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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

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Overview

• 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 

Background

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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: 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 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

• 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

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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

Management of Alzheimer’s Disease

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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.

Medications to Avoid

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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

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

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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

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

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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

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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

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Treatment Options

• 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

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

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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, Inc. (per FDA), Titusville, NJ, 2013.

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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

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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:• 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

• 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 Memantinehttp://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

• Dizziness is the most common side effect

• Confusion and hallucinations have been reported in a small amount of patients

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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.

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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

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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

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Treatment Options

• Acetylcholinesterase inhibitors• NMDA antagonist• Combination regimens• Other medications 

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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

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Combination Regimens

http://dailymed.nlm.nih.gov/dailymed/index.cfm

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Treatment Options

• 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 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

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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• AChEIs: donepezil, galantamine, rivastigmine, (tacrine)• NMDA antagonist: memantine• Combination AChEI + NMDA antagonist: namzaric™