Practical administration is a key element of treatments for AD, as elderly patients are often already receiving multiple medications, and may also require considerable adjustment/switching of AD medications to attain optimal ef?cacy with minimal side effects. Two memantine studies relevant to these concerns have been performed – one investigating the tolerability and ef?cacy of memantine following a switch from AChEI treatment, and the second studying a once-daily memantine treatment regimen.

This multicentre, double-blind study comprised patients with moderate to severe AD (MMSE ≤18), who had been receiving treatment with donepezil (10 mg/day) for at least 6 months, but in whom the ef?cacy of the drug was judged to be waning.

Forty-six patients began treatment with memantine (uptitrated to 20 mg/day over 3 weeks), and at the same time were randomised to undergo either:

·            stepwise discontinuation of donepezil (5 mg/day) over a 2-week period, n=22, or

·            abrupt cessation of donepezil treatment (receiving placebo for 2 weeks), n=24.

From the start of memantine treatment, the study period lasted for 8 weeks. The primary endpoint was tolerability (occurrence of adverse events, AEs), and the secondary endpoint was ef?cacy (CGI-C).

            There were no clinically important differences between the two switch schedules in terms of AEs or ef?cacy.

            Overall, 18 patients (39%) reported one or more AE, but only accidental injury (4 patients), vertigo (2 patients), and anxiety (2 patients) occurred in more than 1 patient.

            The majority of AEs were mild or moderate and only 5 patients had AEs that were judged as related to treatment. The withdrawal rate was low (3 patients).

·            CGI-C was stabilised or improved in 74% of patients (Figure 6.21), and MMSE was stabilised or improved in 53% of patients, with no clinically relevant differences between groups.

 

Once-daily vs twice-daily dosing study (10113) (Jones et al, 2007)⁶⁴

In the Ebixa^? SmPC, a three-step titration regimen is recommended over the ?rst 3 weeks of treatment, to a ?nal maintenenace dose of memantine 20 mg once-daily.^1,65 Previously, the memantine dosing regimen was 20 mg/day (as 10 mg twice-daily). As memantine has a terminal half-life of 60–100 hours, there is no pharmacological rationale supporting the need for twice-daily dosing. The results of the study described below provided the clinical support for the revision of the dosing regimen for memantine to once-daily dosing. This change has been implemented in the EU and will be taken up by countries outside of the EU.

The aim of the once-daily vs twice-daily dosing study was to provide data to indicate whether or not memantine can be administered once daily. This UK-based study was double-blind, multicentre and comprised patients with moderate to severe AD (MMSE ≤18). A total of 78 patients were randomised to one of three treatment arms:

            memantine 20 mg once daily with 3-step titration

            memantine 20 mg once daily with 1-step titration

            memantine 20 mg (10 mg bid) with 3-step titration (current indication).

The study compared the treatment arms in terms of safety and tolerability, with ef?cacy (CGI score) as a secondary outcome measure.

            There were no statistically signi?cant differences between the three arms.

            Once-daily treatment with memantine is well tolerated, with an adverse event pro?le similar to that described in the SmPC.

            No difference in ef?cacy (CGI) was observed between the three treatment schedules.

            Overall, the switch from donepezil to memantine is safe and well tolerated in patients with moderate to severe AD, with the majority of patients experiencing a stabilisation or improvement in global status (CGI-C).

            Memantine is well tolerated when administered once daily or twice daily, and in 1-step or 3-step titration schedules. Memantine is now indicated as once-daily dosing.

 

The document about switch and daily dosing studies was translated by Huayiwang Mandarin Translation Company.

 

实际管理是治疗AD过程中的一个重要因素，因为老年患者通常已经接受多个药物治疗，并且也需要对AD治疗药物进行调整及切换，以达到最优的治疗效果，且副作用最小。

已开展两个关于上述问题的美金刚研究 – 其中的一项研究AD患者经AChEI治疗后，然后改用美金刚治疗的耐受性及有效性，另一项则研究每天给药一次的治疗方案。

该多中心、双盲研究入组的受试者为中、重度AD患者（MMSE≤18），患者至少已接受多奈哌齐治疗（10mg/天）6个月以上，并且多奈哌齐的治疗效果判断为正在减弱。

56名患者开始接受美金刚治疗（在3周的滴定期内将美金刚剂量滴定至20mg/天），与此同时，患者被随机到以下各组：

         在2周内，渐进性中断多奈哌齐（5mg/天）治疗，n=22，或者

         忽然中断多奈哌齐的治疗（服用2周安慰剂），n=24

自接受美金刚治疗开始，研究期持续8周。主要的观察终点为耐受性（不良事件的发生情况），次要观察终点为有效性（CGI-C）。

         根据不良事件及有效性的结果，上述两种切换方案之间无临床意义上的重要差异。

         总的来说，18名受试者（39%）报告发生一次或者多次不良事件，但仅仅意外受伤（4名受试者）、眩晕（2名患者）及焦虑（2名患者）发生的受试者数目超过1人。

         大部分不良事件为轻、中度不良事件，并且仅仅5名受试者所发生的不良事件被判断为与治疗相关。受试者的退出率低（3名受试者）。

         74%的患者CGI-C稳定或者改善（图6.21），并且53%的受试者MMSE稳定或者改善，组间比较无临床相关的差异。

 

在易倍申^?的产品特性摘要中，在治疗的前3周推荐进行3步滴定方案，最终将美金刚的剂量维持在20mg，一天给药一次^1,65。之前，美金刚的剂量方案为20mg/天（10mg一次，每天给药两次）。美金刚的终末半衰期为60-100小时，因而需要一天给药两次的方案缺乏药理学理论基础。下面的研究结果提供了美金刚一天一次给药方案的临床支持。在欧洲已经执行该给药方案，并且将被欧洲以外的其他国家采纳。

比较一天一次给药及一天两次给药的目的是提供证据证实美金刚可否一天给药一次。这项研究在美国开展，为一项双盲、多中心研究，所入组的受试者为中、重度AD患者（MMSE≤18）。78名受试者被随机分配至下面的三个治疗组：

         美金刚 20毫克，一天一次，3步滴定

         美金刚 20毫克，一天一次，1步滴定

         美金刚 20毫克（10毫克一次，一天两次），3步滴定（目前的适应症）

该研究比较了组间的安全性及耐受性，有效性（CGI评分）为次要评价指标

 

         三组之间无显著的统计学差异。

         每天给药一次具有良好的耐受性，所发生的不良事件与产品特性摘要所描述的相似。

         三种治疗方案在有效性（CGI）方面无差异。

         总之，中、重度AD患者从多奈哌齐切换到美金刚进行治疗比较安全，且耐受性良好，大部分患者整体状况（CGI-C）稳定或者出现改善。

            采用一步滴定或者三步滴定方案，美金刚一天给药一次或者一天给药两次，均具有较好的耐受性。美金刚现行的说明书为一天给药一次。

 

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