1. Dementia in the LTC Environment: Choices in Management

2. “Doctor, just what is Dementia?” “Globally decreasing cognitive function.”

3. Symptoms of Alzheimer’s Disease 1.Memory loss affecting job skills or other activities 2.Difficulty performing familiar tasks 3.Problems with language 4.Disorientation regarding time or place 5.Impaired judgment 6.Problems with abstract thinking 7.Misplacing objects 8.Changes in mood or behavior 9.Changes in personality 10.Loss of initiative 1.Memory loss affecting job skills or other activities 2.Difficulty performing familiar tasks 3.Problems with language 4.Disorientation regarding time or place 5.Impaired judgment 6.Problems with abstract thinking 7.Misplacing objects 8.Changes in mood or behavior 9.Changes in personality 10.Loss of initiative

4. Alzheimer’s Disease in the Long-Term Care (LTC) Setting Large patient population but overall low diagnosis and treatment l 1.8 million patients in skilled nursing facilities 70-90% incidence rate for AD 22% of those with AD are diagnosed * 30% of those diagnosed are treated with AChI’s Thus, only 6-7% of potential patients treated with AChI’s *Beverly Nursing Home Analysis, 2002.

5. Know Thy Diagnostic Code$! ► Alzheimer’s disease = 331.0 ► Mild Cognitive Impairment = 780.93 (Memory Loss) ► Frontotemporal / Picks = 331.11 ► Senile degeneration of the brain = 331.2 (useful for initial encounters when diagnosis uncertain) ► Dementia with Lewy bodies = 331.82 ► Parkinson’s disease = 332.0 ► Vascular Cognitive Impairment / Dementia = 438.0 (cognitive deficits causing late effects in cerebrovascular disease)

6. AAN Practice Parameters 2001 Evidence supports the following tests in the routine evaluation of the demented patient: ► Complete blood cell count ► Serum electrolytes ► Glucose: BUN/creatinine ► Serum B 12 levels ► Liver function tests ► Thyroid function tests ► Depression screening Knopman DS, DeKosky ST, Cummings JL, et al. Neurology. 2001(May 8);56(9):1143-1153

7. Short Geriatric Depression Scale ► Are you basically satisfied with your life? ► Do you often get bored? ► Do you often feel helpless? ► Do you prefer to stay at home, rather than going out and doing new things? ► Do you feel pretty worthless the way you are now? 2 or more “yes” answers [“no” to #1] may signal significant clinical depression! Hoyl MT, Alessi CA, Harker JO, et al. J Am Geriatr Soc. 1999(July);47(7):873-878

8. Scales and Evaluation Instruments to Monitor Natural History of Alzheimer’s Disease ► Mini-Mental State Examination (MMSE) ► Function Activities Questionnaire (FAQ) ► Physical Self-Maintenance Scale and Instrumental Activites of Daily Living ► Neuropsychiatric Inventory (NPI) ► Alzheimer’s Disease Assessment Scale: Cognitive Section (ADAS-COG) ► Severe Impairment Battery (SIB)

9. MMSE “Cutoff” Scores at Lower Quartile by Education and Age 2526272728  16 23232526279-12 21222224245-8 15161819190-4  85 80-8475-7970-7465-69 Age (Years) Education(Years) Crum RM, Anthony JC, Bassett SS, Folstein MF. JAMA. 1993(May 12);269(18):2386-2391

10. Cognitive MildModerateSevere 1.Santacruz KS, Swagerty D. Am Fam Physician. 2001;63(4):703-713. 2.Alzheimer’s Society of Canada. Available at: www.alzheimer.ca/english/disease/progression-3stages.htm. Accessed 8/23/04. Emotional Behavioral Function Mood swings Personality changes Irritability Anxiety Depression Extreme personality changes Anxiety and apprehension Suspiciousness, paranoia, hostility, and anger Possible withdrawal Delusional behavioral Diminished short-term memory Language and speech difficulties (aphasia) Agnosia Limited attention span Diminished short-term and long-term memory Increased language and speech difficulties Declining ability to concentrate Severe memory impairment Severe impairment of verbal communication skills Inability to process information Misidentification Passiveness Restlessness Impaired judgment Repetitious behaviors Increased passivity Restlessness, pacing, wandering Disinhibition Increased potential for hostility and aggression Moaning and gesturing replace verbal communication Apraxia Impairment of coordination Initial signs of difficulties with ADLs Impaired ability to perform ADLs Urinary incontinence Sleep disruptions Perceptual disturbances Dependent on caregiver for ADL’s; bedridden Urinary & fecal incontinence Sleeps longer and more often Difficulty eating and swallowing Stages of Alzheimer’s Dementia

11. Unpaid Community Caregiver Time: Relation to Alzheimer’s Dementia Severity Hux MJ, et al. CMAJ. 1998;159(5):457-465. SevereModerateMild MMSE 21-26 MMSE 10-14 Hours per Day Severity of Alzheimer’s Dementia MMSE <10

12. Nursing Time in Long-Term Care per Patient, per 8-Hour Shift ► RN: 8 minutes ► LPN: 12 minutes ► Nurse Aide: 40 minutes CMS: 1999 US national average.

13. Pathophysiologic Hypothesis of AD MitochondrialDysfunction Inflammation Other Factors  -Amyloid Glutamate Excitotoxicity Cell Damage/ Loss (ACh deficit) Dementia NeurofibrillaryTangles Serotonin Loss Norepinephrine Loss Loss Lipid Metabolism HormonalChanges Other Factors

14. Cholinergic Hypothesis of AD ► Memory disturbance caused by loss of cholinergic neuronal functioning ► Muscarinic antagonists (scopolomine) produce memory disturbance in normals ► Procholinergic agents reverse scopolomine and enhance memory in AD

15. Examples of Drugs with Anticholinergic Effects ► Antispasmodics ► Tricyclic antidepressants ► Antihistamines ► Low-potency conventional antipsychotics ► Hyoscyamine (Cystospaz, Urised) ► Belladonna alkaloids ► Warfarin ► Furosemide, Nifedipine, Triamterene, HCTZ Lu & Tune, L.I. Am J Geriatr Psychiatry 11: 458-461: 2003.

16. Medications Reported to Cause Psychotic Symptoms ► Levodopa/carbidopa (Sinemet) ► Cimetidine (Tagamet) ► Anti-inflammatory agents ► Antiparkinson agents ► Antihistamines ► Tricyclic antidepressants ► Anticonvulsants ► Antiarrhythmics

17. Benadryl Use in the Inpatient Elderly ► Prospective study of 426 hospitalized patients age 70 and over ► 114 received Benadryl during hospital stay ► 68% for sleep, 21% for allergic reaction, 3% for puritis ► Cognitive decline observed in 42% of Benadryl treated patients and 24% on non-Benadryl treated patients ► Observed declines included delirium, disorganized speech, inattention, abnormal psychomotor activity and altered sleep-wake cycles Archives of Internal Medicine, 2001; 161:2091-2097

18. Normal Cholinergic Function AChE Acetyl CoA Choline ACh Presynaptic neuron Synaptic cleft Postsynaptic neuron Acetate Choline + + ACh AChE ChAT MR NR MRNR Glial cell BuChE ACh ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor. Adapted from Adem, 1992.

19. Flynn et al, 1995; Perry et al,1978; Rodriguez-Puertas et al, 1997; Whitehouse et al, 1982. Major Cholinergic Changes in AD ► Depletion of ACh: especially in moderate to severe disease stages ► Decline in choline acetyltransferase (ChAT) activity ► Loss of cholinergic neurons l Loss of muscarinic (M2) receptors l Loss of nicotinic receptors (nAChR) ►  AChE ►  BuChE

20. Dementia Symptom Continuum MildModerateSevere 00.511.522.5365.554.543.598.587.576.5 Years from Diagnosis Minimum Maximum Adapted from Mintzer J et al., 2002 AAGP Annual Meeting 2002 Adapted from Doraiswarny PM et al. Neurology, 1997:48 1511-1517. Cognitive Ability Functional Ability Behavioral Problems Caregiver Time

21. ► Improved ► Unchanged (symptoms are no better or worse) ► Slightly worse, but better than expected with no treatment ► With no treatment, the patient would be expected to decline more rapidly Goals of Alzheimer’s Disease Therapy Therapy may be working if the patient is

22. Mean Change from Baseline Exelon®6–12mg/day Placebo Pooled studies (OC analysis); *p<0.05; **p<0.02; ***p=0.003 Potkin SG, et al. The World Alzheimer Congress 2000, July 9-13, 2000. Washington DC. ‡ PDS = Progressive Deterioration Scale; GDS = Global Deterioration Scale n=158n=180n=189n=193n=142n=149 1 0 –1 – 2 – 3 – 4 – 5 – 6 – 7 – 8 Mild Moderate Severe GDS  3 GDS = 4 GDS  5 * ** *** Effect of Rivastigmine on ADL by Disease Severity: PDS ‡ Mean Change at Week 26

23. Grossberg GT, et al. The Gerontological Society of America 52 nd Annual Scientific Meeting, November 19-23, 1999. San Francisco, California. Impact of Disease Severity on Response of ADL to Rivastigmine Treatment Mild ADModerate ADSevere AD Item(GDS ≤3)(GDS = 4)(GDS ≥5) Ability to Handle Moneya Ability to Tell Timea Time Spent on Hobbiesa Participation in Family Financesa Ability to Dress Properlya a Reduced Forgetfulnessa a Time Rearranging Objectsa a Ability to Use Phonea Confusion in Different Settingsa Proper Eating Mannersa PCP-3

24. Rivastigmine Long-term Effects On Cognition In Moderately Severe Patients ADAS-Cog MEAN CHANGE Study B352 (OC) patients with baseline GDS >5 *P<0.05 rivastigmine vs placebo. † A negative value indicates improvement. Sohn et al. In: Proceedings of the CPNP. April 2000. Study Week Mean Change From Baseline † * * * * * * * * * All Patients Receive Rivastigmine

25. Donepezil Use in Moderate to Severe AD ► H. Feldman et al. ► Double blind study of donepezil in moderate to severe AD patients ► Neurology: Aug 2001:57:613-620 ► MMSE 5-17 (Average MMSE = 11.7) ► All patients in community or assisted living setting ► Average age 73.6

26. Lease squares (LS) mean ± SE change from baseline scores for donepezil- and placebo-treated patients through 24 weeks of treatment, as measured using the standardized Mini-Mental State Examination (MMSE) and Severe Impairment Battery (SIB); LOCF = last observation carried forward. Cognitive Outcome MMSE LS Mean Change From Baseline ± SE Donepeziln=131127119(131) Placebon=139129124(139) 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 01224 Week 24 LOCF Study Week P=0.0004 P<0.0019 P<0.0001 Clinical decline Baseline Clinical improvement Placebo Donepezil Feldman et al. Neurology. 2001;57:613-620.

27. Behavior: NPI Domains *P<0.05 vs placebo. ClinicalImprovement ClinicalDecline Baseline LS Mean Change From Baseline Item Score at Week 24 (ITT LOCF) -2.0 -1.5 -0.5 0.0 0.5 1.0 * * * Donepezil Placebo Delusions Hallucinations Agitation/aggression Elation Disinhibition Irritability Aberrant motor behavior Night-time behavior Appetite/eating Depression Anxiety Apathy Feldman et al. Neurology. 2001;57:613-620.

28. Severe Impairment Battery (SIB) Clinical improvement Clinical decline Baseline 241812840ITT LOCF Study week -6 -4 -2 0 2 4 6 LS Mean Change From Baseline ± SE P=0.0078 P=0.0051 P<0.0001 P<0.0009 P<0.0001 P=0.0001 Donepezil Placebo

29. DAD Basic ADL Results Clinicalimprovement Clinicaldecline Baseline 2412 Study week ITT LOCF 0 -12 -10 -8 -6 -4 -2 0 2 4 LS Mean Change From Baseline ± SE P=0.0025 P=0.0011 P<0.0001 Donepezil Placebo

30. Donepezil Use in Nursing Homes ► P. Tariot et al. ► Placebo-Controlled, 6-Month, Multicenter, Nursing Home Study of Donepezil ► MMSE range 5-26 (average 14.4) ► J Am Geriatric Soc. 2001;49:1590-1599

31. 14 16 BaselineWeek 24 PSMS PSMS Score Donepezil (n = 103)Placebo (n = 105) Effect of Donepezil on ADLs in Nursing Home Patients With Mild to Severe AD Decline Improvement ► No statistically significant differences were seen between patients treated with donepezil and those given placebo at any time point Mean MMSE=14.4 PSMS = Physical Self-Maintenance Scale. Tariot PN et al. J Am Geriatr Soc. 2001;49:1590-1599. (MMSE 5-26)

32. Mean Change From Baseline NPI-NH Individual Item Score at Week 24 Delusions Hallucinations Agitation/ aggression Depression/ dysphoria Anxiety Elation/ euphoria Apathy/ indifference Disinhibition Irritability/ lability Aberrant motor behavior Night-time behavior Appetite/ eating Placebo (n = 105) Donepezil (n = 103) Improvement Baseline Decline ITT, LOCF analysis. NPI-NH=Neuropsychiatric Inventory Nursing-Home Version. *P  0.05 for second analysis; no significant difference on overall analysis. Effects of Donepezil on ADLs in Nursing Home Patients With Mild to Severe AD (MMSE 5-26) -3 -2 0 1 2 3 4 * Total NPI score at baseline Total NPI score at Week 24 Change from baseline in total NPI score 20.5 15.6 - 4.9 21.0 18.7 -2.3 PlaceboDonepezil Tariot PN et al. J Am Geriatr Soc. 2001;49:1590-1599.

33. Donepezil in the LTC Setting in Mild to Severe AD (MMSE 5-26) Study Week * * * * 0.8 24201612840 0.6 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 MMSE: Mean Change From Baseline Mean MMSE = 14.4. *P<0.05 vs placebo.. Donepezil Placebo Tariot PN et al. J Am Geriatr Soc. 2001;49:1590-1599

34. Rivastigmine Use in the Nursing Home ► 173 patients ► Multicenter nursing home trial ► 52 week study ► Open-label ► Patients begun at 1.5 mg bid with titration to 6 mg bid or max. tolerated dose ► Mean NPI-NH score = 15.8 ► Mean MMSE 9.3 Cummings J et al. Presented at American Psychiatric Association 2000 Annual Meeting. May 13 -18, 2000. Chicago, Ill.

35. Improve -3.5 -3 -2.5 -2 -1.5 -0.5 0 Agitation Irritability Anxiety Aberr. motor behavior Apathy Depression Delusion Disinhibition Hallucinations Euphoria Night-time behavior Appetite Mean Change from Baseline † † † † ** † † † Cummings J et al. Presented at American Psychiatric Association 2000 Annual Meeting. May 13 -18, 2000. Chicago, Ill. Effects of Rivastigmine on Behavior Following 52 Weeks of Therapy* * In patients with symptoms at baseline. † P<0.05 vs baseline. **P<0.001 vs baseline.

36. 0 5 10 15 20 25 30 35 Increased dose Terminated medication Antipsychotics (n = 55) Anxiolytics (n = 33) Antidepressants (n = 57) Reduced dose Patients taking psychotropic drugs during rivastigmine treatment (%) Nursing Home Patients at Week 52 Anand, Koumaras, Hartman 2000. Effects of Rivastigmine on Psychotropic Medication Use

37. Antipsychotic Drug Use Among Nursing Home Residents Taking Rivastigmine ► MDS data from 452 US nursing facilities from 2000-2002 ► Pts. With diagnosis of AD given rivastigmine vs those diagnosed but not given a cholinesterase inhibitor ► All patients began study antipsychotic naïve Narayanan et al. Antipsychotic Drug Use Among Nursing Home Residents Taking Rivastigmine. JAMDA 2006; Vol 7 No 1: 12-16.

38. Comparison of Baseline Characteristics Between Study Groups Rivastigmine (n=845) % Control (n=517) % P Value Sex Male3427.007 Female6673<.0001 Age <74 126 75-844832 >85 4062 MDS dist. Verbal dist. 3119<.0001 Sleep issues 125<.0001 Sad4027<.0001 Loss of interest 84.0093 Behav. sx 4536.0003 Narayanan et al. Antipsychotic Drug Use Among Nursing Home Residents Taking Rivastigmine. JAMDA 2006; Vol 7 No 1: 12-16.

39. Usage Pattern of First Antipsychotic Drug After Index Date Antipsychotic Drug Rivastigmine (n=845) % Control (n=517) % Any antipsychotic 8.617.0 Haloperidol0.22.7 Risperidone4.47.1 Olanzapine3.25.6 Quetiapine0.81.5 Each antipsychotic drug was initiated approximately twice as frequently in the control group than in the rivastigmine group. Narayanan et al. Antipsychotic Drug Use Among Nursing Home Residents Taking Rivastigmine. JAMDA 2006; Vol 7 No 1: 12-16.

40. Reasons for Changing ChE Inhibitors Tolerability concerns ► Sleep disturbances ► Muscle cramps, weakness ► Acute cholinergically mediated AEs, eg, nausea and vomiting ► Cardiovascular problems ► Extrapyramidal symptoms Safety concerns ► Drug-drug interaction ► Drug-disease interaction Declining long-term efficacy Rationale for Changing Cholinesterase Inhibitor Therapy Adapted from Emre. 2002; Inglis. 2001.

41. Aricept/Exelon Switching Study ► 382 outpatients with mild to moderately severe AD who failed to show sustained benefit within previous 12 months ► Median treatment period of 14 months at 10 mg/day, 5 mg/day if poorly tolerated ► 80% failed due to lack of efficacy, 11% due to tolerability problems, 9% for both ► Lack of benefit defined by minimum of 6 month decline of MMSE or noticeable loss of function

42. ► Exelon begun at 1.5 mg bid and titrated every four weeks to max dose of 6 mg bid ► 56.2% responded via stabilization (30.1%) or improving (26.1%) based on Clinicians’ Global Impression of Change ► MMSE improved or stabilized in 48.9% ► Instrumental Activities of Daily Living Scale improved or stabilized in 57% ► Serious adverse events were reported in 2.4% ► 84.6% who were intolerant to donepezil tolerated rivastimine ► 54.5% who discontinued donepezil for lack of efficacy responded to rivistigmine Aricept/Exelon Switching Study

43. Nausea Vomiting Anorexia Diarrhea GalantamineDonepezil 12 6 3 11 Adverse Event (%) Placebo (n=868) Physicians’ Desk Reference ®, 2002; Wilcock GK, et al, 2000. 47 31 17 19 6-12 mg/d (n=1189) 12 4 0 7 Placebo (n=215) 37 20 10 7 24 mg/d (n=220) 63256325 Placebo (n=315) 19 8 7 15 10 mg/d (n=315) Rivastigmine Most Frequent Adverse Events with 1-Week Titration

44. Role of Glutamate in AD ► The normal activity of the neurotransmitter glutamate plays an integral role in the neural pathways associated with learning and memory ► In AD, abnormal glutamatergic may impair learning and may contribute to neuronal toxicity Greenamyre JT, et al. Prog Neuropsychopharmacol Biol Psychiatry. 1988;12:421-430.

45. Normal NMDA Receptor Transmission MagnesiumGlutamateCalcium Normal Rest Ca 2+ NMDA Receptor Noise Cognitive Activity Signal Detected NoiseSignal Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages 735-767, copyright 1999, with permission from Elsevier.

46. SignalNoise Chronic Neurodegeneration Impairment of Signal Detection Signal Not Detected Pathological Activation of NMDA Receptors NoiseRest Abnormal MagnesiumGlutamateCalcium Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages 735-767, copyright 1999, with permission from Elsevier. Pathological Activation of NMDA Receptors

47. Memantine Voltage Dependent Receptor Blocking Magnesium Physiological Magnesium Block MinorDepolarization Synaptic Activity Resting State Ca 2+ –70 mV –50 mV –20 mV Low to Moderate Affinity Antagonist Memantine (Ki = 0.5 µM) Memantine M M Ca 2+ M M Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages 735-767, copyright 1999, with permission from Elsevier.

48. Pathological Activation of NMDA Receptors Ca 2+ Memantine Blocks Pathological Glutamatergic Activation Memantine Allows Signal Detection NoiseNoise Ca 2+SignalNoiseRest Abnormal MagnesiumGlutamateCalcium Memantine M M M Memantine Selectively Blocks Pathological Activation of NMDA Receptors, but Does Not Impair Normal Transmission Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages 735-767, copyright 1999, with permission from Elsevier.

49. Pivotal Trials Study Design Monotherapy in Moderate to Severe AD 1 Combination Memantine and Donepezil in Mod. To Severe AD 2 Nursing Home Patients With Severe Dementia 3 Memantine dose 10 mg bid 10 mg bid (plus donepezil) 10 mg qd Duration in weeks 282412 MMSE range 3-145-14<10 Principal Efficacy Measures Global change Global changeCIBIC-PlusCIBIC-PlusCGI-C Cognition CognitionSIBSIB Function Function ADCS-ADL 19 BGP-Care 1.Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. 2.Tariot P, et al. JAMA. 2004;291:317-324. 3.Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146.

50. Memantine Monotherapy in Mod-Severe AD ► Male or female outpatients aged  50 years ► Diagnosis of probable AD consistent with DSM- IV, NINCDS-ADRDA criteria ► CT or MRI scan consistent with AD ► MMSE scores of 3 to 14 at screening and baseline ► Global Deterioration Scale (GDS), stages 5 or 6 ► Functional Assessment Staging (FAST),  6a Reisberg B, et al. N Engl J Med. 2003;348:1333-1341.

51. Withdrawal design Time Performance Randomized phase Placebo phase Placebo Active Symptomatic effect Disease-modifying effect Leber, 1997 Discrimination Between Disease Modification and Symptomatic Benefit Staggered-start design Time Performance Randomized phase Placebo phase Placebo Active Disease-modifying effect Symptomatic effect

52. Patients who switched from placebo to memantine improved relative to their projected rate of decline *p=0.048; ITT-OC analysis Cognition: SIB in Mod-Severe Monotherapy Double-Blind PhaseOpen-Label Extension -20 -15 -10 -5 0 SIB Score Mean Change from Baseline Worsening Improvement 122840524 * Week0 N=80 N=95 N=80 N=94 N=74 N=79 N=75 N=66 N=70 5 Memantine Placebo-memantine Placebo Reisberg B et al. N Engl J Med. 2003;348: 1333-1341. Ferris S et al. Presented at the 16th Annual Meeting of the American Association for Geriatric Psychiatry; Honolulu, Hawaii; March 1-4, 2003; Forest Laboratories, Inc. (Data on file)

53. ADCS-ADL (Modified) Score Mean Change from Baseline Open-Label Extension Patients who switched from placebo to memantine improved relative to their projected rate of decline *p=0.018; ITT-OC analysis -12 -10 -8 -6 -4 -2 0 2 N=80 N=95 N=80 N=95 N=75 N=80 N=75 N=66 N=71 012284052 Week Double-Blind Phase 4 * Memantine Placebo-memantine Placebo Improvement Worsening Reisberg B et al. N Engl J Med. 2003;348: 1333-1341. Ferris S et al. Presented at the 16th Annual Meeting of the American Association for Geriatric Psychiatry; Honolulu, Hawaii; March 1-4, 2003; Forest Laboratories, Inc. (Data on file) Function: ADCS-ADL Effect in Memantine Monotherapy for Mod-Severe AD

54. Patients who switched from placebo to memantine improved relative to their projected rate of decline; *p<0.001; ITT-OC analysis Double-Blind Phase Open-Label Extension 3.4 3.6 3.8 4.0 4.2 4.4 4.6 4.8 5.0 012284052 CIBIC+ Global Score Mean Change from Baseline N=95 N=79 N=95 N=75 N=80 N=65 N=74 N=69 N=79 Memantine Placebo-memantine Week Placebo * Improvement Worsening Reisberg B et al. N Engl J Med. 2003;348: 1333-1341. Ferris S et al. Presented at the 16th Annual Meeting of the American Association for Geriatric Psychiatry; Honolulu, Hawaii; March 1-4, 2003; Forest Laboratories, Inc. (Data on file) Global Impression: CIBIC+ Effect in Memantine Monotherapy for Mod-Severe AD

55. Completed n=172 (85%) * Withdrew n=30 (15%) Completed n=150 (75%) Withdrew n=51 (25%) Memantine+Donepezil n=202 Placebo+Donepezil n=201 Patients Randomized** n=404 Patients Treated n=403 *P=.011; a significantly higher number of patients taking memantine/donepezil completed the study, compared with those taking placebo/donepezil. Tariot P, et al. JAMA. 2004;291:317-324. Data on file, Forest Laboratories, Inc. Combination Memantine + Donepezil in Mod. to Severe (MMSE 5-14) AD Study **Ave. 2 yrs on donepezil Ave. > 9 mg/d Ave. > 9 mg/d

56. Results: Cognition—SIB *OC analysis. † LOCF analysis. Tariot P, et al. JAMA. 2004;291:317-324. Data on file, Forest Laboratories, Inc. Memantine + Donepezil Combination Therapy in Moderate to Severe AD n = Placebo+Donepezil Memantine+Donepezil 0481218 Treatment Week 24 Mean Change From Baseline in SIB Score End Point Improvement Deterioration * P<.001 † P<.001P=.006P<.001P=.030P=.057 198192190185181171198 n = 197194180169164153196

57. Results: Function—ADCS-ADL 19 *OC analysis. † LOCF analysis. Tariot P, et al. JAMA. 2004;291:317-324. Data on file, Forest Laboratories, Inc. 048121824 Mean Change From Baseline in ADCS-ADL 19 Score End Point Deterioration Placebo+Donepezil Memantine+Donepezil Treatment Week n = 198198190185181172198 197195182170163152197 † P=.028*P=.020P=.027P=.020P=.012P=.028 Improvement Memantine + Donepezil Combination Therapy in Moderate to Severe AD

58. Results: Global Change—CIBIC-Plus *OC analysis. † LOCF analysis. Data on file, Forest Laboratories, Inc. Deterioration Improvement 3.6 3.8 4.0 4.2 4.4 4.6 048121824 Memantine+Donepezil Placebo+Donepezil 4.8 End Point Mean CIBIC-Plus Score Treatment Week n = 198197190182180172198 196194181170164152196 † P=.027 *P=.028 P=.008 P=.123 P=.014 P=.032 Memantine + Donepezil Combination Therapy in Moderate to Severe AD

59. Memantine in Nursing Home Patients With Severe Dementia Design ► Eastern European, phase 3, multicenter (7), randomized, double-blind, placebo- controlled study Population ► 167 nursing home patients with severe primary dementia (AD or VaD), MMSE score <10 Treatment ► Memantine 10 mg/d or placebo ► 2-week titration (5  10 mg) Duration ► 12 weeks Principal Efficacy Measures ► BGP-Care, CGI-C, D-Test Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146.

60. Disposition of Patients: AD Population Memantine n=82 Completed n=78 (95.1%) Withdrew n=4 (4.9%) Completed n=80 (95.2%) Withdrew n=4 (4.8%) Placebo n=84 Patients Randomized n=166 Completed n=41 Completed n=38 TotalPopulation ADPopulation Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146. Data on file, Forest Laboratories, Inc. Memantine in Moderate to Severe Dementia Study

61. Memantine Significantly Reduces Care Dependence in Nursing Home Patients With Dementia Memantine Monotherapy in Nursing Home Patients with Severe Dementia † P=.012 * P=.010 P=.093P=.109P=.983 Improvement Worsening n = 828282807882 n = 848484828084 Placebo Memantine Treatment Week -6 -5 -4 -3 -2 0 1 2 014812End Point Mean (SEM) Change From Baseline *OC analysis. † LOCF analysis. Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146. Function: BGP-Care

62. Results: Global Change—CGI-C 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6 0412End Point Mean (SEM) Change From Baseline n = 82827882 n = 84848084 † P<.001 * P<.001 P=.006 Treatment Week Placebo Memantine Improvement Worsening *OC analysis. † LOCF analysis. Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146. Memantine Monotherapy in Nursing Home Patients with Severe Dementia

63. Results: Function—D-Test Frequency of Improvement (%) Mobility When Bed Is Made Ability of Standing Up Ability to Move Ability to Wash Ability to Take a Shower/Bath Ability to Dress Ability to Eat Fluid Intake Toilet Use Communication Understanding Communication Expression Orientation in Space Recognition of Persons Group Activities Hobbies/ Interest Undisturbed Sleep Behavior ** * OC analysis, n=151. *Trend to treatment difference. Assessed by Wilcoxon rank sum test on the detailed scale of change (P<.10). **Statistically significant treatment difference (P<.05). Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146. ** Memantine Monotherapy in Nursing Home Patients with Severe Dementia

64. Memantine Clinical Pharmacokinetics ► Bioavailability: 100% ► T max : 3 to 7 hours ► Protein binding: 45% ► T ½ : 60 to 80 hours ► PharmokineticsLinear ► Time to [C SS ]: within 21 days ► CSF/serum ratio = 0.52 ► MetabolismNo CYP450 ► Elimination57-82% Renal Source: Namenda package insert, Forest Pharmaceuticals, Inc.

65. Memantine Clinical Pharmacokinetics ► Can be administered with or without food ► Limited metabolism—eliminated mostly in urine as parent drug, metabolites inactive ► No or minimal effects on CYP450 isoenzymes ► No interactions with cholinesterase inhibitors ► Dose reduction in patients with moderate renal impairment should be considered ► Effect of severe renal impairment has not been evaluated and is not recommended HCTZ/TA = hydrochlorothiazide/triamterene Source: Namenda package insert, Forest Pharmaceuticals, Inc.

66. Tolerability Profile From Double-Blind, Placebo-Controlled Monotherapy Trials Adverse Events Reported in  5% of Either Treatment Group Agitation Accidental injury Fall Constipation Confusion Headache Adverse Event Any adverse event Dizziness Placebo(n=922) n (%) 624 (67.7) 98 (10.6) 98 (10.6) 42 (4.6) 31 (3.4) 28 (3.0) 50 (5.4) 64 (6.9) 49 (5.3) Memantine(n=940) n (%) 662 (70.4) 63 (6.7) 58 (6.8) 54 (5.7) 50 (5.3) 48 (5.1) 44 (4.7) 64 (6.8) Data on file, Forest Laboratories, Inc. No adverse event was reported at an incidence of  5% in the memantine group and  2x placebo

67. 9 (4.5) 9 (4.5) 10 (5.0) 15 (7.4) 16 (7.9) 11 (5.4) 12 (5.9) 4 (2.0) 4 (2.0) 10 (5.0) 13 (6.4) 14 (6.9) 19 (9.4) Memantine+Donepezil % (n=202) 17 (8.5) 8 (4.0) 8 (4.0) 14 (7.0) 13 (6.5) 4 (2.0) 4 (2.0) 13 (6.5) 10 (5.0) 16 (8.0) 6 (3.0) 6 (3.0) 5 (2.5) 5 (2.5) 16 (8.0) 24 (11.9) 24 (11.9) Placebo+Donepezil % (n=201) % (n=201) Diarrhea Peripheral edema Fall Influenza-like symptoms Confusion Urinary incontinence Accidental injury Fecal incontinence Urinary tract infection Upper respiratory tract infection Headache Dizziness Agitation Adverse Event Tolerability Profile of Combination Therapy Study Adverse Events Reported in  5% of Either Treatment Group Adapted from Tariot P, et al. JAMA. 2004;291:317-324.

68. ► Treat comorbid conditions conservatively 1 ● Consider risk vs. benefit ratio ● Mortality rate increased in demented patients with comorbid hospitalization 2 ► Stress importance of preparing for increasing caregiver burden ● financial planning ● durable power of attorney for finances and healthcare ● “expanded” advanced directives ● Include thresholds for hospitalization, feeding tube placement, treatment of infections, intubation and resuscitation efforts ► Be vigilant of overall patient/caregiver needs and capabilities 1. Tariot PN. J Am Geriatr Soc. 2003 May;51(5 Suppl Dementia):S305-S313. 2. Morrison RS, Siu AL.. JAMA. 2000;284(1):47-52. General Guidelines for Care of Institutionalized Patients with Moderate to Severe Dementia

69. Dementia in the LTC Environment: Choices in Management ► Minimize anticholinergic load ► Be aware of and treat depression ► Use psychotropics (antipsychotics, antiepileptics, benzodiazepines etc.) cautiously and only to treat definable symptoms ► Obtain history of prior AChI use and continue treatment unless no further treatment interventions desired

70. Dementia in the LTC Environment: Choices in Management (cont) ► Consider switching AChI in patients who are declining on current therapy ► For patients with mod. to severe dementia on no therapy consider beginning memantine monotherapy ► For patients already receiving AChI’s consider adding memantine if patient has mod to severe dementia and has active caregiver burden issues ► Consider discontinuing AChI’s and memantine only with thorough documentation of family goals