ORIGINAL PAPER. Introduction. G. Alva, 1 J. L. Cummings, 2 J. E. Galvin, 3 X. Meng, 4 D. M. Velting 4

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1 ORIGINAL PAPER Skin reactions at the application site of rivastigmine patch (4.6 mg/24 h, 9. mg/24 h or 13.3 mg/24 h): a qualitative analysis of clinical studies in patients with Alzheimer s disease G. Alva, 1 J. L. Cummings, 2 J. E. Galvin, 3 X. Meng, 4 D. M. Velting 4 1 ATP Clinical Research, Costa Mesa, CA, USA 2 Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas/Cleveland, NV/OH, USA 3 Alzheimer Disease Center, New York University Langone Medical Center, New York, NY, USA 4 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Correspondence to: Gustavo Alva, MD, ATP Clinical Research, 31 Airway Avenue, Suite T-3, Costa Mesa, CA 92626, USA Tel.: Fax: galva@theatpgroup.net Data were previously presented as a poster at the Alzheimer s Association International Conference, Boston, MA, USA, July 13 18, 213 and the American Society of Consultant Pharmacists Annual Meeting & Exhibition, Seattle, WA, USA, November 2 22, 213. Disclosures GA has received honoraria for acting as scientific advisor, investigator or consultant for: Pfizer, Accera, Merck, Novartis, Forest, Otsuka, Lundbeck, Bristol-Myers Squibb, Takeda, Shire, Precision Med, Astra- Zeneca, Janssen and Avanir. JLC has provided consultation to Acadia, ADAMAS, Anavex, Avanir, Avid, Baxter, Bristol- Myers Squibb, Eisai, Elan, EnVivo, GE, Genentech, Lilly, Lundbeck, MedAvante, Merck, Neuronix, Novartis, Otsuka, Pain Therapeutics, Pfizer, Prana, QR pharma, Sanofi, Takeda, Toyama and UBC pharmaceutical companies. JLC owns stock in ADAMAS, Prana, SUMMARY Background and objectives: Rivastigmine patch is approved for the treatment of all stages of Alzheimer s disease (AD). site reactions may be a concern to clinicians and we used two large clinical trial databases to investigate the incidence of skin reactions in patients receiving rivastigmine patch. Methods: Data from a 24-week, randomised, double-blind (DB) evaluation of 13.3 vs. 4.6 mg/24 h rivastigmine patch in severe AD (ACTION) and a 72- to 96-week study comprising an initial open-label (IOL) phase followed by a 48-week randomised, DB phase (13.3 vs. 9. mg/24 h rivastigmine patch) in declining patients with mild-to-moderate AD (OPTIMA) were analyzed. The incidence, frequency, severity, management and predictors of application site reactions were assessed. Results: site reactions were mostly mild or moderate in severity and reported by similar proportions in each treatment group (ACTION: 13.3 mg/24 h, 24.% and 4.6 mg/24 h, 24.2%; OPTIMA: IOL 9. mg/24 h, 22.9%; DB 13.3 mg/24 h, 11.4% and 9. mg/24 h, 12.%); none were rated serious. In both studies, < 9 required treatment for application site reactions. site reactions led to discontinuation of 1.7% and 2.% of the 13.3 mg/ 24 h and 4.6 mg/24 h groups, respectively, in ACTION, 8.7% in OPTIMA IOL and 1.8% and 3.% of the 13.3 mg/24 h and 9. mg/24 h groups, respectively, in OPTIMA DB. Conclusions: site reactions were experienced by < 2% of patients in both studies, with no notable effect of dose. No reactions qualified as serious and skin reactions were uncommon as a reason for study discontinuation. Introduction Transdermal patches offer the potential for minimally fluctuating and continuous drug delivery with low maximum concentrations, thereby allowing access to higher, more efficacious doses with improved systemic tolerability, compared with oral formulations (1,2). In some patients, the use of a transdermal patch may be associated with application site reactions (for definitions see Table 1) (3). The most common skin reactions reported with transdermal delivery are erythema (localised redness), pruritus (localised itching) and oedema (localised swelling) (3). These reactions are typically classified as irritant contact dermatitis, i.e. an irritant (nonimmunologic) reaction to the patch, or to an active What s known Rivastigmine patch is used in all stages of Alzheimer s disease (AD). The majority of patients in clinical trials of rivastigmine patch in AD do not experience application site reactions; however, they do occur in some patients. What s new If application site reactions do arise with rivastigmine patch, they are typically not allergic and are mild-tomoderate in severity. Localised application site reactions can be managed and are not a barrier to treating a patient with AD with rivastigmine patch. ingredient. Less frequently, skin reactions may arise because of a localised allergic reaction to a constituent of the patch, termed allergic contact dermatitis (3). Rivastigmine transdermal system (Exelon â Patch; Novartis Pharmaceuticals Corporation, East Hanover, NJ) is approved in the USA [at doses of 4.6 mg/24 h ( cm 2 ), 9. mg/24 h (1 cm 2 ), or 13.3 mg/24 h ( cm 2 )] for the symptomatic treatment of mild-tomoderate Alzheimer s disease (AD) (4). The highdose 13.3 mg/24 h patch is also indicated for the symptomatic treatment of severe AD (4). The rivastigmine transdermal system is a small ( cm 2 ), alcohol-free patch that uses polymeric matrix technology combining the active drug (in an acrylic matrix), a silicone polymer membrane that controls 18. doi: /ijcp.12621

2 Skin reactions with rivastigmine patch 19 Table 1 Definition of terms used to describe application site skin reactions Term Dermatitis Oedema Erythema Pruritus Definition A condition of the skin whereby it becomes red, swollen and sore, sometimes with small blisters, resulting from direct irritation of the skin by an external agent or an allergic reaction to the agent (contact and allergic forms, respectively) Swelling or puffiness of the skin because of the build-up of fluid in the tissue beneath Superficial reddening of the skin as a result of injury or irritation causing dilatation of the blood capillaries Severe itching of the skin the rate of drug diffusion, and the silicone adhesive into a single combined layer (). In the ACTION (ACTivities of daily living and cognition) trial, patients with severe AD treated with the high-dose rivastigmine (13.3 mg/24 h) patch experienced superior efficacy to those who received 4.6 mg/24 h patch on measures of cognition [severe impairment battery (SIB)] and daily function [Alzheimer s Disease Cooperative Study Activities of Daily Living scale Severe Impairment Version (ADCS-ADL-SIV)], without a marked increase in adverse events (AEs) (6). The OPTIMA (OPtimising Transdermal Exelon In Mild-to-moderate AD) trial, demonstrated that, in patients with mild-to-moderate AD who experienced decline on the 9. mg/24 h patch, the 13.3 mg/24 h rivastigmine patch was associated with significantly less functional deterioration [as assessed using the Instrumental ADL domain of the Alzheimer s Disease Cooperative Study Instrumental Activities of Daily Living scale (ADCS-IADL)] compared with those continuing treatment with the 9. mg/24 h dose (7). Despite a modest increase in reported AEs with 13.3 mg/24 h rivastigmine patch, fewer patients discontinued treatment because of AEs compared with those treated with 9. mg/24 h patch (7). Thus, the 13.3 mg/24 h rivastigmine patch has shown efficacy, safety and tolerability across all stages of AD (4,6,7). OPTIMA and ACTION provide important data pertaining to the skin tolerability of rivastigmine transdermal patch in patients with mild-to-moderate and severe AD, respectively, and provide an opportunity to investigate the effect of patch size (and drug dose) on the reported incidence of these reactions. The objective of this retrospective analysis was to determine the incidence frequency, severity, management and predictors of skin reactions in patients with AD treated with the rivastigmine patch through the course of clinical trials, based on data from ACTION and OPTIMA. Methods Patients and study design Full details of the methodology and results of ACTION and OPTIMA have been published previously (6 8). ACTION (clinicaltrials.gov identifier NCT948766) was a 24-week, randomised, doubleblind (DB) evaluation of 13.3 mg/24 h vs. 4.6 mg/ 24 h rivastigmine patch in patients with severe AD in the USA (6). OPTIMA (clinicaltrials.gov identifier NCT64) was an international, 72- to 96-week, multicenter trial in patients with mild-to-moderate AD (7). The trial was comprised of a 24- to 48-week initial open-label (IOL) phase, followed by a 48- week, randomised, DB, double-dummy (i.e. all patients received two patches; one placebo and one active), parallel-group phase (7). The protocols and amendments for both trials were reviewed by Independent Ethics Committees or Institutional Review Boards, and both studies were conducted in accordance with Good Clinical Practice and the ethical principles of the Declaration of Helsinki. All patients or, if they lacked capacity, their legally authorised representative provided written informed consent before participating (6 8). Patients in both trials were male or female outpatients aged years, with a diagnosis of probable AD, according to the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association (NIN- CDS/ADRDA) criteria (9). In ACTION, patients with probable AD and Mini-Mental State Examination (MMSE) (1) scores of 3 12 (inclusive), indicating severe AD, were randomised to 13.3 mg/24 h or 4.6 mg/24 h rivastigmine patch (6,8). In OPTIMA, patients with probable AD and MMSE scores of 1 24 (inclusive), indicating mild-to-moderate AD, were enrolled in the IOL phase with the target maintenance dose of 9. mg/24 h rivastigmine patch (7). Patients who met the functional (as assessed by the investigator) and cognitive decline criteria ( 2 point decline in MMSE score from previous visit or 3 point decline from baseline) during IOL treatment were randomised to 13.3 mg/24 h or 9. mg/24 h rivastigmine patch in the DB phase (7). Outcomes Primary outcome measures in ACTION (6,8) were the change from baseline to Week 24 on the SIB (11) and ADCS-ADL-SIV (12,13). Primary outcome measures for the OPTIMA DB phase (7) were the change from DB baseline to week 48 on the Sonexa, MedAvante, Neurotrax, Neurokos and QR pharma. He has participated as a speaker/ lecturer for Eisai, Forest, Janssen, Novartis, Pfizer and Lundbeck. JLC owns the copyright of the Neuropsychiatric Inventory. JLC has provided expert witness consultation regarding olanzapine and ropinirole. JEG receives research support from the National Institutes of Health, Michael J Fox Foundation, Center for Disease Control, Alzheimer Association, Alzheimer Drug Discovery Foundation and Morris and Alma Schapiro Fund. He has worked as a paid consultant for Novartis, Pfizer, Eisai, Forest, Accera and Baxter. He has served as a clinical trial investigator for Novartis, Accera, Merck, Roche, Neuronix, Lundbeck, Bristol- Myers Squibb and Takeda. He owns no stock or equity in any pharmaceutical company. XM and DMV are employees and stock holders of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

3 2 Skin reactions with rivastigmine patch Table 2 Patient demographics and baseline characteristics in ACTION and OPTIMA (safety populations stratified with and without application site reactions) ACTION OPTIMA (IOL phase) OPTIMA (double-blind phase) 9. mg/24 h rivastigmine patch 13.3 mg/24 h rivastigmine patch 9. mg/24 h rivastigmine patch 4.6 mg/24 h rivastigmine patch 13.3 mg/24 h rivastigmine patch (n = 87) (n = 268) (n = 87) (n = 272) (n = 362) (n = 122) (n = 32) (n = 248) (n = 34) (n = 249) site reaction Mean age, years (SD) 76.4 (8.4) 77.9 (8.8) 74. (8.6) 77.1 (9.) 74.6 (7.3) 7. (7.1) 7.1 (6.9) 7.7 (7.4) 7.2 (6.7) 76. (6.9) Female patients (%) Race (%) Caucasian Black Asian Other Mean time since AD 4.7 (2.8) 4.1 (2.7) 4.3 (3.2) 4. (2.) 1.6 (1.9) 1.7 (1.9) 1.4 (1.9) 1.9 (1.8) 1.8 (1.7) 2.1 (2.2) diagnosis, years (SD) 8.6 (3.) 8.9 (2.8) 8.3 (3.2) 9. (2.8) 18.1 (3.3) 17.7 (3.6). (4.1) 13.9 (4.9) 14.7 (.2) 14.2 (4.) Mean baseline MMSE score (SD) ACTION, ACTivities of daily living and cognition; AD, Alzheimer s disease; IOL, initial open label; MMSE, Mini-Mental State Examination; OPTIMA, OPtimising Transdermal Exelon In Mild-to-moderate AD; SD, standard deviation. For summary purpose only, OPTIMA and ACTION cannot be compared as a result of differences in trial design and patient populations. ADCS-IADL (12) and the Alzheimer s Disease Assessment Scale cognitive subscale (14). Safety and tolerability assessments in both studies included reporting of AEs, serious AEs (SAEs) and discontinuation because of AEs (7,8). In ACTION, skin irritation, if presenting as an AE, was evaluated by the investigator during scheduled visits at weeks 4, 8, 16 and 24. Evaluation was based on visual inspection of the skin at the reaction site, or through interview with the caregiver. The severity of application site reactions (e.g. erythema, oedema, scales, pruritus, stinging and burning) was rated on a four-point scale, ranging from very mild to severe. The investigator was asked to classify cases of dermatitis as either (i) contact dermatitis, (ii) allergic dermatitis or (iii) cannot be determined. If the skin irritation arose between scheduled outpatient visits, the patient/caregiver was asked to assess the reaction and provide a summary irritation rating. Episodes of skin irritation related to patch application were captured on the AE Case Report Form (CRF) and analyzed according to the randomised treatment group. In addition, the patch size related to the irritation was noted on the Skin Irritation Rating/Investigator s Rating CRF, allowing determination of whether the skin irritation was associated with the active or placebo patch after unblinding. In OPTIMA, application site reactions were reported as AEs; data were analyzed according to the randomised treatment group. Skin reactions occurring at the site of application were required to be reported as an AE at the application site, to differentiate them from systemic reactions. AEs reported during or between study visits, or detected during physical examination, laboratory test or other assessments were recorded on the AE CRF. The following information was collected: severity grade (mild, moderate, severe); relationship with the study drug; duration; and whether it constitutes a SAE. In both studies, investigators were provided with instructions for prescribing and administering the study drug, including guidance for caregivers on patch application and removal. All concomitant medications/significant non-drug therapies administered after the start of study drug were collected and entered onto the CRF. Statistical analysis In the current retrospective analysis, the incidence, frequency and severity of application site reactions (reported as AEs), as well as treatment and discontinuation because of these application site skin reactions during ACTION and OPTIMA were calculated.

4 Skin reactions with rivastigmine patch 21 (A) mg/24 h rivastigmine patch (n = 3) 4.6 mg/24 h rivastigmine patch (n = 39) 1 (B) 2 9. mg/24 h rivastigmine patch (n = 82) 2 1 Any application site reaction (s) site hypersensitivity site dermatitis site edema site eczema site pain site reaction site dryness site erosion site induration site inflammation site vesicles Any application site reaction (s) site dermatitis site edema site pain (C) mg/24 h rivastigmine patch (n = 28) 9. mg/24 h rivastigmine patch (n = 283) 2 1 Any application site reaction (s) site hypersensitivity Figure 1 Percentage of patients in safety populations with application site reaction AEs in (A) ACTION, (B) OPTIMA (IOL) and (C) OPTIMA (double-blind). ACTION, ACTivities of daily living and cognition; AE, adverse event; IOL, initial open label; n, number of patients in each group; OPTIMA, OPtimising Transdermal Exelon In Mild-to-moderate AD. Preferred terms are presented by descending frequency, as reported in the 13.3 mg/24 h rivastigmine patch group. Only AEs occurring in 2 patients are shown. A patient with multiple occurrences of an AE was counted only once within that category. Only AEs that started on or after the date of first application of study medication were included

5 22 Skin reactions with rivastigmine patch (A) 1.6 Number of episodes per patient mg/24 h rivastigmine patch (n = 3) 4.6 mg/24 h rivastigmine patch (n = 39). site exfoliation site reaction site edema site pain site dermatitis Mild site edema site dermatitis site vesicles Moderate Severe (B) mg/24 h rivastigmine patch (n = 82) Number of episodes per patient (C) 1.2 Number of episodes per patient site dryness site discoloration site edema site reaction site eczema site erosion site induration site dermatitis site hypersensitivity site pain site discoloration site eczema site erosion site edema site edema site reaction site eczema site dermatitis site hypersensitivity site pain site inflammation site swelling site vesicles site edema site eczema site erosion site induration site dermatitis site hypersensitivity site pain site ulcer site vesicles Mild Moderate Severe site swelling site vesicles site hypersensitivity Mild Moderate Severe 13.3 mg/24 h rivastigmine patch (n = 28) 9. mg/24 h rivastigmine patch (n = 283) site vesicles site hypersensitivity

6 Skin reactions with rivastigmine patch 23 Figure 2 Frequency of application site reaction and irritation episodes (number per patient with event) in safety populations stratified by severity in (A) ACTION, (B) OPTIMA (IOL) and (C) OPTIMA (double-blind). ACTION, ACTivities of daily living and cognition; IOL, initial open label; n, number of patients in each group; OPTIMA, OPtimising Transdermal Exelon In Mild-to-moderate AD. Frequency of application site reaction and irritation episodes calculated by dividing number of episodes by the number of patients in the treatment group who experienced that preferred term as the denominator, regardless of severity. Preferred terms are presented by descending frequency, as reported in the 13.3 mg/24 h rivastigmine patch group. All reported AEs are shown. Only AEs that started on or after the date of first application of study medication were included reactions were defined as AEs within the MedDRA high-level term application and instillation site reactions (137) or within the MedDRA preferred terms dermatitis contact (112442), dermatitis allergic (112434), administration site reaction (113), administration site pain (849) and administration site infection (166214). In addition, the proportion of patients in the ACTION study with skin irritation at the patch application site was summarised for active (13.3 mg/24 h and 4.6 mg/24 h) and placebo patches, based on data collected on the Skin Irritation Rating/Investigator s Rating CRF. For both studies, analyses were based on the safety population, which included all patients who received at least one dose of study medication and had at least one safety assessment postbaseline. Data were analyzed according to the OPTIMA IOL phase (9. mg/24 h patch) and the DB treatment phase of both studies (ACTION: 13.3 mg/24 h or 4.6 mg/ 24 h patch; OPTIMA: 13.3 mg/24 h or 9. mg/24 h patch). Potential factors that may predispose patients to application site reactions were investigated using a logistic regression model on AE data from ACTION and OPTIMA safety populations, with the following potential explanatory variables in addition to treatment: age, gender and baseline MMSE score. Odds ratios (ORs) were calculated. Results Participants Overall, in ACTION the majority (64.4%) of patients were female, with a mean age of 77 years, MMSE score of 8.8 points and time since diagnosis of AD of 4.1 years (6); the safety population consisted of 714 patients (3 patients randomised to 13.3 mg/24 h patch and 39 patients randomised to 4.6 mg/24 h patch). In total, 84 patients were enrolled in the OPTIMA IOL; 62.6% were female, the mean age, MMSE score and time since diagnosis of AD were 74.9 years, 17.8 points and 1.7 years, respectively; the safety population comprised 82 patients. In the DB phase of OPTIMA 64.7% were female; the mean age, MMSE score and time since diagnosis of AD were 7.7 years, 14.2 points and 1.9 years, respectively (7); the safety population consisted of 63 patients (28 patients randomised to 13.3 mg/24 h patch and 283 patients randomised to 9. mg/24 h patch). Baseline demographics and characteristics for the treatment groups in both studies (stratified by patients with and without application site reactions) are presented in Table 2. Incidence, frequency and severity of application site reactions In ACTION, 24.% (87/3) of patients treated with the 13.3 mg/24 h patch and 24.2% (87/39) of patients treated with 4.6 mg/24 h patch experienced application site reactions reported as AEs (Figure 1A). This translates into a number needed to harm (NNH) of 333, i.e. for every 333 people treated with 13.3 mg/24 h vs. 4.6 mg/24 h patch, one will experience an application site reaction. Of the 714 patients, 174 patients experienced a total of 261 application site reactions; 14 reactions were reported in patients treated with 13.3 mg/24 h patch and 121 reactions were reported in patients treated with 4.6 mg/24 h patch. At week 24, the proportion of patients with skin irritation at the application site, according to the Skin Irritation Rating/Investigator s Rating CRF, was 16.9% (39/231) with rivastigmine patch and 11.7% (27/231) with placebo patch in patients randomised to 13.3 mg/24 h patch and 11.6% (27/232) and 11.2% (26/232), respectively, in patients randomised to 4.6 mg/24 h patch. In the OPTIMA IOL phase, application site reactions were reported by 22.9% (362/82) of patients (Figure 1B). Of the 82 patients receiving 9. mg/ 24 h patch, a total of 43 application site reactions were reported in 362 patients (22.9%). In the OPTIMA DB phase, application site reactions were reported by 11.4% (32/28) of patients treated with 13.3 mg/24 h patch and 12.% (34/283) of patients treated with 9. mg/24 h patch (Figure 1C). The associated NNH is negative because of the number of application site reactions experienced with the high-dose 13.3 mg/24 h patch being lower than that of the 9. mg/24 h patch. Of the 63 patients, a total

7 24 Skin reactions with rivastigmine patch (A) mg/24 h rivastigmine patch (n = 3) 4.6 mg/24 h rivastigmine patch (n = 39) 1 (B) 2 9. mg/24 h rivastigmine patch (n = 82) 2 1 Any treated application site reaction (s) site dermatitis site hypersensitivity site eczema site edema (C) mg/24 h rivastigmine patch (n = 28) 9. mg/24 h rivastigmine patch (n = 283) 1 Any treated application site reaction (s) Any treated application site reaction (s) site dermatitis

8 Skin reactions with rivastigmine patch 2 Figure 3 Percentage of patients in safety populations with treated application site reaction AEs in (A) ACTION, (B) OPTIMA IOL phase and (C) OPTIMA double-blind phase. ACTION, ACTivities of daily living and cognition; AE, adverse event; IOL, initial open label; n, number of patients in each group; OPTIMA, OPtimising Transdermal Exelon In Mild-to-moderate AD. Preferred terms are presented by descending frequency, as reported for the percentage of patients with application site reaction AEs in the 13.3 mg/24 h rivastigmine patch group. Only AEs occurring in 2 patients are shown. A patient with multiple occurrences of an AE was counted only once within that category. Only AEs that started on or after the date of first application of study medication were included. Dashed bars represent the total proportion of patients reporting the event, and shaded bars the total proportion of patients requiring treatment for that event of 88 application site reactions were reported in 66 patients; 4 reactions were reported in patients treated with 13.3 mg/24 h patch and 43 reactions were reported in patients treated with 9. mg/24 h patch. Thus, within the DB phases of each trial, application site reactions were reported by similar proportions in each treatment group. None of the application site reactions were rated as serious. Erythema was the most commonly reported application site reaction in both studies, and similar proportions were seen between DB treatment groups within each trial. Overall, 12.% (89/714) of patients in ACTION experienced application ; by treatment group, 13.2% (47/3) of patients treated with the 13.3 mg/24 h patch and 11.7% (42/39) of patients treated with the 4.6 mg/24 h patch experienced erythema (Figure 1A). In the OPTIMA IOL phase, 11.6% (184/82) of patients experienced application (Figure 1B) and in the DB phase, the proportion of patients experiencing application was 6.% (34/63) overall, 6.4% (18/28) with 13.3 mg/24 h patch and.7% (16/283) with 9. mg/24 h patch (Figure 1C). In ACTION, 8.4% (6/714) of patients experienced application site dermatitis collectively; by treatment group, 7.6% (27/3) of patients treated with the 13.3 mg/24 h patch and 9.2% (33/39) of patients treated with the 4.6 mg/24 h patch experienced dermatitis (Figure 1A). In the OPTIMA IOL phase,.9% (/82) experienced application site dermatitis (Figure 1B); no cases of dermatitis were reported in the DB phase of OPTIMA. The incidence of pruritus, irritation, oedema, rash, or pain at the patch application site in ACTION and OPTIMA (DB phase) was less than 4% [ACTION: pruritus (2.9%, 21/714), irritation (2.8%, 2/714), oedema (1.4%, 1/714), rash (1.3%, 9/714) and pain (.6%, 4/714); OPTIMA (DB phase): pruritus (3.9%, 22/63), irritation (1.2%, 7/63), oedema (.2%, 1/ 63), rash (2.%, 11/63) and pain (not reported)] (Figure 1A and C). In the OPTIMA IOL phase, the incidences were: pruritus, 8.8% (139/82); irritation, 2.7% (42/82); oedema,.4% (7/82); rash, 3.% (6/82); and pain,.2% (3/82) (Figure 1B). No cases of allergic contact dermatitis were reported during OPTIMA or ACTION. The majority of all application site reactions and irritation episodes reported were of mild or moderate severity in ACTION (98%; mild 83.1% and moderate 14.9%) and OPTIMA IOL (92.8%; mild 6.4% and moderate 32.4%) and DB (93.2%; mild 6.9% and moderate 27.3%) phases. With the exception of any application site reactions and irritation, erythema and irritation in ACTION, the frequency of episodes per patient with application site-related events across the studies was 1 (Figure 2). Treatment of application site reactions In ACTION, treatment was required for application site reactions in 3.9% (14/3) of patients treated with the 13.3 mg/24 h patch and 2.8% (1/39) of the patients treated with 4.6 mg/24 h patch (Figure 3A). In the OPTIMA IOL phase, 8.7% (138/ 82) of patients required treatment for application site reactions (Figure 3B). In the OPTIMA DB phase, 3.2% (9/28) of patients treated with the 13.3 mg/ 24 h patch and 2.8% (8/283) of patients treated with the 9. mg/24 h patch required treatment for application site reactions (Figure 3C). Discontinuations as a result of application site reactions In ACTION, application site reactions led to discontinuation in 1.7% (6/3) of patients treated with the 13.3 mg/24 h patch and 2.% (9/39) of patients treated with the 4.6 mg/24 h patch (Figure 4A). In the OPTIMA IOL phase, 8.7% (137/ 82) of patients discontinued treatment because of the application site reactions (Figure 4B). In OPTIMA (DB), 1.8% (/28) of patients treated with the 13.3 mg/24 h patch and 3.% (1/283) of patients treated with the 9. mg/24 h patch discontinued treatment because of the application site reactions (Figure 4C). Potential factors that may predispose patients to application site reactions Covariates were available for all but two patients in ACTION, leaving a total of 714 subjects (3 in the 13.3 mg/24 h patch group and 39 in the 4.6 mg/ 24 h patch group) to be included in the logistic regression model; covariates were available for 82

9 26 Skin reactions with rivastigmine patch (A) mg/24 h rivastigmine patch (n = 3) 4.6 mg/24 h rivastigmine patch (n = 39) 1 Any application site reaction (s) leading to discontinuation site dermatitis (B) 2 9. mg/24 h rivastigmine patch (n = 82) 2 1 Any application site reaction (s) leading to discontinuation site hypersensitivity site dermatitis site eczema site edema site vesicles (C) mg/24 h rivastigmine patch (n = 28) 9. mg/24 h rivastigmine patch (n = 283) 1 Any application site reaction (s) leading to discontinuation site hypersensitivity

10 Skin reactions with rivastigmine patch 27 Figure 4 Percentage of patients in safety populations with application site reaction AEs leading to discontinuation in (A) ACTION, (B) OPTIMA IOL phase, (C) OPTIMA double-blind phase. ACTION, ACTivities of daily living and cognition; AE, adverse event; IOL, initial open label; n, number of patients in each group; OPTIMA, OPtimising Transdermal Exelon In Mild-to-moderate AD. Preferred terms are presented by descending frequency, as reported for the percentage of patients with application site reaction AEs in the 13.3 mg/24 h rivastigmine patch group. Only AEs occurring in 2 patients are shown. A patient with multiple occurrences of an AE was counted only once within that category. Only AEs that started on or after the date of first application of study medication were included. Dashed bars represent the total proportion of patients reporting the event, and shaded bars the total proportion of patients discontinuing because of that event patients in the OPTIMA IOL phase (all received 9. mg/24 h rivastigmine patch) and for 63 patients in the DB phase (28 in the 13.3 mg/24 h patch group and 283 in the 9. mg/24 h patch group). The single factor identified as predisposing patients to application site skin reactions based on ACTION data was age (OR of experiencing an application site reaction per 1-year and 1-year increase in age =.98 and.8, i.e. reduced by 2% and 2%, respectively (p =.2); gender and baseline MMSE score were not significant predictors. The single factor identified as predisposing patients to application site skin reactions based on OPTIMA IOL data was total MMSE score at baseline (OR = 1.4; p =.2). There were no statistically significant predictors identified as predisposing patients to application site skin reactions based on OPTIMA data in the DB phase. Discussion In both of these large clinical trials of rivastigmine transdermal patch in patients with AD, application site reactions were experienced by under a quarter of patients (24.4% in ACTION, 22.9% in OPTIMA IOL phase and 11.7% in OPTIMA DB phase), of which none were considered serious. Rivastigmine patch size increases with dose. There was no notable effect of dose, with comparable proportions of application site reactions reported as AEs between treatment groups in DB phases of both studies (ACTION: 24.% vs. 24.2%, 13.3 mg/24 h and 4.6 mg/24 h patch, respectively; OPTIMA: 11.4% vs. 12.%, 13.3 mg/24 h and 9. mg/24 h patch, respectively) (6,7). The double-dummy design of these trials controlled for patch size; all patients received two patches (one active, one placebo), therefore, within each trial, all patients had the same total surface area of skin covered by a patch. This should be taken into consideration when interpreting the current findings, as in both studies, AE data were reported by randomised treatment, and as such, it is not possible to distinguish between application site reactions associated with the active vs. placebo patch. Although in OPTIMA, data were derived purely based on AE reporting, in ACTION, investigators were asked to complete the Skin Irritation Rating/ Investigator s Rating CRF, which included reporting of the patch size related to the irritation. These data suggest that a greater proportion of patients receiving high-dose rivastigmine patch experienced skin reactions at Week 24 (16.9%) compared with placebo (11.7%); however, it is not known whether this is a clinically meaningful difference. Based on AE reporting, erythema was the most commonly reported application site reaction in both ACTION (12.%) and OPTIMA (IOL, 11.6%; DB, 6.%). Erythema can arise from abrasive damage caused during patch adhesion or removal (3). The second most common application site reaction reported in ACTION was application site dermatitis, experienced by 8.4 overall. This form of contact dermatitis describes a broad-spectrum of skin conditions indicative of skin irritation caused by chemical or physical irritants. These reactions are characterised by localised erythema and/or itching, and are occasionally accompanied by oedema (3). In the IOL phase of OPTIMA,.9 experienced application site dermatitis. No cases of application site dermatitis were reported in the DB phase of OPTIMA. The majority of patch application site reaction and irritation episodes experienced occurred once and were of mild or moderate severity, with severe accounting for less than 6%. In the first randomised controlled trial of rivastigmine patch, application site reactions assessed as moderate or severe in intensity were slightly higher with 9. mg/24 h rivastigmine patch vs. the comparably sized placebo patch, but those percentages were low (). It is reassuring that the incidence of moderate-to-severe application site reactions remains low in this analysis despite the inclusion of studies with the high-dose 13.3 mg/24 h rivastigmine patch. Overall, more skin reactions were seen in the DB phases of ACTION compared with OPTIMA. This could be attributed to the withdrawal of several patients experiencing application site reactions from the study during the IOL phase i.e., prior to the DB phase (34.% of the patients who discontinued treatment before the DB phase experienced an application site reaction, compared

11 28 Skin reactions with rivastigmine patch with 16.4% of those patients who declined and went onto the DB phase). The exclusion criterion of a current diagnosis of an active skin lesion/disorder that would prevent daily transdermal patch use in both studies may have also influenced findings, i.e., introduced a selection bias. The principal difference between the two trials was the severity of the dementia syndrome at randomization severe in ACTION and mild moderate in OPTIMA. However, it should be noted that because of substantial differences in trial design, the incidence of application site reactions in OPTIMA and ACTION cannot be directly compared. In the DB phase of OPTIMA, the overall incidence of AEs decreased over time (week 24 vs. week > 24) (7). This observation was accounted for in part by a reduction in the incidence of application site erythema and application, which suggests that similar to gastrointestinal events, skin tolerability also improves over time (7). In both OPTIMA and ACTION, a minority of patients required treatment for application site reactions (3.4 in ACTION, 8.7 in OPTIMA IOL phase, and 3. in OPTIMA DB phase), and few application site reactions led to withdrawal of treatment (2.1% of patients in ACTION, 8.7 in OPTIMA IOL phase and 2.7 in OPTIMA DB phase). Together these findings indicate that, for the majority of patients, application site reactions were manageable and did not lead to study discontinuation. Treatment was not specified and most clinicians chose a low-dose steroid cream to treat application site reactions (data not shown). The percentage of patients who discontinued treatment because of the application site AEs in the IOL phase of OPTIMA was higher than that seen in the DB phases of OPTIMA or ACTION. The main contributing application site skin reactions occurring in > 1% were erythema, pruritus and rash. However, the discontinuation rate reported in the OPTIMA IOL phase is comparable to that observed in other open-label/real-world studies of the 9. mg/24 h rivastigmine patch: % (16 18). Undoubtedly the trial design, i.e. open-label vs. DB, double-dummy, is a major factor contributing to the between-study differences observed in discontinuation rates. A blinded trial is generally regarded as being less subject to bias than an open trial because it minimises the impact of knowledge of treatment allocation on postrandomised treatment decisions and on reporting of outcomes. Discontinuation rates because of the application site reactions in the registration trial for rivastigmine patch were slightly higher with rivastimgine patch vs. placebo patch (), so it is again reassuring to see similarly low rates reported in this analysis including the high-dose 13.3 mg/24 h rivastigmine patch. Factors identified as potentially predisposing patients to application site reactions were inconsistent between the two trial populations. Although patients with a past medical history of increased frequency of allergic reactions or incidence of contact dermatitis were not excluded from participating in the ACTION or OPTIMA studies, they accounted for only approximately 1% of the overall population. Predisposing factors, including previous medical history, should be investigated in future studies using a prespecified approach. The acceptable skin tolerability profile of rivastigmine patch within each study may be in part attributable to the technological design and properties of the patch. Rivastigmine is a small (~2 kda), amphiphilic molecule, which enables it to penetrate human skin via both the hydrophobic intercellular space and hydrophilic cellular environment (). The speed and ease of rivastigmine skin penetration generates a sufficient dosing gradient from a minimal drug load in the patch (). This allows the patch to be small, reducing the surface area in contact with the skin (). Within the patch, rivastigmine is incorporated into a polymer matrix, avoiding the need to include irritant solvents such as alcohol (). The backing layer of the patch is made of waterproof material designed to increase drug penetration and prevent leaching of additives from the drug-containing matrix or alteration of the drug constitution (). Although not measured directly in OPTIMA and ACTION, there are a number of steps that can be taken to minimise the risk of developing skin reactions with rivastigmine transdermal patch (19). Patch adhesion can result in sweat accumulation and sweat duct occlusion, leading to skin irritation or miliaria rubra an itchy, erythematous papulovesicle manifestation of dermatitis (2). Therefore, it is recommended that the skin be clean (using water alone), dry and free from powder or lotions before patch application (3). After removing the rivastigmine patch, any residual adhesive on the skin can be removed using soap and water or an oil-based substance (such as baby oil). Alcohol or other dissolving liquids (such as nail polish remover) should not be used (4). Additional recommendations to minimise skin reactions relate to the choice of application site (19). The site of application should be rotated daily and applying the patch to the same area of skin within a 14-day period should be avoided (4). Only one patch should be applied at a time, to avoid the risk of accidental overdose, and the previous day s patch should

12 Skin reactions with rivastigmine patch 29 be removed before placing a new patch in an alternative body location (4). The patch should be applied in an area that will not suffer friction from tight clothing or be prone to substantial movement or skin folding the upper or lower back, or upper arm is recommended (1,4). The patch should not be applied over irritated or broken skin, as this increases the risk of infection and can affect drug absorption (1). To avoid follicular damage to the skin, hirsute areas should be avoided for patch application, and skin should not be depilated before application of a patch (1,). Age-related deterioration in skin integrity and mechanical strength increases the risk of skin trauma and irritation in elderly populations (21). Age was a risk factor of application site reactions in the ACTION study. With these particularly fragile patients, extra care should be taken to choose the healthiest skin application site, gently remove the old patch, and to treat promptly any signs of skin irritation. In cases of allergic contact dermatitis, indicated by application site reactions spreading beyond the patch size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, vesicles) and if symptoms do not significantly improve within 48 h after patch removal, treatment should be discontinued (4,19,22). Symptoms of irritant dermatitis usually self-resolve over the course of a few days; no cases of allergic contact dermatitis were recorded during OPTIMA (IOL and DB phases) or ACTION. Conclusions This qualitative analysis of the skin tolerability of rivastigmine patch in trials of patients with AD is consistent with observations with other approved patch medications, e.g. lidocaine, methylphenidate, oxybutynin, rotigotine and selegiline (3). In summary, our findings suggest that most patients do not experience application site reactions associated with rivastigmine transdermal patch and that rivastigmine and excipients used in the patch are well suited to transdermal application. Gastrointestinal symptoms are substantially reduced with the patch compared with oral delivery of rivastigmine; the low incidence of skin reactions is a preferable trade-off to optimise patient care. When skin reactions do occur, they are generally mild-to-moderate in severity and do not cause significant discomfort. Localised application site reactions can be managed using proper patchsite rotation, treatment and care of skin and need not be a barrier to treatment with rivastigmine patch. Author contributions All authors contributed to the content, drafting, critical revision and approval of this manuscript. Xiangyi Meng performed the statistical analyses. Acknowledgement ACTION and OPTIMA were funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Medical writing and editorial assistance in the development of this manuscript were provided by Christina Mackins-Crabtree at Fishawack Communications, Oxford, UK and this service was supported by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. References 1 Nitti VW, Sanders S, Staskin DR, et al. Transdermal delivery of drugs for urologic applications: basic principles and applications. Urology 26; 67: Priano L, Gasco MR, Mauro A. Transdermal treatment options for neurological disorders: impact on the elderly. Drugs Aging 26; 23: Ale I, Lachapelle JM, Maibach HI. Skin tolerability associated with transdermal drug delivery systems: an overview. Adv Ther 29; 26: Rivastigmine patch (Exelon Patch â ) US Prescribing Information (accessed 24 July 214). Winblad B, Machado JC. Use of rivastigmine transdermal patch in the treatment of Alzheimer s disease. 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