Effectiveness & Use of Cholinesterase Inhibitors in

Dementia

Dr. Donna Kay Buna, Pharm D Dr. Dean Foti, MD, FRCP(C)

February 22, 2012 Some graphs are not included in this handout

because of copyright

Disclosures for Dr. Buna

• Paid honorarium from MSD, Glaxo and Pfizer

Disclosures for Dr. Dean Foti

• Honoraria for speaking engagements

• Consultant for Canadian Advisory Boards

• No stock or financial interests

• Novartis Canada • Pfizer Canada

Learning Objectives

• Role of medications in management of Mild Cognitive Impairment (MCI) and dementia

• Understand when initiation, discontinuation, or switching of cholinesterase inhibitors is appropriate

Outline

• Overview of the drugs, benefits, expectations • Optimizing therapy • Counseling Points • Stopping, switching and when to avoid using

them • Lots of time for questions!

Chertkow H. Diagnosis & treatment of dementia: Introduction. CMAJ 2008;178(3):316.

The prevalence of dementia will triple by 2031!

dkbuna 2010

Pharmacotherapy

• Cholinesterase Inhibitors – Donepezil (Aricept®) – Rivastigmine (Exelon®) – Galantamine (Reminyl®)

• Memantine (Ebixa®)- NMDA antagonist

dkbuna 2010

Mechanism of Action

Cholinesterase Inhibitors

ChAT=choline acetyltransferase Ach=acetylcholine AChE=acetylcholinesterase VAChT= vesicles of ChAT nα7AChR= nicotinic Ach receptor M1AChR= muscarinic receptor HACU= high affinity choline transporter AChEI=acetylcholinesterase inhibitor

Adapted Figure 1.Beyond the Cholinergic Hypothesis: Do Current Drugs Work in AD? CNS Neuroscience & Therapeutics 2010;16:235-245.

• First CHEI on the market – August 1997 • Indicated for mild, moderate and severe AD • Starting dose 2.5-5mg and titrate up to maximum of 10mg

daily • Extensively metabolized to 4 metabolites; 2 active; minor

substrates for Cytochrome P450 – 2D6 & 3A4 – not usually clinically significant drug interactions.

• No dose adjustments necessary in hepatic or renal dysfunction

• Best tolerated of the 3 available

Donepezil 5 & 10mg regular tablets 5 & 10mg rapidly disintegrating tablets

Approved in Canada since ~ 2000 Inhibits both ACHE and BuCHE-”pseudo-irreversible” Indicated for mild to mod AD and mild to mod Parkinson’s

dementia Start 1.5mg twice daily, increase by 3mg/day q4 weeks to MAX

of 12mg/day Minimally involved in cytochrome P450 systems , so reduced

risk of drug interactions No dose adjustment in renal or hepatic disease

Rivastigmine 1.5, 3, 4.5 and 6mg capsules 2mg/ml solution Also available generically – PMS, Ratio, Sandoz, Teva

• Exelon 5 – 5 cm2 patch contains 9mg base – release 4.6mg/ 24 hours

• Exelon 10 – 10 cm2 patch contains 18mg base – releases 9.5mg/24 hours

Introduced in 2007 Indicated for mild to mod AD Improved tolerability over oral formulation- 3x

fewer reports N/V IDEAL Study* Health Canada warning April 2010

*IDEAL. Int J Geriatr Psych 2007;22:456-67.

Introduced in 2001, indicated for mild-mod AD Unique dual mechanism-reversible competitor inhibitor ACHE AND

allosteric modulator of nicotinic receptor Start with 8mg ER daily and titrate up to 8mg to MAX 24mg/day Extensively metabolized by cytochrome P450 – 2D6 and 3A4 to

metabolites of low activity Hepatic insufficiency; Max dose 16mg/day in mod disease (C-P 7-0)

and not recommended in severe disease (C-P 10-15) Renal insufficiency: Max dose 16mg/day in mod disease; not

recommended in severe disease (CrCL < 10 mL/min)

• Galantamine • 8, 16, 24mg ER

tablets • Generic - Patriot

Canadian Dementia Guidelines 2007

14.Recommendations regarding the use of cholinesterase inhibitors

a) All three cholinesterase inhibitors available

in Canada are modestly efficacious for mild to moderate AD. They are all viable treatment option for most patients with mild to moderate AD. (Grade A, Level I)

benefit no benefit

Efficacy-Cognitive Improvement

Lanctot et al, CMAJ, 2003

Donepeziln=134 125 121 (134) Placebo n=140 129 126 (140)

Mod-Severe AD: Donepezil v. Placebo Activities of Daily Living

Feldman et al 2000

Galantamine Reduces Caregiver Time by One Hour per Day in Mild-Mod AD

*P < .05 vs baseline.

–50

–40

–30

–20

–10

0

10

20

30

Change From Baseline in Daily Time

Spent Assisting With

ADL (min)

*

Sano M, Wilcock GK et al., Int J Ger Psy, 2003:942-50.

Initiating Cholinesterase Therapy: It’s all about expectations

• 20 % will improve noticeably • 50 % will remain unchanged • 20 % will continue to worsen • 10-15 % are intolerant Expect the majority to remain unchanged

ChEI’s: Use Across Dementias

• Mild - Moderate AD • Moderate - Severe AD • Dementia with Lewy Bodies &

Parkinson Disease Dementia • Vascular/Mixed Dementia

Which ChEI to use for mild-moderate AD?

• All equal efficacy • Ask patient and family: Pill or Patch? • Influences:

– Familiarity – Cost – Side effect profile

Optimizing Therapy

• Early vs Late start • Hi dose vs low dose • Low dose start with high dose

“rescue” later • Adherence • Counseling – set expectations; ensure

adherence

Early VS Late Treatment

“Defining optimal treatment”. Alzheimer’s & Dementia 2011;7:177-184.

“Defining optimal treatment”. Alzheimer’s & Dementia 2011;7:177-184

High Dose vs Low Dose

“Defining optimal treatment”. Alzheimer’s & Dementia 2011;7:177-184

Lower dose Start with “Rescue” Later

Compliance/Adherence

• Average treatment duration 4-5 months • Susceptible to poor compliance – age,

comorbidities, memory deficits, pill burden

• Educate patient/family/caregivers- establish expectations

• Ensure a follow-up plan

Counseling Point Symptomatic, not curative

Higher Function

Lower Function

Outcome

Time

Symptomatic

No Treatment

Can delay progression

dkbuna 2010

Counseling point Some respond, some don’t

Responder Average response = mild improvement or same for 1 year (Brain Cancer)

Non-Responder

(Continued worsening)

Super Responder (Much better)

Dalziel B. Dementia Newsletter for Physicians 2008; 6(4):3-4.

25%

25% 50%

dkbuna 2010

Counseling Point How do you know if it is working?

• What target symptoms are important to the patient & their family? – A- ADL, functional measure – B-behavioral – C-cognitive

• Document at baseline • Persist for the duration to realize long

term benefits.

dkbuna 2010

Counseling Point Watching for side effects

• Start low, titrate up if tolerated • Visit physician at 4-6 weeks to assess • Common side effects:

– N/V, diarrhea – Anorexia with weight loss – Sleep disturbances – Muscle/leg cramps – Syncope/dizziness

dkbuna 2010

Counseling Point 6 month Follow-up

• Assess if it is working • Compare to baseline • Documentation required to continue

coverage • Key components:

– FMMSE still between 10-26 – GDS still between 4 & 6 – Global assessment

dkbuna 2010

How long to continue ChEI’s in Alzheimer Disease?

• No specific reason to discontinue if function & behaviour reasonable

• NOT correct that only effective for 6-12 months • Trial discontinuation not recommended • Consider discontinuation when limited

contribution to self-care and interactions

The Declining Patient • Consider alternate medication when:

– significant clinical progression – caregiver dissatisfaction – medication intolerance

• Treatment Options

– Switch ChEI’s – Memantine (combined with ChEI > monotherapy)

Should you change ChEI’s?

• Generally not too helpful in gradually declining patient on prolonged therapy

• Switch ChEI’s when: – Intolerant due to side effects – Significant early progression: ‘nonresponder’ – family strongly requests and is motivated

How to Switch ChEI’s

• Generally no wash out period required when switching for declining patient – Usual titration schedule for new medication – When changing from high dose donepezil or

rivastigmine, start at galantamine ER 16mg • Combining ChEI’s not recommended • When switching for tolerability issues, wait

about one week for resolution of s/e’s

When not to use ChEIs?

• Normal Aging • Mild Cognitive Impairment • Frontal-temporal lobar dementias

(eg Pick’s disease)

MCI Definition

• Memory complaint • Objective memory impairment • Normal general cognitive function • Activities of daily living generally intact • Not demented

Petersen et al., Neurology, 2001

Mild Cognitive Impairment

MCI Becoming Dementia

• MCI is a high risk state for future dementia – 10 % per year over the first 5 years

• 30 % stay the same

• 20 % of MCI may revert to normal

Should MCI patients be treated with cholinesterase inhibitors?

• Generally Not • Clinical trials with all 3 ChEI’s negative • …..but……

– Positive early results from donepezil MCI trial – Some patients are very amnestic and have early

AD but do not meet the criteria for dementia

Summary

• ChEI’s have modest but significant benefits in meaningful outcomes to patients and families across a spectrum of dementia severities and types

• Tolerability and formulation of ChEI’s vary between patients – try different ones

Questions

• Please type your questions below in the Q&A box