Donepezil

Additional information

A systematic review of 33 RCTs on cholinesterase inhibitors (in all: 6868 men, 9103 women) concludes an almost complete lack of sex-specific reporting of data in clinical trials for dementia drug therapies, and no sex-specific reporting of adverse events [1]. Another review identified 48 RCTs of which two had taken patient’s sex into account when evaluating Alzheimer dementia (AD) treatment efficacy [2].

Pharmacokinetics and dosing

Pharmacokinetic studies of donepezil do not indicate sex differences regarding plasma concentration or clearance of donepezil [8]. Higher doses of donepezil (23 mg vs. 10 mg daily) have a better effect in both men and women [9] .

Effects

The effect of donepezil measured by GBS (Gottfries-Bråne-Steen) and mini mental state examination (MMSE) at week 52 was studied in a randomized placebo controlled trial of patients with Alzheimer Dementia (AD) (102 men, 184 women). No sex difference in effect was found [10]. In a 36-week open-label trial of patients with mild to moderate AD (35 men, 82 women) response to donepezil (5-10 mg/d) was not affected by APOE genotype, patient’s sex, or both factors combined [11].

In contrast, some studies report different treatment effects regarding sex. In a Japanese cohort Okayama Late Dementia Study (OLDS) of older patients with AD (19 men, 36 women) men, but not women, had worse MMSE at 12 months compared to  baseline [12]. A similar pattern was noted in an Italian sample of patients with late onset AD (26 men, 70 women). Women, but not men, responded to treatment with donepezil with improved MMSE compared to a control group [13]. In an open-label, retrospective cohort 2-year study (107 men, 229 women) in patients with AD treated with donepezil (mean dose 0f 8.1 mg/d), women had lower mortality rates than men (10% and 20%, respectively). The study reported that male sex was one of several variables associated with a higher mortality [14]. It has been noted that women seems to be overrepresented in populations of patients with AD but have similar prevalence in MCI populations indicating a faster  transition from MCI to AD in women [3]. The increased risk for disease progression from MCI to AD in women  has also been linked to certain genetic variants (e.g. butyrylcholineesterase wild type genotype) as suggested by a publication based on data from the InDDEX trial [4]. In a review of 14 studies (in all 1820 men, 2942 women) the evidence relating to patient functioning as an outcome measure in the treatment with donepezil, galantamine, rivastigmine or memantine for AD was evaluated and showed that the pooled effect size was not significantly affected by patient's sex [5].In addition, a review of seven double-blind, open-label clinical trials and 13 case studies of donepezil, galantamine and rivastigmine did not produced support of an association between treatment outcomes and patient's sex [6].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

An American retrospective data analysis investigated the relationship between adherence to oral AD therapy (rivastigmine, donepezil, galantamine or memantine) and other variables. Male AD patients were approximately 18% more likely to be adherent to index oral AD therapy than female patients [7].