Download Alzheimer`s Disease Therapy - Maine Pharmacy Association

Alzheimer’s Disease Therapy
Cassandra White, PharmD, BCACP
Assistant Professor of Pharmacy Practice
Husson University School of Pharmacy
Clinical Pharmacy Specialist
VA Maine Healthcare System
Maine Pharmacy Association Spring Convention
March 20, 2015
1
Overview
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Alzheimer’s Disease background
Management of Alzheimer’s Disease patients
Medications to avoid
Treatment options
 Acetylcholinesterase inhibitors
 NMDA antagonist
 Combination regimens
 Other medications
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Objectives
• Recognize the most commonly used tools for cognitive assessment
• Explain non-pharmacologic ways to manage patients with
Alzheimer’s Disease (AD)
• Identify medications that can temporarily cause or worsen
symptoms of AD
• Use individual patient characteristics to select appropriate
pharmacotherapy for AD
• Relate key counseling points to patients with AD
3
Background
Dementia
• Alzheimer’s Dementia
• Vascular Dementia
• Lewy Body Dementia
• Parkinson’s Dementia
• Frontotemporal Dementia
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Alzheimer’s Disease (AD)
• Most common type of dementia


Occurs in 60-80% of dementia diagnoses
Affects ~5 million U.S. adults
• Progressive neurodegenerative disorder with no cure
 Uncertain cause and pathogenesis
 Majority of cases occur after age 65
 Incidence & prevalence increase exponentially with age
• Selective memory impairment is the most essential
and often earliest clinical manifestation
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Cognitive Assessment
• Multiple tools to assess cognition
• Clinicians typically utilize:
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Mini-Mental State Examination (MMSE)
Mini-Cog
Functional Assessment Staging Tool (FAST)
Montreal Cognitive Assessment (MoCA)
St. Louis University Mental Status (SLUMS)
• Clinical trials typically utilize:
 MMSE
 Alzheimer’s Disease Assessment Scale-cognitive subscale
(ADAS-cog)
 Severe Impairment Battery (SIB)
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MMSE
•
11 “copyrighted” questions
•
5 domains: short-term memory (recall), orientation,
attention, language, & short-term memory (retention)
•
Education level, age, and language barriers can adversely
influence the results
•
Maximum score = 30
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24-30 = No cognitive impairment
17-23 = Mild cognitive impairment
10-16 = Moderate cognitive impairment
< 10 = Severe cognitive impairment
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MoCA
• Freely accessible online and in several languages at
www.mocatest.org
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8 domains: Visuospatial/executive, naming, short-term
memory (recall), attention, language, abstraction, shortterm memory (retention), & orientation
•
Maximum score = 30
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26-30 = No cognitive impairment
18-25 = Mild cognitive impairment
10-17 = Moderate cognitive impairment
< 10 = Severe cognitive impairment
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MMSE vs. MoCA
• Both stage AD as mild, moderate, or severe
 MoCA emerging as the preferred brief assessment tool
 Superior sensitivity in detecting mild cognitive impairment
 Increased sensitivity to executive & language dysfunction
 Sensitivity and Specificity (%) MoCA and MMSE:
Cut-Off
≥ 26
< 26
< 26
Group (n)
Normal controls
(90)
Mild Cognitive
Impairment (94)
Alzheimer’s
Disease (93)
MoCA
87
90
100
MMSE
100
18
78
http://www.mocatest.org/normative_data.asp
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Management of
Alzheimer’s Disease
Management of AD
• Management of medical problems can be more
complex in patients with AD
 Decreased ability to make decisions
 Less likely to adhere to treatment plans
 More difficulty reporting adverse effects of therapy
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Management of AD
• Treat correctable causes
 Hypothyroidism, vitamin B12 deficiency, infections,
diabetes, etc.
 Avoid alcohol
• Provide comfort/support to patients AND caregivers
• Treat behavioral and psychiatric disturbances
• Manipulate the environment to support function
• Remove cognition-impairing medications
Kahn D, Gwyther LP, Frances A, et al. A Guide for Families and Caregivers. In The Expert Consensus Guideline Series: Treatment of Agitation
in Older Persons with Dementia, Postgrad Med Special Report April 1998, pp 81–88.
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Medications to Avoid
Medications to Avoid
• Review patient profile for medications that can
temporarily cause or worsen symptoms of AD
• Medications with strong anticholinergic side effects
are well known for causing cognitive impairment in AD
patients
 Effects are additive: more drugs = more likely to cause
mental status change
 Anticholinergic medications and cholinesterase
inhibitors antagonize each other!
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Medications to Avoid: Examples
• Antiemetics
 Dimenhydrinate, meclizine, promethazine, scopolamine
• Tricyclic Antidepressants
 Amitriptyline, doxepin, imipramine, nortriptyline
• Antiparkinsonian Anticholinergics
 Benztropine, trihexyphenidyl
• Antipsychotics*
 Clozapine, olanzapine, thioridazine, chlorpromazine
*Preferred antipsychotic agents when used to treat behavioral problems in
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elderly with dementia include: Haloperidol & Risperidone
Pharmacist's Letter 2008;24(5):240510.
Medications to Avoid: Examples
• Antihistamines
 Diphenhydramine, chlorpheniramine, hydroxyzine,
doxylamine
• Anxiolytics
 Benzodiazepines (diazepam, alprazolam, etc.)
• GI/Urinary Antispasmodics
 Atropine, scopolamine, dicyclomine, hyoscyamine,
oxybutynin, tolterodine, solifenacin, darifenacin
• Muscle Relaxants
 Cyclobenzaprine, metaxolone, tizanidine
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Pharmacist's Letter 2008;24(5):240510.
Treatment of
Alzheimer’s Disease
Clinical Pearl
• THERE ARE NO TREATMENTS that can definitely stop
loss of brain cells
• Medications are used to help slow the progress of cell
loss and cognitive impairment associated with
dementia
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Benefit of Therapy
Placebo
AChEI +/Memantine
Birks J. Cholinesterase Inhibitors for Alzheimer’s Disease (Review). The Cochrane Library 2012 Issue 5.
http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1842
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Treatment Considerations
• Decision to initiate treatment and the choice of agent
must be individualized
 Quality of life
 Treatment goals
 Potential benefit
 Adverse effects
 Cost
 Comorbid conditions
• If pharmacotherapy is initiated, benefit should be seen
within three months
 Treatment considered successful if memory remains
unchanged for 6 months
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American Psychiatric Association
Selecting a Medication
• Not enough evidence to recommend one agent over
another based on efficacy
• No way to determine if or how a particular patient will
respond to therapy
• Guidelines suggest initiating therapy early, as soon as
diagnosis is made, to maximize clinical benefits
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Ann Intern Med 2008; 148:370-8
Treatment Options
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Acetylcholinesterase inhibitors
NMDA antagonist
Combination regimens
Other medications
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Acetylcholinesterase Inhibitors
(AChEIs)
• Drugs that prevent the breakdown of acetylcholine, a
brain chemical involved in memory & other functions
related to thinking
 ↑ acetylcholine = ↑ cognitive abilities
• FDA-approved medications*
 Donepezil (Aricept)
 Galantamine (Razadyne)
 Rivastigmine (Exelon)
*Tacrine, the first cholinesterase
inhibitor approved in 1993, is
rarely used now due to its
potential to cause liver damage
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By inhibiting acetylcholinesterase,
these drugs allow more
acetylcholine to remain activated
Increased levels of acetylcholine
can help maintain or improve
cognitive abilities in some people
with dementia
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www.dementiaguide.com/
AChEIs
• All approved for mild-moderate Alzheimer’s disease
• Donepezil and Rivastigmine patch approved for severe
disease
• Most common side effects are gastrointestinal
 Nausea / Vomiting / Diarrhea / Abdominal Cramping
• Side effects may become more tolerable over a few
weeks. Can improve tolerability with:
 Slow titration
 Administration with food
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Donepezil (Aricept )
®
• Once-daily dosing at bedtime
 Brand: 5 mg, 10 mg, & 23 mg tablet
 Generic: 5 mg & 10 mg tablet
 Also supplied in an ODT form (5 mg & 10 mg)
• Dose: 5 mg daily x 4 weeks, may ↑ to 10 mg daily
after 4-6 weeks
 Patients should be on 10 mg daily for ≥ 3 months
before starting the 23 mg tablet
 Marginal improvement compared to 10 mg/day dose
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Donepezil (Aricept )
®
• Relatively little peripheral anticholinesterase activity;
generally well tolerated
• Dose related side effects (N/V/D)
 ↑ dose = ↑ side effects
 Tend to resolve with continued use
• Withdrawal due to adverse events: 8% of patients on
10 mg, compared to 19% on 23 mg
Product Information: ARICEPT(R) oral tablets. Eisai Inc. (per FDA), Woodcliff Lake, NJ, 2014.
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Donepezil (Aricept®) 23 mg SR
• 23 mg strength showed improvement over 10 mg on
cognitive symptoms
 No improvement on overall patient functioning
 Failed to meet both secondary efficacy criteria
 Activities of Daily Living (ADL)
 Mini-Mental Status Examination (MMSE)
• Manufacturer Warning: “Many more people taking
ARICEPT 23 mg experienced nausea and vomiting than
those taking ARICEPT 10 mg”
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Rivastigmine (Exelon )
®
• Capsules (twice-daily dosing)
 1.5 mg, 3 mg, 4.5 mg, & 6 mg (brand & generic)
 Initially, 1.5 mg PO BID w/ food, can ↑ by 3 mg/day
increments after ≥ 2 weeks of treatment
• Oral Solution
• Transdermal patch (per 24 hours)
 4.6 mg, 9.5 mg, 13.3 mg (brand only)
 Initially 4.6 mg once daily, can ↑ to 9.5 mg
and then 13.3 mg after ≥ 4 week intervals
• MDD = 12 mg (6 mg PO BID) or one patch delivering
13.3 mg per 24 hours once daily
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Rivastigmine (Exelon )
®
•
Despite much higher
exposure (reported
to result in greater
efficacy), GI
tolerability appears
more favorable
following patch
administration
compared with oral
rivastigmine
Lefèvre G et al. J Clin Pharmacol 2008;48:246-252
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Galantamine (Razadyne®)
• Razadyne ER® = once-daily dosing
 Capsule: 8 mg, 16 mg, 24 mg
• Immediate release = twice-daily dosing
 Tablet: 4 mg, 8 mg, 12 mg
 Solution: 4 mg/mL
 Generic available in all forms
• Initially 8 mg/day, can ↑ by 8 mg/day increments after
≥ 4 weeks of treatment
 MDD = 24 mg/day
MDD = Maximum Daily Dose. Product Information: RAZADYNE(R) oral tablets, oral solution, galantamine hydrobromide oral tablets, oral
solution. Janssen Pharmaceuticals, Inc. (per FDA), Titusville, NJ, 2013.
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Galantamine (Razadyne®)
• Similar efficacy to donepezil but may have increased
GI side effects
 Counsel patients to take with food
 Maintain adequate hydration
• Prevents breakdown of ACh and works by stimulating
nicotinic receptors in the brain
 Improves nicotinic transmission and increases release
of more ACh
Product Information: RAZADYNE(R) oral tablets, oral solution, galantamine hydrobromide oral tablets, oral solution. Janssen Pharmaceuticals, 33
Inc. (per FDA), Titusville, NJ, 2013.
Target (Effective) Doses
• Donepezil (Aricept) = 5 – 10 mg
• Galantamine (Razadyne) = 16 – 24 mg
• Rivastigmine (Exelon) = 6 – 13.3 mg
• Interruption of therapy for > 3 days requires retitration from the starting dose
 Increase dose at recommended intervals to avoid
possibility of significant adverse effects
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Monitoring
 Improvement in cognitive performance

MMSE & caregiver impression at 4 to 6 weeks then every 6
months
 s/sxs of bradycardia or AV block
 s/sxs of gastrointestinal bleeding; especially with
history of ulcer disease or concomitant NSAID use
 Hepatic and renal function
 Body weight (rivastigmine)
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Discontinuation of Therapy
 Clinical controversy: when to discontinue therapy?
 Generally administer for 8-12 weeks at
recommended or maximum tolerated dose
 Review patient’s response with family/caregivers
 Continue treatment if benefit is noted either on
bedside testing or by the family/caregiver
 Consider stopping treatment if:
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No benefit, poor compliance, persistent side effects
(diarrhea, bradycardia, weight loss, etc.), severe
decline in functional status, hepatic failure
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Treatment Options
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Acetylcholinesterase inhibitors
NMDA antagonist
Combination regimens
Other medications
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NMDA Antagonist: Memantine
• N-methyl-D-aspartate (NMDA) receptor antagonist
• Modifies function of NMDA brain receptor to ↓ the
negative effect of having too much exposure to the
brain chemical glutamate
• ↑ glutamate = ↑ death of nerve cells which can
worsen memory loss
• Appears to be neuroprotective
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MOA of Memantine
http://development.epgonline.org/
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Memantine
®
(Namenda )
 Used in moderate-severe dementia
•
Little evidence that patients with milder disease
benefit from memantine
 Appears to have fewer side effects than
acetylcholinesterase inhibitors
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Dizziness is the most common side effect
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Confusion and hallucinations have been reported in a
small amount of patients
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Memantine
®
(Namenda )
 Available in brand-only
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Oral IR Tablet: 5 mg & 10 mg
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Oral XR Capsule: 7 mg, 14 mg, 21 mg, & 28 mg
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Initiate at 5 mg once daily
Increase by 5 mg/day as tolerated at 1 week intervals
Target dose = 20 mg/day (10 mg BID)
Initiate at 7 mg once daily
Increase by 7 mg/day as tolerated at 1 week intervals
Target dose = 28 mg once daily
Oral Solution: 2 mg/mL
•
Same as IR tablet
Product Information: Namenda. Forest Pharmaceuticals, Inc. (per FDA), St. Louis, MO, 2014.
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Memantine
®
(Namenda )
 Dose adjust for renal impairment (CrCl < 30 mL/min)
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Oral IR Tablet: 5 mg BID
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Oral XR Capsule: 14 mg once daily
 Administered with or without food
•
Can open XR capsule and sprinkle contents on
applesauce
 Monitoring: improvement in cognitive function and
activities of daily living is indicative of clinical response
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Memantine Antitrust Lawsuit

Actavis previously announced plan to discontinue the sale of
Namenda (IR) tablets in August 2014
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Currently still selling Namenda tablets due to court order
(which they are appealing)
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Company accused of “forcing patients to switch to the newer
version of the widely used medicine to thwart competition
from generic manufacturers” –IR patent expires April 2015

Actavis claims “less frequent dosing is a good thing for
patients” and admitted that “the switch would make it harder
for generic manufacturers to gain market share”
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Pollack, Andrew. Judge rules drug maker can’t shelve old pill [Internet]. 2014 Dec 11[cited 2015 March 10). Available from:
http://www.nytimes.com/2014/12/12/business/judge-says-actavis-must-continue-to-sell-namenda-a-drug-for-alzheimers-disease.html?_r=0
Treatment Options
•
•
•
•
Acetylcholinesterase inhibitors
NMDA antagonist
Combination regimens
Other medications
44
Combination Regimens
 The combination of an AChEI and memantine can be
used in advanced disease or if the person does not
respond to an AChEI by itself
•
Evidence (and its interpretation) of adding memantine to
acetylcholinesterase inhibitors is mixed
 Namzaric, a fixed-dose combination of extendedrelease memantine and donepezil approved in
December 2014
•
Two strengths: 28/10 mg and 14/10 mg
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Indicated for treatment of mild-moderate AD in patients
already taking the two drugs
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Combination Regimens
http://dailymed.nlm.nih.gov/dailymed/index.cfm
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Treatment Options
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•
•
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Acetylcholinesterase inhibitors
NMDA antagonist
Combination regimens
Other medications
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Other Medications
 Lack of evidence or positive outcomes associated with
the following agents discourages their use for
treatment of AD (until further data is available):
• Estrogen-based therapy
• Vitamin E (α-tocopherol)
• Selegiline
• Anti-inflammatory drugs
• Ginkgo biloba
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The Future of AD
 Failure rate for Alzheimer’s disease drugs during 20022012 was 99.6%
 Clinical trials currently being conducted
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Drugs in development aim to prevent or modify AD itself
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Need more patient volunteers and federal research funding
 “Alzheimer’s diagnostic tests inch forward, but
treatments are still lacking”
Harrington, Rebecca. Scientific American. 27 Feb 2015. Available from: http://www.scientificamerican.com
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Conclusion
 No cure for Alzheimer’s Disease: medications can help
slow the progress of cognitive decline
 Rule out other causes and review patient profile for
medications that can temporarily cause or worsen
symptoms of AD
 Two types of FDA-approved medications for AD
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AChEIs: donepezil, galantamine, rivastigmine, (tacrine)
NMDA antagonist: memantine
Combination AChEI + NMDA antagonist: namzaric™
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