Rivastigmine

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

No studies with a clinical relevant sex analysis regarding the pharmacokinetics of rivastigmine have been found. The dose is titrated based on tolerability and the manufacturer does not recommend different doses in men and women [8]. In a randomized placebo-controlled trial (486 men, 532 women), the InDDEx trial [9], the mean daily doses of rivastigmine were 5.84 mg/day in men and 3.93 mg/day in women to achieve effect.

Effects

A small clinical study (13 men, 48 women) reported a positive response to rivastigmine in women, but not in men with AD [10]. With so few men included in the study and thus a low statistical power it is hard to draw any conclusions regarding sex and treatment outcome. A Japanese cohort study, the Okayama Late Dementia Study OLDS included patients with AD treated with rivastigmine (20 men, 43 women) [11] reported stable Mini-Mental State examination (MMSE) with rivastigmine in both men and women with no significant sex differences.

A post hoc analysis of a randomized placebo-controlled trial (486 men, 532 women) the InDDEx trial [9], evaluated the effect of sex on treatment response of rivastigmine 3- to 12 mg/day capsules in patients with mild cognitive impairment (MCI) [3]. The mean daily doses of rivastigmine were 5.84 mg/day in men and 3.93 mg/day in women. In women, rivastigmine decreased the rate of progression from MCI to AD from 24.8 % in the placebo group to 17.4 % in the treatment group. The disease progression in men was similar in the placebo group but not affected by rivastigmine treatment [3]. 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].

Adverse effects

In the post hoc analysis of the randomized placebo-controlled InDDEx trial (486 men, 532 women), the prevalence of serious adverse events in the rivastigmine groups were 27.0% in women and 29.0% in men [3].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (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].