1. Alzheimer’s Disease Therapy Maine Pharmacy Association Spring Convention March 20, 2015 Cassandra White, PharmD, BCACP Assistant Professor of Pharmacy Practice Husson University School of Pharmacy Clinical Pharmacy Specialist VA Maine Healthcare System 1

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 2

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 3

4. Background

5. Dementia Alzheimer’s Dementia Vascular Dementia Lewy Body Dementia Parkinson’s Dementia Frontotemporal Dementia 5

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 6

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) 7

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 8

9. MoCA Freely accessible online and in several languages at www.mocatest.org 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 9

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: 10 Cut-Off≥ 26< 26 Group (n) Normal controls (90) Mild Cognitive Impairment (94) Alzheimer’s Disease (93) MoCA8790100 MMSE1001878 http://www.mocatest.org/normative_data.asp

11. 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 12

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 13 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.

14. Medications to Avoid

15. 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! 15

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 16 Pharmacist's Letter 2008;24(5):240510. *Preferred antipsychotic agents when used to treat behavioral problems in elderly with dementia include: Haloperidol & Risperidone

17. 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 17 Pharmacist's Letter 2008;24(5):240510.

18. 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 19

20. Benefit of Therapy 20 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 21  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 22 Ann Intern Med 2008; 148:370-8

23. Treatment Options Acetylcholinesterase inhibitors NMDA antagonist Combination regimens Other medications 23

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) 24 *Tacrine, the first cholinesterase inhibitor approved in 1993, is rarely used now due to its potential to cause liver damage

25. www.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 25

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 26

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 27

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 28 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” 29

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 30

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 31 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 32 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 33 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 34

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) 35

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 36

37. Treatment Options Acetylcholinesterase inhibitors NMDA antagonist Combination regimens Other medications 37

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 38

39. MOA of Memantine 39 http://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 40

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 41 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 42

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” 43 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 44

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 45

46. Combination Regimens 46 http://dailymed.nlm.nih.gov/dailymed/index.cfm

47. Treatment Options Acetylcholinesterase inhibitors NMDA antagonist Combination regimens Other medications 47

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 48

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” 49 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™ 50