Once-daily luliconazole cream 1% for the treatment of interdigital tinea pedis.

Luliconazole is an imidazole antifungal agent with a unique chemical structure. In this article, we summarize the in vitro data, animal studies and clinical trial data relating to the use of topical luliconazole cream 1% in the treatment of tinea pedis. Preclinical studies have demonstrated potent activity against dermatophytes. Luliconazole has strong fungicidal activity against Trichophyton spp., similar to that seen with terbinafine. Evidence from clinical trials in tinea pedis have shown once-daily application of luliconazole cream 1% for 14 days to be effective and well tolerated.

A randomized, evaluator-blinded, controlled study of effectiveness and safety of small particle hyaluronic acid plus lidocaine for lip augmentation and perioral rhytides.

OBJECTIVE: To compare the safety and effectiveness of small particle hyaluronic acid plus lidocaine (SPHAL) versus no treatment for lip augmentation and perioral rhytides. METHODS AND MATERIALS: Adults scoring 1 (very thin) to 2 (thin) on the Medicis Lip Fullness Scale (MLFS) for upper and lower lips were randomized (3:1) to SPHAL or no treatment. Treatment success was an MLFS increase ≥1 point at Week 8. Secondary end points (MLFS score, independent photographic review, Global Aesthetic Improvement Scale, Wrinkle Assessment Scale for Upper Lip Lines) and safety were assessed throughout. RESULTS: Statistically significantly more patients were treatment successes with SPHAL (upper lip [80.2% vs 11.9%], lower lip [84.2% vs 18.4%], and upper and lower lips combined [76.1% vs 11.6%]), compared with no treatment (p <.001, all outcomes). Patients treated for both lip augmentation and perioral rhytides were rated as having an aesthetically meaningful improvement in perioral rhytides (p <.001). Most common treatment-emergent adverse events (AEs) included lip bruising, swelling, and pain and were mostly mild and transient in nature, without anticipated device AEs. CONCLUSION: Small particle hyaluronic acid plus lidocaine was effective and well tolerated and significantly more effective when both lips and perioral rhytides were treated, with improvement evident up to 6 months after treatment.

Efinaconazole 10% solution in the treatment of onychomycosis of the toenails.

BACKGROUND: Efinaconazole 10% solution is a new triazole antifungal agent developed for the topical treatment of onychomycosis. This article reviews the pooled results of the two pivotal clinical trials of this drug that have been performed in the United States, Canada, and Japan. METHODS: The two studies of 1,655 patients were both double-blind, vehicle-controlled, parallel-group, randomized, multicenter studies designed to determine the efficacy and safety of efinaconazole 10% solution in the treatment of mild-to-moderate onychomycosis of the toenails caused by dermatophytes. Treatment was provided once daily for 48 weeks, and the primary end point was at week 52. RESULTS: The combined results show a 56% mycologic cure rate compared with 17% for vehicle at week 52. Clinical treatment success was achieved in 43% of patients treated with efinaconazole 10% solution at follow-up (week 52). Clinical treatment success was achieved in 47% of patients. As expected for a topical agent, the use of efinaconazole 10% solution was found to be safe, with mild, transient irritation at the site of application reported as the most common adverse event. CONCLUSIONS: The efficacy and safety profile of efinaconazole 10% solution suggests that it may represent an important advance in the topical treatment of onychomycosis. Further studies will help us better understand the role of this agent for the treatment of this widespread podiatric medical condition.

The efficacy and safety of efinaconazole 10% solution for treatment of mild to moderate onychomycosis: a pooled analysis of two phase 3 randomized trials.

BACKGROUND: Onychomycosis is a fungal infection of the nail apparatus that can be challenging to treat due to the modest efficacy of existing antifungal therapies and a high rate of relapse and recurrence. OBJECTIVES: To investigate the efficacy and safety of efinaconazole 10% solution in pooled Phase III clinical trial participants with mild to moderate onychomycosis. METHODS: Phase III clinical trials data from NCT01008033 and NCT01007708 were pooled. Efficacy analysis for the primary and secondary outcome variables was conducted using the mITT population and analysed using Cochran-Mantel-Haenszel tests. Subgroup analysis was conducted for prognostic factors that may affect drug efficacy. Safety analysis was conducted on all recipients of a single drug dose. RESULTS: Efinaconazole 10% nail solution was superior to vehicle for all primary and secondary outcome measures assessed. Complete cure was 18.5% vs 4.7% P< 0.001 [mITT] and mycological cure was 56.3% vs 16.6%, P< 0.001 [mITT]. Complete or almost complete cure and treatment success were achieved in 27.7% and 47.2% compared to 7.9% and 18.2% with vehicle, respectively (P< 0.001 [mITT]). In all subgroups, efinaconazole 10% solution had statistically higher cures rates compared to vehicle. Higher complete cure rates were observed in women and individuals with mild disease (≤33% involvement), but not in any other subgroup assessed. Treatment associated adverse events in the efinaconazole 10% solution group were similar to vehicle and limited to local site reactions (2%). CONCLUSIONS: The findings from this pooled analysis suggest that efinaconazole 10% solution may become the preferred topical agent for mild to moderate onychomycosis.

Efficacy and safety of once-daily luliconazole 1% cream in patients ≥12 years of age with interdigital tinea pedis: a phase 3, randomized, double-blind,vehicle-controlled study.

BACKGROUND: Interdigital tinea pedis is one of the most common clinical presentations of dermatophytosis. OBJECTIVE: This phase 3 study evaluated the safety and efficacy of luliconazole cream 1% in patients with tinea pedis. METHODS: A total of 321 male and female patients aged ≥12 years with tinea pedis and eligible for modified intent-to-treat analysis were randomized 1:1 to receive luliconazole cream 1% (n=159) or vehicle (n=162) once daily for 14 days. Efficacy was evaluated at days 28 and 42 (i.e., days 14 and 28 posttreatment) based on clinical signs (erythema, scaling, pruritus) and mycology (KOH, fungal culture). The primary outcome was complete clearance at day 42. Safety evaluations included adverse events and laboratory assessments. RESULTS: Complete clearance at day 42 was achieved in 26.4% (28/106) of patients treated with luliconazole cream 1% compared with 1.9% (2/103) of patients treated with vehicle (P< 0.001). Similar safety profiles were obtained for luliconazole cream 1% and vehicle. LIMITATIONS: This study was conducted in a relatively small population under controlled clinical trial conditions. CONCLUSION: Luliconazole cream 1% applied once daily for 14 days is well tolerated and more effective than vehicle in patients with tinea pedis.

Access of efinaconazole topical solution, 10%, to the infection site by spreading through the subungual space.

OBJECTIVE: To evaluate the ability of efinaconazole vehicle to reach the site of toenail onychomycosis by spreading through the subungual space between the nail plate and nail bed. Lacquer-based vehicles are primarily limited to application on the nail plate and dependent on nail plate permeation. METHODS: 11 patients (mean age 48.5 years) were entered with clinically determined onychomycosis. Presence of fungal infection was confirmed by KOH testing in eight patients. Two separate applications of vehicle (with fluorescein incorporated for better visualization) were applied at the hyponychium, avoiding application to the exterior nail plate surface. Affected nails were later clipped to allow examination of the nail bed and further examination of the underside of the nail. Spread of formulation was assessed under visible and UV light conditions by photographing target toenails after vehicle application, and after nail clipping. RESULTS: Assessments under both visible and UV light indicated that the vehicle had spread into the subungual space, with deposition of flourescein wherever vehicle had reached, including in the nail bed. Nail clippings also indicated deposition to the underside of the nail plate. LIMITATIONS: The relative contributions of spreading into the subungual space, or permeation through the nail plate to the efficacy of efinaconazole topical solution, 10% in treating onychomycosis were not assessed. CONCLUSIONS: This study suggests that the vehicle developed for efinaconazole topical solution, 10%, when applied at the hyponychium, spreads into the subungual space between the nail plate and nail bed, reaching the site of infection.

Efinaconazole solution in the treatment of toenail onychomycosis: a phase 2, multicenter, randomized, double-blind study.

BACKGROUND: Onychomycosis is a common nail infection that is difficult to treat successfully. The prevalence increases with age and is associated with diabetes. Oral treatments are limited by drug interactions and potential hepatotoxicity; topical treatments, by modest efficacy. OBJECTIVE: We investigated the efficacy and safety of a solution using a novel topical triazole antifungal, efinaconazole, in distal lateral subungual onychomycosis (DLSO). METHODS: Multicenter, randomized, double-blind, vehicle-controlled phase 2 study in mild to moderate toenail DLSO (n=135). Subjects randomized (2:2:2:1 ratio) to receive efinaconazole 10% solution (with or without semiocclusion), efinaconazole 5% solution, or vehicle, once daily for 36 weeks, with one 4-week posttreatment follow-up (week 40). Efficacy assessments included complete cure, mycologic cure, clinical efficacy, and other assessments of overall treatment effectiveness. No efficacy variables were designated as primary. RESULTS: At follow-up, complete cure was numerically higher in all active groups (16%-26%) compared with vehicle (9%). Mycologic cure rates with efinaconazole 10% semiocclusion, efinaconazole 10%, and efinaconazole 5% were 83%, 87%, and 87%, respectively. Efinaconazole 10% (with or without semiocclusion) demonstrated significantly greater clinical efficacy and treatment effectiveness when compared with vehicle (P=.0088 and .0064; .0056 and .0085, respectively, for both efinaconazole 10% groups). Adverse events were generally similar and mild. Local-site reactions were restricted to few subjects and did not differ meaningfully from those produced by vehicle. CONCLUSIONS: This study provided evidence that once-daily efinaconazole 10% solution (with or without semiocclusion) applied topically for 36 weeks was more effective than vehicle in treating DLSO and was well tolerated. Based on these results, efinaconazole 10% solution was chosen for the phase 3 development program.

Efinaconazole 10% solution in the treatment of toenail onychomycosis: Two phase III multicenter, randomized, double-blind studies.

BACKGROUND: Onychomycosis is a common nail infection, often resulting in nail plate damage and deformity. Topical lacquer treatments have negligible efficacy. Oral treatments, although more efficacious, are limited by drug interactions and potential hepatotoxicity. OBJECTIVE: We investigated the safety and efficacy of efinaconazole 10% solution (efinaconazole), the first triazole antifungal developed for distal lateral subungual onychomycosis. METHODS: Two identical, multicenter, randomized, double-blind, vehicle-controlled studies were conducted in patients with toenail distal lateral subungual onychomycosis (20%-50% clinical involvement [study 1: N = 870, study 2: N = 785]). Patients were randomized (3:1) to efinaconazole or vehicle, once daily for 48 weeks, with 4-week posttreatment follow-up. Debridement was not performed. The primary end point was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture) at week 52. RESULTS: Mycologic cure rates were significantly greater with efinaconazole (study 1: 55.2%, study 2: 53.4%) compared with vehicle (P < .001). The primary end point, complete cure, was also significantly greater for efinaconazole (study 1: 17.8% vs 3.3%, study 2: 15.2% vs 5.5%, P < .001). Treatment success (percent affected target toenail [0%-≤10%]) for efinaconazole ranged from 21.3% to 44.8% in study 1 and from 17.9% to 40.2% in study 2, compared with 5.6% to 16.8% and 7.0% to 15.4%, respectively, with vehicle. Adverse events associated with efinaconazole were local site reactions (2%) and clinically similar to vehicle. LIMITATIONS: A period of 52 weeks may be too brief to evaluate a clinical cure in onychomycosis. CONCLUSIONS: Once daily topical efinaconazole appears to be a viable alternative to oral treatment options for onychomycosis.

Efficacy of rivastigmine transdermal patch on activities of daily living: item responder analyses.

OBJECTIVE: In Alzheimer's disease (AD), rivastigmine has demonstrated statistically significant efficacy versus placebo on cognition and activities of daily living (ADL). The aim of this retrospective analysis was to further evaluate the treatment effects of rivastigmine on individual ADL items. METHODS: This exploratory analysis focused on the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) outcome from a large, international, 24-week, controlled trial of rivastigmine once-daily transdermal patch and twice-daily capsules in AD (CENA713D2320, NCT00099242). Percentages of patients "improving" or "not worsening" on individual ADL items were calculated and changes from baseline with rivastigmine versus placebo were evaluated. RESULTS: Patients received rivastigmine patch (9.5 mg/24 h; n = 247), capsule (12 mg/day; n = 254), and placebo (n = 281). Statistically significant changes from baseline in composite ADCS-ADL scores in both rivastigmine treatment groups versus placebo (p < 0.05) had previously been reported. In this responder analysis of the subset of patients who showed baseline functional impairments on each item, statistically significant differences favoring rivastigmine were seen on the following functions: bathing, clearing dishes, obtaining a beverage, garbage disposal, traveling, shopping, writing, using household appliances, and talking about current events. A responder analysis of emergence of ADL impairment was not as sensitive to treatment effects. CONCLUSIONS: These findings suggest that rivastigmine may benefit specific ADL, particularly in patients who are already exhibiting functional impairment. Further research is required to improve understanding of how drugs such as rivastigmine exert their clinical effects.

Impact of rivastigmine patch and capsules on activities of daily living in Alzheimer's disease.

BACKGROUND: Rivastigmine patches provide similar efficacy to rivastigmine capsules with a lower incidence of gastrointestinal side effects in patients with probable Alzheimer's disease (AD). METHODS: Post hoc analysis of a 24-week, prospective, international, randomized, double-blind, placebo- and active-controlled trial. Patients (n = 892) with probable AD received rivastigmine transdermal patches (9.5 mg/24 hours [10 cm(2)]), rivastigmine capsules (6 mg twice daily), or placebo, and impact on activities of daily living (ADLs) was assessed utilizing 3 subscales: basic, high-level function, and autonomy. RESULTS: At week 24, both rivastigmine groups demonstrated significantly superior performance in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Total Score versus placebo (rivastigmine patch, P = .013; capsules, P = .039). Overall, both rivastigmine formulations provided benefits in ADL subscales. For basic ADLs, rivastigmine capsules performed significantly better than placebo (P = .012). For high-level function ADLs, rivastigmine patch performed better than placebo (P = .056). For autonomy ADLs, rivastigmine patch performed significantly better than placebo (P = .017). CONCLUSION: Rivastigmine patches and capsules provide significant effects in both total and subscale ADLs in patients with probable AD.

Efficacy of rivastigmine on executive function in patients with Parkinson's disease dementia.

BACKGROUND AND OBJECTIVE: Rivastigmine is approved in the USA for the treatment of mild to moderate Alzheimer's disease and Parkinson's disease dementia (PDD). Executive function (EF) deficits are a core symptom of PDD. The current objective was to investigate the effects of rivastigmine capsules versus placebo on EF in PDD, focusing on secondary outcome measures from a large, international, randomized, double-blind, placebo-controlled, 24-week trial (EXPRESS, CENA713B2311). METHODS: Secondary outcomes included Delis-Kaplan Executive Function System (D-KEFS) measures of EF. Data from three D-KEFS subtests (Card Sorting, Letter Fluency, Color-Word Interference), plus the Symbol Digit Modalities Test were analyzed in the observed case (OC) population. Changes from baseline in the rivastigmine versus placebo groups were evaluated using the van Elteren test blocking for country. RESULTS: Of 541 patients in the EXPRESS study, 402, 71, 97, and 65 patients provided data for Letter Fluency, Card Sorting and Color-Word Interference subtests, and the Symbol Digit Modalities Test, respectively. On Letter Fluency, rivastigmine was associated with improvements in correct responses, set loss errors, and responses made (all P < 0.05), but not repetition errors. Higher Card Sorting recognition description score (P= 0.03), and more correct substitutions on the Symbol Digit Modalities Test (P= 0.02) were also recorded. CONCLUSION: Rivastigmine was associated with significant improvements over placebo on EF tests evaluating flexibility of thinking, problem solving and planning in patients with PDD. These findings support the hypothesis that rivastigmine may affect frontal subcortical circuits, which potentially contributes to observed clinical improvement associated with EF.

The ACTION study: methodology of a trial to evaluate safety and efficacy of a higher dose rivastigmine transdermal patch in severe Alzheimer's disease.

BACKGROUND: Two sizes of rivastigmine patch (5 cm(2) and 10 cm(2)) are currently approved in the US and Europe, while a 20 cm(2) rivastigmine patch has also been tested. A 15 cm(2) rivastigmine patch may provide an optimal balance between efficacy and safety. Earlier studies have demonstrated the efficacy of rivastigmine in severe Alzheimer's disease (AD), and supported the use of a higher dose patch in AD. OBJECTIVE: The ACTION (ACTivities of daily living and cognitION) trial (Study CENA713DUS44) is designed to evaluate the efficacy and safety of low-dose versus high-dose rivastigmine transdermal patch in patients with severe AD. METHODS: ACTION is a prospective, randomized, parallel-group, double-blind, multicenter study of patients (aged ≥50 years) with severe AD and a Mini-Mental State Examination score of 3-12. Novartis began recruitment in July 2009 and is conducting the trial in the United States. Patients are randomized to receive either a 5 cm(2) (4.5 mg/24 h) or a 15 cm(2) rivastigmine patch (13.3 mg/24 h) for 24 weeks. Patients receiving the 15 cm(2) patch will be up-titrated over 8 weeks, via 5 and 10 cm(2) patches. The primary efficacy outcomes include activities of daily living (ADLs), assessed with the Alzheimer's Disease Cooperative Study - Activities of Daily Living - Severe Impairment Version (ADCS-ADL-SIV), and cognition, assessed with the Severe Impairment Battery (SIB). Secondary outcomes include behavior (Neuropsychiatric Inventory), global functioning (Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change), response rates, and safety. CONCLUSIONS: The ACTION trial examines the efficacy and tolerability of a 15 cm(2) rivastigmine patch over a 24-week period in patients with severe AD. This is a novel trial in the development of rivastigmine, as it uses a design that does not include a placebo arm, is recruiting patients with severe AD, and includes an ADL measure as a co-primary efficacy variable. CLINICAL REGISTRATION NUMBER: CENA713D US44.

Rivastigmine in the treatment of dementia associated with Parkinson's disease: effects on activities of daily living.

AIMS: To investigate the effects of rivastigmine capsule 3-12 mg/day over 24 weeks on activities of daily living (ADLs) in patients with dementia associated with Parkinson's disease (PDD). METHODS: Post hocanalysis of a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with PDD (>or=50 years) randomized to rivastigmine 3-12 mg/day (capsules bid) or placebo over 24 weeks. This analysis was carried out with three subscales derived from a factor analysis of the 23 items in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale. These subscales were basic ADLs (10 items), high-level function ADLs (eight items) and autonomy ADLs (five items). RESULTS: 541 patients were randomized (362 to rivastigmine, 179 to placebo) and 410 (75.8%) completed the study. Rivastigmine was associated with significantly better outcomes in basic ADLs (-0.5 +/- 6.19 vs. -1.7 +/- 5.46; p = 0.025; effect size 22.1%) and high-level function ADLs (0.1 +/- 4.95 vs. -1.0 +/- 4.49; p = 0.017; effect size 22.9%) compared with placebo, at week 24. CONCLUSION: In patients with PDD, treatment with rivastigmine may show beneficial effects on overall ADLs, as well as modest, statistically significant improvements in basic ADLs and high-level function ADLs.

Effects of rivastigmine transdermal patch and capsule on aspects of clinical global impression of change in Alzheimer's disease: a retrospective analysis.

BACKGROUND: The Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale is widely used in Alzheimer trials. It assesses cognition, activities of daily living (ADLs), behavior and global functioning. To advance the understanding of relationships between the ADCS-CGIC and scores from other commonly used tools, this analysis investigated the ability of each domain to measure change. This was a hypothesis-forming study, designed to provide a basis for possible future research. METHODS: This retrospective analysis used data from a 24-week, randomized, placebo-controlled trial [study ENA713D2320 (IDEAL)] that evaluated rivastigmine patches and capsules in AD patients. RESULTS: At week 24, significant treatment effects versus placebo were seen on the ADCS-CGIC cognitive domain with rivastigmine 17.4 mg/24 h patch (p < 0.01), 9.5 mg/24 h patch (p = 0.02) and capsules (p < 0.01); similarly on the ADCS-CGIC ADL domain. The cognition portion of the CGIC correlated with the Alzheimer's Disease Assessment Scale cognitive subscale and the ADL section with the ADCS-ADL trial measures. Variance ascribable to these tools was small, indicating that CGIC detects changes not measured by the domain-specific tools. CONCLUSIONS: The results of this post hoc analysis suggest that the ADCS-CGIC accurately reflects changes in cognitive and functional domains measured by other tools; it captures changes not assessed by domain-specific instruments. Cognitive alterations show greatest correlation with total CGIC. These results may assist in analyzing and interpreting CGIC results in other trials.

Evaluating rivastigmine in mild-to-moderate Parkinson's disease dementia using ADAS-cog items.

Rivastigmine has been shown to improve cognition in patients with Parkinson's disease dementia (PDD). To further explore the impact of anticholinesterase therapy on PDD, Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) items were assessed in a retrospective analysis of a 24-week, double-blind, placebo-controlled trial of rivastigmine. Mean changes from baseline at week 24 were calculated for ADAS-cog item scores and for 3 cognitive domain scores. A total of 362 patients were randomized to 3 to 12 mg/d rivastigmine capsules and 179 to placebo. Patients with PDD receiving rivastigmine improved versus placebo on items: word recall, following commands, ideational praxis, remembering test instructions, and comprehension of spoken language (P < .05), with standardized mean differences ranging from 0.04 to 0.30. Rivastigmine also showed significant effects versus placebo on all domains: memory, language, and praxis. The ADAS-cog is sensitive to broad cognitive changes in PDD. Overall, rivastigmine was associated with improvements on individual cognitive items and general cognitive domains.

Effects of oral rivastigmine on cognitive domains in mild-to-moderate Alzheimer's disease.

Rivastigmine has beneficial effects on cognitive functioning in Alzheimer's disease (AD). Effects of cholinesterase inhibitors, particularly rivastigmine, on AD Assessment Scale-cognitive subscale (ADAS-cog) domains and individual items have rarely been analyzed. Results from 4 randomized, double-blind, placebo-controlled, 26-week rivastigmine capsule trials in patients with mild-to-moderate AD were pooled and ADAS-cog domains and individual items were evaluated. Data were available from 878, 1053, and 863 patients in the 1 to 4 mg/d, 6 to 12 mg/d, and placebo groups, respectively. Rivastigmine-treated groups were superior to placebo on total ADAS-cog and memory domain scores (P < or = .0001). Rivastigmine 6 to 12 mg/d was also significantly better versus placebo on language (P < .001) and praxis (P < .001); greatest treatment responses were seen on memory items (P < .0001). Although rivastigmine was associated with dose-dependent improvements in all cognitive domains, largest effects were on memory items. Evaluation of ADAS-cog domain scores provides insight into test items most likely to respond to treatment.

Switching from oral donepezil to rivastigmine transdermal patch in Alzheimer's disease: 20-week extension phase results.

OBJECTIVE: To evaluate the long-term safety, tolerability, and efficacy of 2 strategies for switching from donepezil to rivastigmine transdermal patches in patients with mild to moderate Alzheimer's disease. METHOD: This was a prospective, 25-week, randomized, open-label, parallel-group study to evaluate an immediate or delayed switch (7-day withdrawal) from donepezil (5 to 10 mg/d) to rivastigmine transdermal patches (4.6 mg/24 h). Participants included male and female patients, aged ≥ 50 years, with a DSM-IV-TR diagnosis of mild to moderate dementia of the Alzheimer's type, defined as a Mini-Mental State Examination score of 10-24, inclusive. Patients were enrolled between February 2007 and February 2008. The study was split into a 5-week core phase and a 20-week extension phase. Safety and efficacy results from the extension phase are presented. RESULTS: Both switching strategies were well tolerated. Rates of discontinuation for any reason were similar between the groups. Discontinuations due to adverse events were also similar, and the incidence of gastrointestinal adverse events was low. Apart from Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale scores, at the end of the study, there was no statistically significant change from baseline in cognitive, behavioral, or global outcomes. Over half of the patients preferred rivastigmine transdermal patches to a tablet. CONCLUSIONS: This study suggests that the majority of patients receiving donepezil tablets can be safely switched to rivastigmine transdermal patches without significant deterioration in cognition, behavior, and global functioning. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00305903.

A 25-week, open-label trial investigating rivastigmine transdermal patches with concomitant memantine in mild-to-moderate Alzheimer's disease: a post hoc analysis.

OBJECTIVE: To investigate the tolerability and efficacy of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease receiving concomitant memantine. RESEARCH DESIGN AND METHODS: Post hoc analysis of a 25-week, randomized, prospective, open-label, parallel-group study. Patients receiving donepezil were switched to rivastigmine patches (4.6 mg/24 h) immediately or following a 7-day withdrawal for 4 weeks (core phase), before titrating up to 9.5 mg/24 h for a further 20-week extension phase. Prior memantine therapy was continued throughout. MAIN OUTCOME MEASURES: Tolerability (adverse events [AEs], serious AEs [SAEs] and discontinuations) and efficacy (cognition, global functioning and activities of daily living [ADLs]) were assessed for the rivastigmine transdermal patch, with or without concomitant memantine. RESULTS: Overall, 135 and 126 patients received rivastigmine with and without memantine, respectively. Of these, 122 (90.4%) and 118 (93.7%) patients with and without memantine, respectively, completed the core phase; 120 and 114 patients, respectively, entered the extension phase, and 90 (75.0%) and 86 (75.4%) completed the study. The incidences of AEs (73.3 vs. 67.5%) and SAEs (10.4 vs. 7.1%) were both slightly larger in patients receiving concomitant memantine, but the differences were not statistically significant (95% CIs: -5.2, 16.9 and -3.6, 10.1 for AEs and SEAs, respectively). The incidence of gastrointestinal AEs was low in both groups. Discontinuation due to AEs was higher in patients who received memantine (17.0 vs. 11.9%). Changes in cognitive and global function were similar between groups. ADL scores worsened in both groups; significantly more in those treated with memantine. CONCLUSION: Use of the rivastigmine transdermal patch in patients on established memantine appears to be well-tolerated, with only modest, non-significant increases in AEs compared with monotherapy, and did not seem to affect cognition or global functioning adversely.

Safety and tolerability of rivastigmine capsule with memantine in patients with probable Alzheimer's disease: a 26-week, open-label, prospective trial (Study ENA713B US32).

OBJECTIVE: Rivastigmine, a dual cholinesterase inhibitor (ChEI), is widely approved for the symptomatic treatment of both mild-to-moderate Alzheimer's disease (AD) and Parkinson's disease dementia. Orally administered ChEIs may be associated with gastrointestinal (GI) side effects and add-on therapy with memantine, an N-methyl-d-aspartate receptor antagonist, approved for moderate-to-severe AD, may ameliorate such side effects. This was a 26-week, prospective, multicenter, single-arm, open-label pilot study to assess the safety and tolerability of rivastigmine capsules plus memantine in patients with moderate AD. METHODS: The primary objective was to assess the safety and tolerability of rivastigmine capsules 6-12 mg/day plus memantine (5-20 mg/day) as measured by the incidences of vomiting and nausea compared with those reported in the rivastigmine United States Prescribing Information (US PI). A total of 117 patients were enrolled with 116 receiving at least one dose of study medication. RESULTS: The incidences of nausea and vomiting (30% and 13%, respectively) observed in patients who received 6-12 mg/day rivastigmine plus memantine were lower than those stated in the US PI for rivastigmine monotherapy 6-12 mg/day (47% and 31%, respectively). The most common adverse events were nausea, vomiting, and dizziness. CONCLUSION: Results from this study suggest the combination of rivastigmine capsule and memantine in patients with moderate AD is safe and tolerable. A greater reduction in the GI tolerability of rivastigmine has been established with rivastigmine transdermal patch.

Rivastigmine transdermal patch skin tolerability: results of a 1-year clinical trial in patients with mild-to-moderate Alzheimer's disease.

BACKGROUND AND OBJECTIVES: Transdermal patches provide non-invasive, continuous drug delivery, and offer significant potential advantages over oral treatments. With all transdermal treatments a proportion of patients will experience some form of skin reaction. The rivastigmine patch has been approved for the treatment of mild-to-moderate Alzheimer's disease (AD) since July 2007 in the US. The aim of the component of the trial reported here was to evaluate the skin tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate AD. METHODS: The pivotal IDEAL trial was a 24-week, randomized, double-blind, placebo-controlled, multicentre trial of the efficacy and tolerability of the rivastigmine transdermal patch in 1195 patients with mild-to-moderate AD. This was followed by a 28-week open-label extension. Although not prospectively defined as a secondary assessment, during both phases of the study the condition of the patients' skin at the application site was evaluated. These data are reviewed in this article. RESULTS: During the 24-week, double-blind phase of the study, 89.6% of patients in the target 9.5 mg/24 h patch treatment group had recorded 'no, slight or mild' signs or symptoms for their most severe application-site reaction. Erythema and pruritus were the most commonly reported reactions. No patient in any patch treatment group experienced a skin reaction that was reported as a serious adverse event. In the 9.5 mg/24 h treatment group, 2.4% of patients discontinued treatment due to an application-site reaction. During the 28-week open-label extension, the skin tolerability profile was similar to that seen in the double-blind phase. Overall, 3.7% of patients discontinued treatment due to application-site skin reactions. There was no indication that the severity of the skin reactions increased over time. CONCLUSION: Overall, the data support a favourable skin tolerability profile for the rivastigmine transdermal patch, and provide reassurance that the benefits of rivastigmine patch therapy for patients with AD are not confounded by significant skin irritation problems. Nevertheless, care should be taken to follow manufacturer's advice about patch application, such as daily rotation of the application site, to minimize the risk of skin reactions.