Effectiveness of the 10 cm2 Rivastigmine Patch in Taiwanese Patients with Mild-to-Moderate Alzheimer's Dementia: A 48-Week Real-World Observational Study.

INTRODUCTION: The current study aimed to provide data on the effectiveness of the 10 cm2 rivastigmine patch in patients with Alzheimer's disease (AD) in a real-world setting in Taiwan. METHODS: This was a 48-week, single-arm, open-label, observational, and post-marketing study conducted across seven centers in Taiwan between May 5, 2016 and July 10, 2017. Eligible patients (aged 55-95 years) treated with the 10 cm2rivastigmine patch were enrolled based on physicians' judgment and according to the Taiwan reimbursement criteria of the drug. Data were prospectively collected at Week 0 (baseline), Week 24, and Week 48. The primary endpoint was the change in the cognitive assessment screening instrument (CASI) scores at Week 48 versus baseline. The changes from baseline in clinical dementia rating (CDR), mini-mental state examination (MMSE), and neuropsychiatric inventory (NPI) scores were evaluated, as were treatment persistence and the safety profile. RESULTS: Of the 285 eligible patients [full analysis set (FAS)], 216 (75.8%) completed the study protocol while 180 (63.2%) persisted on the 10 cm2 rivastigmine patch for the full 48 weeks. At baseline, 89.8% of patients had a CDR score of 0.5 or 1, while the change in CDR score at Week 48 was not significant. In the FAS, both the CASI and MMSE scores had numerical improvement at Week 24 but declined by 2.1 and 0.4 points, respectively, at Week 48 (p = 0.005 and p = 0.022). The increment in NPI scores was not significant. The most common drug-related adverse events (AEs) were pruritus (11.2%), nausea (3.5%), rash (3.2%), and vomiting (2.8%). CONCLUSIONS: The use of the 10 cm2 rivastigmine patch in the mild stage of AD maintained cognitive function at Week 24 and neuropsychiatric function at Week 48. The treatment persistency and safety profile support the clinical tolerability of the rivastigmine patch in the management of mild-to-moderate AD in Taiwan.

Real-world Utilisation of the Rivastigmine Transdermal Patches Accompanying the Use of Risk Minimisation Tools in Patients with Dementia.

BACKGROUND: Transdermal patches are convenient to use, especially in Rotkreuz ZG Rotkreuz ZG patients with Alzheimer's disease (AD)-associated dementia. However, various identified risks of errors in administering the patches cannot be disregarded. Patient Reminder Cards (PRCs, included a Medication record sheet [MRS]) have been recently introduced as a risk minimisation tool to prevent incorrect patch use (IU). OBJECTIVES: This study aimed to assess the effectiveness of PRCs to prevent IU and to investigate the dose titration pattern of rivastigmine patches in a real-world setting. METHODS: This multinational, observational, 11-month study included patients with AD currently using rivastigmine patches (4.6 mg/day, 9.5 mg/day, 13.3 mg/day) accompanied by a caregiver. Study outcomes were IU, including multiple patch use (MPU), incorrect patch placement, other IUs, perceived usefulness of the PRCs, and titration patterns of the patches. RESULTS: Of the total 614 patients included, most were aged ≥ 65 years and had mild-to-moderate AD. Before and during the study, 27.7% and 18.0% of patients reported IU, respectively. Most patients used MRS, and 73.5% rated it 'helpful' and reported lower rates of IU than those who reported it 'not helpful' (13.9%-16.5% vs. 20.2%). Overall, 141 patients had dose titrations, with 75.8% being up-titrated from 4.6 mg/day to 9.5 mg/day after a mean duration of 58 days. Safety findings were consistent with the established profile for the rivastigmine patch. CONCLUSION: PRC was effective as a risk minimisation tool in limiting the inappropriate use of rivastigmine patches. The majority of patients requiring dose-change were up-titrated to 9.5 mg/day patches.

Skinfold thickness for rivastigmine patch application in Alzheimer's disease.

RATIONALE: Rivastigmine patches are used for patients with Alzheimer's disease (AD), but little is known about the serum concentration of rivastigmine and its metabolite or clinical adherence in relation to skinfold thickness after rivastigmine patch application. OBJECTIVES: The aim of this study was to examine the association between rivastigmine and NAP 226-90 serum concentration and skinfold thickness and to determine the appropriate skinfold thickness for the use of rivastigmine patch in patients with AD. METHODS: Patients with AD who continuously used rivastigmine patches (4.6 mg/24 h, 5 cm2) for more than 6 months were recruited. The serum concentrations of rivastigmine and NAP 226-90 were measured. Skinfold thickness was measured using a Lange Skinfold Caliper. RESULTS: In total, 91 patients with AD (40 men and 51 women) participated in this study on skinfold thickness measurement. Among them, 27 patients were examined for rivastigmine and NAP 226-90 serum concentrations, with mean concentrations of 1.0 ± 0.6 ng/mL and 3.6 ± 3.6 ng/mL, respectively. The skinfold thickness in the subscapular area was significantly negatively correlated with the NAP 226-90 serum concentration (Spearman's rank correlation coefficient = - 0.47, P = .01). In addition, patients with AD and a subscapular skinfold thickness of ≥25 mm exhibited a significantly high risk of decreased Mini-Mental Status Examination score and nonadherence to a rivastigmine patch (odds ratio 3.00; 95% confidence interval = 1.076-8.366, P = .03). CONCLUSIONS: Subscapular skinfold thickness was significantly negatively correlated with the NAP 226-90 serum concentration and may be considered an appropriate predictor of response and adherence to clinical application of a rivastigmine patch.

Adverse drug events affecting medication persistence with rivastigmine patch application.

PURPOSE: The rivastigmine transdermal patch, the only existing cholinesterase inhibitor available as a transdermal delivery system for treating Alzheimer's disease, has been reported to inhibit progression of cognitive impairment and impairment in activities of daily living, in addition to reducing care burden and improving adherence. However, application of the rivastigmine patch also frequently results in erythema, pruritus, contact dermatitis, and other cutaneous adverse events at the application site, making it difficult to increase the effective dose and continue treatment. Therefore, we conducted a survey to examine the manifestation of adverse events and medication persistence in patients who were prescribed the rivastigmine patch. PARTICIPANTS AND METHODS: Three hundred and twelve patients diagnosed with Alzheimer's disease between July 1, 2011 and March 31, 2015 at the Toki Medical Clinic and who were prescribed a rivastigmine patch at the Sasayuri Community Pharmacy were involved in the study. Outcomes such as manifestation of adverse events, dose at manifestation, and dose reduction as well as discontinuation were retrospectively examined through medication counseling records. RESULTS: Adverse drug events developed in 209 of the 312 patients (67.0%). Approximately 70% of patients who developed adverse events did so before reaching the maintenance dose of 18 mg. The main adverse drug events were cutaneous reactions at the application site such as rash and erythema in 186 patients (59.6%) and gastrointestinal disorders such as nausea, vomiting, and diarrhea in 29 patients (9.3%). Also, of the 312 patients, 118 patients (37.8%) discontinued the rivastigmine patch; reasons for discontinuation included cutaneous application site reactions in 74 patients (62.7%), gastrointestinal disorders in 5 patients (4.2%), and psychiatric disorders in 6 patients (5.1%). Among the 74 patients who discontinued the rivastigmine patch due to application site disorders, the dose at the time of discontinuation was 4.5 mg in 22 patients (29.7%), 9 mg in 37 patients (50.0%), 13.5 mg in 10 patients (13.5%), and 18 mg in 5 patients (6.8%). CONCLUSION: Approximately 60% of patients who used the rivastigmine patch developed application site reactions, suggesting difficulty in increasing the dose to the effective dose and in continuing application. Also, ~80% of the patients who discontinued the rivastigmine patch due to application site reactions developed these reactions when the dose was increased to 9 mg.

Effects on agitation with rivastigmine patch monotherapy and combination therapy with memantine in mild to moderate Alzheimer's disease: a multicenter 24-week prospective randomized open-label study (the Korean EXelon Patch and combination with mEmantine Comparative Trial study).

AIM: Memantine is known to be effective in the treatment of the behavioral symptoms of dementia, especially agitation in moderate to severe Alzheimer's disease (AD). However, memantine and rivastigmine patch combination therapy has not been well studied in determining treatment effectiveness with mild to moderate AD patients. METHODS: This was a multicenter, 24-week, prospective, randomized, open-label study design. A total 147 AD patients with Mini-Mental State Examination scores from 10 to 20 were randomly assigned to rivastigmine patch monotherapy and combination therapy with memantine groups. Agitation symptoms, using the Korean Version of the Cohen Mansfield Agitation Inventory were evaluated at baseline and at study end. Suppression and emergence of agitation symptoms were also evaluated. We carried out factor analyses to evaluate the interrelationship of agitation symptoms and to investigate treatment response in these symptoms. RESULTS: Factor analyses showed two symptom clusters: factor A - aggressive agitated behaviors - versus factor B - non-aggressive agitated behaviors. The rivastigmine patch monotherapy group showed significantly decreased factor B scores and had a tendency of decreased Korean Version of the Cohen Mansfield Agitation Inventory total scores and factor A scores. Conversely, the combination therapy group showed significantly increased Korean Version of the Cohen Mansfield Agitation Inventory total scores and factor B scores. Neither monotherapy nor combination therapy reduced the emergence of new agitation symptoms. CONCLUSIONS: In this trial of mild to moderate AD patients, the rivastigmine patch monotherapy group experienced a reduction of non-aggressive agitated behaviors. However, combination therapy with memantine did not show any benefit on the agitation associated with mild to moderate AD. Geriatr Gerontol Int 2017; 17: 494-499.

The Effect of Rivastigmine Transdermal Patch on Sleep Apnea in Patients with Probable Alzheimer's Disease.

BACKGROUND AND PURPOSE: This study was designed to evaluate the effect on sleep of rivastigmine transdermal patch in patients with probable Alzheimer's disease (AD). METHODS: Patients with probable AD underwent a sleep questionnaire, overnight polysomnography and neuropsychological tests before and after rivastigmine transdermal patch treatment. We analyzed the data from enrolled patients with AD. RESULTS: Fourteen patients with probable AD were finally enrolled in this study. The respiratory disturbance index after the rivastigmine patch treatment was improved in patients with probable AD and sleep breathing disorder, compared with that of before treatment (p<0.05). CONCLUSIONS: Rivastigmine transdermal patch application are expected to improve the symptoms of sleep disordered breathing in patients with probable AD. Further placebo controlled studies are needed to confirm these results.

Cognitive Efficacy (SIB) of 13.3 Versus 4.6 mg/24 h Rivastigmine Patch in Severe Alzheimer's Disease.

Severe Impairment Battery (SIB) data from the 24-week, randomized, double-blind ACTivities of daily living and cognitION (ACTION) study suggest that patients with severe Alzheimer's disease (AD) benefit from treatment with 13.3 versus 4.6 mg/24 h rivastigmine patch. The objective of this retrospective analysis was to further examine the cognitive efficacy of 13.3 versus 4.6 mg/24 h rivastigmine patch on individual SIB items, and SIB domains derived using factor analysis of these items. Change from baseline at Week 24 on 9 new factor-defined domains and individual items was calculated and compared using effect sizes (Cohen's d). Numerically less decline was observed with 13.3 versus 4.6 mg/24 h patch on all domains and the majority of individual items. Largest least squares mean treatment differences were observed on "visuospatial reasoning," "object naming," "recognition," "design copying," "social agency," "ideational praxis," and "comprehension" domains. These findings suggest 13.3 mg/24 h rivastigmine patch demonstrates broad cognitive efficacy across a range of SIB items and domains in patients with severe AD.

The Effect of Rivastigmine Transdermal Patch on Sleep Apnea in Patients with Probable Alzheimer's Disease

BACKGROUND AND PURPOSE: This study was designed to evaluate the effect on sleep of rivastigmine transdermal patch in patients with probable Alzheimer's disease (AD). METHODS: Patients with probable AD underwent a sleep questionnaire, overnight polysomnography and neuropsychological tests before and after rivastigmine transdermal patch treatment. We analyzed the data from enrolled patients with AD. RESULTS: Fourteen patients with probable AD were finally enrolled in this study. The respiratory disturbance index after the rivastigmine patch treatment was improved in patients with probable AD and sleep breathing disorder, compared with that of before treatment (p<0.05). CONCLUSIONS: Rivastigmine transdermal patch application are expected to improve the symptoms of sleep disordered breathing in patients with probable AD. Further placebo controlled studies are needed to confirm these results.

A 24-Week, Randomized, Controlled Study to Evaluate the Tolerability, Safety and Efficacy of 2 Different Titration Schemes of the Rivastigmine Patch in Japanese Patients with Mild to Moderate Alzheimer's Disease.

AIM: To investigate whether 1-step titration of the rivastigmine patch (initiated at 5 cm(2) and titrated to 10 cm(2) after 4 weeks) is well tolerated in Japanese patients with Alzheimer's disease (AD) as compared to 3-step titration (initiated at 2.5 cm(2) and titrated by 2.5 cm(2) every 4 weeks to 10 cm(2)). METHODS: A 24-week, multicenter, randomized, double-blind study was conducted in Japan between July 2012 and May 2014. Patients with mild to moderate AD aged 50-85 years were randomized 1:1 to 1-step or 3-step titration of the rivastigmine once-daily patch. The primary endpoint was the proportion of patients with adverse events leading to discontinuation. RESULTS: Of 216 patients randomized, 215 (1-step, n = 107; 3-step, n = 108) were included in the safety analysis. The primary endpoint outcome was 15.0% in the 1-step group and 18.5% in the 3-step group. The observed treatment difference was -3.6% (95% confidence interval: -17.0, 9.6), falling within the prespecified acceptance range. CONCLUSION: The tolerability of two different titration schemes was similar in Japanese patients with AD.

Effects of cholinesterase inhibitor on brain activation in Alzheimer's patients measured with functional near-infrared spectroscopy.

RATIONALE: Neurobiological effects of neuropsychiatric medication can contribute to the understanding of mechanisms of action and to the evaluation of target medication effects. Cholinesterase inhibitors (ChEI) have been used in patients with Alzheimer's disease (AD) for years with only small knowledge about the underlying neurobiological effects. The measurement of brain activation links neurobiological and functional aspects but is challenging in the group of demented patients; here, an alternative method, functional near-infrared spectroscopy (fNIRS), is introduced to measure those medication effects. OBJECTIVES: The current study investigated the influence of ChEI on cortical activation of patients with AD measured using fNIRS during a verbal fluency task (VFT). METHODS: In this study, 24 probable AD patients were investigated three times using fNIRS: before medication with rivastigmine was given (t0), when the medication was at the target dose after 4 weeks (t1), and after the target dose was kept constant for a further 8 weeks (t2). RESULTS: The results show a concentration increase of oxygenated hemoglobin as measured with fNIRS from t0 to t2 in speech relevant areas and a general decrease in prefrontal areas. Behaviorally, an improvement was found for the VFT used to measure cortical activation during fNIRS. In the neuropsychological test battery, no significant changes were found, yet high effect sizes for the mini mental status examination, immediate and delayed word list recall were found. CONCLUSIONS: The results indicate a positive effect of ChEI on cognitive function. The underlying cortical changes can be imaged using fNIRS.

Effects of a Rivastigmine Patch on Self-Care Activities in Patients with Alzheimer's Disease plus Cerebrovascular Disease.

BACKGROUND/AIMS: In dementia patients, a deficit in activities of daily living (ADL) is one of the main problems. Our objective was to assess ADL using the Korean Modified Barthel Index (K-MBI) in patients with Alzheimer's disease (AD) plus cerebrovascular disease (CVD) treated with a rivastigmine patch for 24 weeks in an open-label, observational study. METHODS: 29 patients were enrolled who met the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ ANDRA) criteria and had a score of 10-26 on the Korean version of the Mini-Mental State Examination (K-MMSE). After the rivastigmine patch had been applied for 24 weeks, changes in self-care activities were assessed using the K-MBI. RESULTS: The average age of the patients was 62.8 years, and they had an average K-MMSE score of 16.2. Patients showed a mean improvement of 21.9 points, as compared with the baseline K-MBI score of 30.3 (p < 0.05). Significantly better outcomes were seen in secondary outcome variables, for example the K-MMSE and backward digit span. The most frequent adverse events were skin problems, such as itching sensation (10%). CONCLUSION: In this multicenter, open-label, observational study, the rivastigmine patch was associated with improvements in ADL in patients with AD plus CVD.

Transdermal rivastigmine in the treatment of Alzheimer's disease: current and future directions.

Despite the fact that the prevalence of Alzheimer's disease (AD) is exponentially increasing, we have not yet been able to develop a new treatment to modify the course of the disease. This vacuum makes the traditional cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonist the only accessible pharmacotherapy options for the treatment of this disease. Among these medications, the only available transdermal patch at this time is the rivastigmine patch. This patch provides significantly lower gastrointestinal adverse effects. A higher tolerability rate provides the option for physicians to continue treatment with higher doses of rivastigmine in advanced stages of AD. Moreover, ease of use, easy-to-follow schedule, less administration time spent by the caregiver result in greater adherent to the treatment. This article aims to provide a comprehensive drug profile for transdermal rivastigmine, to review currently available treatment options, and to try to anticipate future treatment directions for AD.

Which rivastigmine formula is better for heart in elderly patients with Alzheimer's disease: oral or patch?

OBJECTIVE: Rivastigmine is commonly used for the treatment of Alzheimer's disease (AD). All cholinesterase inhibitors, including rivastigmine, may cause cardiac side effects. The aim of this study is to compare the electrocardiographic (ECG) and hypotensive effects of formulations of rivastigmine. METHODS: Eighty-five newly diagnosed patients with AD who were treated with rivastigmine were retrospectively evaluated. The ECG records were reviewed at baseline and at administration of either 12 mg of oral rivastigmine or 10 cm(2) transdermal rivastigmine. RESULTS: When compared with the baseline, there were no changes in any of the ECG parameters in all of the patients (P > .05). Moreover, when compared with the mean change from baseline for each treatment group, there were no changes, except heart rate (P = .035). CONCLUSION: It was demonstrated that rivastigmine formulations were not associated with increased arrhythmogenic or hypotensive effects in elderly patients with AD and was not superior to each other.

Efficacy of higher dose 13.3 mg/24 h rivastigmine patch on instrumental activities of daily living in patients with mild-to-moderate Alzheimer's disease.

BACKGROUND: Stabilizing/reducing decline in the ability to perform activities of daily living (ADLs) is important in management of Alzheimer's disease (AD). METHODS: Post hoc analysis of OPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer's disease (OPTIMA), a double-blind trial comparing 13.3 and 9.5 mg/24 h rivastigmine patch in patients with AD demonstrating functional and cognitive decline with 9.5 mg/24 h patch. Efficacy on Alzheimer's disease Cooperative Study-instrumental ADL (ADCS-IADL) items, higher level function (HLF), and autonomy factors was assessed. RESULTS: The ADCS-IADL, HLF, and autonomy factors favored 13.3 mg/24 h patch at all time points, reaching significance from weeks 16 to 48, 24 to 48, and 32 to 48, respectively. Higher dose patch demonstrated significantly greater efficacy on 10 of 17 ADCS-IADL items at 1 or more time points (P < .05 vs 9.5 mg/24 h patch). More adverse events were observed with higher dose patch; study discontinuations were similar between the doses. CONCLUSIONS: Greater efficacy of 13.3 versus 9.5 mg/24 h patch on ADL, including autonomy and HLF factors, supports this additional dosing option to prolong patients' independence.

Effectiveness and tolerability of transdermal rivastigmine in the treatment of Alzheimer's disease in daily practice.

BACKGROUND: Oral cholinesterase inhibitors at doses efficacious for the treatment of Alzheimer's disease (AD) are often prematurely discontinued due to gastrointestinal side effects. In controlled clinical trials, transdermal rivastigmine demonstrated less such effects at similar efficacy. The current study aimed to verify the validity of this data in daily practice. METHODS: This was a prospective, multicenter, observational study on transdermal rivastigmine in Germany. Eligible patients were those with AD who had not yet been treated with rivastigmine. Outcome measures were changes in clock-drawing test, Mini-Mental State Examination (MMSE), Caregiver Burden Scale, Clinical Global Impression (CGI), physicians' assessments of tolerability, and the incidence of adverse events (AEs) over 4 months of treatment. RESULTS: In 257 centers 1113 patients were enrolled; 614 women and 499 men, mean age 76.5 years. In 58% of patients AD was treated for the first time and in 42% therapy was switched to transdermal rivastigmine, mostly due to lack of tolerability (13.6%) or effectiveness (26.9%). After 4 months, 67.4% of patients were on the target dose of 9.5 mg/day and 21.8% were still on 4.6 mg/day. MMSE significantly improved in patients with and without pretreatment (ΔMMSE, 0.9 ± 3.4 and 0.8 ± 3.4, respectively, both P < 0.001); the CGI score improved in 60.9% and 61.3% of patients, respectively. Overall 11.7% of patients had AEs, mainly affecting the skin or the gastrointestinal tract; in 1.1% of cases AEs were serious; 14.7% of patients discontinued therapy, 6.0% due to AEs. With rivastigmine treatment the percentage of patients taking psychotropic comedication decreased, particularly in first-time treated rivastigmine patients (from 27.1% to 22.6%; P < 0.001). CONCLUSION: Results were in line with data from controlled clinical trials. Switching from any other oral acetylcholinesterase inhibitor to transdermal rivastigmine may improve cognition.