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1
Alzheimer’s Disease Therapy
Maine Pharmacy Association Spring ConventionMarch 20, 2015
Cassandra White, PharmD, BCACP
Assistant Professor of Pharmacy PracticeHusson University School of Pharmacy
Clinical Pharmacy SpecialistVA Maine Healthcare System
2
Overview
• Alzheimer’s Disease background• Management of Alzheimer’s Disease patients• Medications to avoid• Treatment options
Acetylcholinesterase inhibitors NMDA antagonist Combination regimens Other medications
3
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
Background
5
Dementia
• Alzheimer’s Dementia
• Vascular Dementia
• Lewy Body Dementia
• Parkinson’s Dementia
• Frontotemporal Dementia
6
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
7
Cognitive Assessment• Multiple tools to assess cognition
• Clinicians typically utilize: 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)
8
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 24-30 = No cognitive impairment 17-23 = Mild cognitive impairment 10-16 = Moderate cognitive impairment < 10 = Severe cognitive impairment
9
MoCA• Freely accessible online and in several languages at
www.mocatest.org
• 8 domains: Visuospatial/executive, naming, short-term memory (recall), attention, language, abstraction, short-term memory (retention), & orientation
• Maximum score = 30 26-30 = No cognitive impairment 18-25 = Mild cognitive impairment 10-17 = Moderate cognitive impairment < 10 = Severe cognitive impairment
10
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
Management of Alzheimer’s Disease
12
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
13
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.
Medications to Avoid
15
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!
16
Medications to Avoid: Examples
• Antiemetics Dimenhydrinate, meclizine, promethazine, scopolamine
• Tricyclic Antidepressants Amitriptyline, doxepin, imipramine, nortriptyline
• Antiparkinsonian Anticholinergics Benztropine, trihexyphenidyl
• Antipsychotics* Clozapine, olanzapine, thioridazine, chlorpromazine
Pharmacist's Letter 2008;24(5):240510.
*Preferred antipsychotic agents when used to treat behavioral problems inelderly with dementia include: Haloperidol & Risperidone
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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
Pharmacist's Letter 2008;24(5):240510.
Treatment of Alzheimer’s Disease
19
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
20
Benefit of Therapy
Birks J. Cholinesterase Inhibitors for Alzheimer’s Disease (Review). The Cochrane Library 2012 Issue 5.http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1842
Placebo
AChEI +/- Memantine
21
Treatment Considerations
• Decision to initiate treatment and the choice of agent must be individualized
• If pharmacotherapy is initiated, benefit should be seen within three months
Treatment considered successful if memory remains unchanged for 6 months
Quality of life Treatment goals Potential benefit
Adverse effects Cost Comorbid conditions
American Psychiatric Association
22
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
Ann Intern Med 2008; 148:370-8
23
Treatment Options
• Acetylcholinesterase inhibitors• NMDA antagonist• Combination regimens• Other medications
24
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
25www.dementiaguide.com/
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
26
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
27
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
28
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.
29
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”
30
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
31
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
32
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.
33
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, Inc. (per FDA), Titusville, NJ, 2013.
34
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 re-titration from the starting dose
Increase dose at recommended intervals to avoid possibility of significant adverse effects
35
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)
36
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:• No benefit, poor compliance, persistent side effects
(diarrhea, bradycardia, weight loss, etc.), severe decline in functional status, hepatic failure
37
Treatment Options
• Acetylcholinesterase inhibitors• NMDA antagonist• Combination regimens• Other medications
38
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
39
MOA of Memantinehttp://development.epgonline.org/
40
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
• Dizziness is the most common side effect
• Confusion and hallucinations have been reported in a small amount of patients
41
Memantine (Namenda®) Available in brand-only
• Oral IR Tablet: 5 mg & 10 mg • 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)
• Oral XR Capsule: 7 mg, 14 mg, 21 mg, & 28 mg• 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.
42
Memantine (Namenda®) Dose adjust for renal impairment (CrCl < 30 mL/min)
• Oral IR Tablet: 5 mg BID
• 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
43
Memantine Antitrust Lawsuit Actavis previously announced plan to discontinue the sale of
Namenda (IR) tablets in August 2014
Currently still selling Namenda tablets due to court order (which they are appealing)
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”
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
44
Treatment Options
• Acetylcholinesterase inhibitors• NMDA antagonist• Combination regimens• Other medications
45
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 extended-release memantine and donepezil approved in December 2014
• Two strengths: 28/10 mg and 14/10 mg
• Indicated for treatment of mild-moderate AD in patients already taking the two drugs
46
Combination Regimens
http://dailymed.nlm.nih.gov/dailymed/index.cfm
47
Treatment Options
• Acetylcholinesterase inhibitors• NMDA antagonist• Combination regimens• Other medications
48
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
49
The Future of AD Failure rate for Alzheimer’s disease drugs during 2002-
2012 was 99.6%
Clinical trials currently being conducted
• Drugs in development aim to prevent or modify AD itself
• 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
50
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• AChEIs: donepezil, galantamine, rivastigmine, (tacrine)• NMDA antagonist: memantine• Combination AChEI + NMDA antagonist: namzaric™