspartate antagonists in patients with advanced dementia. Nov 20, 2020; www.choosingwisely.org. Available at: https://www.choosingwisely.org/clinician-lists/14amda-dont-routinely-prescribe-or-continue-acetyl-cholinesterase-inhibitors-or-n-methyl-d-aspartate-antagonists-in-patients-with-advanced-dementia/?highlight=dementia  [accessed 5/1/2021]

6.  Mitchell SL. Care of patients with advanced dementia. In: UpToDate, Morrison RS and Yaffe K (Section Editors), Wilterdink JL (Deputy Editor). Available at: https://www.uptodate.com/contents/care-of-patients-with-advanced-dementia   [accessed 5/5/2021]

7.  Liao P, Perri GA. Fast Facts and Concepts #354: Deprescribing cholinesterase inhibitors at the end of life. May 2018. Available at: https://www.mypcnow.org

8.  Morrison LJ, Liao S. Fast Facts and Concepts #174: Dementia medications in palliative care. Revised August 2016. Available at: https://www.mypcnow.org

9.  Parsons C, et al. Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia. Cochrane Database of Systematic Reviews. Feb 3, 2021. [Abstract]

10.  Kwak YT, Han I-W, Suk S-H, Koo M-S. Two cases of discontinuation syndrome following cessation of memantine. Geriatr Gerontol Int. 2009 June; 9(2): 203-5. [Abstract]

11.  Steinman M, Reeve E. Deprescribing. In: UpToDate, Schmader KE (Section Editor), Givens J (Deputy Editor). Available at: https://www.uptodate.com/contents/deprescribing?sectionName=Cholinesterase%20inhibitors%20and%20memantine&topicRef=86250&anchor=H4018874073&source=see_link#H4018874073  [accessed 5/5/2021]

 

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ProCare HospiceCare is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s Commission on Accreditation.