1. Rivastigmine benefit in ADL and BPSD
楊詠仁 醫師
草屯療養院

2. Effect rivastigmine on cognitive symptoms

3. Rationale for a transdermal patch in Alzheimer’s disease
Providing continuous drug delivery over 24 hours for longer duration of action
Allowing easier and faster access to higher doses
Reducing side effects by providing smooth drug delivery
Simplifying treatment for elderly patients often taking many other medicines
Making administration independent of food intake
Avoiding the first-pass effect
Helping family members to monitor treatment compliance
Providing visual reassurance of treatment
Transdermal patch therapy may offer advantages over older oral therapies in the dementia setting. Alzheimer’s disease is characterized by a progressive loss of memory and cognitive functions, resulting in an impaired ability to perform ADLs. Even at an early stage of the disease, patients have difficulty performing instrumental ADLs, such as managing medication regimens. Although caregivers are often responsible for medical management, they too are often older people themselves, and this responsibility has been associated with significant caregiver strain.1
People typically have AD for more than 7 years, yet the average duration of treatment with orally administered cholinesterase inhibitors is just 3 to 4 months,2 suggesting a problem with treatment compliance. In addition, due to adverse effects such as nausea and vomiting, which are particularly associated with dose titration, not all patients reach target doses of oral cholinesterase inhibitors.
There is a medical need for effective, well-tolerated treatment options that have the potential to enhance compliance and improve treatment outcomes in Alzheimer’s disease. The next generation of cholinesterase inhibition therapy, a transdermal patch, may help to address this need, by offering advantages over older oral therapies: smooth drug delivery with reduced side effects; access to high dose efficacy; a simple treatment option for patients on multiple medications; and compliance that is readily monitored by family members.3
The rivastigmine transdermal patch allows easy access to the therapeutic dose, with a simple one-step dose increase from the starting-dose patch (4.6 mg/24 h) to target-dose patch (9.5 mg/24 h) within 1 month (compared with at least 4 months with rivastigmine capsules). At study endpoint in the IDEAL study, 96% of patients in the 9.5 mg/24 h patch group were receiving target dose, compared with 64% of patients in the capsule group.4,5
References:
Travis SS, Bethea LS, Winn P. Medication administration hassles reported by family caregivers of dependent elderly persons. J Gerontol A Biol Sci Med Sci 2000;55:M412–M417.
Singh G, Thomas SK, Arcona S, Lingala V, Mithal A. Treatment persistency with rivastigmine and donepezil in a large state medicaid program. J Am Geriatr Soc 2005;53:1269–1670.
Priano L, Gasco MR, Mauro A. Transdermal treatment options for neurological disorders: impact on the elderly. Drugs Aging 2006;23:357–375.
Sadowsky C, Cummings J, Tekin S, Lane R. Achieving optimal therapeutic doses – rivastigmine (Exelon®) patch and capsule. Poster presentation at the ANA, October 2007.
Cummings J and Winblad B. A rivastigmine patch for the treatment of Alzheimer’s disease and Parkinson’s disease dementia. Expert Rev Neurother 2007;7:1457–1463.
Priano L, et al. Drugs Aging 2006;23:357–375.

4. Su et al. (China) Impact factor=2.783
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5. Background and objective
Despite the report of the positive outcome of rivastigmine patch on AD treatment, the overall results delivered by current articles are inconsistent and uncomprehensive
The study aims to generate a full evaluation of the effectiveness of rivastigmine on the treatment of AD in terms of ADAS-Cog and ADAS-ADL
Compared with capsule administration, patch administration shows a stronger effect on decreasing ADAS-Cog
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6. Method 5 studies including 17 clinical trials
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9. ADAS-Cog improve Mixed
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10. ADAS-ADL improve Patch 5 Small sample size
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11. Mild to moderate AD improve
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12. Capsule
ADAS-Cog
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14. Effect rivastigmine on behavioral symptoms

15. Peak frequency of behavioral symptoms throughout the course of AD
Grossberg GT et al. Curr Med Res Opin Oct;21(10):1631-9
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16. Frequency of each behavioral disturbance at the various levels of mental impairment
Piccininni M et al. Dement Geriatr Cogn Disord. 2005;19(5-6):276-81
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17. Frequency of each behavioral disturbance at the various levels of mental impairment in Taiwan survey
Fuh JL et al. Acta Neurol Taiwan 2006;15:
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18. BPSD treatment algorism
JAMA. 2005;293:
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19. Significant sustained effects on BPSD for up to 2 years
Improvements from baseline in scores on individual items of the Behavioral Pathology in Alzheimer's Disease scale after 12 and 24 months of rivastigmine therapy in an open-label extension study in patients with mild to moderate Alzheimer's disease (n = 29, observed-case analysis). A negative change indicates symptom improvement.*P = 0.02 versus baseline.
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R sler M et al. Behav Neurol. 1998;11:

20. Prevention of activity disturbances
3 randomized, placebo-controlled, double-blind, 6-month trials, involving 1840 mild to moderate AD pts
Receipt of antipsychotics was an exclusion criterion
Baseline 63.7% activity disturbance, 44.8% aggressiveness, 42.8% delusion, 20.9% hallucination
Paranoia & Delusions
*P = versus placebo
Aggressiveness
*p = versus placebo
Prevention of activity disturbances
*P = versus placebo
Lane R et al. Poster presented at: American Association for Geriatric Psychiatry
Annual Meeting; March 1-4, 2003;
Lane R et al. Poster presented at: 7th Annual Meeting of the European Federation of Neurological Societies; August 30-September 3, 2003
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21. EXACT (Exelon* Therapy to ACT on the four As in patients with mild-to-moderate AD in a real-world clinical setting)
Gauthier S et al. Int J Clin Pract Jun;61(6):886-95
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22. The impact of BPSD symptom after rivastigmine discontinuation
Case 1
76 y/o woman with 5-year history of AD (MMSE=11)
Switch from rivastigmine patch (18 mg/day) to donepezil (3 mg/day) after she completed IDEAL trial
Suffered from insomnia 3 days later
DC donepezil and prescribed herbal medicine
Kimura T, et al. Neuropsychiatr Dis Treat ;9:49-53.

23. The impact of BPSD symptom after rivastigmine discontinuation
Case 2
56 y/o woman with 5-year history of AD (MMSE=12)
Switch from rivastigmine patch (18 mg/day) to donepezil (3 mg/day) after she completed IDEAL trial
Began to go our early 4 days later
DC donepezil and prescribed anxiolytic
Kimura T, et al. Neuropsychiatr Dis Treat ;9:49-53.

24. Open-label BPSD study Objective and design
Objective To evaluate the effects of four drugs (memantine, donepezil, rivastigmine, galantamine) in BPSD in AD patients.
Study design
The dosing strategy was to treat patients at the highest doses individually well tolerated.
Treatment effects were evaluated at baseline, 6, and 12 month using two multidimensional rating scales, NPI and BEHAVE-AD.
Prospective, longitudinal, randomized, open-label, 4-arm, parallel-group, 12-month study
Rivastigmine
12 mg/day
(n = 46)
Donepezil
10 mg/day
(n = 42)
Galantamine
24 mg/day
(n = 41)
Memantine
20 mg/day
(n = 48)
BPSD, behavioral and psychological symptoms of dementia; AD, Alzheimer’s Disease; NPI, Neuropsychiatric Inventory; BEHAVE-AD, Behavioural Pathology in Alzheimer’s Disease.
Cumbo E, et al. J Alzheimers Dis 2014;39: 24

25. Open-label BPSD study Results – Demographics
Demographic and clinic characteristics of patients at baseline
ADL, activities of daily living; APOE, apolipoprotein; BEHAVE-AD, Behavioural Pathology in Alzheimer’s Disease; HIS, Hachinski Ischemic Score; IADL, instrumental activities of daily living; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory.
Cumbo E, et al. J Alzheimers Dis 2014;39:

26. Open-label BPSD study Results – Efficacy
Results of NPI and BEHAVE-AD in the four groups of treatment
LOCF analysis. Values are means±SD. p values refers to changes from baseline to month 12.
Summary
The NPI and BEHAVE-AD total scores improved from baseline to month 12 in all groups. The improvements in both scales were statistically significant in the memantine, donepezil, and rivastigmine groups, but not in the galantamine group.
Responder analyses showed that treatment with memantine and rivastigmine resulted in more patients improving on NPI and BEHAVE-AD score, respectively.
NPI, Neuropsychiatric Inventory; BEHAVE-AD, Behavioural Pathology in Alzheimer’s Disease.
Cumbo E, et al. J Alzheimers Dis 2014;39:

27. Open-label BPSD study Results – Efficacy
Percentage of patients with improved, unchanged or worsened scores from baseline to month 12
NPI
BEHAVE-AD
NPI, Neuropsychiatric Inventory; BEHAVE-AD, Behavioural Pathology in Alzheimer’s Disease.
Summary
The rate of improved patients for both scales was lower in the galantamine group than in the other three groups, with reversed trends for worsened patients.
Cumbo E, et al. J Alzheimers Dis 2014;39: 27

28. Open-label BPSD study Results – Efficacy
Results of NPI and BEHAVE-AD in the four groups of treatment
NPI, Neuropsychiatric Inventory; BEHAVE-AD, Behavioural Pathology in Alzheimer’s Disease.
Cumbo E, et al. J Alzheimers Dis 2014;39:
Kimura T, et al. Neuropsychiatr Dis Treat ;9:49-53.