Download What is memantine (Ebixa®)?

Pharmacy 735
Module 4
Sample Case Presentation
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Patient Description
OH, a 85-year-old female
 Previously was independent with basic
activities of daily living
 Gradual functional and cognitive decline
due to Alzheimer’s Disease, ↑ behavioral
disturbances
 Referred by family physician for inpatient
admission to Auckland City Hospital (ACH)
geriatrics program for further assessment.
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Psychiatric and Medical History
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Axis I: Cognitive impairment due to Alzheimer’s Disease
(AD)
 Diagnosed with AD in 2005  start donepezil
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March 2007 – switched to rivastigmine
May 2007 – moved from home to Silver Birch Lodge
July 2007 – switched to galantamine
Last MMSE prior to this admission = 9/30 Hypertension
Current presentation - Behavioral and psychological symptoms of
dementia (BPSDs): wandering, agitation, anxiety, insomnia,
paranoia, disinhibition, depression
Axis II: Deferred
Axis III: Osteoarthritis (knees + shoulder), Osteoporosis,
Urinary incontinence, Hypertension, Glaucoma
Axis IV: Loss of independence due to cognitive decline
Axis V: GAF = 35-40
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Medications
Dementia
Galantamine ER 24 mg po in the morning
BPSDs
Quetiapine 25 mg po daily + 50 mg at bedtime
Depression
Citalopram 10 mg po daily
CVS
prevention
Enteric Coated Aspirin 81 mg po daily
Hypertension Hydrochlorothiazide 12.5 mg + Losartan 50 mg po
daily
Osteoporosis Calcium elemental 500 mg po BID
Vitamin D 1000 IU po daily
Alendronate 70 mg po q1wk
Glaucoma
Timolol XE 0.25% eye drops 1 gtt OS daily
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Vaccinations
Flu yearly, Pneumococcal
Alzheimer’s Disease
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Most common type of dementia
Chronic, progressive, irreversible
Dementia - Latin “de mens” = “without mind”…?
DSM-IV: memory impairment + ≥1 of:
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Aphasia
Apraxia
Agnosia
Disturbance in executive function
Impairs independent daily function
Decline from previous level of function
NOT due to course of delirium
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Treatment – Nonpharmacological
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Family/caregiver education, counseling, support
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Structured environment
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Therapeutic alliance between medical team and
caregiver(s)
Cueing and scheduling
Orientation
Environmental modification
Exercise, physiotherapy, group therapy, music
therapy, occupational therapy
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Treatment Options Pharmacological
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Medications to slow
cognitive decline:
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Cholinesterase
inhibitors (CI)
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Donepezil (Aricept®)
Rivastigmine (Exelon®)
Galantamine (Reminyl®
ER)
NMDA receptor
antagonist
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Symptomatic
therapies for BPSDs
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CIs
Memantine
Antidepressants
Short-term:
antipsychotics,
benzodiazepines
Memantine (Ebixa®)
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Back to the case…
Drug-Related Problems
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OH is experiencing:
worsening cognition and requires
optimization of drug therapy for dementia
 worsening BPSDs and requires optimization
of drug therapy
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OH is at risk of worsening urge
incontinence due to an increased dose of
galantamine
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Therapeutic Alternatives
Continue galantamine alone
 Discontinue galantamine and initiate
memantine alone (switch)
 Continue galantamine and initiate
memantine (combine)
 Nonpharmacological measures
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Clinical Question:
“In an elderly patient with AD who is already
on galantamine, is the addition of
memantine superior to addition of placebo
for slowing the rate of cognitive and
functional decline?”
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What is memantine (Ebixa®)?
Approved by the US FDA in 2003 for
treatment moderate-severe AD
 Available in New Zealand since Feb 2005
 NOT funded by Pharmac
 NOT on the hospital formulary
 Cost = approx $180/month
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Mechanism of Action
Glutamate
Binds to postsynaptic
NMDA receptor
Controlled amount
of Ca2+ influx
Chronically elevated
MEMANTINE
↑↑ Ca2+ influx
Excitatory signal
Excitotoxicity
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Literature Review
Memantine in Moderate-Severe AD
Dementia
subtype
All-cause
RCT
Winblad
1999
Alzheimer’s Reisberg
2003
Tariot
2004
Van Dyck
2007
Intervention
MMSE Mean
range MMSE
Monotherapy
<10
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Monotherapy
3-14
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Combination
with donepezil
Monotherapy
5-14
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5-14
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Summary of Evidence
Moderate-severe AD: small beneficial
effect in combination with CI on cognition,
function, behavior, and global scales at 6months
 Some conflicting results in monotherapy
RCTs
 May help agitation
 Well-tolerated
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What do the guidelines say?
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“Memantine is an option for patients with
moderate to severe stages of AD” (Gr B, Level
1)
“Its use in mild stages of AD is not
recommended” (Grade D, Level 1)
“Combination therapy… is rational…appears to
be safe, and might lead to additional benefits for
patients with moderate-severe AD” (Grade B,
Level 1)
“Patients can be switched from a CI to
memantine…based on the judgment of the
prescribing physician and the patient (or their
proxy)” (Grade B, Level 3)
Hogan et al. Alzheimer's and Dementia
2007;3:355-84.
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Recommendation:
Continue galantamine ER at 24 mg po
daily
 Add memantine
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5 mg po qAM x 1 week, then
 5 mg po BID x 1 week, then
 10 mg qAM + 5 mg po qPM x 1 week, then
 10 mg po BID
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Rationale
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Efficacy?
 Evidence of efficacy in moderate-severe AD,
although effect sizes are small
 Recent evidence (Van Dyck 2007) show
discrepancies in efficacy for monotherapy
 Benefit in combination with donepezil
 Patient has trialed other CIs
 May be helpful for agitation
Toxicity?
 Well tolerated
 No drug-drug, drug-disease interactions
Compliance? – will get med-assist
Cost? – family willing and able to pay, eager to try
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Monitoring Plan - Efficacy
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Cognition
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Function/ADLs – weekly
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no change
BPSDs – weekly
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MMSE = 9/30 @ ~4wk
MMSE = 11/30 (7’s), 13/30 (WORLD) @ ~2mo
Improvement in sleep, combativeness, agitation
Less withdrawn
Responded well to environmental/nondrug measures
Gradual ↓ of quetiapine
Caregiver satisfaction/stress
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Caregivers report improvement, caregiver satisfaction
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Monitoring Plan - Toxicity
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Memantine
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Ongoing monitoring of: nausea/vomiting,
constipation, headache, confusion, worsening
of urge incontinence
Galantamine
Bradycardia – repeat ECG after dose
increase
 Ongoing monitoring of: nausea/vomiting,
insomnia, vivid dreams, muscle cramps,
fatigue
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References
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McShane R, Sastre A, Minakaran N. Memantine for dementia (review). The Cochrane
Collaboration 2006;2.
Van Dyck CH, Tariot PN, Meyers B, et al. A 24-week randomized, controlled trial of
memantine in patients with moderate-severe Alzheimer Disease. Alzheimer Dis Assoc
Disord 2007;21(2):136-143.
Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with
moderate to severe Alzheimer Disease already receiving donepezil: a randomized
controlled trial. JAMA 2004;291(3):317-24.
Van Dyck CH, Schmitt FA, Olin JT. A responder analysis of memantine treatment in
patients with Alzheimer Disease maintained on donepezil. Am J Ger Psych
2006;14(5):428-37.
Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-severe Alzheimer’s
Disease. NEJM 2003;348(14):1333-41.
Livingston G, Katona C. The place of memantine in the treatment of Alzheimer’s
disease: a number needed to treat analysis. Int J Ger Psych 2004;19:929-25.
Reisberg B, Doody R, Stoffler A, et al. A 24-week open-label extension study of
memantine in moderate-severe Alzheimer Disease. Arch Neurol 2006:63:49-54.
Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-BEST study
(benefit and efficacy in severely demented patients during treatment with
memantine). Int J Ger Psych 1999;14:135-46.
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