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

Effect rivastigmine on cognitive symptoms

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.

Su et al. (China) Impact factor=2.783 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

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 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Method 5 studies including 17 clinical trials | Presentation Title | Presenter Name | Date | Subject | Business Use Only

| Presentation Title | Presenter Name | Date | Subject | Business Use Only

| Presentation Title | Presenter Name | Date | Subject | Business Use Only

ADAS-Cog improve Mixed | Presentation Title | Presenter Name | Date | Subject | Business Use Only

ADAS-ADL improve Patch 5 Small sample size | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Mild to moderate AD improve | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Capsule ADAS-Cog | Presentation Title | Presenter Name | Date | Subject | Business Use Only

| Presentation Title | Presenter Name | Date | Subject | Business Use Only

Effect rivastigmine on behavioral symptoms

Peak frequency of behavioral symptoms throughout the course of AD Grossberg GT et al. Curr Med Res Opin. 2005 Oct;21(10):1631-9 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

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 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Frequency of each behavioral disturbance at the various levels of mental impairment in Taiwan survey Fuh JL et al. Acta Neurol Taiwan 2006;15:154-60. | Presentation Title | Presenter Name | Date | Subject | Business Use Only

BPSD treatment algorism JAMA. 2005;293:596-608 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

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. | Presentation Title | Presenter Name | Date | Subject | Business Use Only R sler M et al. Behav Neurol. 1998;11:211-216.

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 = 0.002 versus placebo Aggressiveness *p = 0.046 versus placebo Prevention of activity disturbances *P = 0.016 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 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

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. 2007 Jun;61(6):886-95 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

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. 2013;9:49-53.

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. 2013;9:49-53.

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;39:477-85. 24

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;39:477-85.

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;39:477-85.

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;39:477-85. 27

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;39:477-85. Kimura T, et al. Neuropsychiatr Dis Treat. 2013;9:49-53.